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Title:
TREATING NEUROMUSCULAR OR NEUROLOGIC DISEASE THROUGH REDUCING GABAERGIC AND/OR GLYCINERGIC INHIBITORY NEUROTRANSMITTER OVERSTIMULATION
Document Type and Number:
WIPO Patent Application WO/2017/065602
Kind Code:
A1
Abstract:
The disclosure provides novel methods of treating neuromuscular or neurologic disease, for example, Amyotrophic lateral sclerosis (ALS), through reducing GABAergic and Glycinergic inhibitory neurotransmitter activity overstimulation. Pharmaceutical compositions comprising one or more compounds capable of reducing Glycinergic activity and/or one or more compounds capable of reducing GABAergic activity are also provided. Pharmaceutical compositions comprising Penicillin G and, optionally, glucocorticoid are especially useful in the present invention. Methods for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation (e.g., muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction) in an individual afflicted with ALS or an ALS- like disorder are also provided.

Inventors:
TUK, Lambertus (4797 AC Willemstad, 4797 AC, NL)
Application Number:
NL2016/050490
Publication Date:
April 20, 2017
Filing Date:
July 07, 2016
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
RY PHARMA B.V. (Hofstraat 1, 4797 AC Willemstad, 4797 AC, NL)
International Classes:
A61K31/365; A61K31/43; A61K31/475; A61K31/50; A61K31/5517; A61K31/573; A61K45/06; A61P25/28
Domestic Patent References:
1997-04-10
1996-03-21
2000-09-08
2005-10-06
2005-03-10
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Foreign References:
FR2782008A12000-02-11
US5735814A1998-04-07
US20110224278A12011-09-15
EP1167353A12002-01-02
US5735814A1998-04-07
US6524629B12003-02-25
US20110224278A12011-09-15
US20110092572A12011-04-21
US20100234451A12010-09-16
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DATABASE WPI Week 201240, Derwent Publications Ltd., London, GB; AN 2012-A01001, XP002737153
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Attorney, Agent or Firm:
JANSEN, C.M. (V.O, Carnegieplein 5, 2517 KJ Den Haag, 2517 KJ, NL)
Download PDF:
Claims:
Claims

1. A method for treating one or more symptoms caused by inhibitory

neurotransmitter overstimulation (e.g., one or more symptoms selected from tables 7 and/or 8, preferably those listed in tables 7a- 7f and 8, more preferably tables 7a- 7d and 8, most preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction; even more preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties) in an individual afflicted with ALS or an ALS-like disorder, the method comprising providing an effective amount of

Penicillin G to an individual in need thereof. 2. A method for treating one or more symptoms caused by inhibitory

neurotransmitter overstimulation in an individual afflicted with ALS or an ALS- like disorder, the method comprising decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, wherein said glycinergic activity is decreased by administrating a therapeutically effective amount of a compound that modulates the glycine receptor and / or leads to an increase in availability or efficacy of compounds that exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity, wherein said

GABAergic activity is decreased by systemically administrating to said individual a GABA receptor inhibitor and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action at least partly through the GABA receptor thereby causing the reduction of net GABAergic activity, wherein the one or more compounds which reduce GABAergic inhibitory activity is not ginkgo extract, ginkgolide or a ginkolide derivative, bilobalide or a bilobalide derivative, or linalool, preferably wherein the treatment is a multi-day treatment administered using an escalating dosage scheme.

3. The method of claim 1 or 2 wherein the one or more symptoms are selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, and gastrointestinal dysfunction. 4. The method of claim 1 or 2, wherein the GABA receptor inhibitor and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action at least partly through the GABA receptor causing the reduction of net GABAergic activity is a GABA receptor channel blocker, preferably Penicillin G.

5. The method of claim 1 or 4, wherein Penicillin G is administered intravenously at a dosage of between 0.5 million to 40 million units per day, preferably between 1 million to 30 million units per day. 6. The method of any one of claims 1, 4 or 5, wherein Penicillin G is administered intravenously at a dosage of at least one million units per day for at least four days within an 8 day period, preferably for at least four consecutive days.

7. The method of any one of claims 1, or 4-6, wherein Penicillin G is administered using an escalated dosage scheme, preferably, such that a dosage of at least one million units per day is provided intravenously for at least two days and a dosage of at least three million units per day is provided intravenously for at least two days. 8. The method of claim 6, wherein Penicillin G is intravenously administered using an escalated dosage scheme such that a dosage of at least one million units per day is provided for at least two days, a dosage of at least five million units per day is provided for at least one day, and a dosage of at least 10 million units per day is provided for at least one day.

9. The method of claim 6, wherein Penicillin G is intravenously administered using an escalated dosage scheme such that a dosage of at least one million units per day is provided for at least one day, a dosage of at least three million units per day is provided for at least one day, a dosage of at least 5 million units per day is provided for at least one day, a dosage of at least 10 million units per day is provided for at least one day, and a dosage of at least 20 million units per day is provided for at least one, preferably at least 5 days. 10. The method of any one of claims 1 or 4-9, wherein the Penicillin G is administered intravenously over a period of between 4 and 12 hours, preferably as a continuous infusion.

11. The method of any one of claims 1-10, wherein a glucocorticosteriod is also administered to the patient, preferably wherein a glucocorticosteriod is

administered intravenously, preferably as a continuous infusion.

12. The method of claim 11, wherein the glucocorticoid is hydrocortisone. 13. The method of claim 12, wherein hydrocortisone is administered at a dosage of between lOmg to 200 mg per day.

14. The method of any one of claims 11- 13, wherein the hydrocortisone is administered at a dosage of at least 20mg per day for at least four days within an 8 day period, preferably for at least four consecutive days.

15. The method of any one of claims 12 to 14, wherein hydrocortisone is

administered using an escalated dosage scheme such that a dosage of at least 20 mg per day is provided for at least two days and a dosage of at least 50mg per day is provided for at least two days, preferably wherein the hydrocortisone is administered using an escalated dosage scheme such that a dosage of at of at least 20 per day is provided for at least two days, a dosage of at least 50mg per day is provided for at least two days, and a dosage of at least 100 mg is provides for at least one, preferably at least 5 days.

16. The method of claim 2 or 3, wherein the one or more compounds are selected from Table 5 or Table 6.

17. A method of any one of the preceding claims, wherein the ALS-like disorder is selected from one of the disorders listed in tables 1, 2, 3 or 4.

18. A method of any one of the preceding claims, wherein the disorder is a neuromuscular disorder.

19. A method of any one of the preceding claims, wherein the disorder is a motoneuron disorder. 20. A method of any one of claims 1-16, wherein the individual is afflicted with ALS.

21. The method of any one of the preceding claims, further comprising

administering a compound capable of reducing glutaminergic activity to said individual.

22. The method of claim 21, wherein said compound is riluzole.

23. The method of any one of the preceding claims, wherein the individual is not afflicted with syphilis or Lyme's disease, and/or is not seropositive for syphilis or

Lyme's disease, and/or does not test positive for syphilis or Lyme's disease in cerebrospinal fluid.

24. A pharmaceutical composition comprising one or more compounds capable of reducing GABAergic activity, preferably selected from Table 5, and one or more compounds capable of reducing Glycinergic activity, preferably selected from Table 6, wherein the one or more compounds which reduce GABAergic inhibitory activity is not ginkgo extract or a component of ginko extract, ginkgolide or a ginkolide derivative, bilobalide or a bilobalide derivative, or linalool.

25. The pharmaceutical composition of claim 24, for use in the treatment of more symptoms caused by inhibitory neurotransmitter overstimulation.

26. A pharmaceutical composition comprising one or more GABAergic inhibitory activity reducing compounds selected from a GABA receptor inhibitor and a compound that leads to an increase in availability or efficacy of compounds that exert their action at least partly through the GABA receptor thereby causing the reduction of net GABAergic activity, said composition for use in the systemic treatment of one or more symptoms caused by inhibitory neurotransmitter overstimulation.

27. A pharmaceutical composition comprising one or more Glycinergic activity reducing compounds selected from a compound that modulates the glycine receptor and a compound that leads to an increase in availability or efficacy of compounds that exert their action through the glycine receptor, thereby causing the reduction of net Glycinergic activity, said composition for use in the treatment of one or more symptoms caused by inhibitory neurotransmitter overstimulation.

28. The pharmaceutical composition of any one of claims 25-27 wherein said one or more symptoms caused by inhibitory neurotransmitter overstimulation are selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, and gastrointestinal dysfunction.

29. A pharmaceutical composition comprising one or more GABAergic inhibitory activity reducing compounds and a glucocorticoid, preferably hydrocortisone.

30. The pharmaceutical composition of claim 29, wherein the GABAergic inhibitory activity reducing compound is a GABA receptor channel blocker, preferably Penicillin G.

Description:
Title: Treating neuromuscular or neurologic disease through reducing

GABAergic and/or Glycinergic inhibitory neurotransmitter

overstimulation. FIELD OF THE INVENTION

The disclosure provides novel methods of treating neuromuscular or neurologic disease, for example, Amyotrophic lateral sclerosis (ALS), through reducing

GABAergic and/or Glycinergic inhibitory neurotransmitter activity overstimulation. Pharmaceutical compositions comprising one or more compounds capable of reducing Glycinergic activity and/or one or more compounds capable of reducing GABAergic activity are also provided. Pharmaceutical compositions comprising Penicillin G and, optionally, glucocorticoid are especially useful in the present invention.

Methods for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation (e.g., muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction) in an individual afflicted with ALS or an ALS-like disorder are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of PCT NL2016/050021 filed 12 January 2016 which claims the benefit of NL Application No. 2015712, filed 3 November 2015, NL Application No. 2015608, filed 13 October 2015, NL Application No. 2014123, filed 13 January 2015, and NL Application No. 2014114, filed 12

January 2015, the contents of which are herein incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Motor neuron diseases (MNDs) are a group of progressive neurological disorders in which the motor neurons of the patient become dysfunctional. Amyotrophic lateral sclerosis (ALS) is the most common MND and is characterized by progressive muscular weakness and atrophy that is related to motoneuron cell death. The disease generally progresses rapidly and is inevitably fatal with respiratory failure as the relatively uniform cause of death.

ALS incidence ranges from 1.5 to 2.5 patients per 100,000 annually, with a lifetime risk of circa 1 in 400 persons. The mean age of onset is circa 60 years, with a median survival of two to four years from symptom onset, although a small percentage of patients lives longer than ten years.

ALS is part of a broad spectrum of neurodegenerative indications that are

characterized by the progressive degeneration of motoneurons. Other syndromes related to this spectrum of disorders are listed in table 1 under neuromuscular disease among others including Progressive bulbar palsy (PBP), Progressive muscular atrophy (PMA), Primary lateral sclerosis (PLS), Flail arm syndrome (Vulpian- Bernhardt syndrome), Flail leg syndrome, ALS with multi-system involvement such as observed in ALS with fronto temporal dementia (Silani et al. 2011).

ALS symptoms overlap with the group of neuromuscular disorders leading to a gradual muscle weakness and to a common set of physical symptoms including difficulty with speech, difficulty with mobility and fine motor skills as listed in table 1, and with the group of muscle diseases listed in table 2. Furthermore it in this disclosure will be concluded that ALS symptoms clinically relevant overlap with the (neurologic) diseases listed in table 3 and 4.

Currently there is no effective treatment available for ALS or ALS like disease.

Riluzole (Rilutek®) displays minor efficacy in ALS, only prolonging tracheostomy-free survival with three months. Baclofen has been used for the treatment of anti-spastic treatment in ALS patients and is thought to exert its effects through exerting

GABAergic action through binding at GABA-B receptors.

One of the objects of the invention is to provide improved treatments for ALS and ALS-like disorders as listed in tables 1, 2, 3 and 4.

SUMMARY OF THE INVENTION

Methods and compositions are provided for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation. Symptoms may include those listed in tables 7 and/or 8, preferably muscle wasting, loss of muscle function, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and

gastrointestinal dysfunction, more preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction. Symptoms may include those listed in tables 7a- 7f and 8, preferably tables 7a-7d and 8.

Methods and compositions are provided for treating ALS and ALS-like disorders, such as those listed in tables 1, 2, 3 and 4, preferably for the treatment of ALS. As demonstrated in the examples, these disorders exhibit symptoms which herein are concluded to be caused by inhibitory neurotransmitter overstimulation.

The methods comprise decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, preferably using compounds disclosed in Tables 5 and/or 6. The methods result in an overall (or net) decrease in GABAergic and/or Glycinergic activity.

Preferred embodiments are summarized as follows.

1. A method for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation (e.g., one or more symptoms selected from tables 7 and/or 8, preferably those listed in tables 7a- 7f and 8, more preferably tables 7a-7d and 8, most preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction) in an individual afflicted with ALS or an ALS-like disorder, the method comprising decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof. Preferably glycinergic activity is decreased by

administrating a therapeutically effective amount of a compound that modulates the glycine receptor or that leads to an increase in efficacy of compounds that (at least partly) exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity, or that increase the availability of compounds that (at least partly) exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity. Preferably, GABAergic activity is reduced by the systemic administration of a therapeutically effective amount of a GABA receptor inhibitor and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action (at least partly) through the GABA receptor thereby causing the reduction of net GABAergic activity.

2. A method for treating one or more symptoms selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, gastrointestinal dysfunction and/or symptoms as listed in tables 7 and/or 8 and/or tables 7a- 7f and 8, preferably tables 7a- 7d and 8, in an individual afflicted with ALS or an ALS-like disorder, the method comprising decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof.

3. The method of any of the preceding embodiments comprising administering to said individual a therapeutically effective amount of one or more compounds which reduce GABAergic activity.

The method of any of the preceding embodiments comprising administering to said individual a therapeutically effective amount of Penicillin G, as described herein. The method of any of the preceding embodiments comprising administering to said individual a therapeutically effective amount of one or more compounds which reduce the net GABAergic inhibitory activity in the central nervous system of said individual. The method of any of the preceding embodiments, wherein when the individual is afflicted with ALS, the one or more compounds which reduce GABAergic inhibitory activity is not ginkgo extract or a component of ginko extract (e.g., a ginkgolide or bilobalide). The method of any of the preceding embodiments, wherein when the individual is afflicted with syphilitic lateral amyotrophic sclerosis i.e., ALS in the presence of (latent) syphilic infection, the one or more compounds which reduce GABAergic inhibitory activity is not Penicillin G. 4. The method of embodiment 3, wherein the compound which reduces inhibitory activity is a GABA receptor blocker, preferably Penicillin G. The method of embodiment 3, wherein the one or more compounds are selected from Table 5, preferably from Bicuculline, Picro toxin,

Salicylidene salicylhydrazide, Flumazenil, Gabazine (SR 95531), Thiocolchicoside, 6,2- dihydroflavone, RU5135, Ro 15-4513, Ro 15-4603, BTD-001, RG-1662, CGP 36742, SGS-742 and FG 7142.

5. The method of any of the preceding embodiments comprising administering to said individual one or more compounds which reduce Glycinergic activity. 6. The method of embodiment 5, wherein the one or more compounds are selected from Table 6, preferably Bicuculline, Brucine, Picrotoxin, Strychnine and Tutin.

7. The method of any of the preceding embodiments wherein symptoms of the ALS- like disorder include those selected from tables 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a-7d and 8, preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction.

8. The method of any of the preceding embodiments wherein the individual exhibits one or more symptoms selected from tables 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a-7d and 8, preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction.

9. A method of any of the preceding embodiments where the disorder is selected from one of the disorders listed in tables 1, 2, 3 or 4.

10. A method of any of the preceding embodiments where the disorder is selected from one of the disorders listed in tables 1, 2, or 3.

11. A method of any of the preceding embodiments where the disorder is selected from one of the disorders listed in tables 1 or 3.

12. A method of any of the preceding embodiments where the disorder is selected from one of the disorders listed in tables 1 or 2.

13. A method of any of the preceding embodiments where the disorder is selected from one of the disorders listed in table 1.

14. A method of any of the preceding embodiments where the disorder is a

neuromuscular disorder.

15. A method of any of the preceding embodiments where the disorder is a

motoneuron disorder.

16. A method of any of the preceding embodiments wherein the disorder is ALS-like disease.

17. A method of any of the preceding embodiments wherein the disorder is ALS.

18. The method of any one of the proceeding embodiments further comprising decreasing glutaminergic activity in said individual. 19. The method of embodiment 18, comprising administering a therapeutically effective amount of riluzole or other compounds capable of reducing glutaminergic activity to said individual.

20. The method of any one of the proceeding embodiments further comprising the tapering down of medication reducing GABAergic or Glycinergic activity in said individual.

21. The method of any one of the proceeding embodiments further comprising the tapering down of medication reducing GABAergic or Glycinergic activity in said individual, in the combination of the tapering down of medication aiming at the reduction of glutamatergic activity in said individual.

Preferably, a method is provided for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation (e.g., one or more symptoms selected from tables 7 and/or 8, preferably those listed in tables 7a- 7f and 8, more preferably tables 7a-7d and 8, most preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction); in an individual afflicted with ALS or an ALS-like disorder, the method comprising decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, wherein said glycinergic activity is decreased by administrating a therapeutically effective amount of a compound that modulates the glycine receptor and / or leads to an increase in availability or efficacy of compounds that exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity, and wherein said GABAergic activity is decreased by systemically administrating to said individual a therapeutically effective amount of a compound that reduces the net GABAergic activity in the central nervous system of said individual, wherein when the individual is afflicted with ALS, the one or more compounds which reduce GABAergic inhibitory activity is not ginkgo extract or a component of ginko extract (e.g., a ginkgolide or bilobalide). Preferably wherein the compound that reduces the net GABAergic activity is a GABA receptor inhibitor and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action (at least partly) through the GABA receptor thereby causing the reduction of net GABAergic activity.

Preferably, a method is provided for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation (e.g., one or more symptoms selected from tables 7 and/or 8, preferably those listed in tables 7a- 7f and 8, more preferably tables 7a-7d and 8, most preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction); in an individual afflicted with ALS or an ALS-like disorder, the method comprising decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, wherein said glycinergic activity is decreased by administrating a therapeutically effective amount of a compound that modulates the glycine receptor and / or leads to an increase in availability or efficacy of compounds (preferably glycine) that exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity, and wherein said GABAergic activity is decreased by systemically administrating to said individual a GABA receptor inhibitor and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action (at least partly) through the GABA receptor thereby causing the reduction of net GABAergic activity, wherein when the individual is afflicted with ALS, the one or more compounds which reduce GABAergic inhibitory activity is not ginkgo extract or a component of ginko extract (e.g., a ginkgolide or bilobalide) and wherein when the individual is afflicted with syphilitic lateral amyotrophic sclerosis i.e., ALS in the presence of (latent) syphilic infection, the one or more compounds which reduce GABAergic inhibitory activity is not Penicillin G.

In preferred embodiments, the individual afflicted with ALS or an ALS-like disorder is not afflicted with syphilis or Lyme's disease, more preferably the individual is not afflicted with an infection (in particular a bacterial infection). Preferably the individual does not have an elevated risk of infection (in particular a bacterial infection).

22. A pharmaceutical composition comprising one or more compounds capable of reducing GABAergic activity, preferably selected from Table 5 and one or more compounds capable of reducing Glycinergic activity, preferably selected from Table 6, preferably for use in the manufacture of a medicament.

23. A pharmaceutical composition comprising one or more compounds capable of reducing GABAergic activity, preferably selected from Table 5, for use in the manufacture of a medicament. 24. A pharmaceutical composition comprising one or more compounds capable of reducing Glycinergic activity, preferably selected from Table 6, for use in the manufacture of a medicament.

25. A pharmaceutical composition comprising one or more GABAergic inhibitory activity reducing compounds as disclosed herein for use in the treatment of one or more symptoms caused by inhibitory neurotransmitter overstimulation, preferably selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, gastrointestinal dysfunction and/or symptoms as listed in table 7 and/or 8 and/or tables 7a-7f and 8, preferably tables 7a-7d and 8, preferably in an individual afflicted with ALS or an ALS-like disorder as disclosed herein.

26. A pharmaceutical composition comprising one or more Glycinergic activity reducing compounds as disclosed herein for use in the treatment of one or more symptoms caused by inhibitory neurotransmitter overstimulation, preferably selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression and/or symptoms as listed in table 8, preferably in an individual afflicted with ALS or an ALS-like disorder as disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Graphical representation of the pivotal role of GABAergic and Glycinergic overstimulation in ALS pathogenesis.

Figure 2: Limb-, bulbar- and respiratory onset ALS are caused by a continuum of separately increasing gradients of GABAergic and Glycinergic overstimulation.

Figure 3: diseases in the MND (motor neuron disease) continuum also are the result of a continuum of separately increasing gradients of GABAergic and Glycinergic mediated recurrent inhibition overstimulation during initial and progressive disease stages where PMA is progressive muscular atrophy, PLS is primary lateral sclerosis, PBP is progressive bulbar palsy, PB is Pseudobulbar palsy.

Figure 4: (4A) Diseases where GABAergic and glutaminergic overstimulation occur in parallel do not lead to the clinical manifestation of disease as homeostasis is maintained. (4B) Diseases where glutaminergic overstimulation no longer increases in parallel with GABAergic overstimulation due to, for instance, the occurrence of glutaminergic excitatory overstimulation induced neuronal cell death, will lead to the clinical manifestation of GABAergic overstimulation symptoms at the same time that clinical manifestation related to glutaminergic excitatory overstimulation induced neuronal cell death are observed. (4C) GABAergic overstimulation increases where glutaminergic overstimulation also increases but at a slower pace will lead to the clinical manifestation of GABAergic overstimulation symptoms where over time clinical manifestations develop that are related to glutaminergic excitatory

overstimulation induced neuronal cell death, the latter depending on the point in time where glutamate overstimulation reaches levels capable of inducing glutaminergic excitatory overstimulation induced neuronal cell death. Depending on the threshold for GABAergic and glutaminergic overstimulation symptoms, clinical manifestations of glutaminergic excitatory overstimulation induced neuronal cell death may appear before GABAergic overstimulation symptoms become apparent. (4D) Diseases where GABAergic overstimulation occurs in the absence of glutaminergic overstimulation will lead to the clinical manifestation of GABAergic overstimulation in the absence of glutaminergic excitatory overstimulation induced neuronal cell death.

DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENTS

The present invention is based, in part, on the surprising finding that the GABAergic and Glycinergic inhibitory neurotransmitter systems are at least partly responsible for the onset, progression, and/or clinical profile of ALS and ALS-like disorders.

The leading theory for explaining the clinical features of ALS is that elevation of the central nervous system's most abundant excitatory neurotransmitter glutamate leads to excitatory neuronal death, and consequently leads to the clinical manifestation of ALS. This theory finds its origin in the in ALS patients observed 100% elevated plasma serum glutamate levels, the 100% to 200% increased glutamate levels in cerebrospinal fluid (CSF) (Spreux-Varoquaux 2002), the deficiency of leukocyte glutamate dehydrogenase and the in ALS patients observed glutamate transport system defects that can lead to decreased clearance of extracellular glutamate.

Excitotoxicity is the pathological process by which nerve cells are damaged and killed through excessive stimulation by the glutamate excitatory neurotransmitter system leading to overstimulation of the glutamate receptors such as the NMDA and AMPA receptor. Pathologically high levels of glutamate cause excitotoxicity by allowing high levels of calcium ions to enter the cell, activating enzymes such as phospholipases, endonucleases, and proteases that damage vital cell structures such as the

cytoskeleton, membrane, and DNA. Excitotoxicity is involved in neurodegenerative diseases of the central nervous system (CNS) such as multiple sclerosis (MS),

Alzheimer's disease (ALZ), amyotrophic lateral sclerosis (ALS), Parkinson's disease, alcoholism or alcohol withdrawal and especially over-rapid benzodiazepine

withdrawal, and also Huntington's disease. The excitatory neurotransmitter glutamate is therefore currently seen as the most important contributor to the ALS pathogenesis and has become a major target for the development of new ALS treatments. Many current clinical trials aim at reducing the ALS disease burden through reducing the observed elevated levels of glutamate.

The examples herein demonstrate that in the presence of an overstimulated inhibitory neurotransmitter system, an excitatory reaction can be expected that aims at maintaining neuromotor function and homeostasis and that can lead to

overstimulation of the excitatory glutamate neurotransmitter system aiming at the stabilization of the equilibrium between the systems. Otherwise stated, an

overstimulated inhibitory neurotransmitter system can lead to elevated glutamate levels (as observed in ALS), which can lead to glutamate-mediated excitatory motoneuronal cell death (as observed in ALS), which can lead to clinical

manifestations (as observed in ALS).

The examples also show that ALS is a disease where GABAergic and Glycinergic mediated recurrent inhibition overstimulation progressively increases over time leading to either GABAergic and Glycinergic overstimulation clinical manifestations during disease onset, and to both GABAergic and Glycinergic overstimulation clinical manifestations becoming identifiable during progressive disease. The effect of overstimulation on clinical symptoms is depicted in Figures 1 and 2. Based upon the examples herein, it can be concluded that late stage clinical manifestations of ALS are related to both GABAergic and Glycinergic overstimulation, where bulbar onset ALS is related to the clinical manifestation of GABAergic overstimulation and limb onset ALS is related to the clinical manifestation of Glycinergic overstimulation. Even further, the disclosure provides that GABAergic inhibitory overstimulation is at the basis of neurologic diseases listed in table 3 including frontotemporal dementia, dementia, Alzheimer's disease, Multiple Sclerosis, Huntington's disease, Duchenne muscular dystrophy, Peripheral Neuropathy, schizophrenia, dementia, restless legs syndrome and Parkinson's disease, where progressive and diffuse neuronal clinical manifestations present themselves in combination with clinical manifestations as observed in GABAergic overstimulated ALS patients. These diseases can therefore be classified as a common group based on their clinical symptoms. The disclosure further provides that GABAergic and /or Glycinergic inhibitory overstimulation is the cause of these disorders and that these disorders can be effectively treated by reducing

GABAergic and/or Glycinergic activity.

Even further, the disclosure provides that GABAergic overstimulation is at the basis of other diseases listed in table 4 including diabetes, mitochondrial disease, and lysosomal storage disorders.

In contrast to prior art methods which aim to decrease glutamatergic activity, the present disclosure relates to decreasing inhibitory and/or GABAergic and/or

Glycinergic overstimulation. When excitatory overstimulation is involved in disease pathology, the administration of a GABA activity antagonist would be predicted to lead to severe seizures. Surprisingly, the present disclosure demonstrates that the inhibitory system is overstimulated in ALS and ALS-like disorders. The methods disclosed herein comprise decreasing GABAergic activity without leading to severe seizures.

In one aspect, the disclosure provides a method for treating a disorder in an individual, preferably wherein the disorder is ALS or an ALS-like disorder as disclosed herein. As used herein, "treating" includes reducing the onset, severity, and/or progression of one or more sympoms of the disorder. In one aspect the disclosure provides a method for treating one or more symptoms of said disorder, preferably wherein said symptoms are selected from table 7 and/or 8 and/or tables 7a- 7f and 8, preferably tables 7a- 7d and 8, preferably from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction.

The methods comprise decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, in particular in the central nervous system. The invention relates to reducing inhibitory activity that is mediated by the GABA and glycine neurotransmitter systems. As is known to a skilled person, GABAergic compounds which increase the inhibitory activity of GABA in the central nervous system (e.g., GABA receptor agonists) are CNS depressants that have been used for inhibitory action including sedation, anti-convulsant activity, anxiolysis, muscle relaxant, anterograde amnesia and anesthetic activity. Compounds which decrease the inhibitory activity of GABA in the central nervous system (e.g., GABA receptor antagonists) lead to excitatory action that, when over stimulated, can lead to seizures. As used herein, decreasing GABAergic and/or Glycinergic inhibitory activity refers to the "net" activity of the central nervous system. As is known to a skilled person, systemic administration of compounds reducing GABAergic action leads to a reduction of inhibitory activity. When such compounds become available in specific brain regions including the thalamus, ventrolateral thalamus, (Thai), internal segment of globus pallidus (GPi), substantia nigra pars reticulata (SNr), subthalamic nucleus (STN), external segment of globus pallidue (GPe), neostriatum, cerebral ventricle, subdural space and intrathecal space, these compounds can also exert increases or decreases in glutamate excitatory activity outside these regions.

Depending on the specific brain region where such compounds become available this causes the thalamus to either excert more or less glutamatergic activity. However, as systemic administration of compounds reducing GABAergic action is known to lead to seizures, it can be concluded that the net effect of systemic administration of such compounds leads to the net reduction of inhibitory action.

Accordingly, the present invention is preferably directed to providing a

therapeutically effective amount a compound that reduces GABAergic activity or Glycine receptor mediated activity to an individual systemically. Systemic

administration includes both enteral administration (e.g., orally and rectally) and parenteral (e.g., intraveneous, subcutaneous or intramuscular) or topical (e.g. topical admistration through creams, nasally and through eye drops). As herein defined, and as is known to a skilled person, intracranial administration is not a form of systemic administration. Preferably, the administration is enteral. The invention also relates to the systemic administration using formulations that are known to increase the distribution and availability of compounds (in)to the CNS, for example through the administration of the compounds through formulations that increase the bio- availabilty of compounds into the CNS such as for example, but not limited to, lipid formulations. The invention also relates to systemic administration through formulations that lead to the sustained release of the compound and that

consequently lead to increased concentrations of the compound in the CNS.

The disclosure does not encompass the direct, localized administration of compounds to a particular brain region, such as the intracranial administration described in US5735814. US5735814 is concerned with modulating glutamate excitation for treatment of ALS, Huntington's Disease, and Parkinson's Disease. In contrast, the present disclosure concludes that glutamate hyperexcitation is not the cause of the diseases mentioned in US5735814, but rather a physiologic reaction aimed at reestablishing homeostasis. In particular embodiments, the methods do not comprise direct, i.e., local, administration (e.g., via brain infusion at particular locations) of a GABAergic or glycinergic reducing activity compound as described herein to the ventrolateral thalamus (Thai), internal segment of globus pallidus (GPi), substantia nigra pars reticulata (SNr), subthalamic nucleus (STN), external segment of globus pallidus (GPe), neostriatum, cerebral ventricle, subdural space, or intrathecal space. In particular, methods do not comprise the direct administration referred to in US5735814 in patients afflicted with Parkinson's disease, ALS, or Huntington's disease.

Preferably, the method comprises decreasing GABAergic net inhibitory activity. As described above, the "net" inhibitory activity of the CNS is then decreased. This is in contrast, for example, to AMPA receptor antagonists. Such antagonists may reduce the amount of GABA released by an individual neuron, or groups of neurons, or in some parts of the neuronal system but their overall net effect on the whole is an increase of inhibitory activity as for example reflected in their efficacy in reducing seizures rather than provoking these. Accordingly, it is clear that the administration of an AMPA receptor antagonist does not decrease GABAergic net activity and is not encompassed by the invention. Preferably, GABAergic inhibitory activity is reduced by the systemic administration of a GABA receptor antagonist and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action through the GABA receptor thereby causing the net reduction of inhibitory activity. Preferably the compound is a GABA receptor antagonist.

Preferably, the method comprises decreasing Glycinergic activity. Preferably, decreasing Glycinergic activity is through modulation of the Glycine receptor.

Preferably, glycinergic inhibitory activity is decreased by the administration of a glycine receptor antagonist. Preferably, the method comprises decreasing GABAergic and Glycinergic activity. Preferably, the method also comprises the administration of an additional compound for decreasing glutaminergic activity for maintaining the equilibrium between the excitatory and inhibitory systems for avoiding seizures.

In preferred embodiments, the methods disclosed herein also comprise a step of diagnosing an individual as having ALS or an ALS like disorder. Such diagnosing steps are well within the purview of a skilled person. For example, in order to diagnose ALS the following data may be collected: patient symptomology, creatine kinase blood levels, electrical activity in the muscle (e.g., using an electromyogram), and genetic testing (e.g., for familial forms of ALS). Preferably, the methods disclosed herein comprising a step of diagnosing an individual having ALS or an ALS like disorder as exhibiting a symptom selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction.

Preferably, the ALS-like disorder presents at least one of the symptoms in table 7 and/or 8 and/or tables 7a-7f and 8, preferably tables 7a- 7d and 8. Preferably, the ALS- like neuromuscular disorder presents at least one of, preferably all of, the following symptoms: muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction. It is understood that the symptoms do not need to be present in the same individual, but rather, that the symptoms are a characteristic of a particular disorder in the patient population as a whole. Preferably, an individual to be treated exhibits one or more symptoms selected from tables 7 and/or 8 and/or tables 7a-7f and 8, preferably tables 7a-7d and 8. Preferably, an individual to be treated exhibits one or more symptoms selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy,

supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction. The presence of these symptoms can be readily determined by a physician. In preferred embodiments, the method comprising determining whether the individual exhibits at least one or more of the symptoms. Preferably, the symptoms are muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria and / or eye movement difficulties.

Respiratory depression, as used herein, refers to general respiratory depression and not a sleep-related breathing disorder such as hypopnea or apnea.

Preferable, the disorder is selected from ALS, MND, progressive muscular atrophy (PMA), flail arm MND, flail leg MND, primary lateral sclerosis (PLS), progressive bulbar palsy (PBP), pseudobulbar palsy (PB), Duchenne muscular dystrophy (DMD), Facioscapulohumeral muscular dystrophy (FSHD), Friedreich's ataxia,

Frontotemporal dementia (FTD), Frontotemporal degeneration, Behavioral variant FTD (bv-FTD), Primary progressive aphasia (PPA), FTD movement disorders, Dementia, Pugilist dementia, Alzheimer's disease (ALZ), Vascular dementia,

Dementia with Lewy bodies (DLB), Progressive supranuclear palsy (PSP),

Corticobasal degeneration, Multiple Scleroses (MS), Huntington's disease (HD), Peripheral Neuropathy (PN), Parkinson's disease (PD), Schizophrenia, Diabetes, and Traumatic brain injury (TBI) or other diseases listed in tables 1, 2, 3 or 4

More preferably, the disorder is selected from ALS, FTD-ALS, FTD, dementia, Alzheimer's disease (ALZ), Huntington's disease, Parkinson's disease, Duchenne muscular dystrophy, Multiple Scleroses, peripheral neuropathy, schizophrenia, diabetes, Facioscapulohumeral muscular dystrophy. In some embodiments, the disorder is not ALS, Parkinson's disease, or Huntington's disease.

In one aspect, the disclosure provides a method for treating ALS or an ALS-like disorder and pharmaceutical compositions for use in said treament. As used herein, an ALS-like disorder is a disorder with one or more symptoms as listed in Table 7, 8 or 7a- 7f, preferably tables 7a-d and 8, wherein the one or more symptoms results from inhibitory neurotransmitter overstimulation. The disclosure demonstrates that the symptoms listed in Tables 7 and 8 and 7a- 7f and 8 when presented in disorders such as those listed in Tables 1-4 are the result of GABAergic and/or Glycinergic

overstimulation. Collectively, ALS and ALS-like disorders may also be referred to herein as inhibitory neurotransmitter overstimulation disorders. The present disclosure is the first to recognize that inhibitory neurotransmitter overstimulation is a common pathology linking the disorders listed in Tables 1-4. Preferably, the disorder is a muscular dystrophy, an inflammatory myopathy, an MND, a

neuromuscular junction disease, a peripheral nerve disease, a myopathy, an atrophy disorder, a metabolic muscle disease or an ataxy as disclosed in Table 1. Most preferably, the disorder is ALS. Preferably, the disclosure provides a method and pharmaceutical compositions for treating one or more symptoms of said disorder, preferably wherein said symptoms are selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, gastrointestinal dysfunction and/or symptoms listed in table 7 and/or 8 and/or tables 7a- 7f and 8, preferably tables 7a- 7d and 8, in an individual afflicted with ALS or an ALS-like disorder. The methods comprise decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, for example by administering the pharmaceutical compositions disclosed herein. Preferably, the method comprises decreasing GABAergic activity. Preferably, the method comprises decreasing Glycinergic activity. Preferably, the method comprises decreasing GABAergic and Glycinergic activity. Preferably, the method also comprises the administration of a further compound for decreasing glutaminergic activity for maintaining the equilibrium between the excitatory and inhibitory systems for avoiding seizures.

In preferred embodiments of the method, a therapeutically effective amount of a compound capable of reducing GABAergic activity and/or Glycinergic inhibitory activity is administered to an individual in need thereof. Based upon tables 7 and 8 and tables 7a- 7f, preferably tables 7a- 7d and 8, it is well within the purview of a skilled person to determine whether GABAergic and/or Glycinergic inhibitory activity should be decreased in the individual based on the symptoms an individual presents. For example, when an individual having an ALS or ALS-like disorder presents with symptoms selected from table 7, then GABAergic activity should be decreased. When an individual having an ALS or ALS-like disorder presents with symptoms selected from table 8, then GABAergic activity, Glycinergic activity, or both activities should be decreased. Most disorders will benefit from decreasing both GABAergic and Glycinergic activities. However, diabetes, due to its specific symptomology/pathology as first described herein, can also be treated by decreasing GABAergic activity alone.

An "individual" as used herein refers to any mammal, e.g., primates, domesticated animals including dogs, cats, sheep, cattle, goats, pigs, mice, rats, and rabbits.

Preferably the individual is a human.

The disclosure further provides pharmaceutical compositions comprising a compound reducing GABAergic activity and/or a compound reducing Glycinergic activity.

Preferably, the composition comprises a compound reducing GABAergic activity.

Preferably, the composition comprises a compound reducing Glycinergic activity.

Preferably, the composition comprises a compound reducing GABAergic activity and a compound reducing Glycinergic activity. Said compositions are useful for the treatments disclosed herein. The compounds reducing GABAergic or Glycinergic activity described herein are therefore useful for the preparation of medicaments for the treatments disclosed herein. It is clear to a skilled person that a pharmaceutical compositions comprising a compound reducing GABAergic activity and a compound reducing Glycinergic activity refers to a composition comprising at least two compounds, wherein a first compound reduces GABAergic activity and a second compound reduces Glycinergic activity.

Preferably, the neuromuscular disease is not associated with an elevated risk of seizure. As used herein, "elevated risk" refers to a significantly increased risk of seizures in the general patient population as compared to a control population.

In preferred methods, an individual in need thereof is administered a pharmaceutical composition which decreases GABAergic and/or Glycinergic activity. The GABAergic and Glycinergic inhibitory neurotransmitter pathways have been extensively studied. A skilled person is therefore well aware of suitable means to reduce GABAergic and Glycinergic overstimulation. Suitable means for reducing activity include reducing GABA and / or Glycine levels available for binding to receptors, GABA and / or Glycine synthesis inhibition, stimulation of GABA and / or Glycine metabolism, the prevention of binding of GABA and / or Glycine to their receptors through

administration of inverse agonists, antagonists, partial agonists, synaptic uptake inhibitors, synaptic reuptake inhibitors, steric hindrance compounds, and the administration of compounds modulating other neurotransmitter systems, for example the dopaminergic system, that are capable of (indirectly) reducing

GABAergic or Glycinergic mediated recurrent inhibition overstimulation. Suitable means for reducing GABA activity also include modulation of protein kinase C. It is also clear to a skilled person that a compound may be chosen which decreases both GABAergic and Glycinergic activity. Such compounds may be preferred in disorders which result from overstimulation of both the GABAergic and Glycinergic systems. Preferably, a compound for reducing GABAergic activity is a GABA receptor antagonist. Preferably, a compound for reducing Glycinergic activity is a glycine receptor antagonist.

As used herein, a "direct" GABAergic activity reducer exerts its effects directly on the GABAergic pathway, for example, by directly targeting GABA (synthesis, uptake, etc.) or a GABA receptor. An "indirect" GABAergic activity antagonist exerts its effects on a different neurotransmitter system, which in turn alters GABAergic activity.

Preferably the GABAergic and /or Glycinergic activity reducer exerts its action to the GABA receptor or to the Glycine receptor. Preferably the GABAergic and /or

Glycinergic activity reducer exerts its action through interacting with both the GABA receptor and the Glycine receptor, preferably the GABAergic and /or Glycinergic activity reducer is Bicuculline, Picrotoxin, Salicylidene salicylhydrazide, Flumazenil, Gabazine (SR 95531), Thiocolchicoside, 6,2-dihydroflavone, RU5135, cicutoxin, Ro 15- 4513, Ro 15-4603, FG 7142, BTD-001, RG- 1662, strychnine, CGP 36742, SGS-742 or Tutin. Preferably, the GABA antagonist is a GABA receptor channel blocker.

Preferably, the compound is a 6-Lactam with GABA antagonistic activity, preferably the β-Lactam is selected from penicillin, cephalosporin, and a carbapenem. More preferably the β-Lactam is a penicillin, more preferably Penicillin G. Preferably the compound is selected from Table 5. In addition to GABA receptor antagonists, compounds that lead to an increase in availability or efficacy of compounds that (at least partly) exert their action through the GABA receptor thereby causing the reduction of net inhibitory activity are also encompassed by the invention. In particular, compounds that decrease the availability of GABA are preferred.

Preferably, the compound is a GABA receptor inhibitor. As used herein, a GABA receptor inhibitor refers to a compound that reduces the activity or expression of the GABA receptor and includes compounds, e.g., antisense oligonucleotides as well as compounds that bind to the GABA receptor and prevent or reduce GABAergic activity. A preferred GABA receptor inhibitor is a GABA receptor antagonist. As is known to a skilled person partial receptor agonists can also act as a competitive antagonist in the presence of a full agonist. It is known to a skilled person that if inhibitory disease is the result of the presence of GABAergic activity through the presence of full agonists (administrated to or synthesized in the patient's body) binding at receptors that cause inhibitory overstimulation, inhibitory overstimulation in this patient can be reduced through the administration of partial agonists at these receptors, as this will lead to the net reduction of inhibitory activity. As is known to a skilled person, providing a partial agonist in the absence of a full agonist does not lead to the reduction of

GABAergic activity. In some embodiments, GABA receptor partial agonists are not encompassed by the invention.

Preferably the GABA receptor inhibitor specifically inhibits GABA-A, GABA-B, GABA-C or other receptor subtypes with higher affinity than it inhibits other GABA receptor subtypes. As it is clear to a skilled person, differences in binding between the GABA-A, GABA-B, GABA-C or other GABA subtype receptors can for example be established by determining receptor affinity as reflected in the Kd or IC50 values of a GABA receptor inhibitor for each of the GABA receptor subtypes, as for example established in in vitro receptor binding or functional assays.

In some embodiments, the GABA receptor inhibitor is selected from a selective GABA- A receptor inhibitor, a selective GABA-B receptor inhibitor, or a selective GABA-C receptor inhibitor. In preferred embodiments the inhibitor is a selective GABA-B receptor inhibitor, more preferably a GABAB antagonist from Table 5. In some embodiments, when the individual is afflicted with ALS, the GABA receptor inhibitor is not a GABA-A receptor inhibitor. In some embodiments, when the individual is afflicted with ALS, the GABA receptor inhibitor is a selective GABA-B receptor inhibitor. In some embodiments the compound is a GABAA antagonist selected from a fluoroquinine or a 6-Lactam.

In preferred embodiments, the GABA receptor inhibitor is a GABA receptor channel blocker, more preferably the GABA receptor inhibitor is a GABA receptor open channel blocker. As known to a person skilled in the art, a GABA receptor open channel blocker molecule exerts its GABA antagonistic activity through the binding of the molecule within the GABA receptor channel pore. As such, an open channel blocker can only exert efficacy once GABA has bound to the GABA receptor, leading to the opening of the GABA receptor channel pore. GABA receptor open channel blockers are known to a skilled person and include penicillin G and picrotoxin. Preferably, the GABA receptor inhibitor is penicillin G.

For example, suitable compounds reducing GABAergic activity include compounds having one or more of the following properties:

a. Decreasing GABA synthesis

i. for example, through inhibition of GAD enzymes

ii. for example, through inhibition of GAD65for example, through inhibition of GAD 67

b. Decreasing GABA uptake in neuron cell vesicles

c. Inhibiting GABA release into the synapse

d. Stimulating GABA presynaptic receptors

e. Inhibiting GABA postsynaptic receptors

f. Stimulating neuronal GABA uptake from the synapse

i. for example, through modulation of ATPases

ii. for example, through modulation of ATPase 6

iii. for example, through modulation of ATPase 8

iv. for example, through modulation of mitochondrial processes

g. Stimulating gial GABA uptake from the synapse

i. for example, through modulation of ATPases ii. for example, through modulation of ATPase 6

iii. for example, through modulation of ATPase 8

iv. for example, through modulation of mitochondrial processes

h. Blocking GABA action

i. Stimulating GABA degradation

j. Decreasing the concentrations of GABA available for binding to the GABA receptor

k. Inhibiting the post synaptic GABA receptor

i. Inhibition of binding to the GABA binding site of the GABA receptor a. for example, inverse agonists, antagonists, partial agonists to the GABA binding site of the GABA receptor, preferably selected from Bicuculline, Picrotoxin, Salicylidene salicylhydrazide, Flumazenil, Gabazine (SR 95531), Thiocolchicoside, 6,2-dihydroflavone, RU5135, Ro 15-4513, Ro 15- 4603 or FG 7142.

ii. Inhibition of binding to the barbiturate binding site of the GABA receptor a. for example, inverse agonists, antagonists, partial agonists to the barbiturate binding site of the GABA receptor

iii. Inhibition of binding to the alcohol (ethanol) binding site of the GABA

receptor

a. for example, inverse agonists, antagonists, partial agonists to the alcohol binding site of the GABA receptor

Preferred compounds reducing GABAergic activity are selected from table 5, preferably a GABA receptor antagonist. Reduction of GABAergic activity has been shown to be clinically feasible through the administration of the GABA receptor antagonist flumazenil leading to the reversal of GABAergic effects of benzodiazepine administration, even leading to sublingual applications. Furthermore, GABAergic activity in cats can be reduced through the administration of compounds reducing GABAergic activity such as GABA antagonists picrotoxin and bicuculline (Hockman et al. 1996).

In some embodiments, the one or more compounds which reduce GABAergic activity is not ginkgo extract (in particular the extract of Ginkgo biloba) or a component of ginko extract (e.g., terpene trilactones (ginkgolide or bilobalide) or flavonoids).

Preferably, the one or more compounds is not a terpene trilactone or a derivative thereof,, morepreferably not a ginkgolide or a ginkgolide derivative, bilobalide or a bilobalide derivative. Ginkgolides include natural ginkgolides, e.g., ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, and ginkgolide M, as well as synthetic ginkgolides and their derivates such as compounds of the formula:

in which W, X, Y and Z represent independently the H, OH, linear or branched alkoxy or O-GS radicals, GS-OH representing a mono- or a disaccharide, or one of their derivatives or analogues, it being understood that at least one of W, X, Y or Z represents an O-GS radical. Further ginkogolides and their derivatives are described in US Pat No. 6524629, WO2005/092324, and WO2005/021496 which are not encompassed by the present disclosure. Ginkgolides are known to have a number of different effects incuding hippocampal insulin receptor binding, affecting 5HT1A receptor density, increasing extracellular dopamine levels, increasing the muscarin receptor population in the hippocampus, binding to the kainite excitatory amino acid site, activatin the Pregnane X ligand-activated nuclear hormone receptor, displaying Antioxidant/Anti-inflammatory effects that can compensate for the SOD1 deficiency, inhibiting Monoamine oxidase (MAO), affecting levels of serotonin, melatonin, epinephrine, norepinephrine, phenethylamine, trace amines and dopamine, increasing serotonin levels, increasing muscarinic binding sites, increasing serum levels of acetylcholine and norepinephrine, and inhibiting nitric oxide. In particular, in the methods and pharmaceutical compositions described herein for the treatment of an individual afflicted with ALS, the one or more compounds which reduce GABAergic activity is not ginkgo extract (in particular the extract of Ginkgo biloba) or a component of ginko extract (e.g., a ginkgolide or bilobalide). In particular, in the methods and pharmaceutical compositions described herein for the treatment of an individual afflicted with ALS, the one or more compounds which reduce GABAergic activity is not ginkgo extract (in particular the extract of Ginkgo biloba) or a component of ginko extract (e.g., a ginkgolide or bilobalide). Preferably, methods and pharmaceutical compositions are provided for treating muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and/or gastrointestinal dysfunction) in an individual afflicted with ALS or an ALS-like disorder, the method comprising decreasing GABAergic and/or

Glycinergic activity in an individual in need thereof, wherein when the individual is afflicted with ALS and the symptom is muscle wasting, loss of muscle function, and/or respiratory depression, the one or more compounds which reduce GABAergic activity is not ginkgo extract (in particular the extract of Ginkgo biloba) or a component of ginko extract (e.g., a ginkgolide or bilobalide).

It is also clear to a skilled person that linalool is not a GABA antagonist (see, e.g., Brum et al. Phytother Res. 2001 Aug; 15(5):422-5) and is therefore not a compound which reduces GABAergic activity as disclosed herein. Accordingly, it is clear to a skilled person that linalool is not encompassed by the present disclosure.

US20110224278 describes the use of gamma aminobutyric acid (GABA) receptor signaling inhibitors to treat CNS injury. The references further suggestes treatment of CNS injuries associated with trauma, multiple sclerosis, cerebral vasospasm, status epilepticus, perinatal asphyxia, anoxia, Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral ischemia, cerebral infarction, ischemic brain damage, spinal cord injury, tissue ischemia, reperfusion injury or any other CNS injury resulting in physical damage to CNS tissue and combinations thereof. In contrast, the present disclosure treats the GABAergic inhibitory overstimulation which can lead to CNS injury. Therefore, the present disclosure provides for the treatment of

individuals even before significant injury has occurred.

In addition, it is clear that a skilled person would not have treated diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, or multiple sclerosis with a GABA antagonist described in US20110224278 due to the risk of inducing seizures. It is only after understanding that such disorders are related to GABAergic inhibitory overstimulation, as taught herein, would such treatments be feasible. In addition, the present disclosure provides treatments in which the compounds are preferably provided at a dosage level where no seizures or only mild seizures occur. These dosages are not disclosed in US20110224278. In addition, the present disclosure provides treatments in which the compounds are preferably provided using escalating dosage regimes. These dosages are not disclosed in US20110224278.

Nevertheless, in some embodiments, the present disclosure does not encompass the treatment of CNS injuries associated with trauma, multiple sclerosis, cerebral vasospasm, status epilepticus, perinatal asphyxia, anoxia, Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral ischemia, cerebral infarction, ischemic brain damage, spinal cord injury, tissue ischemia, or reperfusion injury. In some embodiments, the GABA antagonist of the present invention is not L655,708, a5IA, PWZ-029, 6,6-Dimethyl-3-(2-hydroxyethyl)thio- l-(thiazol-2-yl)-6,7-dihydro-2- benzothiophen-4(5H)-one, R04938581, and pharmaceutically acceptable salts thereof, and mixtures thereof.

Suitable compounds that indirectly reduce GABAergic activity include those which interact with the activity of the GABAergic neurotransmitter system through interactions with other neurotransmitter systems selected from the dopamine neurotransmitter system, the glutamine neurotransmitter system, the acetylcholine neurotransmitter system, the serotonin neurotransmitter system, the norepinephrine neurotransmitter system, the epinephrine neurotransmitter system, the protein kinase C system, and the histamine neurotransmitter system.

Preferably the Glycinergic activity reducing compound modulates the glycine receptor and / or leads to an increase in availability or efficacy of compounds that (at least partly) exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity. Such compounds have one or more of the following properties: a. Decreasing Glycine synthesis

b. Decreasing Glycine uptake in neuron cell vesicles

c. Inhibiting Glycine release into the synapse

d. Stimulating Glycine presynaptic receptors e. Inhibiting Glycine postsynaptic receptors

f. Stimulating neuronal Glycine uptake from the synapse

i. for example, through modulation of ATPases

ii. for example, through modulation of ATPase 6

iii. for example, through modulation of ATPase 8

iv. for example, through modulation of mitochondrial processes

g. Stimulating glial cell Glycine uptake from the synapse

v. for example, through modulation of ATPases

vi. for example, through modulation of ATPase 6

vii. for example, through modulation of ATPase 8

viii. for example, through modulation of mitochondrial processes

h. Stimulating Glycine degradation

i. Decreasing the concentrations of Glycine available for binding to the Glycine receptor

j. Inhibition the post synaptic Glycine receptor

a. for example, inverse agonists, antagonists, partial agonists to the GABA binding site of the GABA receptor, preferably selected from Bicuculline, Brucine, Picrotoxin, Strychnine and Tutin.

Preferably, the Glycinergic activity reducing compound is a Glycine receptor antagonist.

Suitable compounds that indirectly reduce Glycinergic activity include those which interact with the activity of the Glycinergic neurotransmitter system through interactions with other neurotransmitter systems selected from the dopamine neurotransmitter system, the glutamine neurotransmitter system, the acetylcholine neurotransmitter system, the serotonin neurotransmitter system, the norepinephrine neurotransmitter system, the epinephrine neurotransmitter system, and the histamine neurotransmitter system.

Preferred compounds reducing Glycinergic activity are found in table 6, preferably a glycine receptor antagonist.

The compounds reducing GABAergic activity and / or Glycinergic activity provided herein, also referred to as "compounds", include polypeptides, small molecules, and nucleic acid based inhibitors. Preferably, the compound is a nucleic acid molecule (such as an antisense oligonucleotide, an RNA interference molecule) or a binding molecule (e.g., an antibody or antibody fragment), or a small molecule receptor antagonist.

In some embodiments, the compound is a nucleic acid molecule whose presence in a cell causes the degradation of or inhibits the function, transcription, or translation of its target gene in a sequence-specific manner. Exemplary nucleic acid molecules include aptamers, siRNA, artificial microRNA, interfering RNA or RNAi, dsRNA, ribozymes, antisense oligonucleotides, and DNA expression cassettes encoding said nucleic acid molecules.

Suitable target genes for reducing GABAergic activity include GABRA1, Gabral, GABRA2, Gabra2, GABRA3, Gabra3, GABRA4, Gabra4, GABRA5, Gabra5, GABRA6, Gabra6, GABRB1, Gabrbl, GABRB2, Gabrb2, GABRB3, Gabrb3, GABRG1, Gabrgl, GABRG2, Gabrg2, GABRG3, Gabrg3, GABRD, Gabrd, GABRE, Gabre, GABRQ, Gabrq, GABRP, Gabrp, GABRR1, Gabrrl, GABRR2, Gabrr2, GABRR3, Gabrr3, GABBR1, Gabbrl, GABBR2, Gabbr2, KCTD8, Kctd8, KCTD12, Kctdl2, Kctdl2b, KCTD16, Kctdl6, SLC6A1, Slc6al, SLC6A13 (Hs), Slc6al3 (Mm), Slc6al3 (Rn), SLC6A11 (Hs), Slc6all (Mm), Slc6all (Rn), SLC6A12 (Hs), Slc6al2 (Mm), Slc6al2 (Rn), SLC6A6 (Hs), Slc6a6 (Mm), Slc6a6 (Rn), SLC32A1 (Hs), Slc32al (Mm), Slc32al (Rn), HTR1B, Htrlb, KCNC1, Kcncl, KCNJ6, Kcnj6, KCNJ3, Kcnj3, ADRA1A,

Adrala, KCNC2, Kcnc2, SLC6A8 (Hs), Slc6a8 (Mm), Slc6a8 (Rn), CHRNA4, Chrna4, CHRNB2, Chrnb2, ABAT, Abat, ALDH5A1, Aldh5al, GAD1 (Hs), Gadl (Mm), Gadl (Rn), GAD 2 (Hs), Gad2 (Mm), Gad2 (Rn), ALDH9A1 (Hs), Aldh9al (Mm), Aldh9al (Rn), GRM4, Grm4, GRM3, Grm3, TACR3, Tacr3, SCTR, Sctr, GRPR, Grpr,. MT- ATP8 (Hs), mt-Atp8 (Mm), Mt-atp8 (Rn), ATP5J (Hs), Atp5j (Mm), Atp5j (Rn).

Suitable target genes for reducing Glycinergic activity include GLRAl, Glral, GLRA2, Glra2, GLRA3, Glra3, GLRA4, Glra4, GLRB, Glrb, SLC32A1 (Hs), Slc32al (Mm), Slc32al (Rn), GATM (Hs), Gatm (Mm), Gatm (Rn), SLC6A9 (Hs), Slc6a9 (Mm), Slc6a9 (Rn), SLC6A5 (Hs), Slc6a5 (Mm), Slc6a5 (Rn), SLC6A14 (Hs), Slc6al4 (Mm), Slc6al4 (Rn), SLC6A7 (Hs), Slc6a7 (Mm), Slc6a7 (Rn), MT-ATP8 (Hs), mt-Atp8 (Mm), Mt-atp8 (Rn), ATP 5 J (Hs), Atp5j (Mm), Atp5j (Rn), PRKCB, Prkcb, Prkcb, PRKCG, Prkcg, Prkcg, PRKCI, Prkci, Prkci, PRKCH, Prkch, Prkch, PRKCZ, Prkcz, Prkcz, PRKCQ, Prkcq, Prkcq, PRKCE, Prkce, Prkce, PRKCD, Prkcd, Prkcd, PRKCA, Prkca, Prkca. It is understood that homologous genes in the relevant species can also be targeted. Preferably, the nucleic acid molecule is an antisense oligonucleotide. Antisense oligonucleotides (AONs) generally inhibit their target by binding target mRNA and sterically blocking expression by obstructing the ribosome. AONs can also inhibit their target by binding target mRNA thus forming a DNA-RNA hybrid that can be a substance for RNase H. AONs may also be produced as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides, oligonucleotide mimetics, or regions or portions thereof. Such compounds have also been referred to in the art as hybrids or gapmers. Methods for designing and modifying such gapmers are described in, for example, U.S. Patent Publication Nos. 20110092572 and

20100234451.

AONs typically comprise between 12 to 80, preferably between 15 to 40, nucleobases. Preferably, the AONs comprise a stretch of at least 8 nucleobases having 100% complementarity with the target mRNA.

Preferably, the nucleic acid molecule is an RNAi molecule, i.e., RNA interference molecule. Preferred RNAi molecules include siRNA, shRNA, and artificial miRNA. siRNA comprises a double stranded structure typically containing 15 to 50 base pairs and preferably 19 to 25 base pairs and having a nucleotide sequence identical or nearly identical to an expressed target gene or RNA within the cell. An siRNA may be composed of two annealed polynucleotides or a single polynucleotide that forms a hairpin structure. As used herein "shRNA" or "small hairpin RNA" (also called stem loop) is a type of siRNA. In one embodiment, these shRNAs are composed of a short, e.g. about 10 to about 25 nucleotides, antisense strand, followed by a nucleotide loop of about 5 to about 9 nucleotides, and the analogous sense strand. Alternatively, the sense strand can precede the nucleotide loop structure and the antisense strand can follow.

The design and production of siRNA molecules is well known to one of skill in the art (Hajeri et al. 2009). Methods of administration of therapeutic siRNA is also well- known to one of skill in the art (Manjunath et al. 2010, Guo et al., 2010). siRNA molecule comprises an antisense strand having about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides, wherein the antisense strand is complementary to a RNA sequence or a portion thereof encoding.

The nucleic acid molecule inhibitors may be chemically synthesized and provided directly to cells of interest. The nucleic acid compound may be provided to a cell as part of a gene delivery vehicle. Such a vehicle is preferably a liposome or a viral gene delivery vehicle. Liposomes are well known in the art and many variants are available for gene transfer purposes. Vectors comprising said nucleic acids are also provided. A "vector" is a recombinant nucleic acid construct, such as plasmid, phase genome, virus genome, cosmid, or artificial chromosome, to which another DNA segment may be attached. The term "vector" includes both viral and nonviral means for introducing the nucleic acid into a cell in vitro, ex vivo or in vivo. Non-viral vectors include plasmids, liposomes, electrically charged lipids (cytofectins), DNA-protein complexes, and biopolymers. Viral vectors include retrovirus, ade no- associated virus (AAV), pox, baculovirus, vaccinia, herpes simplex, Epstein-Barr and adenovirus vectors. Vector sequences may also contain one or more regulatory regions, and/or selectable markers useful in selecting, measuring, and monitoring nucleic acid transfer results (transfer to which tissues, duration of expression, etc.). Lentiviruses have been previously described for transgene delivery to the hippocampus (van Hooijdonk 2009).

There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. The currently preferred in vivo gene transfer techniques include transfection with viral (typically retroviral) vectors and viral coat protein-liposome mediated transfection (Dzau et al 1993).

Preferably, the compound is a "binding agent" that specifically binds to a target and inhibits the function of a target, more preferably the compound is a binding agent or small molecule. Preferred targets for reducing GABAergic activity include GABA receptors and preferred targets for reducing Glycinergic activity include glycine receptors.

Binding agents include antibodies as well as non-immunoglobulin binding agents, such as phage display-derived peptide binders, and antibody mimics, e.g., affibodies, tetranectins (CTLDs), adnectins (monobodies), anticalins, DARPins (ankyrins), avimers, iMabs, microbodies, peptide aptamers, Kunitz domains, aptamers and affilins. The term "antibody" includes, for example, both naturally occurring and non- naturally occurring antibodies, polyclonal and monoclonal antibodies, chimeric antibodies and wholly synthetic antibodies and fragments thereof, such as, for example, the Fab', F(ab')2, Fv or Fab fragments, or other antigen recognizing immunoglobulin fragments.

Antibodies which bind a particular epitope can be generated by methods known in the art. For example, polyclonal antibodies can be made by the conventional method of immunizing a mammal (e.g., rabbits, mice, rats, sheep, goats). Polyclonal antibodies are then contained in the sera of the immunized animals and can be isolated using standard procedures (e.g., affinity chromatography, immunoprecipitation, size exclusion chromatography, and ion exchange chromatography). Monoclonal antibodies can be made by the conventional method of immunization of a mammal, followed by isolation of plasma B cells producing the monoclonal antibodies of interest and fusion with a myeloma cell (see, e.g., Mishell, et al., 1980). Screening for recognition of the epitope can be performed using standard immunoassay methods including ELISA techniques, radioimmunoassays, immunofluorescence, immunohistochemistry, and Western blotting (Ausubel, et al., 1992). In vitro methods of antibody selection, such as antibody phage display, may also be used to generate antibodies (see, e.g.,

Schirrmann et al. 2011).

One of the many potential advantages of the methods described herein is that the choice of treatment can be based on the symptoms that an individual exhibits. This can lead to better efficacy and/or less side effects since the specific cause of the symptoms in addressed. For example, in the case of ALS "bulbar onset" symptoms, (see examples) treatment with a GABAergic activity reducer would be indicated, whereas "limb onset" symptoms (see examples) would indicate a treatment with a GABAergic and / or Glycinergic activity reducer. Respiratory onset symptoms would indicate that both inhibitory pathways should be targeted.

Pharmaceutical compositions are also provided comprising compounds as described herein and, optionally, a pharmaceutically acceptable carrier, filler, preservative, adjuvant, solubilizer, diluent and/or excipient is also provided. Such pharmaceutically acceptable carrier, filler, preservative, adjuvant, solubilizer, diluent and/or excipient may for instance be found in Remington: The Science and Practice of Pharmacy, 20th Edition. Baltimore, MD: Lippincott Williams & Wilkins, 2000.

When administering the compounds thereof to an individual, it is preferred that the compound is dissolved in a solution that is compatible with the delivery method. For intravenous, subcutaneous, intramuscular, intrathecal and/or intraventricular administration it is preferred that the solution is a physiological salt solution.

Preferably, the levels of GABAergic and/or Glycinergic activity are reduced in the individual gradually as a too fast decrease in GABAergic or Glycinergic

overstimulation in the co-presence of elevated excitatory glutamate levels may lead to increased incidences of (epileptic) seizures. GABAergic and Glycinergic

overstimulation reduction therefore should be gradual and preferably a well monitored dose titration is used. Treatment may further be in the presence of compounds that are capable of gradually decreasing glutaminergic excitatory action for reducing the risk at and duration and severity of epileptic seizures. Treatment preferably begins as soon as disorder is diagnosed. Early treatment with the compounds disclosed herein can not only alleviate or reduce the symptoms disclosed in tables 7 and 8 and tables 7a- 7f, preferably tables 7a- 7d and 8, but can also delay or prevent their onset. Actual dosage levels of the pharmaceutical preparations described herein may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic or limiting toxicity to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound, the route of administration, the timing of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

Optimal dosing can be determined on the basis of pharmacokinetic parameters such as Clearance, Volume of distribution, fraction unbound to protein, (elimination) half- life etc. and on the basis of pharmacodynamic parameters such as receptor affinity, potency, and GABA inhibition activity, etc.

In particular, optimal dosing can be determined by titration of individual patients or groups of patients to maximal efficacy in the absence of seizures. However, seizures may be an unavoidable side-effect of treatment for some cases. This is especially true for more severe forms of the disorders. Muscle relaxant treatments such as neuromuscular blockers and midazolam (in hospital setting) and nasal or buccal midazolam or rectal diazepam (in home settings) can be used to reduce the risk at occurrence, duration and/or severity of seizures. Other factors which are useful to consider when determining the optimal dose are patient convenience and patient compliance. In some embodiments, the dosage of the antagonists is reduced slowly over the treatment period, i.e., is tapered down.

The compounds described herein are provided in a therapeutically effective amount. As used herein, the term "therapeutically effective amount" refers to the dosage needed to treat one or more of the following symptoms in an individual afflicted with ALS or an ALS-like disorder: muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, gastrointestinal dysfunction and/or symptoms as listed in table 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a- 7d and 8. In some embodiments, a therapeutically effective amount of said compound, if administered in a healthy patient, may be associated with the induction of seizures or increased risk of seizures. However, a skilled person will appreciate that lower dosages are also encompassed by the invention. As is clear to the skilled person, compounds displaying GABA antagonism may also display efficacy in the treatment of other diseases or symptoms. For example, 6- lactams with GABA antagonistic activity can also be used as antibiotics for the treatment of infections. The present invention however does not relate to the

treatment of infections with compounds that reduce inhibitory activity. Known side effects of high dose penicillin administration include twitching and convulsions, which are indicative of a decrease in net GABAergic activity in the CNS. β-lactams such as penicillin are used as antibiotics, but are also capable of inhibiting GABA-A receptors and are a preferred compound of the invention. The dosage of Penicillin G used to treat infections is provided in the table below. Penicillin G is also referred to as PenG, Pen G, Pen-G or benzylpenicillin. In some embodiments,

penicillin is administered at a dosage higher than that listed in the table. However, a skilled person will appreciate that lower dosages are also encompassed by the

invention. In particular, lower doses are sufficient in individuals having renal impairment (and therefore impaired penicillin clearance). Lower doses are also sufficient when administered, for example, at the early stages of disease when

GABAergic inhibitor activity is only mildly overstimulated or as a "maintenance treatment" after GABAergic activity has been reduced by treatment.

Dosage and administration for Penicillin G Sodium for Injection, USP may be given intravenously or intramuscularly. The usual dose recommendations are as follows:

Adult patients

CLINICAL INDICATION DOSAGE

Serious infections due to susceptible strains of

streptococci (including S. pneumoniae) and 5 to 24 million units/day depending on the staphylococci-septicemia, empyema, infection and its severity administered in equally pneumonia, pericarditis, endocarditis and divided doses every 4 to 6 hours

meningitis

Minimum of 8 million units/day in divided doses

Anthrax every 6 hours. Higher doses may be required depending on susceptibility of organism.

Actinomycosis 1 to 6 million units/day©

Cervicofacial disease 10 to 20 million units/day ©

Thoracic and abdominal disease 10 to 20 million units/day©

Clostridial infections

Botulism (adjunctive

20 million units/day©

therapy to antitoxin)

Gas gangrene Pediatric Use

Incompletely developed renal function in newborns may delay elimination of penicillin; therefore, appropriate reductions in the dosage and frequency of administration should be made in these patients. All newborns treated with penicillins should be monitored closely for clinical and laboratory evidence of toxic or adverse effects. Pediatric doses are generally determined on a weight basis and should be calculated for each patient individually.

*) Because of its short half- life, Penicillin G is administered in divided doses, usually every 4 to 6 hours with the exception of meningococcal meningitis/septicemia, i.e., every 2 hours.

For compounds that, next to GABA antagonism, also have efficacy in the treatment of symptoms that are not part of this invention, the invention relates in some

embodiments to the use of such compounds at higher dosages than those that would be used by a skilled person to treat such other symptoms that are not part of the invention. This is illustrated for the example of Penicillin G that next to GABA

antagonistic activity also displays antibiotic activity. High doses of antibiotics such as Penicillin G have been administered in order to treat particularly dangerous

infections where the risks associated with the infection outweighed the risks

associated with possible side effects of seizures. However, the present disclosure is the first recognition that such antibiotics can be used to treat ALS or an ALS-like disorder because of their GABA antagonistic effects, in particular to treat a symptom such as muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction or gastrointestinal dysfunction in an individual afflicted with ALS or an ALS-like disorder. The present treatment is independent from the antibiotic effects of beta-lactams on bacteria.

In the presence of an infection in a patient with ALS symptoms, the current invention for Penicillin G relates to the treatment of ALS symptoms with Penicillin G dosages that are higher than those that would be used to treat the symptoms not related to the invention in that patient. This not only applies to Penicillin G, but also applies to other antibiotics displaying GABA antagonistic activity. Furthermore, this applies to all compounds that next to displaying GABA antagonistic activity, in addition also display efficacy in symptoms not related to the current invention. In preferred embodiments, the individual afflicted with ALS or an ALS-like disorder is not afflicted with syphilis or Lyme's disease and/or seropositive for syphilis or

Lyme's disease, more preferably the individual is not afflicted with an infection (in particular a bacterial infection). Preferably the individual does not have an elevated risk of developing or being afflicted with an infection (in particular a bacterial infection). As is clear to a skilled person, a person having an "elevated risk" of infection refers to a person having a significantly and/or clinically relevant higher risk of infection than the general population (for example, in patients where antibiotic prophylaxis treatment is warranted). Accordingly, the present disclosure provides the use of GABAergic activity reducing compounds, such as beta-lactams, for treating

ALS or an ALS-like disorder (in particular a symptom such as muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction or gastrointestinal dysfunction) in an individual that would not otherwise have the need for treatment with a beta-lactam (i.e., such individual not suffering from or having an elevated risk of suffering from an

infection).

In some embodiments, the individual treated is not afflicted with one or more of the following disorders:

Serious infections due to susceptible strains of streptococci (including S. pneumoniae) and staphylococci-septicemia, empyema, pneumonia, pericarditis, endocarditis and meningitis Anthrax

Actinomycosis

Cervicofacial disease

Thoracic and abdominal disease

Clostridial infections

Botulism (adjunctive

therapy to antitoxin)

Gas gangrene

(debridement and/or

surgery as indicated)

Tetanus (adjunctive therapy to human tetanus

immune globulin)

Diphtheria (adjunctive therapy to antitoxin and for the prevention of the carrier state) Erysipelothrix endocarditis

Fusospirochetosis (severe infections of the oropharnyx [Vincent's], lower respiratory tract and genital area)

Listeria infections

Meningitis

Endocarditis

Paste urella infections including bacteremia and meningitis

Haverhill fever, Rat-bite fever

Disseminated gonococcal infections, such as meningitis endocarditis, arthritis, etc., caused by penicillinsusceptible organisms

Syphilis (neurosyphilis)

Meningococcal meningitis and/or septicemia

Serious infections, such as pneumonia and endocarditis, due to susceptible strains of streptococci (including S. pneumoniae) and meningococcus

Meningitis caused by susceptible strains of pneumococcus and meningococcus

Disseminated Gonococcal infections (penicillin-susceptible strains)

Arthritis

Meningitis

Endocarditis

Arthritis, meningitis, endocarditis

Syphilis (congenital and neurosyphilis) after the newborn period

Diphtheria (adjunctive therapy to antitoxin and for prevention of the carrier state) Rat-bite fever; Haverhill fever

(with endocarditis caused by S. moniliformis)

The present invention demonstrates that Penicillin G effectively treats ALS and in particular the symptoms of ALS. As already described herein, GABA antagonists as a class are known to have a risk of inducing epileptic seizures. The present invention describes treatment protocols with Penicillin G which treat the symptoms described herein without inducing seizures, or only inducing mild, manageable seizures.

Example 46 conclusively shows that a compound that reduces GABAergic activity, such as Penicillin G, treats ALS and ALS-like symptoms. Example 46 describes the safe treatment of an ALS patient. During treatment no seizures were reported. This is important as in ALS and other neuromuscular and neurological diseases the Blood Brain Barrier can be dysfunctional, which leads to more safety concerns than in non- ALS patients. Preferably, the disclosure provides methods for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation (e.g., one or more symptoms selected from tables 7 and/or 8, preferably those listed in tables 7a- 7f and 8, more preferably tables 7a-7d, most preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement

difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction; even more preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties) in an individual afflicted with ALS or an ALS-like disorder, the method comprising providing an effective amount of Penicillin G to an individual in need thereof.

A skilled person is able to determine the appropriate dosage schedule. Preferably, the dosage of Penicillin G is between 0.5 million to 40 million units per day, more preferably between 0.5 million to 30 million units per day, more preferably between 0.5 million to 25 million units per day. Preferably, the dosage of Penicillin G is between 1 million to 40 million units per day, more preferably between 1 million to 30 million units per day, more preferably between 1 million to 20 million units per day. Preferably, the Penicillin G is administered at a dose of at least one million units per day. Preferably, the Penicillin G is administered at a dose of at least three million units per day. Preferably, the Penicillin G is administered at a dose of at least five million units per day.

Preferably, the above-mentioned dosages of Penicillin G are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration (e.g. oral, intramuscular, subcutaneous). For example, if administered orally, and depending on the bio-availability of the oral formulation, a skilled person is able to calculate the oral dose that leads to comparable blood or plasma concentrations as observed after intravenous administration.

Preferably, the maximal dosage is determined, as described previously herein, by titration of individual patients or groups of patients to maximal efficacy in the absence of seizures or other side effects. Preferably, the Penicillin G is administered for at least 4 days within an 8 day period, more preferably for at least 4 consecutive days, preferably for at least 10 days within an 21 day period, more preferably for at least 10 consecutive days, preferably for at least 20 days within a 40 day period, most preferably for at least 20 consecutive days. Preferably, the Penicillin G is administered at a dosage of at least 1 million units per day for at least 4 days within an 8 day period, more preferably for at least 4 consecutive days, preferably for at least 10 days within an 21 day period, more preferably for at least 10 consecutive days, preferably for at least 20 days within a 40 day period, most preferably for at least 20 consecutive days.

In preferred embodiments, the dosage of Penicillin G varies per day; preferably the dosage scheme comprises 1) at least one day where the dosage is at least one million units per day and 2) at least one day where the dosage is at least two million, preferably at least three million units per day. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration, and knows that plasma concentrations as observed after intravenous administration can also be achieved with different administration routes at different dosages. Preferably, Penicillin G (or any other compound disclosed herein) is administered using an escalated dosage scheme. As is known to a skilled person, escalating dosage schemes of Penicillin G are advised against when treating infectious diseases due to the risk of the development of antibiotic resistance in infectious organisms.

Preferably, Penicillin G (or any other compound disclosed herein) is administered for multiple days, e.g., for at least 2, at least 5, at least 10 or for 21 days. Preferably, the treatment occurs every day of the treatment cycle.

While not wishing to be bound by theory, one of the advantages of providing an escalated dosagae scheme in the present method is based on the hypothesis set hereforth that ALS and ALS like symptoms may be the result of a derailed GABA homeostatis system, which may cause inhibitory overstimulation. As homeostatic processes can be very specific, the administration of specifically increasing doses of the GABAergic and/or Glycinergic inhibitor may lead to more efficacy in the treatment of ALS and ALS like symptoms. In addition, it is believed that an escalating dosage schedule will restore GABA homeostasis but avoid over-inhibition and, in particular, avoid seizures. While it is preferred that an escalated dosage scheme is used with the administration of Penicillin G, a skilled person will appreciate that an escalated dosage scheme is also beneficial for all of the compounds disclosed herein.

Preferably, Penicillin G is administered using an escalated dosage scheme such that a dosage of at of at least one million units per day is provided for at least two days and a dosage of at least three million units per day is provided for at least two days. In an exemplary embodiment, Penicillin G is administered on day 1 and day 2 at a dosage of one million units per day and on day 4 and 5 at a dosage of three million units per day. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration. Preferably, the dosage scheme further comprises 3) at least one day where the dosage is at least three, preferably at least 5 million units per day. Preferably, Penicillin G is administered using an escalated dosage scheme such that a dosage of at of at least one million units per day is provided for at least two days and a dosage of at least five million units per day is provided for at least two days. In an exemplary embodiment, Penicillin G is administered on day 1 at a dosage of one million units per day on day 2 at a dosage of three million units per day and on day 4, 5, and 6 at 5 million units per day. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration. In preferred embodiments, the dosage scheme further comprises 4) at least one day where the dosage is at least six, at least 8, or preferably at least 10 million units per day. Preferably, Penicillin G is administered using an escalated dosage scheme such that a dosage of at of at least one million units per day is provided for at least two days, a dosage of at least five million units per day is provided for at least one day, and a dosage of at least 10 million units per day is provided for at least one day. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration. In preferred embodiments, the dosage scheme further comprises 5) at least one day where the dosage is at least 15, at least 20, or at least 24 million units per day.

Although higher dosages may be effective, in preferred embodiments the maximum dosage is 20 million units per day. In an exemplary embodiment, Penicillin G is administered on day 1 at a dosage of one million units per day on day 2 at a dosage of three million units per day and on day 4, 5, and 6 at 15 million units per day.

Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration.

Preferably, an escalated dosage regime comprises administering Penicillin G at a dosage of least one million units per day for at least one day, a dosage of at least three million units per day for at least one day, a dosage of at least 5 million units per day for at least one day, a dosage of at least 10 million units per day for at least one day, and a dosage of at least 20 million units per day for at least one day, preferably for at least 5 days, more preferably for at least 10 days, most preferably for 17 days or more. Preferably, the administration is performed on consecutive days. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration.

The dosage schedules described herein may also be repeated as needed. For example, after completing a dosage schedule (which usually comprises administering Penicillin G or any other compound disclosed herein) for 4 to 30 days, preferably for 4 to 21 days), the dosage schedule may be repeated after 4 weeks, preferably 6 weeks, preferably after 8 weeks, preferably after 9 weeks, more preferably after 10 weeks of non-treatment. In some embodiments, the time before treatment cycles may be as long as 3 or 4 months. This "on-off dosage schedule may be repeated as often as needed. In a preferred embodiment, one treatment cycle lasts approximately 3 months, i.e., 3 weeks of treatment followed by 10 weeks of non-treatment. An exemplary embodiment of an escalating dosage schedule is as follows.

Day 1: 1 million units in 250 or 500 ml Saline solution + 100 mg hydrocortisone during an 8 hour infusion

Day 2: 3 million units in 250 or 500 ml Saline solution + 100 mg hydrocortisone during an 8 hour infusion

· Day 3: 5 million units in 250 or 500 ml Saline solution + 100 mg hydrocortisone during an 8 hour infusion

Day 4: 10 million units in 250 ml or 500 Saline solution + 100 mg hydrocortisone during an 8 hour infusion

Days 5 to 21: 20 million units in 250 ml or 500 Saline solution + 100 mg

hydrocortisone during an 8 hour infusion.

The 21 day protocol is repeated every 3 months, preferably as four separate treatments.

Preferably the GABA antagonist (in particular, Penicillin G) is administered such that there is an increase in the GABA antagonist in the blood of the individual for a period of between 4 and 12 hours, more preferably between 6 and 10 hours, most preferably over a period of around 8 hours. Preferably, the antagonist is provided intravenously, however, a skilled person can readily provide sustained release formulations (e.g. oral, intramuscular, intravenous lipophilic formulations) which lead to similar effects at lower dosages and / or blood concentrations than observed after intravenous therapy. Preferably, the GABA antagonist (in particular, Penicillin G) is administered intravenously over a period of between 4 and 12 hours. Preferably, the the GABA antagonist is administered intravenously over a period of between 6 and 10 hours, most preferably over a period of around 8 hours.

While not wishing to be bound by theory, it is believed that a several hour long intermittent infusion may result in a prolonged period of GABA inhibition, which has a sort of "electroshock therapy" effect on the CNS. Any treatment that effects GABA can be subject to tolerance, and thus a shock approach minimizes tolerance development. Intermittent treatment, i.e., administering the GABA antagonist for several hours followed by several hours of non-treatment is useful to avoid the development of tolerance by the GABA receptor. In addition, the "on-off treatment schedule discussed above (e.g. providing 3 weeks of intermittent treatment followed by nine weeks of non- treatment) is believed to have a similar "electroshock therapy" like effect on the CNS, this one executed over weeks, in addition to the schock effect executed over 21 days by the administration of 8 hours infusion per day, and 16 hours without infusion. An "on-off treatment schedule per day (8 hours "on", 16 hours "off) and on a weekly basis (3 weeks "on" a daily treatment of 8 hour infusion, 10 weeks without treatment) is therefore useful to avoid the development of tolerance. As is known to a skilled person, the GABA receptor is notorious for its tolerance development which typically begins 4 to 6 weeks from the start of therapy. A shorter treatment schedule, for example of around 3 weeks which can be repeated after an "off treatment period, avoids or reduces the risk of tolerance development.

Penicillin G is an especially useful GABA antagonist for treating the disorders and symptoms disclosed herin due to the nature of the Penicillin G interaction with the GABA receptor. Penicillin G is an open channel blocker to the GABA receptor, which in essence means that Penicillin G turns GABA from a full agonist, into a partial agonist to the GABA receptor. This means that the body's most important and abundant inhibitory neurotransmitter acts as a partial agonist during the

administration period (i.e., 8 hours in the most preferred embodiment), and during the non- administration period (i.e., 16 hours in the most preferred embodiment), as a full agonist to the GABA receptor.

A further advantage of penicillin G's ability to turn GABA into a partial agonist, is that once inhibitory overstimulation is reduced in a patient, the ability of penicillin G to turn GABA into a partial agonist diminishes. This as penicillin G only can block the GABA receptor channel once GABA has opened the channel. As such, when GABA overstimulation diminishes, less GABA receptor channels open, and less penicillin G can enter the GABA channel, and thus the efficacy of penicillin G diminishes. This improves the safety of administration in patients with ALS or an ALS-like disorder characterized by inhibitory overstimulation. As inhibitory overstimulation decreases during the course of treatment, the ability of penicillin G to turn GABA into a partial agonist decreases and therefore the net effect of penicillin G as a reducer of GABA activity is reduced. This reduces the risk that penicillin G will induce seizures in a patient who is improving, and whose inhibitory overstimulation has been reduced as result of treatment with Pen G.

In preferred embodiments, a glucocorticoid is also administered to the individual. The glucocorticoid may be administered simultaneously or sequentially with the compound which decreases GABAergic and/or Glycinergic inhibitory activity. The glucocorticoid may also be administered several hours after the administration of the compound which decreases GABAergic and/or Glycinergic inhibitory activity or on alternate days. Preferably glucocorticoid is administered intravenously. Glucocorticoids are known to a skilled person and include [3H]dexamethasone, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol propionate, corticosterone, Cortisol, deoxycorticosterone, desoximetasone, dexamethasone, diflorasone diacetate, difluprednate, flunisolide, fluocinolone acetonide, fluocinonide, fluorometholone, fluticasone, fluticasone propionate, methylprednisolone,

mometasone, prednisolone, prednisone, RU26988, RU28362, Triamcinolone, triamcinolone acetonide, ZK216348, [3H] aldosterone, aldosterone, Cortisol, deoxycorticosterone, dexamethasone, fludrocortisone, prednisolone, progesterone, Cortisone, Hydrocortisone, Hydrocortisone aceponate, Hydrocortisone buteprate, Hydrocortisone butyrate, Budesonide, Ciclesonide, Deflazacort, Medrysone,

Tixocortol, Halogenated at 6: Cloprednol, Halogenated, with FG at 16: Halcinonide, Rimexolone, Halogenated, with FG at 16: Flunisolide, Triamcinolone, Amcinonide, Fluocinolone, acetonide, Fluocinonide, Prednisone, Meprednisone, Halogenated at 9: Fluorometholone, Halogenated, with FG at 16: Fluocortolone, Clocortolone,

Diflucortolone, Fluocortin, Desoximetasone, Prednisolone, Methylprednisolone, Methylprednisolone aceponate, Prednicarbate, Prednylidene, Desonide, Halogenated: Fluprednisolone, Difluprednate, Fluperolone, Halogenated, with FG at 16:

Dexamethasone, Betamethasone, Clobetasol, Clobetasone, Diflorasone,

Halometasone, Ulobetasol, Beclometasone, Paramethasone, Alclometasone,

Fluclorolone acetonide, Flumetasone, Fluprednidene, Cortivazol, Halogenated, with FG at 16: Fluticasone, Fluticasone propionate, Fluticasone furoate, Halogenated: Loteprednol, Halogenated, with FG at 16: Fludroxycortide, Formocortal, Mometasone furoate, and Promestrien. Preferably, the glucocorticoid is hydrocortisone. Preferably, the glucocorticoid is administered for at least 4 days within an 8 day period, more preferably for at least 4 consecutive days, preferably for at least 10 days within an 21 day period, more preferably for at least 10 consecutive days, preferably for at least 20 days within a 40 day period, most preferably for at least 20 consecutive days.

Preferably, the glucocorticoid is hydrocortisone, which is administered at a dose of at least lOmg/day, preferably at least 20mg/day. Preferably between 10 to 200mg of hydrocortisone is administered per day. Preferably, around lOOmg of hydrocortisone is administered per day. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration.

In preferred embodiments, the hydrocortisone is administered in varying doses;

preferably the dosage scheme comprises 1) at least one day where the dosage is at least lOmg per day, preferably at least 20 mg/day and 2) at least one day where the dosage is at least 40, preferably at least 50mg per day. Preferably, hydrocortisone is administered using an escalated dosage scheme such that a dosage of at of at least 20 mg per day is provided for at least two days and a dosage of at least 50mg per day is provided for at least two days. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration.

Preferably, the dosage scheme further comprises 3) at least one day where the dosage is at least 60, preferably at least 75mg hydrocortisone per day. Preferably,

hydrocortisone is administered using an escalated dosage scheme such that a dosage of at of at least 20mg per day is provided for at least two days and a dosage of at least 75mg per day is provided for at least two days. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration. In preferred embodiments, the dosage scheme further comprises 4) at least one day where the dosage is at least 80, preferably at least lOOmg hydrocortisone per day. Preferably, hydrocortisone is administered using an escalated dosage scheme such that a dosage of at of at least 20mg per day is provided for at least two days, a dosage of at least 50mg per day is provided for at least one day, and a dosage of at least lOOmg is provided for at least one day, preferably for at least five days, more preferably for at least 18 days. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration.

Preferably, an escalated dosage regime comprises administering hydrocortisone at a dosage of least 25mg per day for at least one day, a dosage of at least 50mg per day for at least one day, a dosage of at least 75mg per day for at least one day, and a dosage of at least lOOmg per day for at least one day, preferably for at least 5 days, more preferably for at least 18 days. Preferably, the administration is performed on consecutive days. Preferably, these dosages are for intravenous administration. A skilled person recognizes that the dosages can be adjusted based on the form of administration.

Preferably the glucocorticoid (in particular, hydrocortisone) is administered such that there is an increase in the glucocorticoid in the blood of the individual for a period of between 4 and 12 hours, more preferably between 6 and 10 hours, most preferably over a period of around 8 hours. Preferably, the glucocorticoid is provided

intravenously, however, a skilled person can readily provide sustained release formulations (e.g. oral, intramuscular, lipophilic intravenous administrations) which lead to similar effects at lower dosages than after intravenous therapy, however leading to comparable (free) drug plasma concentrations. An exemplary embodiment of an escalating dosage schedule is as follows.

Day 1: 1 million units mixed with 100 mg Hydrocortison in 250 or 500 ml Saline solution during an 8 hour infusion

Day 2: 3 million units mixed with 100 mg Hydrocortison in 250 or 500 ml Saline solution during an 8 hour infusion Day 3: 5 million units mixed with 100 mg Hydrocortison in 250 or 500 ml Saline solution during an 8 hour infusion

Day 4: 10 million units mixed with 100 mg Hydrocortison in 250 ml or 500 Saline solution during an 8 hour infusion

· Days 5 to 21: 24 million units mixed with 100 mg Hydrocortison in 250 ml or 500 Saline solution during an 8 hour infusion

The 21 day protocol is repeated every 3 months.

The disclosure further provides pharmaceutical compositions comprising Penicillin G and a glucocorticoid. Preferably, the pharmaceutical composition is not an infusion bag, more preferably the pharmaceutical composition is a flacon or ampule.

In preferred embodiments, the methods further comprise decreasing glutaminergic activity in said individual. Preferably, the individual is administered a

pharmaceutical composition that decreases glutaminergic activity. Suitable

compositions are well-known to a skilled person and include riluzole and/or other compounds that reduce glutaminergic activity such as AP7 (2-amino-7- phosphonoheptanoic acid), CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-l- phosphonic acid), Selfotel, Amantadine, Atomoxetine, AZD6765, Chloroform,

Dextrallorphan, Dextromethorphan, Dextrorphan, Diphenidine, Dizocilpine (MK-801), Ethanol, Eticyclidine, Gacyclidine, Ibogaine, Magnesium, Memantine,

Methoxetamine, Nitromemantine, Nitrous oxide, Phencyclidine, Rolicyclidine, Tenocyclidine. Methoxydine, Tiletamine, Xenon, Neramexane, Eliprodil, Etoxadrol, Dexoxadrol, WMS-2539, NEFA, Remacemide, Delucemine, 8A-PDHQ, Aptiganel (Cerestat, CNS- 1102), HU-211, Rhynchophylline, Ketamine, CNQX, DNQX, NS102, Kynurenic acid, Tezampanel, NBQX, GYKI-52,466, GYKI-53,655, Perampanel, Talampanel. Table 1: Progressive neuromuscular disorders relevant to this disclosure leading to a gradual muscle weakness and to a common set of physical symptoms including difficulty with speech, difficulty with mobility and fine motor skills:

myopathies, Myotonia Congenita (MC), Thomsen disease, Becker's disease, Paramyotonia (PP), Paramyotonia Congenita (PC), Periodic Paralysis (Hypokalemic), Periodic Paralysis (Hyperkalemic), Kearns- Sayre syndrome (KSS),

Atrophies Adult Spinal Muscular Atrophy (SMA), Infantile Progressive Spinal

Muscular Atrophy (SMA, SMA1, WH), Werdnig-Hoffman disease, Intermediate Spinal Muscular Atrophy (SMA, SMA2), Juvenile Spinal Muscular Atrophy (SMA, SMA3, KW), Kugelberg-Walander disease, Endocrine abnormalities myopathies, Hyperthyroid myopathy

(HYPTM), Hypothyroid myopathy (HYPOTM), spinal and bulbar muscular atrophy (SBMA), juvenile muscular atrophy, autosomal dominant distal spinal muscular atrophy Spinal muscular atrophy (SMA)

Metabolic Phosphorylase deficiency, MPD, PYGM, McArdle's disease, Acid muscle disease maltase deficiency, AMD, Pompe's disease, Phosphfructokinase

deficiency, PFKM, Tarui's disease

Ataxies Spinocerebellar ataxia type 3 (Machado-Joseph disease), Ataxia,

Cerebellar ataxia, Ataxic cerebral palsy, Sensory ataxia, Vestibular ataxia, Stroke related ataxia, Wilson's disease, Athetoid cerebral palsy, Dyskinetic cerebral palsy, ADCP, Bilirubin encephalopathy, Ataxia Telangiectasia, Friedreich's Ataxia, Spino Cerebellar Ataxias (SCA)

Table 2: Overview of other muscular and neurologic diseases relevant to this disclosure (source: Muscle Disease The Netherlands, www.spierziekten.nl).

Restless legs syndrome (RLS), Willis-Ekbom disease, Wittmaack-Ekbom syndrome, Guillain-Barre syndrome (GBS), Acute idiopathic demyelinating polyneuropathy, Chronic idiopathic demyelinating polyneuropathy, Acute inflammatory polyneuropathy, Chronic inflammatory polyneuropathy, Landry ascending paralysis, Polyneuroradiculopathy, Arthrogryposis multiplex congenita (AMC), Becker myotonia congenital, Becker myotonia, Brody disease, Brody syndrome, Carnitine Deficiency, Primary Carnitine Deficiency, Chronic idiopathic axonal polyneuropathy (CIAP), Congenital muscle dystrophy (CMD), Congenital fibre type disproportion myopathy, Small fiber peripheral neuropathy, fibromyalgia, Hereditary neuropathy with liability to pressure palsies (HNPP), Hereditaire Spastische Paraparese (HSP), Strumpell disease, Hereditary Spastic Paraplegia (HSP), Hereditary Spastic Paraparesis, Familial Spastic Paraplegias, French Settlement Disease, Strumpell-Lorrain Disease, Glycogenose V, MGUS polyneuropathy, Monoclonal gammopathy of undetermined significance polyneuropathy (MGUS-pnp), Miller Fisher syndrome, Minicore myopathy, Multicore myopathy,

Multifocal Motor Neuropathy (MMN), Myasthenia gravis with antibodies against AChR (AChr MG), Proximal myotonic myopathy (PROMM), Non dystrophic myotonia (NDM), Neuralgic amyotrophy (NA), Plexus brachialis neuropathy, Poliomyelitis anterior acuta, Thomsen myotonia congenita, Thomsen myotonia, Werdnig Hoffmann disease, Glycogen storage disease type I, Coats' Disease, retinal telangiectasis, bilateral Sensorineural Hearing Loss, Hypercarbic Respiratory Insufficiency, autism, remote poliomyelitis, Dystonia

Table 3: Overview of neurologic diseases relevant to this disclosure.

Frontotemporal dementia (FTD), dementia, Alzheimer's disease (ALZ), Multiple Sclerosis

(MS), Huntington's disease (HD), Duchenne muscular dystrophy (DMD), Peripheral

Neuropathy (PN), schizophrenia, dementia, Parkinson's disease (PD), Frontotemporal degeneration, Behavioral variant FTD (bv-FTD), Primary progressive aphasia (PPA),

FTD movement disorders, Pugilist dementia, Vascular dementia, Dementia with Lewy bodies (DLB), Lewy body dementia, Progressive supranuclear palsy (PSP), Corticobasal degeneration, Traumatic brain injury (TBI), normal pressure hydrocephalus,

Creutzfeldt-Jakob disease

Table 4: Overview of other diseases relevant to this disclosure.

syndrome (arylsulfatase B deficiency), arylsulfatase A deficiency, MPS type VII, Sly syndrome (beta- glucuronidase deficiency)

Glycoproteinos Aspartylglucos aminuria, Fucosidosis, Alpha-fucosidosis, a- es Mannosidosis, β-Mannosidosis, Mucolipidosis I (sialidosis), Schindler disease

Sphingo- Fabry's disease, Farber's disease, Gaucher's disease type I, Gaucher's lipidoses disease type II, Gaucher's disease type III, gangliosidosis, GM1

gangliosidosis, Tay-Sachs disease, Tay-Sachs/GM2 gangliosidosism, Sandhoff s disease, Sandhoff disease/GM2 gangliosidosis, Krabbe's disease, Metachromatic leucodystrophy, Niemann-Pick disease type A, Niemann-Pick disease type B, sphingomyelinase deficiency

Other lipidoses Niemann-Pick disease type C, Wolman's disease, Neuronal ceroid

lipofuscinosis

Glycogen Glycogen storage disease type II (Pompe's disease)

storage disease

Multiple Multiple sulphatase deficiency, Galactosialidosis, Mucolipidosis II/III, enzyme Mucolipidosis IV

deficiency

Lysosomal Cystinosis, Sialic acid storage disease, Infantile Free Sialic Acid Storage transport Disease/ISSD, Salla disease/Sialic Acid Storage Disease

defects

Other Danon disease, Hyaluronidase deficiency, Lysosomal acid lipase disorders due deficiency

to defects in

lysosomal

proteins

Neuronal CLN6 disease, Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3 disease, Ceroid Finnish Variant Late Infantile CLN5, Jansky-Bielschowsky

Lipofuscinoses disease/Late infantile CLN2/TPP1 Disease, Kufs/Adult-onset

NCL/CLN4 disease, Northern Epilepsy/variant late infantile CLN8, Santavuori-Haltia/Infantile CLN1/PPT disease, Beta-mannosidosis

Aspartylglucos aspartylglucosaminase deficiency, neurobehavioral symptoms, milder aminuria skeletal abnormalities, hepatosplenomegaly, facial coarsening Miscellaneous Activator Deficiency/GM2 Gangliosidosis, Cholesteryl ester storage disease, Chronic Hexosaminidase A Deficiency, Metachromatic

Leukodystrophy, Multiple sulfatase deficiency, Pycnodysostosis, I- Cell

Disease, Phosphotransferase deficiency, Psychomotor retardation,

Corneal clouding, Retinopathy, mucolipidin 1 deficiency, Kanzaki disease, alpha-N -acetylgalactosaminidase deficiency, progressive neuromotor deterioration, coarse facial features, dysostosis multiplex, angiokeratoma corporis diffusum, hepatosplenomegaly, growth retardation, alpha-N -acetyl neuraminidase deficiency, mild form cholesterol ester storage disease, Cholesteryl Ester Storage Disease, beta-glucosidase deficiency, infantile globoid-cell leukodystrophy, galactosylceramidase deficiency, alpha-galactosidase A, GM1

gangliosidosis, Morquio B disease, beta-galactosidase deficiency, GM2 gangliosidoses, disseminated lipogranulomatosis, ceramidase deficiency, subcutaneous nodules, flesh-colored papules, periarticular tumors or nodules, osteopenia, Sulfatase-modifying factor- 1 mutation,

mucopolysaccharidosis, proptosis, ichthyosis, progressive leukoencephalopathy, cathepsin A deficiency, deficiency of lysosomal beta-galactosidase and neuraminidase as a result of a defect in the protective protein/cathepsin A (PPCA), renal Fanconi syndrome

Table 5: Preferred compounds reducing GABAergic activity

( ' a l cgofv ( ' ()iii | )i )ii nd I ) i 'j )li >l ion nirl Imd

GABAA antagonist (-)-a-thujone, (+)-a-thujone and (-)-6-thujone, (+)-6-thujone,

[3H]gabazine, 4-(3-biphenyl-5-(4-piperidyl)-3-isoxazole, 17- Phenylandrostenol, Absinthe, Anisatin, arylaminopyridazine derivatives of GABA, aza-THIP, Bemegride, Bicuculline, bicuculline methochloride, Bilobalide, bilobalide from the plant Ginkgo biloba, Cicutoxin, cis-3-ACPBPA, Cocculin, Coriamyrtin, Cyclothiazide, DHEA, DHEA-S,

Dihydrosecurinine, DMCM, Extracts from the plant Ginkgo biloba, Extracts of plants containing C17 conjugated polyactylene with a terminal hydroxyl group and an allylic hydroxyl group attached at C14, Extracts of plants containing cicutoxin, virol A, virol C, isocicutoxin, or oenanthotoxin, Extracts of plants from the genus Thuja, Extracts of the Cicuta species plant, Extracts of the Oenanthe crocata plant, Extracts of the plant arborvitae, Extracts of the plant common sage, Extracts of the plant family Apiaceae, Extracts of the plant family Menispermaceae, Extracts of the plant genus Anamirta, Extracts of the plant genus Oenanthe, Extracts of the plant grand wormwood (Artemisia absinthium), Extracts of the plant junipers, Extracts of the plant mugwort, Extracts of the plant Nootka Cypress, Extracts of the plant oregano, Extracts of the plant species Anamirta cocculus, Extracts of the plant species menthe, Extracts of the plant tansy, Extracts of the plant wormwood, FG-7142 (ZK-31906), Fipronil, Flumazenil, Compounds with a chemical quinolone ring system, Fluoro quinines with GABA antagonistic activity, Fluoroquinolones, Flurothyl, Furosemide, Gabazine (SR 95531), Gaboxadol, Hydrastine, Hyenachin (mellitoxin), Iomazenil (1231), Isocicutoxin, isonipecotic acid,

Isopregnanolone (sepranolone), L-655,708, Laudanosine, Leptazol, Lidocain, Lindane, Morphine, Muira puama, Naloxone, Naltrexone, Oenanthotoxin, Pentetrazol (metrazol),

Phenylsilatrane, Picrotin, Picrotoxin, Picrotoxinin, piperidine-

4-sulphonic acid, Pitrazepin, Pregnenolone sulfate, PWZ-029,

Quinine, Radequinil, RG- 1662, Rol5-4513, Ro4938581,

RU5135, RU-5135, Salicylidene salicylhydrazide (SCS),

Sarmazenil, Securinine, L-Securinine, Sinomenine,

Suritozole, TB-21007, Terbequinil, terpenoids chemically structurally related to picrotoxinin,

Tetramethylenedisulfotetramine, TETS, Theophylline,

Thiocolchicoside, Thujone, TPMPA, trans-3-ACPBPA, tubocurarine, Tutin, U-93631, Virol A, Virol C, Zinc, Zn 2+ , ZK-

93426, a5IA (LS- 193,268), Compounds with a chemical 6- lactam ring, β-Lactams with GABA antagonistic activity, 6-

Lactams, penicillins, cephalosporins, carbapenems; in some embodiments the beta-lactam is not ceftriaxone, t- butylbicyclophosphorothionate (TBPS), 5- [4- (3,3-

Dimethylbutoxycarbonyl)phenyl]pent-4-ynoic acid methyl ester, 5-[4-(3,3-Dimethylbutoxycarbonyl)phenyl]pent-4-ynoic acid, 5-[4-(4,4-Dimethylpentoxy)phenyl]pent-4-ynoic acid methyl ester, 5-[4-(4,4-Dimethylpentoxy)phenyl]pent-4-ynoic acid, 3-(Bicyclo[2.2. l]hept-5-en-2-yl)-6-chloro- 1, 1-dioxo- l,2,3,4-tetrahydro-l,2,4-benzothiadiazine-7-sulfonamide,

Cyclothiazide, Pentylenetetrazol, 4-(3,3-Diphenylpropyl)-5-(4- piperidinyl)isoxazol-3-ol hydrobromide, 4-[l(S)-

Carbamoylpropylamino]butyric acid 2-propylpentyl ester, 4-

[l(S)-Carbamoylpropylamino]butyric acid 2-(l- adamantyl)ethyl ester, l-(l,2-Diphenyl-lH-imidazol-4- ylmethyl) - 4- (2-methoxyphenyl)piper azine, 4- ( 1 -

Bromonaphthalen-2-ylmethyl)-5-(4-piperidinyl)isoxazol-3-o l hydrobromide, 3beta-Hydroxy-5alpha-pregnan-20-one, NSC-

97078, U-0949, UC-1010, 3beta-Allopregnanolone,

Epiallopregnanolone, Isoallopregnanolone, Sepranolone (Rec

INN), 4-(Naphthalen-2-ylmethyl)-5-(4-piperidinyl)isothiazol-3- ol hydrobromide, 4-(3,3-Diphenylpropyl)-5-(4- piperidinyl)isothiazol-3-ol hydrobromide, (-)-[R(N),Ra]-9- Chloro-7-(2-chlorophenyl)-l-methylpyrimido[l,2- a] [l,4]benzodiazepin-3(5H)-one, 4-[6-Imino-3-[4-(2- propynyloxy)phenyl]- 1,6-dihydropyridazin- l-yl]butyric acid hydrobromide, 3-(Dibutylamino)-4-(4-fluorophenoxy)-5- sulfamoylbenzoic acid, NTP-5009, 3-(Dibutylamino)-5- (morpholin-4-ylsulfonyl)-4-phenoxybenzoic acid, NTP-6002, 3- (Dibutylamino)-N,N-dimethyl-5-(morpholin-4-ylcarbonyl)-2- phenoxybenzenesulfonamide, NTP-7009, 3-(Dibutylamino)-4- (4-methylphenoxy)-5-sulfamoylbenzoic acid, NTP-5011, 3- (Dibutylamino)-5-(diethylsulfamoyl)-4-phenoxybenzoic acid, NTP-6008, 5,5,6,6, 7, 7,8,8,9,9-Decadeutero-6, 7,8,9-tetrahydro- 5H-tetrazolo[l,5-a]azepine, 5,5,9,9-Tetradeutero-6,7,8,9- tetrahydro-5H-tetrazolo[l,5-a]azepinem, 5,5,7,7,9,9- Hexadeutero-6,7,8,9-tetrahydro-5H-tetrazolo[l,5-a]azepine, 3- [Bis(nonadeuterobutyl)amino]-4-phenoxy-5-sulfamoylbenzoic acid, l-(Biphenyl-4-yl)-5-(piperidin-4-yl)-lH-pyrazol-3-ol trifluoroacetate, SR-25531, 2,4,6-Trinitro-N-(2,4,6- trinitrophenyl)aniline, DPA, NP-260, 5-(2-Phenyl- lH- imidazol- 4-yl) -4- (piperidin- 4-yl) - 1H -pyr azol- 1 -ol

dihydrobromide, l-(Biphenyl-3-yl)-5-(piperidin-4-yl)-lH- pyrazol-3-ol hydrobromide,

Preferably, GABAA antagonists of table 5 also include PTX, Pen G, cefazolin, cefmetazole, Aztreonam, imipenem, cilastatin, Cephalosporins with GABA antagonistic activity, cefotetan, ceftazidime, and cefepime, Monobactams with GABA antagonistic activity, Carbapenems with GABA antagonistic activity, imipenem, cilastatin, 4-biphenylacetic acid (BPAA), fenbufen, 4-biphenylacetic acid (BPA),

GABAA artial agonist ZK93423, isoguvacine, muscimol

GABAA channel blockers [35S]TBPS, picrotoxin, TBPS. Preferably, GABAA channel blockers of Table 5 also comprisePen G GABAA antagonistic Flumazenil, TP003, [llC]flumazenil, ZK93426, TPA023, allosteric modulators L838417, [18F]fluoroethylflumazenil, ZK93426

GABAA inhibition Zn 2+

allosteric modulators

GABAA inverse agonist MRK016, DMCM, L655708, [3H]L655708, MRK016, Rol5- allosteric modulators 4513, Rol9-4603, R04938581, RY024, a3IA, a5IA (LS- 193,268), 6,2-dihydroflavone

GABAA mixed effects CGS8216, [3H]CGS8216

allosteric modulators

GABAA artial agonist [llC]flumazenil, flumazenil, L838417, ocinaplon, TP003, allosteric modulators TPA023

GABAA potentiation 5a-pregnan-3a-ol-20-one, Tetrahydrodeoxycorticosterone allosteric modulators

GABAB antagonist [3H]CGP 62349, [125I]CGP 64213, [125I]CGP 71872,

[3H]CGP 54626, 2-hydroxy-saclofen, CGP 35348, CGP 36742, SGS-742, DVD-742, (3-Aminopropyl)butylphosphinic acid, CGP 46381, CGP 54626A, CGP 55845, CGP 56999A, CGP 62349, CGP 64213, CGP 71872, Phaclofen, Saclofen, R stereoisomer Saclofen, S stereoisomer Saclofen, SCH 50911, Phosphonobaclofen, CGP 35348, CGP 54626, CGP 64213, SCH 50911, CGP 35348, CGP 46381, CGP 52432, CGP 54626, CGP 55845

GABAc antagonist Muscimol, CACA, 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3- ol hydrochloride (THIP), SKF 97541, 1,2,5,6- Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA)

GAB Ac partial agonist Isoguvacine, THIP, P4S, TPMPA, Muscimol

Peripheral GABA agonist PK 11195

GABA blocking therapy BTD-001

Glutamic acid s-allyl glycine, 3-Mercaptopropionic acid

decarboxylase 1 (GAD1)

modulation

Glutamic acid s-allyl glycine, 3-Mercaptopropionic acid

decarboxylase 2 (GAD2) modulation

GADl co-factor depletion Reducing levels of pyridoxal phosphate

GAD2 co-factor depletion Reducing levels of pyridoxal phosphate

Aldehyde dehydrogenase

modulation

Aldehyde dehydrogenase Reducing levels of NAD

co-factor depletion

GABA-T (4- aminobutyrate

amino tr ansfer ase)

modulation

SSADH (aldehyde

dehydrogenase 5 family)

modulation

SSADH (aldehyde NAD

dehydrogenase 5 family)

co-factor depletion

GABA transporter 1

(GAT1) modulation

GABA transporter 2

(GAT2) modulation

GABA transporter 3

(GAT3) modulation

Betaine/GABA

transporter 1 (BGT1)

modulation

Taurine transporter

(TauT) modulation

CT1 transporter

modulation

Vesicular inhibitory

amino acid transporter

modulation Inhibition of GABA l-[3-(trifluoromethyl)-phenyl]-piperazine, [11C]AZ 10419369, release through 5-HT1 [1251] GTI, [3H]8-OH-DPAT, [3H]alniditan, [3H]eletriptan, receptor modulation [3H]N-methyl-AZ10419369, [3H] sumatriptan, 1- naphthylpiperazine, 2-methyl-5-HT, 5-(nonyloxy)-tryptamine, 5-CT, 5-hydroxytryptamine, 5-MeOT, 7-methoxy- l- naphthylpiperazine, 7-trifluoromethyl-4-(4-methyl- 1- piperazinyl)-pyrrolo[l,2-a]quinoxaline, 8-OH-DPAT,

Alniditan, Aripiprazole, Asenapine, BMS 181, 101, BRL- 15572, Bromocriptine, Cabergoline, CGS- 12066, Clozapine, CP- 122288, CP94253, dihydroergotamine, dipropyl-5-CT, donitriptan, eletriptan, frovatriptan, GR- 127935, L-694,247, L-772,405, L-775,606, Lisuride, LY344864, Lysergol,

Naratriptan, Olanzapine, Oxymetazoline, Pergolide,

Rizatriptan, Roxindole, RU 24969, SB 216641, SL65.0155, Sumatriptan, Terguride, TFMPP, Tryptamine, Vortioxetine, Xanomeline, Ziprasidone, zolmitriptan

Inhibition of GABA N-acetylaspartylglutamate (NAAG), [3H]LY341495, (1S,3R)- release through mGlu3 ACPD, (1S,3R)-ACPD, (2R,3R)-APDC, DCG-IV, Eglumegad, receptor modulation L-CCG-I, L-glutamic acid, LY379268, MNI-135, compound 3

[PMID: 21105727], compound 4 [PMID: 21105727], compound 2 [PMID: 21105727]

Inhibition of GABA [3H]AP4, (R,S)-4-PPG, (S)-3,4-DCPG, ACPT-I, ADX88178, release through mGlu4 compound 1 [PMID: 22465637], compound 11 [PMID:

receptor modulation 20638279], compound 22a [PMID: 21688779], compound 7

[PMID:20638279], FP0429, L-AP4, L-aspartic acid, L-CCG-I, L-cysteine sulphinic acid, L-glutamic acid, L-serine-O- phosphate, LSP1-2111, LSP4-2022, Lu AF21934, MPEP, NAAG, PHCCC, SIB- 1893, VU0001171, VU0080241,

VU0092145, VU0155041, VU0359516, VU0361737,

VU0364770, VU0400195

Reducing GABAergic Fluoxetine, Norfluoxetine, Fampridine, Resiniferatoxin, activity through Kv3.1 Flecainide, Diltiazem, Nifedipine, Capsaicin,

modulation Tetraethylammonium, cromakalim Reducing GABAergic Pimozide, Thioridazine, Haloperidol, Clozapine, SCH-23390, activity through Kv3.2 Fluoxetine, Halothane, Bupivacaine, F3, Verapamil, modulation Dizocilpine, Clomipramine, Desipramine, Imipramine,

Maprotiline, Amitriptyline, Nortriptyline, QX-314

Reducing GABAergic Ba 2+ , tertiapin, AZD2927

activity through Kir 3.1

modulation

Reducing GABAergic Pimozide, Thioridazine, Haloperidol, Clozapine, SCH-23390, activity through Kir 3.2 Fluoxetine, Halothane, Bupivacaine, F3, Verapamil, modulation Dizocilpine, Clomipramine, Desipramine, Imipramine,

Maprotiline, Amitriptyline, Nortriptyline, QX-314

Reducing GABAergic Olanzapine, (+)-cyclazosin, [125I]BE-2254, 5-methylurapidil, activity through alA- A- 119637, A- 123189, Alfuzosin, BMY-7378, Cabergoline, adrenoceptor modulation Clozapine, Cyproheptadine, Doxazosin, Indoramin,

Ketanserin, Lisuride, Mianserin, NAN 190, Phentolamine, Piribedil, Prazosin, Rec 15/2739, rho-TIA, risperidone, ritanserin, Ro- 70-0004, Roxindole, RS- 100329, RS- 17053, S(+)-niguldipine, Silodosin, SNAP5089, Spiperone,

Spiroxatrine, Tamsulosin, Terazosin, Terguride, WB 4101, p- Dala

Reducing GABAergic [Trp7, B-Ala8] neurokinin A-(4- 10), [3H] osanetant, AZD2624, activity through NK3 FK 224, GR138676, GSK 172981, GSK 256471, N',2- receptor modulation diphenylquinoline-4-carbohydrazide 8m, N',2- diphenylquinoline-4-carbohydrazide, Osanetant, PD 154740, PD 161182, PD 157672, Saredutant, SB 218795, SB 222200, SB, SB 235375, SCH 206272, SSR 146977, talnetant

Reducing GABAergic [(CH2NH)4, 5] secretin

activity through secretin

receptor modulation

Reducing GABAergic [125I] [D-Tyr6]bombesin-(6-13)-methyl ester, [(3-Ph-Pr6), activity through BB2 His7,D-Alall,D-Prol3, l3- 14),Phel4]bombesin-(6-14), receptor modulation [125I] [D-Tyr6]bombesin-(6- 13)-methyl ester, [D-Argl,D- Trp 7, 9, Leu 11] sub stance P, [D-Phel2]bombesin, [D- Phe6,Cpal4,¾/13- 14]bombesin-(6-14), [D-Phe6]bombesin(6- 13)methyl ester, [D-Phe6]bombesin(6- 13)propylamide, [D- Pro4,D-Trp7,9, 10]substance P (4-11), [D-Tpi6, Leul3 v(CH2NH)-Leul4]bombesin-(6-14),

[Leul4, ψ 13- 14)]bombesin, Ac-GRP-(20-26)-methylester, bantag- 1, D-Nal, Cys,Tyr,D-Trp,Orn,Val,Cys,Nal-NH2, D-Nal- Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2, JMV594, JMV641, kuwanon H, PD 168368, PD 176252

Reducing GABAergic Dobutamine, Isoproterenol (61 and 62), Xamoterol, activity through epinephrine, Beta2- adrenergic agonist, salbutamol, albuterol, increasing ATPase Levosalbutamol, Levalbuterol, Fenoterol, Formoterol, activity Isoproterenol (61 and 62), Metaproterenol, Salmeterol,

Terbutaline, Clenbuterol, Isoetarine, Pirbuterol, procaterol, ritodrine, epinephrine, arbutamine, befunolol,

bromoacetylalprenololmenthane, broxaterol, cimaterol, cirazoline, denopamine, dopexamine, etilefrine,

hexoprenaline, higenamine, isoxsuprine, mabuterol, methoxyphenamine, nylidrin, oxyfedrine, prenalterol, ractop amine, reproterol, rimiterol, tretoquinol, tulobuterol, zilpaterol, zinterol

Reducing GABAergic Apomorphin, Benzazepine derivatives, SCH-23,390, SKF- activity through 83,959, Ecopipam (SCH-39, 166), acepromazine, amisulpride, dopamine antagonist amoxapine, azaperone, benperidol, bromopride, butaclamol, action clomipramine, chlorpromazine, chlorprothixene, clopenthixol, domperidone, droperidol, eticlopride, llupenthixol,

lluphenazine, lluspirilene, haloperidol, hydroxyzine, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, nafadotride, nemonapride, olanzapine, Penfluridol, perazine, perphenazine, pimozide,

prochlorperazine, promazine, quetiapine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine,

stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, ziprasidone

Reducing GABAergic Staurosporine, 7-hydroxystaurosporine, A-674563, afatinib, activity through protein AG 1024, AG 112, AG 1295, AG 1296, AG 490, AG 9, AG1478, kinase modulation AGL 2043, Akt inhibitor IV, Akt inhibitor V, Akt inhibitor

VIII, Akt inhibitor X, aloisine, aloisine A, alsterpaullone, alsterpaullone 2-cyanoethyl, alvocidib, aminopurvalanol A, arachidonic acid, AST-487, AT-7519, ATM kinase inhibitor, ATM/ATR kinase inhibitor, aurora kinase inhibitor III, aurora kinase/Cdk inhibitor, axitinib, balanol, barasertib- hQPA, BAY 11-7082, Bcr-abl inhibitor GNF-2, BI-2536, bisindolylmaleimide IV BMS-345541, BMS-387032,

Bohemine, Bosutinib, BPIQ-I, Brivanib, Canertinib, casein kinase I inhibitor, casein kinase II inhibitor III, Cdc2-like kinase inhibitor, Cdk/Crk inhibitor, Cdkl inhibitor, Cdkl/2 inhibitor III, Cdkl/5 inhibitor, Cdk2 inhibitor III, Cdk2 inhibitor IV, Cdk4 inhibitor, Cdk4 inhibitor II, Cdk4 inhibitor III, Cediranib, CGP53353, Chelerythrine, CHIR-265, Chk2 inhibitor II, CI-1040, compound 3 [PMID 19097791], compound 52 [PMID:9677190], compound 56 [PMID:8568816], crizotinib, dasatinib, diacylglycerol kinase inhibitor II, DMBI, DNA-PK inhibitor III, DNA-PK inhibitor V,

Doramapimod, Dorsomorphin, Dovitinib, EGFR inhibitor, EGFR/ErbB-2 inhibitor, EGFR/ErbB-2/ErbB-4 inhibitor, Enzastaurin, ERK inhibitor II, ERK inhibitor III, Erlotinib, Fascaplysin, Fasudil, Fedratinib, Flt-3 inhibitor, Flt-3 inhibitor II, Flt-3 inhibitor III, Foretinib, GDC-0879,

Gefitinib, GF109203X, Go 6976, Go6983, GSK-1838705A, GSK-3 inhibitor X, GSK-3 inhibitor XIII, GSK-3beta inhibitor I, GSK-3beta inhibitor II, GSK-3beta inhibitor VIII, GSK- 461364A, GSK690693, GTP- 14564, GW-2580, H-89, herbimycin A, IC261, IKK-2 inhibitor IV, Imatinib, indirubin derivative E804, indirubin-3'-monoxime, IRAK- 1/4 inhibitor, Isogranulatimide, JAK inhibitor I, JAK3 inhibitor II, JAK3 inhibitor IV, JAK3 inhibitor VI, JNJ-28312141, JNK inhibitor

IX, JNK inhibitor V, JNK inhibitor VIII, JNK inhibitor negative control, K-252a, kenpaullone, Ki-20227, KN-62,

KN-93, KW-2449, Lapatinib, Lck inhibitor, Lestaurtinib,

Linifanib, LY 294002, LY 303511, Masitinib, MEK inhibitor I,

MEK inhibitor II, MEK1/2 inhibitor, Midostaurin, MK2a inhibitor, MLN- 120B, MLN-8054, MNK1 inhibitor,

Motesanib, Mubritinib, Neratinib, NF-kB activation inhibitor,

Nilotinib, NU-7026, NVP-TAE684, p38 MAP kinase inhibitor, p38 MAP kinase inhibitor III, pazopanib, PD 158780, PD

169316, PD 174265, PD- 173955, PD98059, PDGF receptor tyrosine kinase inhibitor II, PDGF receptor tyrosine kinase inhibitor III, PDGF receptor tyrosine kinase inhibitor IV,

PDGF RTK inhibitor, PDKl/Akt/Flt dual pathway inhibitor,

PHA-665752, PI 3-Kg inhibitor, PI 3-Kg inhibitor II, PI- 103,

Pictilisib, PKCbeta inhibitor, PKR inhibitor, PKR inhibitor negative control, PLX-4720, PP1 analog II, PP-242, PP3,

PQ401, purvalanol A, quizartinib, R547, Rho kinase inhibitor

III, Rho kinase inhibitor IV, Ro-32-0432, Ruboxistaurin,

Ruxolitinib, SB 202474, SB 218078, SB202190, SB203580,

SB220025, SC-68376, Seliciclib, Selumetinib, semaxanib

SGX-523, SKF-86002, Sorafenib, Sotrastaurin, SP600125, sphingosine kinase inhibitor, Src kinase inhibitor I,

Staurosporine, STO609, SU11274, SU11652, SU- 14813,

SU6656, SU9516, Sunitinib, Syk inhibitor, Syk inhibitor II,

Syk inhibitor III, tamatinib, tandutinib, TG- 100- 115,

TGF-beta RI inhibitor III, TGF-beta RI kinase inhibitor,

Tofacitinib, Tozasertib, Tpl2 kinase inhibitor, TWS 119,

Vandetanib, Vatalanib, VEGF receptor 2 kinase inhibitor I,

VEGF receptor 2 kinase inhibitor II, VEGF receptor 2 kinase inhibitor IV, VEGF receptor tyrosine kinase inhibitor II,

VEGF receptor tyrosine kinase inhibitor III, VX-702,

VX-745, Wortmannin, Y27632, ingenol mebutate, balanol7- hydroxystaurosporine, calphostin C,Ro31-8220,

Table 6: Preferred compounds reducing Glycinergic activity

( a l ( 'H< >|-v ( ()iii | )i )ii nd / 1 ) i 'j )li >l ion nirl Imd

Glycine receptor (12E,20Z, 18S)-8-hydroxyvariabilin, [3H] strychnine, 1- antagonists Aminocyclopropanecarboxylic acid (ACPC), 3- demethylthiocolchicine, 5,7-dichlorokynurenic acid (DCKA), 7- Chlorokynurenic acid, ACEA-1328, Alkylbenzene sulfonate, Atropine, Bicuculline, Bilobalide, Brucine, Cacotheline, Caffeine, Codeine, Colchicine, Colubrine, Cu2+,

Cyanotriphenylborate, Dehydroepiandrosterone, Dendrobine, Dextrorphan, Diaboline, Extracts from the plant Ginkgo biloba, Gelsemine, Ginkgolide, Ginkgolide A, Ginkgolide B, Ginkgolide C, Ginkgolide J, ginkgolide X, HU-210, HU-308, Hyenandrine, Ivermectin, Kynurenic acid, Laudanosine, Levomethadone, Levorphanol, L-phenylalanine, M2,

Morphine, Morphine-3-glucuronide, NBBCC, Nifedipine, Nipecotic acid, Oripavine, Pethidine, Phenylbenzene-ω- phosphono-a-amino acid, Picrotin, Picrotoxin, Picrotoxinin, Pitrazepin, PMBA, Pregnanolone, pregnenolone sulphate, Progesterone, Racemorphan, RU5135, RU-5135, Sinomenine, SL59.0955, Strychnine, terpenoids chemically structurally related to picrotoxinin, Thebaine, Thiocolchicoside, TK-40, Tropisetron, Tutin, WIN55212-2, Zn2+, a-Emtbl

Glycine receptor partial GLYX-13, β-alanine, GABA

agonists

Glycine channel blocker Cyanotriphenylborate

Glycine transporter

GlyTl modulation

Glycine transporter

GlyT2 modulation

Glycine transporter

ATB0,+ modulation

Glycine transporter

PROT modulation SLC32 vesicular

inhibitory amino acid

transporter modulation

Glycine

amidinotransferase

modulation

Reducing Glycinergic Dobutamine, Isoproterenol (61 and 62), Xamoterol, activity through epinephrine, Beta2- adrenergic agonist, salbutamol, albuterol, increasing ATPase Levosalbutamol, Levalbuterol, Fenoterol, Formoterol, activity Isoproterenol (61 and 62), Metaproterenol, Salmeterol,

Terbutaline, Clenbuterol, Isoetarine, Pirbuterol, procaterol, ritodrine, epinephrine, arbutamine, befunolol,

bromoacetylalprenololmenthane, broxaterol, cimaterol, cirazoline, denopamine, dopexamine, etilefrine,

hexoprenaline, higenamine, isoxsuprine, mabuterol, methoxyphenamine, nylidrin, oxyfedrine, prenalterol, ractop amine, reproterol, rimiterol, tretoquinol, tulobuterol, zilpaterol, zinterol

Table 7: Symptoms related to overstimulation of GABAergic activity

Acute pain syndromes, Agitation, Anxiety, Apathy, Aphasia, Aspartylglucosaminuria, Athetoid cerebral palsy, Attention dysfunction, auditory hallucinations, Autism,

Behavioral changes, Behavioral disturbances, bilateral, Bladder dysfunction, Bulbar palsy, Cardiomyopathy, Chorea, Chronic pain syndromes, Cognitive dysfunction, Cognitive impairment, Constipation, Corticobasal degeneration, decline in mental abilities, decreased blink rate, deficient ocular pursuit, deficits of normal emotional responses, deficits of normal thought processes, Delusions, Dementia, Depression, Difficulties with blowing cheeks, Difficulties with cognition, Difficulties with cognitive speech, Difficulties with judgment, Difficulties with lip seal, Difficulties with memory, Difficulties with mood and behaviour, Difficulties with organizing thought, Difficulties with reasoning, Diplopia, Disinhibition, disordered speech, disordered thoughts,

Disorientation or confusion, dry eyes, Dysarthria, Dyskinetic cerebral palsy, Dysphagia, elevated cerebrospinal fluid protein concentrations of lactate, elevated cerebrospinal fluid protein concentrations of pyruvate, Emotional liability, emotional problems, emotional reactions when put in circumstances beyond abilities, encephalomyelopathy, executive dysfunction, exocrine pancreas dysfunction, Eye movement difficulties, Eye tracking problems, Facial muscle dysfunction, Fatigue, Flat expressions, Frontal lobe decline symptoms, Frontotemporal degeneration, Frontotemporal dementia, Gastric dysmotility, Gastrointestinal dysfunction, Glycogen storage disease, Glycoproteinoses, growth hormone deficiency, gustatory hallucinations, Hallucinations, hearing loss, hypertrophic cardiomyopathy, Hypoesthesia, hypoparathyroidism, hypotonia, Impaired sense of smell, impaired sensation of pain, Impulsivity, inability to experience pleasure, incontinence, irritability, lack of desire to form relationships, lack of motivation, lactic acidemia, lactic acidosis, Language skill dysfunction, Lipidoses, little emotion, Loss of judgment, Loss of memory, Loss of restraint, Lysosomal transport defects, Manifestations of autism, Manifestations of diabetes type I, Manifestations of diabetes type II, Manifestations of psychosis, mask-like face expression, memory distortions, Memory dysfunction,

Mitochondrial disease, Moodiness, Mucopolysaccharidoses, Multiple enzyme deficiency, negative neurologic symptoms, Neurological symptoms, Neuronal Ceroid Lipofuscinoses, Nystagmus, Oculomotor gaze palsy, olfactory hallucinations, Ophthalmoplegia, optic neuritis, optic neuropathy, Palsy, paralysis of extraocular muscles, Paranoia,

Paresthesia, Parkinsonism, Perseveration, Personality changes, Phosphenes, pigmentary retinopathy, positive neurologic symptoms, poverty of speech, Problem solving dysfunction, problems with abstract thinking, problems with attention, problems with cognition, problems with cognitive flexibility, problems with inhibiting inappropriate actions, problems with initiating appropriate actions, problems with mood, problems with planning, problems with rule acquisition, problems with selecting relevant sensory information, progressive external ophthalmoplegia, Progressive non-fluent aphasia,

Pseudobulbar symptoms, psychomotor regression, psychomotor retardation, Psychosis,

Ptosis, Reduced IQ, Restless legs, Restless legs syndrome, Restlessness or fidgeting,

Retinal dysfunction, Semantic dementia, Sensory problems, short-term memory loss,

Sialorrhoea, sideroblastic anemia, sleep problems, slowed cognitive speed, social withdrawal, Speech changes, Sphingolipidoses, Stress, subacute necrotizing

encephalomyelopathy, Subacute visual failure, Supranuclear gaze palsy, tactile hallucinations, Tongue muscle wasting, Tongue spasticity, Traumatic brain injury,

Trouble eating, utilization behaviour, Vascular dementia, vertical gaze palsy, visual hallucinations, visual-spatial difficulties, Visual-spatial dysfunction, Visuospatial difficulties, wandering or restlessness, Weakening of the soft patelate, word-finding difficulties, Yawning

Table 7a: Neuromuscular symptoms

Athetoid cerebral palsy, Bulbar palsy, Cardiomyopathy, Chorea, Difficulties with blowing cheeks, Difficulties with lip seal, Dysarthria, Dyskinetic cerebral palsy,

Dysphagia, Facial muscle dysfunction, Flat expressions, hypertrophic

cardiomyopathy, hypotonia, mask-like face expression, Palsy, Parkinsonism,

psychomotor regression, psychomotor retardation, Restless legs, Restless legs

syndrome, Restlessness or fidgeting, Sialorrhoea, subacute necrotizing

encephalomyelopathy, Supranuclear gaze palsy, Tongue muscle wasting, Tongue spasticity, Weakening of the soft patelate, Amyotrophy, Ataxia, Automatic muscle dysfunction, Balance problems, Bradykinesia, Coordination dysfunction, Decreased facial expression, Difficulties with fine motor control, dysdiadochokinesia, Dysmetria, Dyssynergia, Facial movements including grimaces, Falls, falls backwards, Fine movement dysfunction, Flail arms, Flail legs, General lack of coordination, grasp reflex, Hand pill-rolling tremor, Head turning to shift eye position, hypertonia, hypotonia, Involuntary muscle dysfunction, Limb coordination problems, loss of muscle coordination, Muscle atrophy, Muscle dystrophy, Muscle myopathy, Muscle stiffness, muscle stiffness especially in the neck and upper body, muscle wasting, muscle function loss, myoclonus, Myotonia, Paralysis, Paraparesis, Paraplegias,

Postural instability, Problems with sewing, Problems with writing, Quick sudden wild jerking movements of limbs, face, and other body parts, Resting tremors, Restless legs, Respiratory depression, Respiratory failure, Respiratory insufficiency, Rigidity,

Shakiness, Slowness of movement, small handwriting, Spasms, Split-hand syndrome, uncontrolled movements, Unsteady gait, Walking problems, Writing difficulties

Table 7b: Other symptoms

Bladder dysfunction, Constipation, elevated cerebrospinal fluid protein concentrations of lactate, elevated cerebrospinal fluid protein concentrations of pyruvate, exocrine pancreas dysfunction, Fatigue, Gastric dysmotility, Gastrointestinal dysfunction, Glycogen storage disease, Glycoproteinoses, growth hormone deficiency, hearing loss, hypoparathyroidism, incontinence, lactic acidemia, lactic acidosis, Lipidoses,

Lysosomal transport defects, Manifestations of diabetes type I, Manifestations of diabetes type II, Mitochondrial disease, Mucopolysaccharidoses, Multiple enzyme deficiency, Neuronal Ceroid Lipofuscinoses, sideroblastic anemia, sleep problems, Sphingolipidoses, osteopenia, neuropathy

Table 7c: Eye related symptoms

decreased eye blink rate, deficient ocular pursuit, Diplopia, dry eyes, Eye movement difficulties, Eye tracking problems, Nystagmus, Oculomotor gaze palsy,

Ophthalmoplegia, optic neuritis, optic neuropathy, paralysis of extraocular muscles, pigmentary retinopathy, progressive external ophthalmoplegia, Ptosis, Retinal dysfunction, Subacute visual failure, Reading difficulties, vertical gaze palsy,

Table 7d: Sensitory symptoms

Acute pain syndromes, anacusis, auditory hallucinations, Chronic pain syndromes, Deafness, gustatory hallucinations, Hallucinations, Hearing impairment, Hearing loss, Hypoesthesia, Impaired sense of smell, impaired sensation of pain, olfactory hallucinations, Paresthesia, Phosphenes, Sensory problems, tactile hallucinations, visual hallucinations, Numbness and tingling of the limbs, Sensory neuropathy, alien

Table 7e: Symptoms overlapping for cognitive and neuromuscular aspects

encephalomyelopathy, Pseudobulbar symptoms, Speech changes, Traumatic brain injury, Trouble eating, Yawning, Neuropathy, Polyneuropathy

Table 7f: Cognitive symptoms

Agitation, Anxiety, Apathy, Aphasia, Aspartylglucosaminuria, Attention dysfunction, Autism, Behavioral changes, Behavioral disturbances, Cognitive dysfunction,

Cognitive impairment, Corticobasal degeneration, decline in mental abilities, deficits of normal emotional responses, deficits of normal thought processes, Delusions, Dementia, Depression, Difficulties with cognition, Difficulties with cognitive speech, Difficulties with judgment, Difficulties with memory, Difficulties with mood and behaviour, Difficulties with organizing thought, Difficulties with reasoning,

Disinhibition, disordered speech, disordered thoughts, Disorientation or confusion, Emotional liability, emotional problems, emotional reactions when put in

circumstances beyond abilities, executive dysfunction, Frontal lobe decline symptoms, Frontotemporal degeneration, Fronto temp oral dementia, Impulsivity, inability to experience pleasure, irritability, lack of desire to form relationships, lack of motivation, Language skill dysfunction, little emotion, Loss of judgment, Loss of memory, Loss of restraint, Manifestations of autism, Manifestations of psychosis, memory distortions, Memory dysfunction, Moodiness, negative neurologic symptoms, Neurological symptoms, Paranoia, Perseveration, Personality changes, positive neurologic symptoms, poverty of speech, Problem solving dysfunction, problems with abstract thinking, problems with attention, problems with cognition, problems with cognitive flexibility, problems with inhibiting inappropriate actions, problems with initiating appropriate actions, problems with mood, problems with planning, problems with rule acquisition, problems with selecting relevant sensory information,

Progressive non-fluent aphasia, Psychosis, Reduced IQ, Semantic dementia, short- term memory loss, slowed cognitive speed, social withdrawal, Stress, utilization behaviour, Vascular dementia, visual-spatial difficulties, Visual-spatial dysfunction, Visuospatial difficulties, wandering or restlessness, word-finding difficulties Table 8: Symptoms related to overstimulation of GABAergic and / or Glycinergic activity

alien limb condition, Amyotrophy, Ataxia, Automatic muscle dysfunction, Balance problems, Bradykinesia, chorea, Coordination dysfunction, Decreased facial expression, Difficulties with fine motor control, dysdiadochokinesia, Dysmetria, Dyssynergia, Facial movements including grimaces, Falls, falls backwards, Fine movement dysfunction, Flail arms, Flail legs, General lack of coordination, grasp reflex, Hand pill-rolling tremor, Head turning to shift eye position, hypertonia, hypotonia, Involuntary muscle

dysfunction, Limb coordination, Muscle atrophy, Muscle dystrophy, Muscle myopathy, Muscle stiffness, muscle stiffness especially in the neck and upper body, muscle wasting, muscle function loss, myoclonus, Myotonia, Neuropathy, Numbness and tingling of the limbs, osteopenia, Paralysis, Paraparesis, Paraplegias, Polyneuropathy, Postural instability, Problems with sewing, Problems with writing, Quick sudden wild jerking movements of limbs, face, and other body parts, Reading difficulties, Resting tremors, Restless legs, Respiratory depression, Respiratory failure, Respiratory insufficiency, Rigidity, Sensory neuropathy, Shakiness, Slowness of movement, small handwriting, Spasms, Split-hand syndrome, uncontrolled movements, Unsteady gait, Walking problems, Writing difficulties

Definitions

As used herein, "to comprise" and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, the verb "to consist" may be replaced by "to consist essentially of meaning that a compound or adjunct compound as defined herein may comprise additional component(s) than the ones specifically identified, said additional component(s) not altering the unique characteristic of the invention.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

The word "approximately" or "about" when used in association with a numerical value (approximately 10, about 10) preferably means that the value may be the given value of 10 more or less 1% of the value. GABAergic activity refers to the GABA neurotransmitter system. Neurons that release GABA as a neurotransmitter are called GABAergic neurons and the physiological result of GABA neurotransmitter release is called GABAergic action. A reduction in "GABAergic activity" refers to a reduction in, e.g., the production/release of the GABA neurotransmitter as well as for example the reduction in the ability of GABA to be detected by the post-synaptic neuron (e.g., by inhibiting the binding of GABA to a post-synaptic receptor), or other direct or indirect modulations to the GABA neurotransmitter system that result in the decrease of action exerted by the GABA neurotransmitter system.

Glycinergic activity refers to the Glycine neurotransmitter system. Neurons that release Glycine as a neurotransmitter are called Glycinergic neurons and the physiological result of Glycine neurotransmitter release is called Glycinergic action. A reduction in "Glycinergic activity" refers to a reduction in, e.g., the production/release of the Glycine neurotransmitter as well as for example the reduction in the ability of Glycine to be detected by the post-synaptic neuron (e.g., by inhibiting the binding of Glycine to a post-synaptic receptor), or other direct or indirect modulations to the Glycine neurotransmitter system that result in the decrease of action exerted by the Glycine neurotransmitter system.

Glutaminergic activity refers to the glutamate neurotransmitter system. Neurons that release glutamate as a neurotransmitter are called Glutaminergic neurons and the physiological result of glutamate neurotransmitter release is called Glutaminergic action. A reduction in "Glutaminergic" refers to a reduction in, e.g., the

production/release of the glutamate neurotransmitter as well as for example the reduction in the ability of glutamate to be detected by the post-synaptic neuron (e.g., by inhibiting the binding of glutamate to a post-synaptic receptor), or other direct or indirect modulations to the glutamate neurotransmitter system that result in the decrease of action exerted by the glutamate neurotransmitter system.

The term "treating" includes prophylactic and/or therapeutic treatments. The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety. References:

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The invention is further explained in the following examples. These examples do not limit the scope of the invention, but merely serve to clarify the invention.

EXAMPLES

Example 1: Relating ALS disease to the disease epilepsy

The role of glutamate in epilepsy is well evidenced. Elevated glutamate levels for newly diagnosed epilepsy patients in CSF have been reported to be 0.260 ± 0.067 μΜ/L (mean ± SD) relative to 0.204 ± 0.049 μΜ/L for healthy control subjects

(Kalviainen et al. 1993), indicating a statistically significant and clinically relevant 30% elevation of glutamate concentrations. For ALS patients, CSF glutamate levels of 0.340 ± 0.166 μΜ/L (mean ± SD) were observed relative to 0.176 ± 0.015 μΜ/L for control subjects, indicating a statistically significant and relative to epilepsy patients a more than threefold higher elevation of 100% in glutamate levels, with individual ALS patients displaying even up to over 800% higher glutamate levels than control subjects (Spreux-Varoquaux 2002).

Elevated glutamate levels in ALS cause motoneuron cell death leading to the clinical manifestation of ALS, while elevated glutamate levels in epilepsy lead to the clinical manifestation of epilepsy through the occurrence of epileptic seizures. However, the highly elevated glutamate concentrations in ALS patients do not lead to highly elevated epileptic seizure incidences.

Example 2: GABAergic and Glycinergic inhibitory neurotransmitter systems in ALS With the excitatory glutamate CSF levels increased in ALS up to 800% relative to healthy subjects without leading to increased seizure incidences and the

omnipresence of CSF across the central nerve system (CNS), I hypothesize that there is another physiological system that is active in ALS which is capable of exerting strong anticonvulsive actions across the CNS, and that is has to be as omnipresent in the CNS and CSF as the excitatory glutamate system.

Based on these two criteria, I determined two systems that are as omnipresent as glutamate and that are capable of exerting strong anticonvulsant action: the inhibitory neurotransmitter system comprising of the GABA inhibitory

neurotransmitter system and the glycine inhibitory neurotransmitter system. In order to confirm the role of these systems, I performed an analysis of known symptoms in ALS and ALS like disorders to determine if either the GABA inhibitory

neurotransmitter system or the glycine inhibitory neurotransmitter system could be responsible for their clinical presentation in patients. The analysis is as follows:

Example 3: Increased levels of inhibitory neurotransmitter GABA can lead to muscle wasting symptoms as observed in ALS

Next to its potent anticonvulsant capabilities the GABAergic system is also capable of exerting strong muscle relaxant activity as can be deducted from the pharmacological effects of benzodiazepine treatment.

Benzodiazepines are a pharmacologically well-known and validated compound class that exert their pharmacological action by increasing the affinity of GABA for the GABA receptor leading to GABAergic stimulation that is capable of weakening muscles in a similar way as observed in ALS, i.e. through the inhibition of

motoneuron functioning causing otherwise healthy muscles to become dysfunctional. Furthermore, with muscle atrophy already observed clinically in patients being structurally immobilized in hospital beds or that need to be immobilized because of leg fractures, structural GABAergic overstimulation too can be concluded to lead to reduced muscle functioning that upon long term duration can lead to muscle atrophy and / or muscle wasting.

Example 4: GABAergic overstimulation can lead to muscle dysfunction as observed in ALS

GABAergic overstimulation can be concluded to even be capable of leading to complete muscle blockades. This is demonstrated for the pharmacologically well-known and validated compound class of GABAergic benzodiazepine agonists that when overdosed lead to fatal respiratory muscle dysfunction.

It therefore can be concluded that overstimulation of the GABA inhibitory

neurotransmitter system can lead to clinical manifestations on the dysfunction, atrophy and wasting of muscles as is observed in ALS.

Example 5: GABAergic overstimulation leads to muscle wasting symptoms in

SSADHD

In the rare disease succinic semialdehyde dehydrogenase deficiency (SSADHD), the absence of the enzyme succinic semialdehyde dehydrogenase leads to a two to four fold increase of GABA in the brains of SSADH deficiency patients as compared to healthy subjects, where due to the absence of the enzyme, GABA is transferred into gamma-hydroxybutyric acid (GHB) by gamma-hydroxybutyric dehydrogenase leading to elevated GHB levels that are key to diagnosing SSADHD.

The most common observed clinical manifestation of SSADHD is motor delay including the hampering of fine motor skills, a clinical manifestation that this disease shares with ALS disease, and that considering the above can be attributed to an overactive GABA inhibition system in SSADHD as reflected by the in SSADHD patients elevated GABA concentrations. It further can be concluded that the in SSADHD observed seizures occur in the presence of two to four fold elevated GABA levels implicating that the elevated GHB levels are high enough to provoke seizures. Based upon the above it further can be concluded that GABAergic overstimulation is implicated in SSADHD muscle wasting symptoms and that the SSADHD clinical profile provides further evidence for the role of GABAergic overstimulation in muscle wasting clinical profiles as observed in SSADHD and ALS. Example 6: GABAergic overstimulation can lead to respiratory depression as observed in ALS

GABAergic stimulation is capable of exerting strong and even fatal muscle relaxant activity as is demonstrated for the GABAergic pharmacological class of

benzodiazepine agonists that when overdosed lead to fatal respiratory depression. Fatal respiratory depression for the majority of late stage ALS patients is the final cause of death and, like in GABA mediated benzodiazepine agonist overdosing, results from a fatal weakening of respiratory muscles.

It therefore can be concluded that GABAergic inhibitory neurotransmitter system overstimulation can lead to clinical manifestations on respiratory depression as observed in ALS, and on the respiratory related fatalities as observed in ALS.

Example 7: GABAergic overstimulation can lead to dysphagia as observed in ALS Difficulties with swallowing (dysphagia) is another important clinical feature of ALS that can be explained by GABAergic inhibitory system overstimulation. It was reported that dysphagia could be induced through the administration of GABAergic inhibitory system stimulating compounds muscimol and diazepam (Hockman et al. 1996).

Furthermore in this experiment dysphagia could be reversed through the

administration of GABA antagonists picrotoxin and bicuculline, not only further confirming the role of GABAergic stimulation in dysphagia, but also demonstrating that GABAergic overstimulation related clinical manifestations of ALS can be reduced through the administration of compounds that reduce GABAergic overstimulation. It therefore can be concluded that GABAergic inhibitory system overstimulation can lead to clinical manifestations on dysphagia as also are observed in ALS.

Example 8: GABAergic overstimulation can cause dysphagia as observed in ALS in the absence of glutaminergic overstimulation

The conclusion that GABAergic (over)stimulation in the absence of glutaminergic excitatory (over) stimulation can lead to dysphagia as observed in ALS patients (see previous section) provides further evidence that GABAergic overstimulation alone causes dysphagia as observed in ALS, without requiring the glutaminergic excitatory neurotransmitter system to also be over stimulated. On the basis of this observation it therefore can be concluded that relative to glutaminergic overstimulation, GABAergic overstimulation is leading in the pathogenesis of ALS.

Example 9: GABAergic overstimulation can lead to dysarthria as observed in ALS Yet another clinical feature that can be attributed to GABAergic stimulation is the in ALS patients observed slurred speech (dysarthria), a clinical feature it shares with those observed after the ingestion of alcohol / ethanol in humans.

With alcohol being a GABAergic stimulant through its binding to the GABA receptor increasing the receptor's affinity for GABA, it can be concluded that GABAergic stimulation can lead to dysarthria as observed in ALS patients.

Example 10: GABAergic overstimulation can lead to eye movement difficulties

An additional relevant clinical feature to be considered is the in ALS patients observed reduced capability of completing voluntary saccadic eye movements, i.e. the quick, simultaneous movements of both eyes in the same direction. With GABAergic stimulation leading to a reduced capability of saccadic eye movements as observed after the administration of GABAergic pharmacological class of benzodiazepine agonists it can be concluded that GABAergic overstimulation can lead to reduced eye movement as observed in ALS. Furthermore, reduced eye movement capabilities are also observed in SSADHD, a disease where GABA levels are increased two to four fold, further evidencing that GABAergic overstimulation can lead to eye moving difficulties as observed in ALS.

It therefore can be concluded that GABAergic inhibitory neurotransmitter system overstimulation can lead to clinical manifestations on saccadic eye movements as observed in ALS.

Example 11: GABAergic overstimulation can lead to oculomotor and supranuclear gaze palsy as observed in ALS

In late stage ALS patients oculomotor and supranuclear palsy is observed that is caused by the dysfunction of eye muscles leading to patients being unable to move his or her eyes normally. Based on the impact of GABAergic overstimulation on muscle dysfunction and on the relation between GABAergic stimulation benzodiazepine treatment and eye functioning, GABAergic overstimulation can be concluded to be implicated in the in ALS patients observed oculomotor palsy. Example 12: GABAergic overstimulation can lead to bladder dysfunction as observed in ALS patients

GABAergic stimulation can be concluded to be involved in bladder dysfunction as GABAergic overstimulation through the administration of GABA receptor agonists muscimol and baclofen has been shown to lead to a dose-dependent inhibition of micturition with progressive increases in bladder capacity and residual volume, and a decrease in micturition pressure ending with urinary retention and dribbling incontinence. It therefore can be concluded that GABAergic stimulation can lead to bladder dysfunction as observed in ALS.

Example 13: GABAergic overstimulation can lead to gastrointestinal dysfunction as observed in ALS patients

The in ALS patients observed gastrointestinal dysfunction leads to delayed gastric emptying and delayed colonic transit times (constipation) in patients can be explained by GABAergic overstimulation with GABA receptors being involved in intestinal motility, gastric emptying, gastric acid secretion, transient lower oesophageal sphincter relaxation and visceral sensation of painful colonic stimuli. It therefore can be concluded that GABAergic stimulation can lead to gastrointestinal dysfunction as observed in ALS.

Example 14: GABAergic overstimulation can lead to soccer concussion related ALS ALS has been shown to be predominant in soccer players (Chio et al. 2005) where it is postulated that soccer related concussions can lead to (micro)traumas that can lead to the development of ALS.

This is of interest to the current application as (micro)traumas can be linked to changes in GABAergic functioning as increased levels of the GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) have been observed after

(micro)traumas in rats. It here therefore can be concluded as a novel invention that GABAergic overstimulation can provide the linkage between soccer related micro(traumas) and the clinical manifestation of ALS in soccer players.

It was further demonstrated that the by elevated GAD67 levels induced GABAergic overstimulation could be reversed by the administration of dopamine Dl antagonists, providing further support for the role of GABAergic overstimulation in ALS as Dl antagonists are known to reduce GABAergic function. It therefore can be concluded as a novel invention that GABAergic overstimulation in general can lead to clinical ALS manifestation even when this GABAergic

overstimulation is not specifically related to (micro)traumas or to increased GAD67 levels.

Example 15: GABAergic overstimulation can explain SOD predisposition in ALS Genetic mutations in the genome coding for the first superoxide dismutases enzyme (SOD1) are known to lead to ALS predisposition. The by SOD1 malfunctioning induced structural oxidative stress in ALS patients therefore can lead to structural inflammation processes that of a comparable nature to those observed due to soccer concussions related (micro)traumas and GABAergic overstimulation, and that can lead to the clinical manifestation of ALS as observed in soccer related ALS patients. Furthermore, with the multitude of factors that can lead to structural (micro) inflammation it can be concluded that a general inflammation pathway will make ALS a disease of many causes, which is consistent with the absence of epidemiologic relations in the ALS patient population. It therefore is concluded that the genetic SOD predisposition of ALS is caused by oxidative stress induced structural inflammation leading to GABAergic overstimulation eventually causing clinical manifestations as observed in ALS.

Example 16: Analysis of glycinergic overstimulation

-Glycine mediates the recurrent inhibition of motoneurons involved in countering gravity and inertia

Glycine is the inhibitory neurotransmitter involved in neurologic systems that are controlled by both GABAergic inhibitory mediated neurotransmission and Glycinergic neurotransmitter mediated neurotransmission, a physiological process also known as the recurrent inhibition of motoneurons.

In a landmark review of Windhorst (1996) recurrent inhibition is concluded to be present in motoneurons that are involved in locomotion and posture of the body. This based upon the observation that recurrent inhibition is particularly strong in and between motoneuron pools active during the stance phase of locomotion and during upright stance (posture), is fairly strong among neck motoneurons that control the movement of a fairly large mass (i.e. the head), and is relatively weak in motoneurons controlling trunk muscles such as the thoracic intercostal and phrenic motoneurons which is related to the rudimentary postural functions of these motoneurons.

Summarizing it is concluded by Windhorst that the extent of recurrent inhibition of motoneurons depends on the extent of a motoneuron involvement in countering gravity and / or maintaining inertia against forces acting on the body including the forces resulting from the mass of the body. An overview of motoneurons and their recurrent inhibition extent is given in table 9:

Table 9: Overview of the occurrence of recurrent inhibition (RI) for all studies motoneurons demonstrating that RI is observed for all muscles involved concluded that the extent of recurrent inhibition of motoneurons depends on the extent of a motoneuron involvement in countering gravity and / or maintaining inertia against forces acting on the body including the forces resulting from the mass of the body that coincide with the different ALS onset presentations limb, respiratory and bulbar. RI = Recurrent inhibition. Based upon the review of Windhorst (1996).

muscle motoneurons lifting of relatively small fingers of the same hand

(body) masses

abductor digiti minimi stabilization, movement or abducts the body's little toes and / or absent bulbar muscle motoneurons lifting of relatively small little fingers

(body) masses

Mastication muscle food mastication & Mastication or chewing is important absent bulbar motoneurons swallowing for the mastication and swallowing

of food

Ear muscle (tensor food mastication & Mastication or chewing is important absent bulbar tympani) motoneurons swallowing for the mastication and swallowing

of food

Swallowing prevention swallowing & yawning prevents entry of food into the absent bulbar muscle (tensor veli nasopharynx during swallowing and

palatini) motoneurons is involved in yawning

Swallowing and speech swallowing & speaking The mylohyoid elevates the hyoid absent bulbar muscle (mylohyoid and the tongue which particularly is

muscle) motoneurons important during swallowing and

speaking

Mouth opening muscle speaking & eating Opens the mouth absent bulbar (digastric muscle)

motoneurons

Eye movement muscle movement of relatively small Moves the body's eyes absent bulbar (occulomotor muscles) masses

motoneurons

Example 17: GABAergic and Glycinergic overstimulation explain ALS onset of disease differentiation

If next to GABAergic, Glycinergic mediated recurrent inhibition overstimulation also is implicated in ALS it can be expected that, depending on the system being most overstimulated during early stages, ALS will present itself as a disease where the GABAergic onset effects occur in a different time space from the Glycinergic mediated recurrent inhibition overstimulation effects, and ALS patients presenting with

Glycinergic overstimulation related clinical manifestations before sole GABAergic overstimulation manifestations become apparent.

As can be seen from the tables below this indeed is the case with ALS onset

presenting itself with either GABAergic overstimulation symptoms such as dysarthria and dysphagia (also known as bulbar onset ALS), or with Glycinergic mediated recurrent inhibition overstimulation symptoms such as muscle weakness in arms and legs (also known as limb onset ALS).

Furthermore, it can be expected that in patients where both GABAergic and the Glycinergic mediated recurrent inhibition overstimulation are present from the onset of disease in an equally pronounced stage this will lead to early onset of disease in organs that are influenced by both GABAergic and Glycinergic overstimulation, i.e. the lung, also known respiratory onset ALS. Table 10: ALS symptom classification based upon GABA and/or Glycine

involvement.

GABAergic and Glycinergic overstimulation explain ALS progressive disease differentiation

The fact that during the last and fatal stage of ALS disease where respiratory function approaches minimal functional levels ALS patients still are capable of eye muscle movement provides further evidence for the role of Glycinergic

overstimulation in ALS. Hence, with both GABAergic and Glycinergic

overstimulation involved in respiratory function and only GABAergic stimulation involved in eye muscle movement it can be expected that eye muscle movement function can be maintained into further stages of disease than lung muscle related respiratory functioning.

It therefore can be concluded based upon the observation that ALS patients even in final stages of disease are capable of eye movements is due to the fact that ocular motoneurons are not regulated through both GABAergic and Glycinergic mediated recurrent inhibition, but only through GABA neurotransmitter inhibition, thus providing further evidence for the role of Glycinergic mediated recurrent inhibition overstimulation in ALS.

Example 18: Glycinergic overstimulation explains the ALS split-hand syndrome The ALS split-hand syndrome is unique to the ALS indication. ALS hand muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles, with relative sparing of the abductor digiti minimi (ADM). This peculiar pattern of dissociated atrophy of the intrinsic hand muscles is termed the split hand and is rarely seen in diseases other than ALS with rare exceptions in nonALS related autosomal dominant distal spinal muscular atrophy, spinocerebellar ataxia type 3 (Machado- Joseph disease) and juvenile muscular atrophy, as well as spinal and bulbar muscular atrophy (SBMA) and remote poliomyelitis (Eisen et al. 2012). The physiological mechanisms underlying the split hand in ALS are incompletely understood. Here the most delusive factor is the observation that affected (ABP and FDI) and non-affected (ADM) muscles are innervated through the same spinal segments (C8 and Tl), and that the differently affected FDI and ADM muscles are both ulnar nerve innervated and as such cannot be uniquely separated on the basis of for example spinal or cortical involvement criteria, or on the bases of upper motoneuron or lower motoneuron diagnostic criteria.

The physiological mechanisms underlying the split hand in ALS until now have been incompletely understood. It among others has been attributed to the more frequent use of the ABP and FDI during the precision grip where a more frequent use of these muscles may lead to greater oxidative stress and metabolic demands at both upper and lower motoneurons innervating these muscles, consequently leading to a faster function loss of the involved motoneurons and muscles (Eisen et al. 2012).

In the current application it is concluded that the ALS split hand syndrome can be explained on the basis of differences in the extent of Glycine mediated recurrent inhibition for hand muscles involved in a precision grip relative to muscles that (also) are involved in a power grip. Napier (1956) differentiated hand grips into [1] precision grips where fingers and thumb press against each other as for example in pen writing without lifting relatively heavy masses and [2] power grips where fingers, palm and thumb clamp down on an object with the thumb making counter pressure for lifting relatively heavy masses as for example in gripping a hammer, carrying a frying pan or during pull-ups. Through this separation Napier implicitly also has categorized muscles activities into those that are, or are not involved in countering gravity and / or maintaining inertia as described by Windhorst (1996), and that according to the current disclosure will be, or will not subject to Glycinergic mediated recurrent inhibition onset of ALS disease.

With the ADM function of moving the little finger away from the hand and as such solely involved in precision gripping, and motoneurons and muscles not involved in countering gravity and / or maintaining inertia of the body not being subject to Glycine mediated recurrent inhibition, it can be concluded that the ADM

motoneurons are not subject to Glycine mediated recurrent inhibition. This is consistent with the demonstrated absence of Glycine mediated recurrent inhibition in the abductor digiti minimi motoneurons as summarized in table 9. With the APB and FDI muscles involved in the opposition and extension of the thumb (APB) these can be concluded to be also involved in the hand's power grip and countering gravity and / or maintaining inertia of the body. Consequently the ABP and FDI muscles will be subject to Glycine mediated recurrent inhibition, explaining their difference in disease onset relative to the ADM muscle that is not subject to Glycine mediated recurrent inhibition, and as such clarifying the until now unresolved clinical manifestation of the ALS split hand syndrome.

Based upon the above, the current disclosure not only for the first time explains the ALS disease specific split hand syndrome but also further confirms the role of Glycinergic mediated recurrent inhibition overstimulation in ALS.

Example 19: ALS onset manifestation is differentiated by GABAergic and

Glycinergic overstimulation

Based upon the clinical manifestation symptoms of limb-, bulbar- and respiratory ALS onset and their relation to GABAergic and / or Glycinergic overstimulation as summarized in table 10, the differences in ALS onset manifestation can be attributed to the overstimulation pathway that is most pronounced during initial ALS disease. This is summarized in tables 11 to 13 where ALS disease onset symptoms are classified upon their relation to GABAergic and / or Glycinergic overstimulation:

Table 11: ALS BULBAR onset symptoms classification based upon GABA and/ or Glycine overstimulation.

Table 12: ALS LIMB onset symptoms classification based upon GABA and/or Glycine overstimulation.

Based upon the tables it can be concluded that GABAergic overstimulation onset of disease leads to symptoms that currently are classified as bulbar onset of ALS, that combined GABAergic and Glycinergic overstimulation onset of disease leads to symptoms that currently are classified as limb onset ALS, and that onset of disease where GABAergic and Glycinergic overstimulation are both present with

GABAergic overstimulation being most pronounced leads to onset symptoms that currently are classified as respiratory onset ALS.

It here is concluded that with progressive disease both GABAergic and Glycinergic mediated recurrent inhibition overstimulation symptoms becoming increasingly active indicating that progressive ALS disease is the result of progressively increasing overstimulation of both the GABAergic and Glycinergic mediated recurrent inhibition systems as is summarized in tables 14 to 16: Table 14: ALS BULBAR progressive symptoms classification based upon GABA and/ or Glycine overstimulation.

Disease si a 11 Symptom GABA Glycine

lllVoKcillelll involvement

Progressive Progressive bulbar symptoms +

disease Limb symptoms within one to two + +

years

Bulbar, cervical, thoracic and + +

lumbar symptoms

Late stage supranuclear gaze palsy +

Late stage oculomotor palsy +

Respiratory failure + +

Table IS: ALS LIMB progressive symptoms classification based upon GABA and/or Glycine overstimulation.

I )isea.»e .-I ye Symptom (ΊΛΜΛ Glycine

IllVolvelllenl IllVolvelllenl

Progressive limb muscle weakness + +

Progressive Bulbar ALS symptoms +

disease Bladder dysfunction such as urgency +

of micturition

Multi system involvement (e +

dementia, parkinsonism)

Eventually respiratory symptoms + + occur

Table 16: ALS RESPIRATORY progressive symptoms classification based upon

Figure 1 summarizes tables 11-16 graphically, demonstrating the pivotal role of GABAergic and Glycinergic overstimulation in the pathogenesis of ALS. Figure 2 shows that limb-, bulbar- and respiratory onset ALS, and progressive ALS are the result of a continuum of separately increasing gradients of GABAergic and

Glycinergic mediated recurrent inhibition overstimulation during initial and progressive disease stages. Figure 3 depicts how varying degrees of GABAergic and Glycinergic

overstimulation lead to the clinical symptoms of ALS-like diseases.

The progressive muscular atrophy (PMA) disease pathway can be understood by the initial Glycinergic overstimulation related limb onset symptoms that during progressive disease also leads to GABAergic overstimulation related dysphagia, and where 50% of patients develop typical ALS clinical manifestations (Silani et al. 2011).

Flail arm and flail leg MND variants are initially localized forms with

predominantly Glycinergic overstimulation related lower motoneuron

presentations where GABA overstimulation related swallowing difficulties and diaphragmatic weakness develop only during later stages of disease. Primary lateral sclerosis (PLS) presents with GABAergic overstimulation related upper motoneuron manifestations where Glycinergic overstimulation related lower motoneuron symptoms are either absent or observed through minimal hand muscle wasting observed in some patients.

Progressive bulbar palsy (PBP) initial symptoms relate to GABAergic

overstimulation related difficulties with speech, swallowing problems and sialorrhoea related drooling. Disease progression can lead to progressive difficulty with GABAergic overstimulation related chewing, talking, and swallowing, sometimes presenting pseudobulbar emotional changes, with observed GABAergic overstimulation related weak palatal movements and weak movement of the facial muscles and tongue leading to advanced cases where patients are unable to protrude their tongue or manipulate food in their mouth. Because PBP patients have such difficulty swallowing food and saliva can be inhaled into the lungs resulting in gagging and choking and increases the risk of pneumonia. Death, which is often from pneumonia, usually occurs 1 to 3 years after the start of the disorder.

Pseudobulbar palsy (PB) initially manifests itself with GABAergic overstimulation related slurred speech, followed by difficulties with GABAergic overstimulation related chewing and swallowing problems and GABAergic muscle wasting related tongue spasticity, occasionally demonstrating uncontrolled emotional outbursts that in in the following sections herein also will be demonstrated to be GABAergic overstimulation related. The clinical manifestation of ALS and ALS-like disorders therefore can be explained by separately increasing gradients of GABAergic and Glycine mediated recurrent inhibition overstimulation. Example 20: GABAergic overstimulation in ALS-FTD

FTD is a syndrome of progressive changes in behavior and language due to loss of function of neurons in the frontal and temporal lobes. FTD usually has relatively little effect on the parts of the nervous system that control movement, and so many FTD patients remain physically strong and relatively agile until late in the illness. However, in about 10- 15% of patients with FTD, the disease also involves motoneurons. When this occurs, the syndrome is called FTD with motoneuron disease or FTD with ALS (FTD -ALS).

Patients with FTD-ALS may present with the same behavioral and/or language changes as seen in other subtypes of FTD. In the FTD-ALS syndrome however, these changes are accompanied by ALS symptoms such as the deterioration of motoneurons leading to muscles weakness with stiffness, difficulties in making fine movements and muscle atrophy. Muscle changes can affect arms and/or legs on one or both sides of the body, or the face, tongue and mouth, depending on how the nervous system is affected. With progressive disease more parts of the motoneuron system become affected.

On the other side, from the ALS indication perspective, approximately 30% of ALS patients develops signs of frontal lobe decline, which affects organizational function and behavior as observed in FTD. Patients with ALS-FTD may present with features of either FTD or ALS where additional symptoms develop with progressive disease where all ALS-FTD patients experience the gradual and progressive decline in functioning.

From previous sections and table 11 this disclosure demonstrates that the clinical manifestation of ALS can be attributed to GABAergic and Glycinergic

overstimulation. Furthermore, this disclosure demonstrates that the ALS clinical manifestations dysarthria, dysphagia, sialorrhoea, the weakening of the soft palate, muscle wasting and spasticity of the tongue, difficulties with lip seal and blowing cheeks, bladder dysfunction, the oculomotor related aspects of late stage oculomotor and supranuclear gaze palsy are not attributable to Glycine overstimulation as these clinical manifestations are not related to countering gravity or inertia, and therefore can be attributable solely to GABAergic overstimulation. Furthermore, with [1] GABAergic neurotransmission being relevant in

frontotemporal nerve signalling, [2] frontotemporal nerve cells located in close proximity to the by ALS impacted motoneuron cells and [3] the overlap in the clinical manifestation of ALS, ALS-FTD, FTD -ALS and FTD, it can be concluded that GABAergic overstimulation is implicated in the clinical manifestation of ALS, ALS-FTD, FTD-ALS and FTD. This is further confirmed by the in patients observed diffuse clinical progression of ALS into ALS-FTD, and FTD into ALS- FTD. This progressive character is even further confirmed by the for late stage ALS patients observed oculomotor and supranuclear gaze palsy where

manifestation of disease not only includes ALS symptoms but also includes personality changes that may be regarded as a first sign of the progression of disease into the development of ALS-FTD.

GABAergic overstimulation therefore is concluded to not only manifest itself in ALS symptoms, but also in the frontotemporal aspects of ALS, thus implicating GABAergic overstimulation in ALS-FTD where an increasingly over stimulated GABAergic system impacts both motoneurons and frontotemporal neuron cells leading to a reactive overstimulation of the glutaminergic systems and to glutaminergic overstimulation neuronal cell death of these neurons as observed for motoneuron cells in ALS.

Example 21: GABAergic overstimulation is implicated in FTD

Frontotemporal dementia (FTD) or frontotemporal degeneration is a disease indication that separates itself from ALS-FTD in that regard that FTD can be seen as a disease where FTD clinical symptoms occur in the absence of motoneuron related symptoms associated with ALS though it here will be concluded that considerable overlap exists between the clinical manifestations of ALS and FTD. FTD is defined as a group of disorders caused by progressive neuron cell degeneration in the frontal or temporal lobes of the brain that leads to reduced function in the frontal and temporal lobes which control planning, judgment, emotions, speech, understanding speech and certain types of movement.

FTD accounts for ten to fifteen percent of all dementia cases and as such is less common than Alzheimer's disease, vascular dementia and Lewy body dementia. FTD is grouped into three main categories that initially have different clinical manifestations based upon the affected frontotemporal lobes that with progressive disease symptoms becoming increasingly overlapping:

Firstly, behavioral variant FTD (bv-FTD) impacts personality and behavior and initially manifests itself with subtle changes but with progressive disease leads to disinhibition and a loss of restraint in personal relations and social life.

Secondly, primary progressive aphasia (PPA) affects language skills in early stages, but with progressive disease also affects behavior. PPA may manifest itself as semantic dementia in combination with declining language comprehension or as progressive non-fluent aphasia where patients lose the ability to generate words, speech becomes halting, tongue tied and ungrammatical, and the ability to read and write becomes impaired. PPA patients have trouble finding the right words, mostly due to difficulty in coordinating the muscles they need to speak

(dysarthria).

Thirdly, the FTD movement disorders subtype affects involuntary and automatic muscle function, but also impairs language and behavior. FTD movement disorder may manifest itself as corticobasal degeneration causing shakiness, lack of coordination, and muscle rigidity and spasms, or as progressive supranuclear palsy (PSP), causing walking and balance problems, falls, muscle stiffness especially in the neck and upper body. PSP also affects eye movements. FTD movement disorders as such can be regarded as a manifestation of FTD that is in between FTD and ALS-FTD.

Consistently with [1] the implication of GABAergic overstimulation being implicated in ALS-FTD, [2] GABAergic neurotransmission being relevant in frontotemporal nerve signalling, [3] FTD frontotemporal nerve cells located in close proximity to the by ALS and ALS-FTD impacted motoneuron cells, [4] the overlap in the clinical manifestation of ALS, ALS-FTD, FTD -ALS and FTD and [5] the clinical manifestation of FTD movement disorders that are in between the clinical manifestation of the FTD and ALS-FTD disorders, it can be concluded that GABAergic overstimulation is implicated in the clinical manifestations of ALS, ALS-FTD, FTD-ALS and FTD.

In addition, it can be concluded that GABAergic overstimulation not only occurs in motoneuron cells in the co-presence of GABAergic overstimulation in other neuron cells as observed in ALS patients, but that GABAergic overstimulation of frontotemporal brain regions can also occur in the absence of GABAergic motoneuron overstimulation. This leads to the conclusion that GABAergic overstimulation besides leading to motoneuron cell death can also lead to cell death of non-motoneuron nerve cells. Here an increasingly overstimulated GABAergic system affects frontotemporal neuron cells leading to clinical manifestation of disease that is related to the affected frontotemporal part of the brain, and to clinical manifestations that are directly related to GABAergic overstimulation symptoms such as speech problems, movement disorders leading to shakiness, lack of coordination, muscle rigidity and spasms, walking and balance problems, falls, muscle stiffness but also affecting GABA mediated eye movements.

From the above it can be concluded that GABAergic overstimulation not only can impact motoneuron functioning but that GABAergic overstimulation can also impact general neuron function, even in the absence of by GABAergic

overstimulated motoneuron cells. Based upon the above this disclosure therefore concludes that GABAergic overstimulation can manifest itself as a progressive disease where diffusively overlapping neurological neurologic symptoms present themselves in combination with symptoms that can be related to GABAergic overstimulation as observed in ALS. Example 22: GABAergic overstimulation in dementia

Dementia is a broad category of brain diseases that cause long term loss of the ability to think and reason clearly in a way that is severe enough to affect a person's daily functioning. Except for a few treatable types in most cases no cure exists for dementia. Cholinesterase inhibitors are used early in the disease course but only provide slight benefit and treatment therefore focusses on cognitive and behavioral interventions, and the education and providing of emotional support to the caregiver.

Dementia affects a patient's ability to think, reason and remember clearly. The most common affected areas include memory, visual-spatial, language, attention, and problem solving. Most types of dementia occur in a slow and progressive nature where the process affecting the brain precedes the manifestation of disease for a long time.

Circa ten percent of dementia patients display mixed dementia, usually a combination of ALZ and another type of dementia such as frontotemporal dementia or vascular dementia. Additional psychological and behavioral problems that affect dementia patients include: disinhibition, impulsivity, depression, anxiety, agitation, delusions, hallucinations, memory distortions, wandering or restlessness, emotional reactions when put in circumstances beyond abilities, incontinence, balance problems and falls, tremor, speech and language difficulty and trouble eating or swallowing.

The most common form of dementia is ALZ which represents 75% of dementia cases. Other forms of dementia include Lewy body dementia, vascular dementia, frontotemporal dementia, progressive supranuclear palsy, corticobasal

degeneration, normal pressure hydrocephalus and Creutzfeldt-Jakob disease. An overview of the most common forms of dementia is given in following table.

Table 17: Overview of most common forms of dementia

Alzheimer's • ALZ brain atrophy is the most common form of dementia disease representing 75% of cases.

• Its most common symptoms are short-term memory loss, word- finding difficulties, visual- spatial difficulties causing patients to get lost, and difficulties with reasoning, judgment and insight into the realization that the patients has memory problems.

• The part of the brain most affected by Alzheimer's is the

hippocampus. Other parts of the brain that will show atrophy include the temporal and parietal lobes but brain atrophy in ALZ can be variable and diffuse.

Vascular • Vascular dementia is the cause of circa 20% of dementia cases dementia making it the second most common cause of dementia.

• It is caused by disease or injury to blood vessels that damage the brain, including strokes.

• The symptoms of vascular dementia depend on where in the brain the strokes have occurred and whether the affected vessels are large or small.

• Multiple injuries can cause progressive dementia over time, while a single injury located in an area critical for cognition such as the hippocampus or the thalamus) can lead to sudden cognitive decline. Dementia • Dementia with Lewy bodies is a dementia that has the primary with Lewy symptoms of visual hallucinations and Parkinsonism.

bodies (DLB) • Parkinsonism includes tremor, rigid muscles, and a face without emotion.

• The visual hallucinations in DLB are generally very vivid

hallucinations of people and/or animals and they often occur when someone is about to fall asleep or just waking up.

• Other prominent symptoms include problems with attention, organization, problem solving and planning and difficulty with visual-spatial function.

Bv-FTD • Behavioral variant FTD (bv-FTD) impacts personality and

behavior and initially manifests itself with subtle changes but with progressive disease leads to disinhibition and a loss of restraint in personal relations and social life.

PPA • Primary progressive aphasia (PPA) affects language skills in early stages, but with progressive disease also affects behavior.

• PPA may manifest itself as semantic dementia in combination with declining language comprehension or as progressive non- fluent aphasia where patients lose the ability to generate words, speech becomes halting, tongue tied and ungrammatical, and the ability to read and write becomes impaired.

• Patients experience speaking difficulties (dysarthria) due to difficulties in coordinating the muscles they need to speak.

FTD • FTD movement disorders affect involuntary and automatic muscle movement function where this disorder also impairs language and behavior. disorders • FTD movement disorder may manifest itself as corticobasal

degeneration causing shakiness, lack of coordination, and muscle rigidity and spasms, or as progressive supranuclear palsy (PSP) affecting eye movements, causing walking and balance problems, falls, muscle stiffness especially in the neck and upper body.

Progressive • Progressive supranuclear palsy (PSP) is a form of dementia that is supranuclear characterized by problems with eye movements.

palsy (PSP) • Generally the problems begin with difficulty moving the eyes up and/or down (vertical gaze palsy).

• Since difficulty moving the eyes upward can sometimes happen in normal aging, problems with downward eye movements are the key in PSP diagnosis.

• Other key symptoms of PSP include falls backwards, balance problems, slow movements, rigid muscles, irritability, apathy, social withdrawal and depression.

• Patients may display frontal lobe signs such as perseveration, a grasp reflex and utilization behavior.

• PSP patients display progressive difficulty eating and swallowing (dysphagia).

• PSP patients display progressive difficulty with speech

(dysarthria). • Because of the combination of rigidity and slow movements with diffuse other neurological disease manifestations PSP can be misdiagnosed as Parkinson's disease.

• Brains scans of PSP patients generally demonstrate midbrain atrophy where other brain regions appear to be unaffected.

Corticobasal • Corticobasal degeneration is a rare form of dementia that is degeneration characterized by many different types of neurological problems that progress over time.

• This is because the disease affects the brain in many different places, but at different progressive rates.

• One common sign is difficulty with using only one limb.

• One symptom that is extremely rare in any condition other than corticobasal degeneration is the 'alien limb' where the patient experiences the limb to have a mind of its own as it moves without control of the person's brain.

• Other common limb symptoms include jerky movements of one or more limbs (myoclonus), symptoms that are different in different limbs (asymmetric).

• Difficulty with speech due to difficulties with coordinating mouth muscle movement (dysarthria).

• Numbness and tingling of the limbs and neglecting one side of the person's vision or senses.

• Affected limbs may be rigid or have muscle contractions causing dystonia.

• The area of the brain most often affected in corticobasal

degeneration is the posterior frontal lobe and parietal lobe where many other parts of the brain also can be affected.

Dementia as no other neurologic disease displays the hallmark of GABAergic overstimulation symptoms, i.e. the occurrence of diffuse and overlapping neurologic symptoms of a progressive nature in the presence of symptoms that can be directly related to symptoms as observed in GABAergic overstimulated ALS patients such as difficulties with speech, swallowing, bowel control (incontinence), eye

movements and / or other muscle functioning.

Furthermore, with the role of GABAergic stimulation being demonstrated for ALS- FTD, FTD-ALS and FTD and the diffuse character of dementia in all its

appearances it can be concluded that GABAergic stimulation also is implicated in other forms of dementia. Hence, with GABA as the major neurotransmitter in the brain regions affected by dementia, and the diffuse clinical manifestations of dementia being linked to differences in brain regions affected, it can be concluded that GABAergic overstimulation not only occurs in motoneurons as affected in ALS, or in brain regions as affected in FTD, but that GABAergic overstimulation can also occur in other separate parts of the brain leading to progressively overlapping and diffuse neurological manifestations of which the clinical manifestation depends on the brain regions affected by GABAergic

overstimulation. As such, GABAergic overstimulation of the hippocampus and temporal and parietal lobes brain regions in combination with a diffuse pattern of brain atrophies in other brain regions leads to the clinical manifestation of ALZ (Alzheimer's disease), the GABAergic overstimulation of midbrain regions without atrophy in other brain regions leads to PSP, and the GABAergic overstimulation of the cerebral cortex and the basal ganglia brain regions leads to the clinical manifestation of corticobasal degeneration.

Therefore, depending on the brain region affected by GABAergic overstimulation caused neuronal cell death different, even patient individual, disease patterns will occur as those observed in dementia, where disease manifestations can become more and more overlapping as disease progresses into other brain regions that become increasingly affected by GABAergic overstimulation.

Further evidence of the role of GABAergic overstimulation in dementia comes from the implication of GABA in the pathogenesis of temporary dementia as

encountered in hypothyroidism, and vitamin B12 deficiency, alcohol related dementia as alcohol exerts its action through GABA receptor modulationand the increase of dementia symptom severity after administration of the GABA receptor modulating benzodiazepine agonist diazepam.

Furthermore, the role of GABAergic overstimulation in ALZ is further confirmed by the in ALZ patients elevated levels of the excitatory neurotransmitter glutamate in the absence of an increased incidence of epileptic seizures.

The role of glutamate is well-known in the epilepsy indication and has been quantified where increased glutamate levels were reported for newly diagnosed epilepsy patients of 0.260 ± 0.067 μΜ/L (mean ± SD) relative to 0.204 ± 0.049 μΜ/L for control subjects (Kalviainen, 1993), indicating a statistically significant and clinically relevant 30% glutamate level elevation. For ALZ patients, glutamate levels of 0.260 ± 0.087 μΜ/L (mean ± SD) were observed relative to 0.176 ± 0.015 μΜ/L for control subjects, indicating a statistically significant and relative to epilepsy patients an even higher elevation of 50% in glutamate levels, with individual ALZ patients reported to have even up to over 121% higher glutamate levels than control subjects (Spreux-Varoquaux 2002). At such high glutamate levels epileptic seizures would occur in the majority of ALZ patients where the actual percentage of ALZ patients experiencing seizure is at present unclear but appears not to be elevated with the exception of a small increased risk during early onset ALZ (Spencer 2014). This expands the clinical profile of ALZ as to being a disease where elevated excitatory glutamate levels do not lead to an increased incidence in seizures and further implicates GABAergic overstimulation.

Here it therefore is concluded that GABAergic overstimulation is at the basis of the progressively overlapping diffuse clinical manifestation of different forms of dementia.

Example 28: GABAergic overstimulation in Multiple Sclerosis (MS)

MS is another neurologic disease displaying the typical occurrence of diffuse and overlapping neurologic symptoms of a progressive nature in the presence of symptoms that can be directly related to symptoms as observed in GABAergic overstimulated ALS patients such as difficulties with speech, swallowing, bowel control, eye movements and other muscle functioning.

Multiple sclerosis manifests itself with changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, difficulty moving, difficulties with

coordination and balance, problems in speech (dysarthria) or swallowing

(dysphagia), eye movement dysfunction (nystagmus, optic neuritis, diplopia) and eye nerve system problems (phosphenes), fatigue and acute or chronic pain syndromes, bladder and bowel difficulties, cognitive impairment, aphasia, or emotional symptomatology such as major depression.

MS classifies as being a disease where diffuse neuronal clinical manifestations such as cognitive impairment, unstable mood, fatigue and depression present themselves in the presence of GABAergic overstimulation clinical manifestations as observed in GABAergic overstimulated ALS patients such as eye muscle movement problems, problems with speech (dysarthria), difficulties with swallowing (dysphagia), musculoskeletal weakness, spasms and ataxia,

incontinence and regulation of intestinal motility. Based upon the above it herein therefore is concluded that GABAergic overstimulation is implicated in MS. Example 24: GABAergic overstimulation is implicated in Huntington's disease (HD) HD is a disorder in which nerve cells in certain parts of the brain waste away or degenerate. Huntington disease is caused by a genetic defect on chromosome 4 leading to the clinical manifestation of a neurodegenerative disorder that affects muscle coordination and leads to cognitive decline and behavioral symptoms.

Early symptoms are subtle problems with mood or cognition followed by a general lack of coordination and an unsteady gait as disease progresses. With further progressing disease uncoordinated, jerky body movements become apparent, along with a further decline in mental abilities and behavioral symptoms. Physical abilities are gradually impeded until coordinated movement becomes very difficult. Mental abilities generally decline into dementia. Complications related to diminished muscle function such as pneumonia, heart disease, and physical injury from falls reduce life expectancy to around twenty years from the point at which symptoms begin. There is no cure for HD, and full-time care is required in the later stages of the disease. An overview of symptoms is given in the following table.

Table 18 clinical manifestation of HD.

HD is yet another neurologic disease where diffuse and progressive neurological behavior and dementia symptoms are accompanied by the presence of clinical manifestations that also are observed in GABAergic overstimulated ALS patients such as movement disorders, muscle dysfunction, difficulties with swallowing (dysphagia) and difficulties with speech (dysarthria).

It therefore can be concluded that GABAergic overstimulation is implicated in HD, where is can be assumed that this overstimulation is the result of the cascade of reactions and processes resulting from the genetic mutation at chromosome 4 which is further confirmed by implication of GABAergic stimulation in preclinical HD models.

Efforts in the HD field currently however aim at increasing the extent of

GABAergic stimulation due to the observation that HD patients display decreased levels of GABA, a finding that based upon the current disclosure can be concluded to be inconsistent with the clinical manifestation of HD displaying symptoms that are also observed in GABAergic overstimulated ALS patients. This clinical observation however can be explained through the observation that GABAergic stimulation can occur at many physiological levels and that lower GABA concentrations in certain brain regions can implicate GABAergic overstimulation in other upstream GABAergic neurons and / or brain regions. It here therefore is concluded that like in ALS treatment, GABAergic stimulation will not be efficacious in HD, where reducing GABAergic stimulation will be efficacious. Based upon the above, it is concluded that GABAergic overstimulation is implicated in HD.

Example 25: GABAergic overstimulation in Parkinson's disease (PD)

PD is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain. The cause of this cell death nor that of PD in general currently are unknown.

Early in the course of the disease obvious symptoms are movement-related: these include shaking, rigidity, slowness of movement and difficulty with walking and gait. With progressive disease, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems. Parkinson's disease is more common in older people, with most cases occurring after the age of 50.

The pathology of the disease is characterized by the accumulation of alpha- synuclein into Lewy bodies in neurons and the reduced formation and activity of dopamine in certain neurons located in the midbrain. Lewy bodies are the pathological hallmark of idiopathic PD, and distribution of the Lewy bodies throughout the Parkinsonian is different for each individual. Consequently, the anatomical distribution of the Lewy bodies is often directly related to the expression and degree of the clinical symptoms of each individual.

Modern treatments are effective at managing the early motor symptoms of the disease, mainly through the use of levodopa and dopamine agonists. As the disease progresses and dopaminergic neurons continue to be lost, these drugs eventually become ineffective at treating the symptoms. PD symptoms can be classified into motor symptoms affecting movement and posture, neuropsychiatric symptoms affecting mood, cognition, behavior and thought, sensory and sleep symptoms, where non-motor symptoms often precede motor symptoms. A full overview of PD clinical manifestation is given below.

Table 19: clinical manifestation of PD

PD motor symptoms are tremor, rigidity, slowness of movement, and postural instability where tremor is the most apparent and well-known symptom. Though around 30% of individuals with PD do not have tremor at disease onset, most develop this during progressive disease. A feature of tremor is pill-rolling, the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement. The term derives from the similarity between the movement in people with PD and the earlier pharmaceutical technique of manually making pills (Cooper et al. 2008).

Bradykinesia (slowness of movement) is another characteristic feature of PD, and is associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement. Initial manifestations are problems when performing daily tasks which require fine motor control such as writing and sewing.

Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles. In early stages of Parkinson's disease, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities. With progressive disease rigidity typically affects the whole body and reduces the ability to move.

Postural instability is typical in the late stages of the disease, leading to impaired balance and frequent falls leading to bone fractures. Instability is often absent in the initial stages but increases with progressive disease.

Other recognized motor signs and symptoms include mask-like face expression, small handwriting, where the range of possible motor problems that can appear is large and diffuse and differs per patient.

PD causes neuropsychiatric disturbances which can range from mild to severe.

This includes disorders of speech, cognition, mood, behavior, and thought.

Cognitive disturbances can occur in the initial stages of the disease and increase in prevalence with progressive disease. The most common cognitive deficit in affected individuals is executive dysfunction, which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information. Cognitive difficulties include attention and slowed cognitive speed.

Memory is affected, specifically in recalling learned information. Visuospatial difficulties are also part of the disease, seen for example when the individual is asked to perform tests of facial recognition and perception of the orientation of drawn lines.

In addition to cognitive and motor symptoms PD can impair other body functions. Constipation and gastric dysmotility can be severe enough to cause discomfort and even endanger health. PD is related to several eye movement difficulties and vision abnormalities such as decreased blink rate, dry eyes, deficient ocular pursuit (eye tracking) and saccadic movements (fast automatic movements of both eyes in the same direction), difficulties in directing gaze upward, and blurred or double vision. Other recognized symptoms include problems with speech and swallowing.

PD classifies itself as a disease where diffuse neuronal clinical manifestations such as cognitive impairment, dementia and depression present themselves in the presence of GABAergic overstimulated ALS patients such as eye muscle movement problems, problems with speech (dysarthria), difficulties with swallowing

(dysphagia), motoneuron and musculoskeletal weakness, spasms and ataxia, incontinence, difficulties with regulation of intestinal motility (Bayer et al. 2002) and cognitive problems and dementia (see previous section on dementia).

Furthermore, PD pathology is characterized by the accumulation of alpha- synuclein into Lewy bodies in neurons that are the pathological hallmark of idiopathic PD, where distribution of the Lewy bodies is different for each patient. Consequently, the anatomical distribution of the Lewy bodies is often directly related to the expression and degree of the clinical symptoms of each individual. This for the PD indication specific a-Synuclein accumulation further implicates GABAergic overstimulation in PD as a-Synuclein accumulation has been demonstrated to reduce GABAergic inhibitory transmission in a model of multiple system atrophy and as such can be seen as a reaction to GABAergic

overstimulation, not only leading to the conclusion that GABAergic overstimulation is implicated in PD, but also that it is implicated at a higher disease hierarchy level than the formation of α-Synuclein in Lewy bodies. Even further, this leads to the conclusion that PD is a disease where GABAergic overstimulation is implicated in the patient specific localization of Lewy bodies that lead to patient specific clinical manifestation of disease as seen in PD, but also in many other neurologic indications.

Even further, activation of GABAergic neurons have been demonstrated to directly inhibit the function of dopamine neurons. With dopamine suppression being one of the hallmark characteristics of PD this provides even further evidence for the role of GABAergic overstimulation in PD. Even further, it here is concluded that like for GABAergic and / or Glycinergic overstimulation leading to overstimulation of glutaminergic excitatory induced glutaminergic neuronal cell death as described herein, GABAergic and / or Glycinergic overstimulation can also lead to

dopaminergic overstimulation induced dopaminergic neuronal cell death. As such, GABAergic and / or Glycinergic overstimulation is implied in the loss of dopamine producing cells in PD.

Example 26: GABAergic overstimulation causes PD rest tremors

70% of PD patients in the early stages of disease experience a slight rest tremors in the hand (known as pill-rolling tremor) or foot on one side of the body, or less commonly in the jaw or face. The tremor consists of a shaking or oscillating movement and usually appears when muscles are relaxed or at rest. Such tremors are known as rest tremors as the affected body part only trembles when it is not performing an action, and where the tremor disappears when a person begins an action. For example, patients may stop a hand tremor by either keeping the hand in motion or when performing a flexed extension grip.

In this disclosure it is concluded that the clinical manifestation of pill-rolling tremors originates from the movement of muscles that are solely involved in the hand precision grip and not (also) in the hand power grip and as such are not controlled by Glycine mediated recurrent inhibition (see also previous sections).

This explains the for PD characteristic hand pill-rolling tremor movement which in this disclosure is concluded to only involve hand muscles that are solely involved in precision gripping and that are not (also) involved in inertia or maintaining body posture.

Even further, this explains why tremors are solely observed in resting positions as in these positions no muscles are active that are involved in inertia or maintaining body posture. As soon as muscles become involved that are important for inertia or maintaining body posture as for example when flexing the wrist, tremors disappear or become less pronounced as muscle become active that are involved in inertia or maintaining body posture, and as such are under the influence of the Glycine mediated recurrent inhibition feedback loop. This disclosure therefore concludes that PD rest tremors are related to muscles not involved in inertia or maintaining body posture and as such are not controlled by Glycine mediated recurrent inhibition and therefore can be concluded to be a GABAergic related phenomena. Hence, under GABAergic overstimulation, muscles under control of Glycine mediated recurrent inhibition feedback loop can be expected to behave different from muscles that are not under such influence. This makes the PD pill-rolling rest tremor clinical manifestation of importance towards understanding the

pathogenesis of PD.

The PD specific pill-rolling tremor clinical manifestation originates from the movement of muscles that are solely involved in the hand precision grip and not in the hand power grip and as such are not controlled by Glycine mediated recurrent inhibition (see also section 3). The PD pill-rolling tremor therefore provides insight into the pathogenesis of PD as it demonstrates the differentiated impact on muscles that are, or are not under control of Glycine mediated recurrent inhibition. Furthermore it can be concluded on the basis of the pill-rolling tremor clinical manifestation that PD predominantly is GABAergic overstimulation disease related and not a Glycinergic overstimulation disease related as muscle

dysfunction only occurs in muscles that are solely under control of the GABAergic system, where muscles that are also under control of the Glycinergic system at the same time still are functional further confirming that the clinical manifestation of PD (resting tremors) predominantly is GABAergic overstimulation related and not (or only limited) Glycinergic overstimulation related.

Even further, with the Glycinergic neurotransmitter system not (or only limited) involved in cognitive CNS functioning, and PD being a disease with pronounced clinical manifestations of cognitive dysfunction such as dementia, it can be further concluded that PD predominantly is a GABAergic overstimulation disease. This further is confirmed by the GABAergic overstimulation clinical manifestations observed in PD such as dysarthria, dysphagia, bowel control difficulties

(incontinence), eye movements difficulties and other muscle functioning difficulties, leading to the conclusion that it is GABAergic overstimulation that is implicated in PD. The third neurotransmitter that could be involved in the PD resting tremor is the glutaminergic excitatory that, like the Glycinergic system, based upon this observation can also be concluded to be of less relevance than GABAergic overstimulation, which is further confirmed by the observation that glutaminergic overstimulation would lead to clinical manifestations in both GABAergic mediated resting muscle function and GABAergic and Glycinergic mediated active muscle function. Lastly, the conclusion that PD is a GABAergic overstimulation disease is confirmed by the observation that if Glycinergic overstimulation too would be present this would lead to the clinical manifestation of ALS. With the clinical manifestation of ALS being clearly separated from the clinical manifestation of PD, it can therefore can be concluded that it is GABAergic overstimulation that is implicated in PD.

Example 27: GABAergic overstimulation is implied in restless legs syndrome (RLS) Similar to the PD clinical manifestation of rest tremors restless legs syndrome (RLS) too can be concluded to be caused by the differentiated impact of PD on muscles that are, or are not under the influence of Glycine mediated recurrent inhibition. Hence, with restless legs syndrome occurring only when patients are resting (e.g. during quiet wakefulness, relaxing, reading, studying, or trying to sleep) it can be concluded that RLS is a GABAergic related as it demonstrates that muscles under control of Glycine mediated recurrent inhibition behave different from muscles that are not under such influence. It here therefore is concluded that GABAergic overstimulation is implicated in restless legs syndrome.

The implication of GABAergic overstimulation in RLS is further evidenced by the off-label use of quinine for RLS treatment, that further implicates GABAergic overstimulation in this syndrome as quinine has been shown to antagonize

GABAergic treatments, an observation that also further implicates GABAergic overstimulation in rest tremors and PD.

Example 28: GABAergic overstimulation in Duchenne muscular dystrophy (DMD) Duchenne muscular dystrophy (DMD) is disease where GABAergic overstimulation clinical manifestations as dysphagia, dysarthria and eye movement difficulties present themselves in the presence of muscle wasting and atrophy.

Furthermore DMD patients with lowered IQ scores that is related to another GABAergic overstimulation implicated clinical manifestation, i.e. cognitive dysfunction.

DMD is caused by the absence or disruption of the protein dystrophin which is found in skeletal muscle and neurons in particular regions of the CNS leading to neuron loss. Furthermore, GABA has been implicated in DMD (Keuh et al. 2011) providing further evidence for the role of GABAergic overstimulation in DMD. It herein is concluded as a novel invention that the DMD clinical manifestation is caused by GABAergic overstimulation that is a consequence of the absence of the protein dystrophin in DMD patients. As such, the DMD pathogenesis is expanded to a genetically inherited disease where dystrophin absence leads to GABAergic overstimulation that determines the clinical manifestation of DMD. Even further, it here is concluded that DMD can be treated by reducing GABAergic

overstimulation. Lastly, it here is demonstrated that DMD is neuromuscular disease rather than a muscular dystrophy disease, and / or that the neuromuscular aspects of DMD are more important for understanding the clinical manifestation of DMD than the muscular dystrophy aspects of DMD.

Example 29: GABAergic overstimulation is implicated in peripheral neuropathy (PN)

PN is a term for a group of conditions in which the peripheral sensory, motor and / or autonomic nervous system is damaged. Diabetes (both type 1 and type 2) is the most common cause of PN, where a wide range of other causes are also leading to PN such as physical injury to the nerves, viral infections, or side effect of certain medications (see table 20) including the long term use of epilepsy treatment with phenytoin.

Table 20: PN causes.

PN classifies itself as a disease where diffuse neuronal clinical manifestations such as sensitory impairment, present themselves in the presence of clinical

manifestations observed in GABAergic overstimulated ALS patients such as eye muscle movement problems, difficulties with swallowing (dysphagia), motoneuron and musculoskeletal weakness, muscle spasms and twitching, incontinence and difficulties with regulation of intestinal motility Bayer et al. 2002).

The impact of GABAergic overstimulation in PN is further confirmed by the observation that PN can be caused by excessive alcohol intake for years, a process that is related to GABAergic overstimulation due to the GABAergic action of alcohol at the GABA receptor. This is even further confirmed by the observation that the long term use of GABAergic anti-epilepsy medication such as phenytoin causes PN implicating GABAergic overstimulation even further in PN.

In addition to these observations, the observation that PN can be caused by vitamin B12 deficiency has already been shown herein to be related to GABAergic overstimulation. The same is the case for another cause of PN, i.e. hypothyroidism that also has been shown herein to be related to GABAergic stimulation. Based upon the current and previous sections is therefore can be concluded that GABAergic overstimulation is implicated in PN. This implicates it is not the increase in high glucose levels is causing neuron cell death leading to the clinical manifestation of PN, but that it is caused by GABAergic overstimulation leading to neuronal cell death due to a excitatory glutamate overstimulation reaction. This is consistent with the observation of elevated glutamate levels observed in PN (Spreux-Varoquaux 2002) in the absence of increased incidences of epileptic seizures in PN patients. Example 30: GABAergic stimulation is implicated in schizophrenia

Another disease characterized by diffuse neurologic dysfunction in the presence of GABAergic overstimulation clinical manifestations as also observed in ALS patients is schizophrenia. Schizophrenia's diffuse neurological manifestations comprise positive and negative symptoms. Positive symptoms are delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, typically regarded as manifestations of psychosis.

Negative symptoms are deficits of normal emotional responses or of other thought processes. These include flat expressions or little emotion, poverty of speech, inability to experience pleasure, lack of desire to form relationships, and lack of motivation.

GABAergic overstimulation symptoms include dysphagia and eye movement difficulties that even can be used for quantifying schizophrenia disease

progression.

The use of efficacious medication depressing dopamine activity in schizophrenia provides further evidence for the implication of GABAergic overstimulation as the GABAergic and dopamine systems interact. Furthermore, the implication of glutamic acid decarboxylase (GAD67) in post-mortem studies of people with schizophrenia or autism further implicates GABAergic overstimulation in both schizophrenia as autism.

GABAergic stimulation through alcohol abuse can cause the development of a chronic substance-induced psychotic disorder, and exposure to GABAergic related cannabis to the developing brain lead increases the risk of schizophrenia in a dose dependent matter, providing further evidence for the implication of GABAergic overstimulation in schizophrenia. Glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with schizophrenia further implying GABAergic overstimulation in schizophrenia as blocking the function of the glutaminergic excitatory neurotransmitter system can lead to similar clinical manifestations as stimulation of GABAergic activity. Further evidence is provided by the observation that benzodiazepine withdrawal can lead to a long lasting withdrawal syndrome resembling schizophrenia that even can lead to the misdiagnosis of schizophrenia. Example 31: GABAergic overstimulation is implicated in diabetes

The conclusion that GABAergic overstimulation is implicated in diabetes related PN (see previous section) is of even further relevance as GABAergic stimulation is also known to stimulate insulin release from the pancreatic 6-cells.

It therefore can be concluded that GABAergic overstimulation impacts diabetes not only in the clinical manifestation of NP, but also in the clinical manifestation of diabetes itself. Hence, with GABAergic stimulation leading to the release of insulin from pancreatic β-cells structural GABAergic overstimulation will lead to depletion of these cells and to an altered homeostasis of the insulin glucose system.

This confirmed by the observation that increased levels of the GABA producing enzyme GAD67 can induce the development of insulitis and diabetes in mice further implicating neurologic GABAergic overstimulation as cause for diabetes. GABAergic overstimulation therefore can be concluded to be a factor implicated in diabetes that is higher in the disease hierarchy than glucose or insulin. Example 32: GABAergic overstimulation is implicated in Facioscapulohumeral muscular dystrophy (FSHD)

FSHD was first described in 1885 by Landouzy and Dejerine, the reason for which FSHD also is known as Landouzy- Dejerine Muscular Dystrophy. Other names for the disease are Facioscapulohumeral Disease, Facio-Scapulo-Humeral Muscular Dystrophy, Fascioscapuohumeral Muscular Dystrophy, and Scapuohumeral

Muscular Dystrophy for FSHD patients where no demonstrable facial weakness is observed. Other diseases related to FSHD are Coats' Disease also known as retinal telangiectasis, Bilateral Sensorineural Hearing Loss and Hypercarbic Respiratory Insufficiency. Facioscapulohumeral muscular dystrophy or FSHD is the most prevalent of the nine primary types of muscular dystrophy affecting adults and children. The major symptom of FSHD is the progressive variable weakening and loss of skeletal muscles. The usual location of weaknesses at the onset of disease clarifies the origin of the name: face (facio), shoulder girdle (scapulo) and upper arms (humeral). Early weaknesses of the muscles of the eye (open and close) and mouth (smile, pucker, whistle) are distinctive for FSHD. These symptoms, in combination with weaknesses in the muscles that stabilize the scapulae (shoulder blades), are often the basis of the physician's diagnosis of FSHD. Although not typical, some patients with FSHD have respiratory insufficiency, especially those with severe FSHD.

FSHD is disease where GABAergic overstimulation clinical manifestations as dysphagia, dysarthria and eye movement difficulties present themselves in the presence of muscle dystrophy and as such is another disease where GABAergic overstimulation symptoms present themselves in the presence of muscle

weakening.

Though genetic mutations are implicated in (part of) the FSHD patient population, GABAergic overstimulation is implicated in those patients where no genetic mutations are present, but also can be part of the pathogenesis between the genetic mutation and the clinical manifestation of FSHD in those patients where genetic mutations are present. Based upon the above it therefore can be concluded that GABAergic overstimulation is implicated in FSHD.

Example 33: Friedreich 's ataxia

Friedreich's ataxia is an autosomal recessive inherited disease that causes progressive damage to the nervous system. It manifests in initial symptoms of poor coordination such as gait disturbance. It can also lead to scoliosis, heart disease and diabetes, but does not affect cognitive function. The disease progresses until a wheelchair is required for mobility.

The genetic mutation causing Friedreich's ataxia leads to reduced expression of the mitochondrial protein frataxin. Over time this deficiency causes the clinical manifestations listed above, as well as frequent fatigue due to effects on cellular metabolism. The ataxia of Friedreich's ataxia results from the degeneration of nerve tissue in the spinal cord, in particular sensory neurons essential (through connections with the cerebellum) for directing muscle movement of the arms and legs. Friedreich's ataxia presents itself before 25 years of age with progressive staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. The symptoms are slow and progressive.

Friedreich's ataxia symptoms include the following clinical manifestations that in this disclosure have been shown to be GABA mediated: muscle weakness in the arms and legs, loss of coordination, vision impairment, slurred speech, and spine curvature (scoliosis) that is related to muscle dysfunction.

Example 34: Ataxia

Cerebellar ataxia is a form of ataxia originating in the cerebellum and is characterized by symptoms that in this application are concluded to be GABA related such as the inability to coordinate balance, gait, extremity and eye movements. Furthermore, ataxia can be induced by GABAergic stimulation compounds such as alcohol and benzodiazepines, further implying GABAergic overstimulation in ataxia.

Sensory ataxia is a form of ataxia (loss of coordination) caused not by cerebellar dysfunction but by loss of sensory input into the control of movement. Sensory ataxia is distinguished from cerebellar ataxia by the presence of near-normal coordination when the movement in question is visually observed by the patient, but marked worsening of coordination when the eyes are shut. Patients with sensory ataxia usually complain of loss of balance in the dark, typically when closing their eyes in the shower or removing clothing over the head.

Vestibular ataxia is the clinical manifestation of ataxia due to dysfunction of the vestibular system. In slow-onset, chronic bilateral cases of vestibular dysfunction, these characteristic manifestations may be absent, and disequilibrium may be the sole presentation.

Ataxia can be caused by focal lesions of the central nervous system such as stroke, brain tumor, and MS, and can also be caused by Wilson's disease. Ataxic cerebral palsy is clinically observed in approximately 5-10% of all cases of cerebral palsy and causes problems in coordination, specifically in their arms, legs, and trunk. Athetoid cerebral palsy or dyskinetic cerebral palsy (together abbreviated as ADCP) is a type of cerebral palsy primarily associated with damage to the basal ganglia in the form of lesions that occur during brain development due to bilirubin encephalopathy and hypoxic-ischemic brain injury. ADCP is characterized by both hypertonia and hypotonia, due to the affected individual's inability to control muscle tone. Clinical diagnosis of ADCP typically occurs within 18 months of birth and is primarily based upon motor function and neuroimaging techniques.

Example 35: Analysis of failed ALS clinical trials

GABAergic stimulation currently is thought to be beneficial in ALS as it may reduce the clinical effects of the in ALS patients observed glutaminergic excitatory overstimulation. Within this vision glutaminergic excitatory overstimulation is the cause of ALS symptoms, and reduction of glutaminergic activity can be beneficial to ALS patients. This vision has led to clinical investigations into the efficacy of GABAergic stimulation in ALS patients through the administration of the

GABAergic stimulating compound gabapentin that failed to demonstrate beneficial effect in ALS patients, even leading to the observation that a combined analysis of the two trials revealed more rapid ALS disease progression after gabapentin treatment (Miller et al. 2001). This observation can be explained by the further GABAergic stimulation with gabapentin in ALS patients whereas disclosed herein GABAergic function already is overstimulated in ALS.

Like for the administration of the GABAergic stimulating compound gabapentin, administration of the GABAergic stimulation compound topiramate also failed to demonstrate beneficial effects (Cudkowicz et al. 2003). Topiramate administration was even observed to accelerate ALS disease progression for arm strength relative to placebo, an observation that is consistent with the theory presented herein that overstimulation of the GABAergic system leads to clinical the clinical

manifestation of ALS.

These observations confirm that ALS treatment with GABAergic stimulating medication in general will lead to an even faster ALS disease progression. This is of direct clinical relevance to the treatment of ALS as one of the only two registered ALS treatments baclofen mediates its action through GABAergic stimulation for the management of muscle spasms, and based upon the in this application presented novel ALS pathogenesis in fact should be contraindicated in ALS. With both GABAergic stimulation treatments topiramate and gabapentin (see above) leading to a faster ALS disease progression it can be concluded based upon clinical data that GABAergic stimulation is implicated in ALS, where treatment with GABAergic stimulating compounds will lead to an ever faster ALS disease progression. It therefore can be concluded that GABAergic overstimulation can accelerate ALS clinical manifestations as observed in ALS patients after treatment with topiramate and gabapentin.

Example 36: Physiological and molecular pathways in GABAergic and Glycinergic overstimulation

GABAergic and/or Glycinergic overstimulation may be caused by neurons or glial cells that due to stress challenges are no longer able to maintain cellular functions, including those functions that are important for maintaining high intracellular GABA and Glycine levels.

With GABAergic and Glycinergic overstimulation in this application being shown to be implicated in many diseases, it is of interest to investigate what physiological and / or molecular mechanisms can be involved in the occurrence of

overstimulation.

A general mechanism explaining GABAergic and Glycinergic overstimulation is related to the fact that the building up and maintenance of high intracellular

GABA and Glycine levels cost neuronal and glial cells high amounts of energy, for GABA synthesis even leading to the necessity to couple GABA synthesis directly to the major energy source for a cell, i.e. the tricarboxylic acid (TCA or Krebs) cycle, through the GABA shunt.

This close relation confirms the high energy levels required for maintaining high intracellular GABA concentrations that with 1-5 mM display circa 1,000 times higher concentrations than concentrations of the classical monoamine

neurotransmitters in the same regions, leading to intracellular GABA

concentrations that under normal physiological conditions are 200 times higher than extracellular concentrations.

Based upon the above, it can be concluded that maintaining high intracellular GABA concentrations requires extensive neuronal and glial cell energy resources. Furthermore it can be concluded that challenging neuronal cell function with processes such as inflammation, infection, repetitive trauma or aging may lead to suboptimal neuronal cell function where high intracellular GABA concentrations no longer can be maintained and where GABA is released extracellularly leading to GABAergic overstimulation processes.

Though at a lower level than GABA, intracellular Glycine concentrations also are highly elevated relative to extracellular concentrations up to 3 - 6 mM. Similar as for GABA, this indicates that intracellular Glycine concentrations also may no longer be maintained when neuronal cells are exposed to processes such as inflammation, infection, repetitive trauma or aging, or to processes of a genetic origin.

Glutamate intracellular levels of between 0.5 to 1 mM are below the intracellular concentrations of GABA and Glycine in in glial cells, indicating that intracellular glutamate levels may be maintained longer than those of GABA and Glycine in glial cells, as such also implicating glial cells rather than neuronal cells in

GABAergic and/or Glycinergic overstimulation. This in the current example, where GABAergic and / or Glycinergic overstimulation is caused by stress challenges, indicates that glutamate excitatory action is a reaction to GABA and / or

Glycinergic overstimulation rather than vice versa.

At a physiological level, GABAergic and Glycinergic overstimulation therefore can be caused through neuronal cells no longer being able to maintain high

intracellular concentrations of GABA and / or Glycine due to processes such as inflammation, infection, repetitive trauma, aging, energy consuming processes or other processes that impact normal cell function. The resulting chronic release (leakage) of GABA and / or Glycine leads to clinical manifestation of GABAergic and /or Glycinergic overstimulation diseases as described in this disclosure.

Furthermore, due to the release of GABA and / or Glycine, homeostatic processes lead to an increase in glutaminergic activity leading to glutamate excitatory neuronal cell death leading to the further clinical manifestation of GABAergic and /or Glycinergic overstimulation diseases as described in this disclosure.

At a molecular level neuronal cell function therefore may be impacted by processes such as inflammation, infection, repetitive trauma, aging, energy consuming processes or other processes including those of a genetic origin that impact normal cell function through impacting at molecular levels involved in the energy processes required for maintaining the high intracellular GABA and / or Glycine concentrations. As such, GABAergic and / or Glycinergic overstimulation may be caused by molecular functions involved in the TCA (Krebs) cycle, mitochondrial function or ATPases such as ATPase6 and ATPase8. This if further confirmed by the observation that mitochondrial diseases can lead to clinical manifestations of GABAergic overstimulation (see also the examples on mitochondrial diseases and on metabolic muscle disease herein) and the mitochondrial implication in the SODl predisposition in ALS making mitochondrial processes an interesting target for modulating GABAergic and / or Glycinergic overstimulation. This also is the case for mitochondrial DNA mutations involved in GABA and Glycine receptor coupling processes in neuronal and glial cells such as through ATPases, and APTase modulation through for example beta-adrenergic agonists.

Even further, for the example where GABAergic overstimulation occurs in the presence of Glycinergic overstimulation and with the observation that [1] the synthesis and degradation processes of GABA and Glycine is highly energy consuming, for the GABA synthesis even leading to a direct coupling to the Krebs cycle (also known as the tricarboxylic acid cycle and citric acid cycle), [2] the maintenance of relative to extracellular levels high GABAergic and Glycinergic intracellular concentrations is highly energy consuming requiring the maintenance of ATPase functioning dependent high Na+ concentrations, [3] the first reuptake mechanism shared by both GABA and Glycine are ATPase dependent processes required for the building up of the high intracellular glial GABA and Glycine gradients, and [4] ATPase6 and APTase8 mutations being observed in indications such as autism, Huntington's disease (HD), Ataxia Telangiectasia (AT),

Friedreich's Ataxia (FA), Multiple Sclerosis (MS) and Spino Cerebellar Ataxias (SCA) that in this disclosure have been concluded to also be subject to GABAergic and / or Glycinergic overstimulation, it can be concluded that GABAergic and Glycinergic overstimulation disease in this example can be caused through neuronal and / or glia cells no longer being capable of building up high intracellular GABA and / or Glycine levels, possibly through ATPase dysfunction.

Even further, with ATPase 6 and ATPase 8 being coded for by mitochondrial DNA, and mitochondrial disease leading to progressive clinical manifestations depending on [1] which cells over time develop dysfunctional mitochondrial DNA and mitochondria and [2] the energy requirement of the types of cells augmenting those cells with high energy requirements such as muscles and brain cells, not only further implicates ATPase, ATPase 6 and ATPase 8, mitochondria and

mitochondrial DNA, but also GABAergic and Glycinergic overstimulation the disease disclosed herein. Even further, based upon the above it can be concluded that GABAergic and / or Glycinergic overstimulation is implicated in autism, Huntington's disease (HD), Ataxia Telangiectasia, Friedreich's Ataxia, Multiple Sclerosis (MS) and Spino Cerebellar Ataxias (SCA).

Example 37: Mitochondrial DNA Deletion Syndromes

Mitochondrial DNA (mtDNA) deletion syndromes predominantly comprise the following overlapping phenotypes: [1] Kearns-Sayre syndrome (KSS), [2] Pearson syndrome, and [3] progressive external ophthalmoplegia (PEO), where Rarely Leigh syndrome also can be a manifestation of a mtDNA deletion.

Kearns-Sayre syndrome (KSS) is a multisystemic disorder defined by [1] onset before age 20 years, [2] pigmentary retinopathy and Progressive External ophthalmoplegia (PEO), where at least one of the following must also be present:

[1] cardiac conduction block, [2] cerebrospinal fluid protein concentrations of lactate and pyruvate greater than 100 mg/dL and / or [3] cerebellar ataxia (Kearns & Sayre 1958, Rowland et al 1983). Other frequent but not invariable clinical manifestations of KSS include short stature, hearing loss, dementia, limb weakness, diabetes mellitus, hypoparathyroidism, and growth hormone deficiency. Pearson syndrome is a usually fatal disorder of infancy characterized by sideroblastic anemia and exocrine pancreas dysfunction.

Progressive external ophthalmoplegia (PEO) is a mitochondrial myopathy with drooping of the eyelids (ptosis), paralysis of the extraocular muscles

(ophthalmoplegia), and variably severe proximal limb weakness. A few individuals with PEO have other manifestations of KSS but do not fulfil all the clinical criteria for the diagnosis. This clinical manifestation is called KSS minus or PEO plus.

The mitochondrial DNA Deletion Syndromes represent an indication where GABAergic related muscle dysfunction such as eye ptosis, paralysis of the extraocular muscles (ophthalmoplegia), and variably severe proximal limb weakness presents itself in the presence of other clinical manifestations that also can be related to GABAergic overstimulation such as eye movement difficulties. Even further, GABA has been implicated in pigmentary retinopathy with

GABAergic treatments such as vigabatrin and gabapentin causing the clinical manifestation of pigmentary retinopathy. Furthermore GABA is implicated in cardiac conduction blocking as it inhibits vagus nerve outflow mediated through the GABAB receptor.

GABA is even further implicated by the in these syndromes observed high cerebrospinal fluid protein concentrations of lactate that is involved in GABA metabolism and pyruvate that is chemically related to GABA also and may be formed from compounds involved in GABA metabolism such as succinate semialdehyde and L-alanine.

The in mitochondrial deletion observed cerebellar ataxia presents symptoms that in this disclosure have been shown to be related to GABAergic and / or Glycinergic overstimulation such as inability to coordinate balance, gait, extremity and eye movements. Furthermore, lesions to the cerebellum in this indication can cause dyssynergia, dysmetria, dysdiadochokinesia, dysarthria and ataxia of stance and gait, where symptoms related to dementia and diabetes mellitus in this application have been shown to be related to GABAergic overstimulation.

Even further, GABA is implicated in Sideroblastic Anemia and impacts exocrine pancreas function.

Example 38: Mitochondrial Diseases

Besides Mitochondrial DNA Deletion Syndromes, other mitochondrial disease syndromes also present themselves in the presence of GABAergic overstimulation clinical manifestations. Infantile myopathy and lactic acidosis (fatal & non-fatal forms) displays hypotonia in the first year of life, respiratory difficulties, feeding difficulties implying dysphagia and in a fatal form cardiomyopathy and/or the Toni- Fanconi-Debre syndrome that displays mitochondrial myopathy leading to severe insufficiency of the voluntary muscles and lactic acidemia, clinical manifestations that in this application have been shown to be GABAergic and / or Glycinergic overstimulation related.

Leigh syndrome (or subacute necrotizing encephalomyelopathy) is characterized by onset of symptoms that in this disclosure are concluded to be GABA related such as the presence of elevated lactate levels in blood and/or CSF and is associated with psychomotor retardation or regression. Neurologic features include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Extraneurologic manifestations may include hypertrophic cardiomyopathy. About 50% of affected individuals die by age three years, most often as a result of respiratory or cardiac failure.

Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) is characterized by clinical manifestations that in this application have been concluded to be GABA related such as proximal neurogenic muscle weakness with sensory neuropathy, ataxia, and pigmentary retinopathy.

Leber hereditary optic neuropathy (LHON) is characterized by onset of symptoms that in this application are concluded to be GABA related such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders. Some individuals with LHON, usually women, may also develop a multiple sclerosis (MS)-like illness that in this disclosure also has been demonstrated to be

GABAergic overstimulation related. Furthermore, GABAergic overstimulation in this disclosure has been shown to be implicated in the LHON clinical manifestation of bilateral, painless, subacute visual failure. Even further, like for the in this application demonstrated GABAergic disease ALS, the LOHN eye pathology involves superoxide dismutase predisposition implicating GABAergic

overstimulation even further.

Example 39: Lysosomal storage disorders

Over 40 lysosomal storage disorders (LSDs) have been described of which the majority of results from defective lysosomal acid hydrolysis of endogenous macromolecules and their consequent accumulation. Clinical manifestations of LSDs therefore vary according to the predominant cell type involved and LSDs present themselves with GABAergic overstimulation clinical manifestations such as movement disorders, ocular pathology and central nervous system dysfunction. Furthermore, GABA is implicated as LSDs present themselves as diseases leading to changes in GABAergic neurons that display axonal spheroid formation that is specifically confined to GABAergic neurons. Based upon the above it therefore can be concluded that GABAergic overstimulation is implicated in lysosomal storage disorders. Example 40: The pivotal role of GABAergic and Glycinergic overstimulation in the pathogenesis of neuromuscular and neurologic disease

GABAergic and Glycinergic overstimulation herein have been demonstrated to be important contributors to a number of important neuromuscular ad neurologic disease pathogenesis pathways. Within these diseases inhibitory GABAergic and Glycinergic overstimulation clinical manifestations are observed comprising of diffuse and progressive neurologic manifestations in the presence of GABAergic overstimulation symptoms such as muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, loss of muscle coordination, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and / or gastrointestinal dysfunction.

Furthermore, these symptoms in a number of neurologic disease indications such as ALS, ALZ, MS, PD, HD, alcoholism or alcohol withdrawal and over-rapid benzodiazepine withdrawal are accompanied by glutaminergic overstimulation related motoneuron cell death that due to the presence of GABAergic

overstimulation do not lead to elevated (epileptic) seizure incidences.

Based upon the observation above a novel neurologic disease pathogenesis can be constructed that explains the observations above through a novel understanding of the continuum of the inhibitory GABAergic / Glycinergic overstimulation in relation to glutaminergic overstimulation in the diseases reviewed in this disclosure. Diseases where GABAergic and / or Glycinergic overstimulation occurs in parallel with glutaminergic overstimulation will not lead to the clinical manifestation of disease as the parallel increase in GABAergic and Glycinergic overstimulation will not disrupt the net balance between the systems leading to maintained

homeostasis as is shown in figure 4A for GABAergic overstimulation disease. Such a parallel increase in GABAergic and glutaminergic overstimulation is not likely to be coincidental but most likely is related to the maintenance of homeostasis between the systems where the overstimulation of one system leads to a reactive overstimulation in the other. As long as both GABAergic and Glutaminergic overstimulation increase in parallel it in such diseases cannot easily be deducted which system has become overstimulated first and is causing the disruption of homeostasis and which system is reacting to the other and is aiming at the maintenance of homeostasis. Of interest to the diseases mentioned in the current disclosure is the observation that in diseases where glutaminergic overstimulation no longer increases in parallel with GABAergic overstimulation (see figure 4B) due to, for instance, the occurrence of glutaminergic excitatory overstimulation induced neuronal cell death, will lead to the clinical manifestation of GABAergic overstimulation symptoms at the same time that clinical manifestation related to glutaminergic excitatory overstimulation induced neuronal cell death are observed. This clinical manifestation is consistent with the observed clinical manifestation in diseases such as ALS, ALZ, MS, PD, HD, alcoholism or alcohol withdrawal and over-rapid benzodiazepine withdrawal.

The scenario where GABAergic overstimulation increases where glutaminergic overstimulation also increases but at a slower pace (see figure 4C) will lead to the clinical manifestation of GABAergic overstimulation symptoms where over time clinical manifestations may develop that are related to glutaminergic excitatory overstimulation induced neuronal cell death, the latter depending on the point in time where glutamate overstimulation reaches levels capable of inducing glutaminergic excitatory overstimulation induced neuronal cell death. This pathogenesis also can apply to the observed clinical manifestations in diseases such as ALS, ALZ, MS, PD, HD, alcoholism or alcohol withdrawal and over-rapid benzodiazepine withdrawal.

Diseases where GABAergic overstimulation occurs in the absence of, or very weak glutaminergic overstimulation will lead to the clinical manifestation of GABAergic overstimulation in the absence of glutaminergic excitatory overstimulation induced neuronal cell death which is the observed clinical manifestation in the other diseases herein (see the tables for full overview). Interestingly, due to the absence of excessive glutamate overstimulation induced neuronal cell death it can be expected that in such diseases symptoms will be less severe than in diseases where glutamate overstimulation leads to neuronal cell death, which is consistent with the observation that in such diseases symptoms are less severe and life expectancy is higher as for example in ALS. Even further, the absence of neuronal cell death in such diseases implicates that GABAergic and / or Glycinergic overstimulation symptoms may be reversible, where in diseases where neuronal cell death occurs this may not be the case.

It here therefore is concluded that GABAergic and / or Glycinergic overstimulation therefore can occur in the presence and absence of glutaminergic overstimulation. Example 41: Treatment by reducing GABAergic overstimulation

Patients presenting with ALS or an ALS-like disorder will be treated by the administration of compounds reducing GABAergic overstimulation.

Reduction of GABAergic overstimulation should be gradual as a too fast decrease in GABAergic overstimulation in the co-presence of elevated excitatory glutamate levels may lead to increased incidences at (epileptic) seizures and to other side effects related to reducing GABAergic activity. Administration therefore should start with low individualized dosages that are gradually increased as long as no side effects occur or until side effects are present that can be regarded as acceptable in the light of the severity of the condition of the patient.

Individualization of dosage here can be related to correcting for body weight, body surface area, age, creatinine clearance, smoking habits and other factors know to impact individual pharmacokinetic and pharmacodynamic efficacy.

During treatment patients should carry rescue medication that is of GABAergic nature for countering side effects that are related to the reduction of GABAergic activity such as epileptic seizures and / or other side effects. An example of such rescue medication is diazepam that can be administered rectally outside hospitals and intravenously or intramuscular inside hospitals, or midazolam than can be administered buccal and nasal outside hospitals and intravenously and

intramuscular inside hospitals.

Individualized dosing may be (partly) based upon EEG activity and other clinical endpoints indicative for an increased risk at epileptic seizures and other side effects related to the reduction of GABAergic activity, and upon current practices in oncology where narrow therapeutic index treatments also are being applied successfully through active clinical and safety endpoint monitoring and dose titration schedules optimizing the balance between safety and efficacy.

Further individualization of treatment is dependent on the efficacy of treatment as the reduction of GABAergic overstimulation can be expected to lead to a

corresponding reduction of glutaminergic excitatory overstimulation. In this situation dosage can be further increased as the risk as glutaminergic side effects (including seizures) has decreased and individualized dosing is to be re-established and re-evaluated on a regular basis. Treatment further may be by co- administering medication aiming at the reduction of glutaminergic overstimulation leading to a gradual decline of glutaminergic overstimulation, as such leading to an even further reduced risk as side effects such as (epileptic) seizures.

Example 42: Treatment by reducing Glycinergic overstimulation

Patients presenting with ALS or an ALS-like disorder will be treated through the administration of compounds reducing Glycinergic overstimulation.

Reduction of Glycinergic overstimulation should be gradual as a too fast decrease in Glycinergic overstimulation in the co-presence of elevated excitatory glutamate levels may lead to increased incidences at side effects related to reducing

Glycinergic activity. Administration therefore should start with low individualized dosages that are gradually increased as long as no side effects occur or until side effects are present that can be regarded as acceptable in the light of the severity of the condition of the patient. Individualization of dosage here can be related to correcting for body weight, body surface area, age, creatinine clearance, smoking habits and other factors know to impact individual pharmacokinetic and pharmacodynamic efficacy.

During treatment phase patients should carry rescue medication that is of

Glycinergic nature for countering side effects that are related to the reduction of Glycinergic activity such as epileptic seizures and / or other side effects. An example of such rescue medication is diazepam that can be administered rectally outside hospitals and intravenously or intramuscular inside hospitals, or midazolam than can be administered buccal and nasal outside hospitals and intravenously and intramuscular inside hospitals.

Individualized dosing may be (partly) based upon clinical and safety endpoints indicative for an increased risk at side effects related to the reduction of Glycinergic activity such as tremors, and upon current practices in oncology where narrow therapeutic index treatments also are being applied successfully through active clinical and safety endpoint monitoring and dose titration schedules optimizing the balance between safety and efficacy.

Further individualization of treatment is dependent on the efficacy of treatment as the reduction of Glycinergic overstimulation can be expected to lead to a

corresponding reduction of glutaminergic excitatory overstimulation. In this situation dosage can be further increased as the risk as glutaminergic side effects (including seizures) has decreased and individualized dosing is to be re-established and re-evaluated on a regular basis. Treatment further may be by co- administering medication aiming at the reduction of glutaminergic overstimulation leading to a gradual decline of glutaminergic overstimulation, as such leading to an even further reduced risk as side effects such as (epileptic) seizures. Example 43: FSHD treatment through reducing GABAergic overstimulation Patients presenting with FSHD or related disease can be treated through the administration of compounds reducing GABAergic overstimulation.

Reduction of GABAergic overstimulation should be gradual as a too fast decrease in GABAergic overstimulation in the co-presence of elevated excitatory glutamate levels may lead to increased incidences at (epileptic) seizures and to other side effects related to reducing GABAergic activity. Administration therefore should start with low individualized dosages that are gradually increased as long as no side effects occur or until side effects are present that can be regarded as acceptable in the light of the severity of the condition of the patient.

Individualization of dosage here can be related to correcting for body weight, body surface area, age, creatinine clearance, smoking habits and other factors know to impact individual pharmacokinetic and pharmacodynamic efficacy.

During treatment patients should carry rescue medication that is of GABAergic nature for countering side effects that are related to the reduction of GABAergic activity such as epileptic seizures and / or other side effects. An example of such rescue medication is diazepam that can be administered rectally outside hospitals and intravenously or intramuscular inside hospitals, or midazolam than can be administered buccal and nasal outside hospitals and intravenously and

intramuscular inside hospitals. Individualized dosing may be (partly) based upon EEG activity and other clinical endpoints indicative for an increased risk at epileptic seizures and other side effects related to the reduction of GABAergic activity, and upon current practices in oncology where narrow therapeutic index treatments also are being applied successfully through active clinical and safety endpoint monitoring and dose titration schedules optimizing the balance between safety and efficacy.

Further individualization of treatment is dependent on the efficacy of treatment as the reduction of GABAergic overstimulation can be expected to lead to a

corresponding reduction of glutaminergic excitatory overstimulation. In this situation dosage can be further increased as the risk as glutaminergic side effects (including seizures) has decreased and individualized dosing is to be re-established and re-evaluated on a regular basis. Treatment further may be by co- administering medication aiming at the reduction of glutaminergic overstimulation leading to a gradual decline of glutaminergic overstimulation, as such leading to an even further reduced risk as side effects such as (epileptic) seizures.

Example 44: FSHD treatment through reducing Glycinergic overstimulation FSHD patients presenting with disease that can be related to the manifestation of glutaminergic excitatory induced neuronal cell death can be treated through the administration of compounds reducing Glycinergic overstimulation (see preferred antagonists disclosed herein).

Reduction of Glycinergic overstimulation should be gradual as a too fast decrease in Glycinergic overstimulation in the co-presence of elevated excitatory glutamate levels may lead to increased incidences at side effects related to reducing

Glycinergic activity. Administration therefore should start with low individualized dosages that are gradually increased as long as no side effects occur or until side effects are present that can be regarded as acceptable in the light of the severity of the condition of the patient. Individualization of dosage here can be related to correcting for body weight, body surface area, age, creatinine clearance, smoking habits and other factors know to impact individual pharmacokinetic and pharmacodynamic efficacy.

During treatment phase patients should carry rescue medication that is of

Glycinergic nature for countering side effects that are related to the reduction of Glycinergic activity such as epileptic seizures and / or other side effects. An example of such rescue medication is diazepam that can be administered rectally outside hospitals and intravenously or intramuscular inside hospitals, or midazolam than can be administered buccal and nasal outside hospitals and intravenously and intramuscular inside hospitals (Silbergleit et al. 2012).

Individualized dosing may be (partly) based upon clinical and safety endpoints indicative for an increased risk at side effects related to the reduction of

Glycinergic activity such as tremors, and upon current practices in oncology where narrow therapeutic index treatments also are being applied successfully through active clinical and safety endpoint monitoring and dose titration schedules optimizing the balance between safety and efficacy.

Further individualization of treatment is dependent on the efficacy of treatment as the reduction of Glycinergic overstimulation can be expected to lead to a corresponding reduction of glutaminergic excitatory overstimulation. In this situation dosage can be further increased as the risk as glutaminergic side effects (including seizures) has decreased and individualized dosing is to be re-established and re-evaluated on a regular basis. Treatment further may be by co- administering medication aiming at the reduction of glutaminergic overstimulation leading to a gradual decline of glutaminergic overstimulation, as such leading to an even further reduced risk as side effects such as (epileptic) seizures.

Example 45: Treatment for loss of muscle coordination through reducing GABAergic overstimulation

Another clinical feature that can be attributed to GABAergic stimulation is the in ALS patients observed loss of muscle coordination which is a feature ALS shares with the clinical manifestations observed after the ingestion of alcohol / ethanol in humans. With alcohol being a GABAergic stimulant through its binding to the GABA receptor thereby increasing the receptor's affinity for GABA, it can be concluded that GABAergic stimulation can lead to difficulties with coordination of movement as observed in ALS patients.

Example 46: Treatment of ALS and the symptoms muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, and gastrointestinal dysfunction Patient history:

A patient diagnosed with ALS having a six year history of ALS symptoms including Babinsky reflex, muscle wasting, loss of muscle function, loss of muscle

coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, and gastrointestinal dysfunction. The patient had lost the ability to walk during a period of six to twelve months before the start of the treatment, and was wheelchair bound. The patient began treatment using the treatment schedule below.

Treatment:

Treatment schedule:

Doses increasing to Penicillin G NaCl solution 20 milion IE mixed with 100 mg hydrocortisone for intravenous administration:

· Day 1: 1 million units mixed with 100 mg Hydrocortison in 250 or 500 ml Saline solution during an 8 hour infusion

Day 2: 3 million units mixed with 100 mg Hydrocortison in 250 or 500 ml Saline solution during an 8 hour infusion

Day 3: 5 million units mixed with 100 mg Hydrocortison in 250 or 500 ml Saline solution during an 8 hour infusion

Day 4: 10 million units mixed with 100 mg Hydrocortison in 250 ml or 500 Saline solution during an 8 hour infusion

Days 5 to 21: 24 million units mixed with 100 mg Hydrocortison in 250 ml or 500 Saline solution during an 8 hour infusion

The 21 day protocol is repeated after 10 weeks of no treatment.

Efficacy:

The progress of the patient observed during treatment is provided as follows. After only the fourth day, the patient started feeling that muscles were different. Within five days of the start of the first treatment the following symptoms had improved: muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties. In addition, the following observations were noted during examination: disappearance of the Babinsky reflex; regained ability to stretch a foot, to turn the neck backwards, to turn around when laying in bed; regained function in fingers and hands, improved respiratory function, regained ability to swallow large liquid volumes, regained abaility to speak clearly, regained muscle coordination, regained strength in limbs and fingers, regained ability to place a foot flat on the ground.

Even before the end of the 21 day protocol, the patient was able to stand up from his chair and began walking.