Acetyl-leucine for treating parkinson´s disease

Abstract

The present disclosure provides for treating Parkinson´s disease (PD) comprising administering acetyl-leucine or a pharmaceutically acceptable salt thereof to a subject in need thereof.

Description

[0001]Therapeutic Agents for treating Parkinson´s DiseaseParkinson´s disease (PD) is the second-most common neurodegenerative disorder andcharacterized by neuronal loss in the substantia nigra, which causes striatal dopamine deficiency. Although clinical diagnosis relies on the presence of bradykinesia and other motordefects, Parkinson´s disease is associated with many non-motor symptoms including mentaldeterioration. Parkinson´s disease is a progressive disease that lacks any curative treatments.Although the process of neurodegeneration in PD is not fully understood, therapeutic agentsthat are shown to be broadly neuroprotective are thought to be applicable to neurodegenerative diseases generally. In addition, many neurodegenerative diseases are associated with lysosomal dysfunction. This includes both neurodegenerative lysosomal storage disorders (LSDs) and many other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, where links to lysosomal defects have been suggested. The present disclosure addresses a need to develop improved and widely applicable treatments for Parkinson´s disease. In particular, the present disclosure describes acetyl-leucine (e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof)for treating Parkinson´s disease (PD) or one or more symptoms of PD in a subject in needthereof. PD may, but need not, be associated with lysosomal dysfunction.In one embodiment, there is disclosed acetyl-leucine (e.g. acetyl-DL-leucine, acetyl-L-leucine,acetyl-D-leucine, or a combination thereof), or a pharmaceutically acceptable salt thereof, for use in a method of reducing the severity of, eliminate, delay or reverse the progression of Parkinson´s disease (PD) or one or more symptoms of Parkinson´s disease (PD) in a subjectin need thereof, said method comprising administering a therapeutically effective amount ofacetyl-leucine (e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combinationthereof) to the subject.In a further embodiment, the present disclosure includes acetyl-leucine (e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof), or a pharmaceuticallyacceptable salt thereof, for use in a method of treating PD or one or more symptomsassociated with PD in a subject in need thereof, wherein the method comprises administeringa therapeutically effective amount of the acetyl-leucine to the subject in need thereof for aduration chosen from at least about 3 months, at least about 6 months, at least about 1 year,at least about 2 years, and at least about 5 years.In one embodiment, the present disclosure describes acetyl-leucine (e.g. acetyl-DL-leucine,acetyl-L-leucine, acetyl-D-leucine, or a combination thereof), or a pharmaceutically acceptable salt thereof, for use in a method of delaying progression of Parkinson´s disease(PD) or one or more symptoms associated with Parkinson´s disease (PD) over time ascompared to typical disease progression, wherein the method comprises administering a therapeutically effective amount of the acetyl-leucine to the subject in need thereof for a duration chosen from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years. In a further embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, isdisclosed for use in a method of reversing progression of Parkinson´s disease (PD) or one ormore symptoms associated with Parkinson´s disease (PD) over time, wherein the methodcomprises administering a therapeutically effective amount of the acetyl-leucine to the subject in need thereof for a duration chosen from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years. In another embodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, is disclosed for use in a method of improving in a subject in need thereof a biochemical markerof Parkinson´s disease (PD) over time, wherein the method comprises administering atherapeutically effective amount of the acetyl-leucine to the subject in need thereof for a duration chosen from at least about 3 months, at least about 6 months, at least about 1 year,at least about 2 years, and at least about 5 years.In another embodiment, the present disclosure includes acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method of reducing the severity of Parkinson´s disease(PD) or reducing the severity of or eliminating one or more existing symptoms associatedwith Parkinson´s disease (PD) in a subject in need thereof.In a further embodiment, the present disclosure includes acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method of providing neuroprotection ina subject having Parkinson´s disease (PD), wherein the method comprises administering atherapeutically effective amount of the acetyl-leucine to the subject for a duration chosen from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years. Additional embodiments of the present disclosure include, acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method of delaying progression ofParkinson´s disease (PD) or a lysosomal storage disorder (LSD) in a subject. In anotherembodiment, acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in amethod of providing neuroprotection in a subject having Parkinson´s disease (PD) or a LSD. In an embodiment, the acetyl-leucine is in racemate form, in an enantiomeric excess of the L- enantiomer or in an enantiomeric excess of the D-enantiomer. In an embodiment, the acetyl- leucine is in racemate form. In an embodiment, the acetyl-leucine is in an enantiomeric excess of the L-enantiomer. In an embodiment, the acetyl-leucine is in an enantiomeric excess of the D-enantiomer. In another embodiment, the methods further comprise administering the acetyl-leucine in a dose of between 1.5 g and 10 g per day. In one embodiment, the methods further comprise administering the acetyl-leucine, or apharmaceutically acceptable salt thereof, in a therapeutically effective amount. In oneembodiment, the therapeutically effective amount is ranges from 1 g to 15 g per day, from 1 gto 10 g per day, from 1.5 g to 7 g per day, from 4 g to 6 g per day, or from 4 g to 5 g per day. In a preferred embodiment, the therapeutically effective amount is about 5 g per day. In some embodiments, acetyl-leucine, or a pharmaceutically acceptable salt thereof, is administered in one dose, two doses, three doses, four doses or more per day. In a preferred embodiment, the acetyl-leucine, or a pharmaceutically acceptable salt thereof is administered in two doses per day. In one embodiment, the acetyl-leucine, or a pharmaceutically acceptable salt thereof is administered in two doses per day with a total daily dosage of about 4g to 5g, preferably about 5g. Further still, in an embodiment, the methods further comprise administering the acetyl-leucine for a treatment duration of two weeks or more. For example, the methods comprise administering the acetyl-leucine, or a pharmaceutically acceptable salt thereof,before the onset of a symptom of the disease or disorder to be treated. Yet in an additionalembodiment, the methods further comprise administering another therapy or agent intended to prevent or treat the disease or disorder to be treated. In an embodiment of the presentdisclosure provides for a kit for delaying progression of Parkinson´s disease (PD) or a LSD ina subject, the kit comprising a means for diagnosing or prognosing Parkinson´s disease (PD) or a LSD, and acetyl-leucine or a pharmaceutically acceptable salt thereof. For example, thekit comprises a means for diagnosing or prognosing Parkinson´s disease (PD) or a LSD, andacetyl-leucine or a pharmaceutically acceptable salt thereof. In a further embodiment of the present disclosure, it provides for use of acetyl-leucine, or a pharmaceutically acceptable saltthereof, as a neuroprotective agent in a subject having Parkinson´s disease (PD) or a LSD.In some embodiments, acetyl-leucine, or a pharmaceutically acceptable salt thereof, isdisclosed for use in a method of reducing the severity of, eliminate, delay or reverse theprogression of Parkinson´s disease (PD) or one or more symptoms of Parkinson´s disease (PD), wherein the administration of Acetyl-leucine, or a pharmaceutically acceptable salt thereof, improves the biochemical marker and / or the symptoms associated with PD overtime. In some embodiments, the one or more symptoms of Parkinson´s disease (PD)comprises reducing one or more of the severity, frequency or occurrence of any one or moreof the symptoms associated with PD compared to the severity, frequency or occurrence before treatment with acetyl-leucine, wherein the symptoms comprise hypokinesia, rigor, resting tremor, hyposmia, or vegetative dysfunction, cognitive deficits, optionally wherein the cognitive deficits comprise dementia, psychiatric symptoms, optionally wherein the psychiatric symptoms are behavioural disorders, slow movement, decreased fluidity of limb movements, instable gait and mobility, constipation, gait deterioration, increased propensity to falls, speech deterioration associated with fronto-temporal dementia with parkinsonism, REM Sleep Behavior Disorder (RBD), restless-leg syndrome (RLS), neurological symptoms and / or decreased mood. Brief Description of the Figures Figure 1 shows photographs of treated (Figure 1A) and untreated (Figure 1B) Npc1− / −mice at nine weeks of age. Figures 2A and 2B show weight data for Npc1− / −mice compared to wild-type (Npc1+ / +) mice,with and without acetyl-DL-leucine treatment from weaning.Figures 3A - 3G show gait analysis data for Npc1− / − mice compared to wild-type (Npc1+ / +)mice, with and without acetyl-DL-leucine treatment from weaning. For example, diagonalsupport, cadence and step sequence data are shown in Figures 3A - 3C, respectively. Figures3D and 3E show front paw (FP) data (stand mean and step cycle in panel D; duty cycle in panel E). Figures 3F and 3G show hind paw (HP) data (stand mean and step cycle in panel F; duty cycle in panel G).Figures 4A - 4H show motor function analysis data for Npc1− / − mice compared to wild-type(Npc1+ / +) mice, with and without acetyl-DL-leucine treatment from weaning. Centre rearing,activity, rearing and front to back (FR) count are shown in Figures 4A - 4D, respectively.Active time, mobile time, rearing time and total manual rearing count are shown in Figures4E - 4H, respectively.Figure 5 shows that treatment with acetyl-DL-leucine (0.1 g / kg from 3 weeks of age) isassociated with a small but statistically significant increase in lifespan in the Npc1- / - mouse.Figures 6A and 6B shows the reduction of lysosomal volume in non-neuronal NPC cells following treatment with acetyl-DL-leucine. Figures 6C-6H show the effect of treatment with acetyl-DL-Leucine on lysosomal volume in NPA, MLII, MPS IIIB, Aspartylglucosaminuria, MLIIIA, and MPS VII patient fibroblasts, respectively. Figure 7A shows a survival curve representing mortality in untreated or acetyl-leucine- treated wild-type and Sandhoff mice. Figure 7B shows bar crossing scores for untreated and acetyl-leucine-treated Sandhoff model mice. Figure 7C shows the step cycle time for untreated and acetyl-leucine-treated Sandhoff mice assessed at 12 weeks of age. Figures 8A-8C show the effect of treatment with acetyl-DL-leucine on glycosphingolipid (GSL) levels in GM2 gangliosidoses patient fibroblasts (Tay-Sachs disease, Sandhoff disease, and AB variant of Tay-Sachs disease, respectively). Figure 9 shows a gait analysis matrix for a 75 year-old male patient diagnosed with corticobasal-degeneration-syndrome before and during treatment with acetyl-leucine, wherein fewer pink areas in the matrix indicate improvement compared to before treatment. Figures 10A and 10B show the effect of treatment with acetyl-DL-leucine over time on the overall clinical severity score (CSS) and overall annual severity increment score (ASIS), respectively, of ten NPC patients. Figures 11A-11J show the effect of treatment with acetyl-DL-leucine over time on the CSS subscores for each of the ten NPC patients. Figures 12A and 12B show the effect of treating wild type NPC1- / -mice with acetyl-DL-leucine on levels of amyloid precursor protein C-terminal fragments (APP-CTFs) and levels of microtubule-associated protein 1A / 1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II), respectively. Figures 13A-13C show that after treatment with acetyl-DL-leucine, a patient who had been diagnosed with downbeat nystagmus syndrome could partially suppress the nystagmus by visual fixation.Figure 14 shows the reduction of lysosomal volume in NPC Chinese Hamster Ovary (CHO)cells following treatment with acetyl-DL-leucine, acetyl-D-leucine, acetyl-L-leucine, DL- leucine, D-leucine, and L-leucine, respectively. Description Acetyl-leucine in racemate form (acetyl-DL-leucine) and salts of the same are effective in the treatment of vertigo of various origins, notably Meniere’s vertigo and vertigo of inflammatory (vestibular neuritis) or toxic origin. For example, acetyl-leucine is marketed by Pierre Fabre Medicament in racemate form as an anti-vertigo medicament under the name Tanganil®. Clinical results of Tanganil®reported by various authors demonstrate an improvement in vertigo symptomology in more than 95% of cases, including the disappearance of vertigo attacks. Acetyl-DL-leucine has been used in France to treat acute vertigo since 1957 and has an excellent safety profile, but its long-term safety in chronic use has not been determined. Despite numerous hypotheses, including stabilisation of membrane potential, its pharmacological and electrophysiological modes of action remain unclear. (Vibert et al.(2001) Eur J Neurosci; 13(4): 735-48; Ferber-Viart et al. (2009) Audiol Neurootol; 14(1): 17-25). A FDG-µPET study in a rat model of an acute unilateral labyrinthectomy (Zwergal et al. (2016) Brain Struct Funct; 221(1): 159-70) showed a significant effect of an L-enantiomer, N- acetyl-L-leucine, on postural compensation by activation of the vestibulo-cerebellum and adeactivation of the posterolateral thalamus (Gunther et al. (2015) PLoS One; 10(3):e0120891). The symptomatic improvement of cerebellar ataxia using acetyl-DL-leucine wasshown in a case series with cerebellar patients (Strupp et al. (2013) J Neurol; 260(10): 2556-61). Another case series did not find benefit (Pelz et al. (2015) J Neurol; 262(5): 1373-5).Quantitative gait analysis showed that acetyl-DL-leucine improved temporal gait variability in patients with cerebellar ataxia (Schniepp et al. (2015) Cerebellum; 3:8). In a one-month study involving 12 patients with Niemann-Pick Type C (NPC), symptomatic improvement ofataxia was shown (Bremova et al. (2015) Neurology; 85(16): 1368-75). Further, a PET studyin patients with ataxia given acetyl-DL-leucine demonstrated an increased metabolism in the midbrain and lower brainstem in responders (Becker-Bense et al. (2015) Abstract EAN). Acetyl-leucine, however, is not known to treat neurodegenerative diseases, which generally progress over the course of years to decades, such as Parkinson´s disease (PD). The present disclosure surprisingly shows that acetyl-leucine, or a pharmaceutically acceptable salt of thesame, can be used in a method of treating Parkinson´s disease (PD) in a subject in needthereof, for example, by delaying or reversing progression of Parkinson´s disease (PD) or oneor more symptoms of Parkinson´s disease (PD), such as over long durations, as compared totypical disease progression. These exemplary uses according to the present disclosure, as well as others described herein, were entirely unexpected, as such benefits had not been observed, and could not have been deduced, from the prior teaching. As evidenced by the Examples, which demonstrate effectiveness over a wide range of neurodegenerative diseases including Parkinson´s disease, the inventors believe that acetyl-leucine is acting as aneuroprotective agent and so inhibiting and / or reversing the neurodegeneration that wouldotherwise be expected to manifest. In addition, many neurodegenerative diseases, includingPD, are associated with defects in lysosomal storage, and, lysosomal dysfunction, such asaberrantly high levels of lysosomal storage, may be a cause of neuronal dysfunction and death. As evidenced by the Examples, but without wishing to be bound by any specific theory, the present inventors discovered, inter alia, that acetyl-leucine can improve cellular dysfunction (e.g., by reducing lysosomal volumes towards control values) and provideneuroprotection, e.g in patients suffering from PD (Example 23).Consequently, the present disclosure provides acetyl-leucine, or a pharmaceuticallyacceptable salt of the same, for use in a method of treating Parkinson´s disease (PD) or oneor more symptoms of Parkinson´s disease (PD) in a subject in need thereof.A “subject”, as used herein, may be a vertebrate, mammal or domestic animal. Hence,compositions according to the disclosure may be used to treat any mammal, for example livestock (e.g. a horse, cow, sheep or pig), pets (e.g. a cat, dog, rabbit or guinea pig), alaboratory animal (e.g. a mouse or rat), or may be used in other veterinary applications. Inone embodiment, the subject is a human being. “Neurodegenerative disease”, as used herein, refers to any disorder that affects neurons and involves the progressive loss of neuronal structure, the progressive loss of neuronal function, or progressive neuron cell death. As used herein, the singular forms “a,” “an,” and “the” include plural reference. The terms “approximately” and “about” mean to be nearly the same as a referenced number or value including an acceptable degree of error for the quantity measured given the nature or precision of the measurements. As used herein, the terms “approximately” and “about” should be generally understood to encompass ± 20% of a specified amount, frequency or value. Numerical quantities given herein are approximate unless stated otherwise, meaning that term “about” or “approximately” can be inferred when not expressly stated. The terms “administer,” “administration,” or “administering” as used herein refer to (1) providing, giving, dosing and / or prescribing by either a health practitioner or his authorized agent or under his direction a composition according to the disclosure, and (2) putting into, taking or consuming by the patient or person himself or herself, a composition according to the disclosure. References to “acetyl-leucine” throughout include pharmaceutically acceptable salts of the same, even if not expressly stated. The acetyl-leucine may be in racemic form, which means that the compound comprises aboutequal amounts of enantiomers. Alternatively, it may be present in an enantiomeric excess ofeither the L-enantiomer or the D-enantiomer. The acetyl-leucine may be in a single enantiomeric form of either the L-enantiomer or the D-enantiomer. In one embodiment, the single enantiomeric form is the L-enantiomer. The racemic and enantiomeric forms may be obtained in accordance with known procedures in the art. A “pharmaceutically acceptable salt” as referred to herein, is any salt preparation that is appropriate for use in a pharmaceutical application. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chloro- benzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane and the like; alkali metal salts, such as lithium, potassium, sodium and the like; alkali earth metal salts, such as barium, calcium, magnesium and the like; transition metal salts, such as zinc, aluminum and the like; other metal salts, such as sodium hydrogen phosphate, disodium phosphate and the like; mineral acids, such as hydrochlorides, sulfates and the like; and salts of organic acids, such as acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and the like. The acetyl-leucine, or a pharmaceutically acceptable salt of the same, may be formulated and administered to a subject in accordance with known teachings in the art. For example, the acetyl-leucine, or a pharmaceutically acceptable salt of the same, may be formulated as a pharmaceutical composition. The pharmaceutical composition may comprise acetyl-leucine, or a pharmaceutically acceptable salt of the same, and a pharmaceutically acceptable carrier. Reference to the pharmaceutical composition encompasses the active agent alone or in the form of a pharmaceutical composition. The pharmaceutical composition may take any of a number of different forms depending, in particular, on the manner in which it is to be used. Thus, for example, it may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension or any other suitable form that may be administered to a person or animal in need of treatment. A “pharmaceutically acceptable carrier” as referred to herein, is any known compound or combination of known compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions. It will be appreciated that the carrier of the pharmaceutical composition should be one which is tolerated by the subject to whom it is given. In one embodiment, the pharmaceutically acceptable carrier may be a solid, and thecomposition may be in the form of a powder or tablet. A solid pharmaceutically acceptablecarrier may include, but is not limited to, one or more substances which may also act as flavouring agents, buffers, lubricants, stabilisers, solubilisers, suspending agents, wetting agents, emulsifiers, dyes, fillers, glidants, compression aids, inert binders, sweeteners,preservatives, dyes, coatings, or tablet-disintegrating agents. The carrier may also be anencapsulating material. In powders, the carrier may be a finely divided solid that is inadmixture with the finely divided active agents according to the invention. In tablets, theactive agent may be mixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. The powders and tabletsmay, for example, contain up to 99% of the active agents. Suitable solid carriers include, forexample, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. In another embodiment, the pharmaceutically acceptable carrier may be a gel and the composition may be in the form of a cream or the like. The carrier may include, but is not limited to, one or more excipients or diluents. Examples of such excipients are gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. In another embodiment, the pharmaceutically acceptable carrier may be a liquid. In oneembodiment, the pharmaceutical composition is in the form of a solution. Liquid carriers areused in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurizedcompositions. The acetyl-leucine may be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier may contain other suitablepharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteraladministration include water (partially containing additives as above, e.g. cellulose derivatives, such as sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g.fractionated coconut oil and arachis oil). For parenteral administration, the carrier may alsobe an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are usefulin sterile liquid form compositions for parenteral administration. The liquid carrier forpressurised compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, may be utilised by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenousand particularly subcutaneous injection. The active agent may be prepared as a sterile solidcomposition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. The compositions may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like. The compositions may also be administered orally either in liquid or solid compositionform. Compositions suitable for oral administration include solid forms, such as pills,capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs,and suspensions. Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions. Acetyl-leucine and compositions comprising the same may alternatively be administered by inhalation (e.g. intranasally). Compositions may also be formulated for topical use. For instance, creams or ointments may be applied to the skin.Acetyl-leucine may be incorporated within a slow- or delayed-release device. Such devicesmay, for example, be inserted on or under the skin, and the medicament may be released over weeks or even months. Such devices may be advantageous when long-term treatment with acetyl-leucine used according to the present disclosure is required and which would normally require frequent administration (e.g. at least daily administration).In one embodiment, the pharmaceutical composition is in the form of a tablet. In tablets, theactive agent may be mixed with a vehicle, such as a pharmaceutically acceptable carrier, having the necessary compression properties in suitable proportions and compacted in theshape and size desired. The tablets may contain up to 99% by weight of the active agents.For example, the acetyl-leucine, or a pharmaceutically acceptable salt of the same, may be provided in a solid dosage form suitable for oral administration, notably in the form of a tablet. Pharmaceutical compositions in solid oral dosage form, such as tablets, may be prepared by any method known in the art of pharmacy. Pharmaceutical compositions are usually prepared by mixing the acetyl-leucine, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutically acceptable carriers. A tablet may be formulated as is known in the art. Tanganil®, for example, includes wheat starch, pregelatinised maize (corn) starch, calcium carbonate and magnesium stearate as excipients. The same, or similar, excipients, for example, may be employed with the present disclosure. The composition of each 700 mg Tanganil®tablet is as follows: 500 mg acetyl-DL-leucine, 88 mg wheat starch, 88 mg pregelatinised maize (corn) starch, 13 mg calcium carbonate and 11 mg magnesium stearate. The same tablets, for example, may be employed with the present disclosure. The present disclosure describes acetyl-leucine, including compositions and methods thereof,for treating Parkinson´s disease (PD) or one or more symptoms of Parkinson´s disease (PD)in a subject in need thereof. The subject in need thereof may have a genetic, biochemical, or other similar identifiable marker of Parkinson´s disease (PD). For example, the marker ofParkinson´s disease (PD) may be a cellular marker. The subject in need thereof may havebeen diagnosed as having Parkinson´s disease (PD). For example, the subject may have beendiagnosed with Parkinson´s disease (PD) according to a genetic, biochemical, or othersimilar identifiable marker or due to one or more symptoms associated with PD. The subjectin need thereof may be suspected of having PD. For example, the subject may have a geneticpredisposition to Parkinson´s disease (PD) (e.g., the subject may have one or more familymembers with Parkinson´s disease (PD)). The subject in need thereof is symptomatic (i.e.,has one or more symptoms associated with Parkinson´s disease (PD)). It should beunderstood that the term “symptomatic” is used with reference to symptoms of Parkinson´sdisease (PD). Subjects who have a genetic, biochemical, or other similar identifiable marker of Parkinson´s disease (PD), such as subjects who have been diagnosed with Parkinson´sdisease (PD) based on a genetic, biochemical, or other similar identifiable marker, but whohave no further symptoms of the disease are asymptomatic, and thus not included within the scope of “symptomatic” for purposes of the present disclosure.As used herein, “treating Parkinson´s disease (PD) or one or more symptoms of Parkinson´sdisease (PD)” and the like refer to reducing the severity of Parkinson´s disease (PD) orreducing the severity of or eliminating one or more existing symptoms associated withParkinson´s disease (PD), delaying progression of Parkinson´s disease (PD) or one or moresymptoms of Parkinson´s disease (PD) over time as compared to typical disease progression,and / or reversing progression of Parkinson´s disease (PD) or one or more symptoms ofParkinson´s disease (PD) over time. “Treating Parkinson´s disease (PD) or one or moresymptoms of Parkinson´s disease (PD)” may also refer to improving a biochemical marker of Parkinson´s disease (PD).In some embodiments, the subject having PD undergoes co-treatment with L-DOPA andacetyl-Leucine (e.g. acetyl-DL-Leucine). L-DOPA may be administered separately from Acetyl-Leucine or together with Acetyl-Leucine. “Treating Parkinson´s disease (PD) or oneor more symptoms of Parkinson´s disease (PD)” and the like may also refer to reducing oreliminating the need for L-DOPA, e.g., reducing the daily dosage of L-DOPA by at least 500mg, at least 400 mg, at least 300 mg, at least 200 mg, or at least 100 mg. In some embodiments, co-treatment with L-DOPA and acetyl-leucine reduces the rate of typical disease progression of PD. In some embodiments, co-treatment with L-DOPA and acetyl-leucine stabilizes, delays or reverses the progression of Parkinson´s disease (PD) orone or more symptoms of Parkinson´s disease (PD) compared to typical PD progression withL-DOPA monotherapy. As used herein, “typical disease progression,” “disease progression that would typically be expected” and the like refer to the typical or expected progression of Parkinson´s disease (PD), one or more symptoms associated with Parkinson´s disease (PD), or a biochemicalmarker of Parkinson´s disease (PD) if the subject were untreated. Typical or expecteddisease progression may be based, for example, on a known scale, index, rating, or score, or other suitable test, for assessing the progression of Parkinson´s disease (PD), one or more symptoms of Parkinson´s disease (PD), or a biochemical marker of Parkinson´s disease (PD), such as those described as examples herein. The scale, index, rating, score, or other suitable test may correspond to the progression of the disease overall or to the progression of one or more symptoms associated with the disease. For instance, typical or expected diseaseprogression may be based on the typical or expected onset or severity of the PD or a symptomor collection of symptoms associated with PD. The typical or expected disease progression may be determined on a subject-by-subject basis or may be based on what is typically observed for or experienced by a collection of subjects afflicted with PD, such as a population or subpopulation of subjects. Subpopulations may include, for example, subpopulations of the same gender, of the same or similar age, of the same or similar timing for the onset of oneor more symptoms, etc. The disease progression, severity of the disease and / or delay orreduction of PD or the symptoms associated with PD may be monitored using any known scale, index, rating, or score, or other suitable test, for assessing the progression of Parkinson´s disease (PD), e.g., Unified Parkinson's Disease Rating Scale (UPDRS), which is an acknowledged standard in measuring disease progression and to measure the clinical improvement of FDA approved medications in clinical trials of PD.In one embodiment, “treating Parkinson´s disease (PD) or one or more symptoms ofParkinson´s disease (PD)” refers to delaying onset of one or more symptoms of Parkinson´sdisease (PD) that would otherwise be expected to manifest according to typical diseaseprogression. As used herein, “delaying onset of one or more symptoms of Parkinson´sdisease (PD)” and the like refer to increasing the time to, or preventing, onset of the PD orone or more symptoms of PD. For example, onset can be said to be delayed when the time tomanifestation of one or more symptoms of Parkinson´s disease (PD) takes at least 5% longerthan that observed according to typical disease progression. Further, for example, an increase in time of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% is observed. The subject in need of therapy or treatment with acetyl-leucine (e.g. acetyl-DL- leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof) is a symptomatic subject. The administration of acetyl-leucine may be initiated at the time the subject issymptomatic but to delay onset of further symptoms associated with Parkinson´s disease(PD) that would otherwise be expected to manifest according to typical disease progressionThe subject in need thereof may continue to receive treatment with acetyl-leucine in accordance with the durations described herein. In one embodiment, the treatment preventsonset of one or more symptoms of PD in the subject having been diagnosed with PD, thatwould otherwise be expected to manifest according to typical disease progression.In one embodiment, “treating Parkinson´s disease (PD) or one or more symptoms ofParkinson´s disease (PD)” refers to reducing the severity of Parkinson´s disease (PD) orreducing the severity of or eliminating one or more existing symptoms associated withParkinson´s disease (PD). The severity of Parkinson´s disease (PD) or of the existingsymptom(s) may be assessed using a known scale, index, rating, or score, such as those described as examples herein, or another suitable test for assessing severity), e.g., Unified Parkinson's Disease Rating Scale (UPDRS). For example, the scale, index, rating, score, or other suitable test may correspond to the severity of the disease overall or to the severity of one or more symptoms associated with the disease. In one embodiment, the treatment improves such an assessment from a value or degree characteristic of a symptomatic patient to a value or degree characteristic of a non-symptomatic patient.In one embodiment, “treating Parkinson´s disease (PD) or one or more symptoms ofParkinson´s disease (PD)” refers to delaying progression of Parkinson´s disease (PD) or oneor more symptoms associated with Parkinson´s disease (PD) over time as compared totypical disease progression, or reversing progression of Parkinson´s disease (PD) or one ormore symptoms associated with Parkinson´s disease (PD) over time. The time over whichthe treatment delays or reverses progression may coincide with the duration of treatment as described herein. The treatment may delay or reverse progression over a duration of, for example, about seven days or more, about two weeks or more, about three weeks or more, about one month or more, about six weeks or more, about seven weeks or more or about two months or more. The treatment may delay or reverse progression over a duration of, for example, about three months or more, about four months or more, about five months or more or about six months or more. It may delay or reverse progression over a duration of, for example, about 1 year or more, about 2 years or more, about 3 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. The treatment may delay orreverse progression of PD or one or more symptoms associated with PD over the lifetime ofthe patient.In one embodiment, “treating Parkinson´s disease (PD) or one or more symptoms ofParkinson´s disease (PD)” refers to delaying progression of Parkinson´s disease (PD) or oneor more symptoms of Parkinson´s disease (PD) over time as compared to typical diseaseprogression. As used herein, “delaying progression of Parkinson´s disease (PD) or one ormore symptoms associated with Parkinson´s disease (PD) over time” and the like refer toslowing and / or stopping progression of the disease or one or more symptoms of the disease (e.g., slowing and / or stopping the worsening or increasing severity of the disease or one ormore symptoms of the disease) over time. Disease progression may be determined, forexample, using a known scale, index, rating, or score, such as those described as examples herein, or another suitable test for assessing progression. For example, the scale, index, rating, score, or other suitable test may correspond to the progression of the disease overall or to the progression of one or more symptoms associated with the disease. In oneembodiment, “delaying progression of Parkinson´s disease (PD) or one or more symptomsassociated with Parkinson´s disease (PD)” means that a subject’s disease severity value (e.g., overall severity or severity of one or more symptoms) determined by a known scale, index, rating, score, etc., or other suitable test for evaluating severity, does not meaningfully increase (e.g., at least remains substantially constant). In one embodiment, “delayingprogression of Parkinson´s disease (PD) or one or more symptoms of Parkinson´s disease(PD)” means preventing the subject from reaching, or increasing the time taken for a subject to reach (e.g., decreasing the rate of change of increasing severity), a severity value according to a known scale, index, rating, score, etc., or other suitable test, for assessing progression compared to a value corresponding to typical disease progression. For example, progression can be said to be delayed when the time to reach a severity value takes at least 5% longer than that observed according to typical disease progression. Further for example, an increase in time of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% is observed.The time over which the treatment delays progression of Parkinson´s disease (PD) or one ormore symptoms of Parkinson´s disease (PD) may coincide with the duration of treatment asdescribed herein. In one embodiment, the treatment delays progression for at least about three months, at least about four months, at least about five months, or at least about six months. The treatment may delay progression for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years. The treatment may delay progression over the lifetime of the patient.In one embodiment, “treating Parkinson´s disease (PD) or one or more symptoms ofParkinson´s disease (PD)” refers to reversing progression of Parkinson´s disease (PD) or oneor more symptoms of Parkinson´s disease (PD) over time. As used herein, “reversingprogression of Parkinson´s disease (PD) or one or more symptoms of Parkinson´s disease(PD) over time” and the like refer to stopping progression and reducing the severity of thedisease or one or more symptoms of the disease over time. Disease progression and severity may be determined, for example, using a known scale, index, rating, or score, such as those described as examples herein, or another suitable test for assessing progression and severity. For example, the scale, index, rating, score, or other suitable test may correspond to the progression and severity of the disease overall or to the progression and severity of one ormore symptoms associated with the disease. In one embodiment, “reversing progression ofParkinson´s disease (PD) or one or more symptoms of Parkinson´s disease (PD) over time”means that a subject’s disease severity value (e.g., overall severity or severity of one or more symptoms) determined by a known scale, index, rating, score, etc., or another suitable test, for evaluating severity, improves over time (i.e., shows a reduction in severity over time).The time over which the treatment reverses progression of Parkinson´s disease (PD) or oneor more symptoms of Parkinson´s disease (PD) may coincide with the duration of treatmentas described herein. In one embodiment, the treatment reverses progression for at least about three months, at least about four months, at least about five months, or at least about six months. In a further embodiment, the treatment reverses progression for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years. The treatment may reverse progression over the lifetime of the patient.In one embodiment, “treating Parkinson´s disease (PD) or one or more symptoms ofParkinson´s disease (PD)” refers to improving in the subject a biochemical marker ofParkinson´s disease (PD) (e.g., increased levels of the storage metabolite(s) or secondary biochemical changes resulting from the primary storage). A biochemical marker is a signal of disease activity and may provide ongoing indications of disease severity and progression overtime. In one embodiment, the biochemical marker is improved in view of a control value. Inone embodiment, the biochemical marker is chosen from increased lysosomal volume, increased glycosphingolipid (GSL) levels, increased microtubule-associated protein 1A / 1B- light chain 3-phosphatidylethanolamine conjugate (LC3-II) levels, and increased amyloid precursor protein C-terminal fragment (APP-CTF) levels. In one embodiment, the biochemical marker is increased lysosomal volume and the treatment reduces lysosomal volume in the subject. In one embodiment, the biochemical marker is increasedglycosphingolipid (GSL) levels and the treatment reduces GSL levels in the subject. In oneembodiment, the biochemical marker is increased microtubule-associated protein 1A / 1B- light chain 3-phosphatidylethanolamine conjugate (LC3-II) levels and the treatment reduces LC3-II levels in the subject. In one embodiment, the biochemical marker is increased amyloid precursor protein C-terminal fragment (APP-CTF) levels and the treatment reduces APP-CTF levels in the subject. In one embodiment, the treatment improves a biochemical marker over time. For example, in one embodiment, improving a biochemical marker over time means that the treatment improves a biochemical marker over time toward a control value, prevents the progression of a biochemical marker over time, and / or delays the progression of the biochemical marker over time as compared to typical disease progression. The time over which the treatment improves a biochemical marker may coincide with the duration of treatment as described herein. In one embodiment, the treatment improves a biochemical marker for at least about three months, at least about four months, at least about five months, or at least about six months. The treatment may improve a biochemical marker for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years. The treatment may improve the biochemical marker over the lifetime of the patient.A “symptom” of Parkinson´s disease (PD) includes any clinical or laboratory manifestationassociated with Parkinson´s disease (PD) and is not limited to what the subject can feel orobserve. Symptoms as described herein include, but are not limited to, neurological symptoms and psychiatric symptoms. Examples of neurological symptoms include ataxia, other movement disorders such as hypokinesia, rigor, tremor or dystonia, central ocular motor disorders such as vertical and horizontal supranuclear saccade / gaze palsy and neuropsychological deficits such as dementia. Examples of psychiatric symptoms include depression, behavioural disorders or psychosis. Onset of symptoms may range from birth to adulthood. In particular, the symptoms of Parkinson’s Disease may comprise one or more of hypokinesia, rigor, resting tremor, hyposmia, vegetative dysfunction and during the course of the disease cognitive deficits which can lead to dementia as well as psychiatric symptoms such as behavioural disorders, rigidity, tremor, slow movement, decreased fluidity of limb movements, instable gait and mobility, constipation, decreased cognitive function and decreased mood. In some embodiments, the symptoms include hypokinesia, rigor, resting tremor, hyposmia, vegetative dysfunction and cognitive deficits (e.g. dementia). In some embodiments, the symptoms include psychiatric symptoms such as behavioural disorders. Onset of symptoms may range from early to late adulthood. The symptoms of PD may further comprise gait deterioration, increased propensity to falls, and / or speech deteriorationassociated with fronto-temporal dementia with parkinsonism. Neurological symptoms mayinclude ataxia, hypokinesia, rigor, tremor or dystonia, central ocular motor disorders such as vertical and horizontal supranuclear saccade / gaze palsy and neuropsychological deficits suchas dementia. In addition, PD symptoms may be accompanied by REM Sleep BehaviorDisorder (RBD), and restless leg syndrome (RLS).Progression of Parkinson´s disease (PD) over time or through treatment can be monitored,for example, using one or more known tests at two or more time points and comparing the results. Disease progression and / or severity may be monitored using Unified Parkinson's Disease Rating Scale (UPDRS or MDS-UPDRS) (Goetz et al., Movement Disorder Society- sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan. Mov Disord.2007 Jan;22(1):41-7. doi:10.1002 / mds.21198.) Disease progression and / or severity can be assessed, for example, usingthe Scale for the Assessment and Rating of Ataxia (SARA), Spinocerebellar Ataxia Functional Index (SCAFI), the International Cooperative Ataxia Rating Scale (ICARS), the brief ataxia rating scale (BARS), the modified Disability Rating Scale (mDRS), EuroQol 5Q-5D-5L (EQ- 5D-5L), the visual analogue scale (VAS), neuropsychological tests, such as Wechsler AdultIntelligence Scale-Revised (WAIS-R), Wechsler Intelligence Scale for Children-IV (WISC-IV),Montreal Cognitive Assessment (MoCA), as well as scales used in movement disorders, such as the Unified Parkinson’s Rating Scale (UPRS) or the Unified Multiple System Atrophy Rating Scale (UMSARS), or other suitable tests. For certain LSDs, such as NPC, particular scores have been developed and validated over the last decades, for instance the clinical severity score (CSS) and annual severity increment score (ASIS) (see Yanjanin et al., “Linear Clinical Progression, Independent of Age of Onset, in Niemann–Pick Disease, Type C,” Am JMed Genet Part B 153B:132–140) and the modified 6-Domain NP-C disability Scale (mDRSscore). For example, an NPC patient’s severity can be quantified by assigning a CSS, which assesses various parameters of the disease (ambulation, seizures, eye movement, etc.) and gives each parameter a score out of 5. A higher score equals a greater severity. The ASIS quantifies the annual rate of change in the CSS, calculated by dividing the CSS by the patient’s age. In this regard, certain scores in these tests are characteristic of symptomatic neurodegenerative disease patients (e.g. PD patients) and evidence disease progression and / or severity.Thus, “treating Parkinson´s disease (PD) or one or more symptoms of Parkinson´s disease(PD)”, for example, may be equated to achieving an improved assessment, such as those described herein, of a UPDRS or MDS-UPDRS, SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D- 5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and / or MoCA score, or result of anothertest suitable for characterising Parkinson´s disease (PD) patient. For example, in oneembodiment, “reducing the severity of Parkinson´s disease (PD) or reducing the severity ofor eliminating one or more existing symptoms of Parkinson´s disease (PD)” means improving a UPDRS or MDS-UPDRS, SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS,UMSARS, and / or MoCA score, or a result of another suitable test, for evaluating severity, such as improving the score or result from a severity value characteristic of a symptomatic subject to a value characteristic of a non-symptomaticsubject. In another embodiment, “delaying progression of Parkinson´s disease (PD) or oneor more symptoms of Parkinson´s disease (PD)” means that a subject’s UPDRS or MDS- UPDRS, SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and / or MoCA score, or a result of another suitable test for evaluating progression, does not meaningfully increase (e.g., at least remains substantially constant). Ina further embodiment, “delaying progression of Parkinson´s disease (PD) or one or moresymptoms associated with Parkinson´s disease (PD)” means preventing a subject’s UPDRS orMDS-UPDRS, SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS,UPRS, UMSARS, and / or MoCA score, or a result of another suitable test for evaluating progression, from reaching, or increasing the time taken to reach, a value compared to that of typical disease progression. In another embodiment, “reversing progression of Parkinson´sdisease (PD) or one or more symptoms of Parkinson´s disease (PD) over time” means that asubject’s UPDRS or MDS-UPDRS, SARA, SCAFI, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS and / or MoCA score, or a result of another suitable test for evaluating progression,improves over time (i.e., shows a reduction in severity over time). In one embodiment, thebiochemical marker for Parkinson’s disease is identified by a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan, a dopamine transporter (DAT) density as measured by a single photon emission computed tomography (SPECT) scan, or a combination of both. In another embodiment, the biochemical marker for Parkinson’s disease is identified by a EuroQol-5 Dimension-5 Levels (5Q-5D-5L) score, a Montreal Cognitive Assessment (MoCA) score, or a combination thereof. For example, to evaluate overall neurological status, mDRS, a four-domain scale (ambulation, manipulation, language and swallowing), may be applied. Cerebellar function may be evaluated using SARA, an eight-item clinical rating scale (gait, stance, sitting, speech, fine motor function and taxis; range 0–40, where 0 is the best neurological status and 40 the worst), and SCAFI, comprising the 8-m-Walking-Time (8MW; performed by having patients walking twice as quickly as possible from one line to another excluding turning), 9-Hole-Peg- Test (9HPT) and the number of “PATA” repetitions over 10 s. Subjective impairment and quality of life may be evaluated using the EQ-5D-5L questionnaire and VAS. To assess ocular motor function, 3-dimensional videooculography (EyeSeeCam) may be used to measure the peak velocity of saccades, gain of smooth pursuit, peak slow phase velocity of gaze-evoked nystagmus (gaze-holding function), peak slow phase velocity of optokinetic nystagmus, and gain of horizontal vestibulo-ocular reflex. To evaluate the cognitive state, WAIS-R or WISC- IV, and MoCA, assessing different cognitive domains, including attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation with a maximum of 30 points and a cut-off score of 26, may be used. The skilled person will know how to perform these and other such tests.The acetyl-leucine (e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or acombination thereof), or a pharmaceutically acceptable salt of the same, may be administered, for example, at a dose ranging from about 500 mg to about 15 g per day or ranging from about 500 mg to about 10 g per day, from about 1.5 g to about 10 g, from about 1 g to about 15 g per day, from about 1 g to about 10 g per day, from about 1.5 g to about 7 gper day, from about 4 g to about 6 g per day, or from about 4 g to about 5 g per day. In apreferred embodiment, the therapeutically effective amount is about 5 g per day. Theadministration may be by solid oral or liquid oral route. The acetyl-leucine, or a pharmaceutically acceptable salt of the same, may be administered, for example, in a dose according to that of Tanganil®, which is prescribed to adults in a dose of 1.5 g to 2 g per day, 3-4 tablets in two doses, morning and evening.If one enantiomer is administered, the doses may be reduced accordingly. For instance, ifonly acetyl-L-leucine or if only acetyl-D-leucine is administered, the dose may range from about 250 mg to about 15 g per day, range from about 250 mg to about 10 g per day, or range from about 250 mg to about 5 g per day, such as from about 0.75 g to about 5 g per day. Acetyl-leucine as used herein may refer to acetyl-DL leucine. Acetyl-leucine as used hereinmay refer to acetyl-L-leucine, acetyl-D-leucine or a combination thereof.In one embodiment, the administered dose ranges from about 1 g to about 15 g per day, from about 1 g to about 10 g per day, or from about 1.5 g to about 7 g per day. It may be from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 g to about 15 g per day. It may be from about 2, 3, 4, 5, 6, 7, 8 or 9 g to about 10 g per day. It may be more than about 1.5 g per day, but less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 g per day. In one embodiment, the dose ranges from about 4 g to about 6 g per day. In one embodiment, the dose ranges from about 4 g to about 5 g per day. In one embodiment, the dose is about 4.5 g per day. In one embodiment, the dose is about 5 g per day. In one embodiment, these doses are administered in a solid oral dosage form, notably tablets. In another embodiment, these doses are for acetyl-leucinewhen in its racemic form. Doses for acetyl-leucine when an enantiomeric excess is presentmay be lower than those recited here, for example, around 50% lower. The above reciteddose-ranges when halved are thus also explicitly encompassed by the present disclosure. Inone embodiment, acetyl-DL-leucine is administered in a dose of about 5 g per day. In one embodiment, acetyl-DL-leucine is administered in a dose of about less than 5 g per day. In one embodiment, acetyl-DL-leucine is administered in a dose of about 4 to 6 g per day. In one embodiment, acetyl-L-leucine is administered in a dose of about 5 g per day. In one embodiment, acetyl-L-leucine is administered in a dose of about less than 5 g per day. In one embodiment, acetyl-L-leucine is administered in a dose of about 4 to 6 g per day. In one embodiment, acetyl-D-leucine is administered in a dose of about 5 g per day. In one embodiment, acetyl-D-leucine is administered in a dose of about less than 5 g per day. In one embodiment, acetyl-D-leucine is administered in a dose of about 4 to 6 g per day.The total daily dose may be spread across multiple administrations, i.e. administration mayoccur two or more times a day to achieve the total daily dose. As an example, the requirednumber of tablets to provide the total daily dose of acetyl-leucine may be split across twoadministrations (for example, in the morning and evening) or three administrations (for example, in the morning, noon and evening). Each dose may be suitably administered with or without food. For example, acetyl-leucine may be dosed by about 1 or about 2 hours before meals, such as at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, or at least about 1 hour before meals, or may be dosed by about 1, about 2, or about 3 hours after meals, such as waiting at least about 20 minutes, at least about 30 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 2.5 hours after meals. For example, a total daily dose of 4.5 g acetyl-DL-leucine may be administered as three Tanganil®(or equivalent) tablets before, with, or after breakfast, three further tablets before, with, or after lunch and three further tablets before, with, or after dinner. Administration of acetyl-leucine in accordance with the present disclosure may be initiated after a subject is found to have a genetic, biochemical, or other similar identifiable marker of Parkinson´s disease (PD). Administration may be initiated at or around the time a subject is found to have a genetic, biochemical, or other similar identifiable marker of Parkinson´s disease (PD). Administration of acetyl-leucine is initiated when the subject is symptomatic. The symptoms of Parkinson’s Disease may comprise one or more of hypokinesia, rigor, resting tremor, hyposmia, or vegetative dysfunction, cognitive deficits, optionally wherein the cognitive deficits comprise dementia, psychiatric symptoms, optionally wherein the psychiatric symptoms are behavioural disorders, slow movement, decreased fluidity of limb movements, instable gait and mobility, constipation, gait deterioration, increased propensity to falls, speech deterioration associated with fronto-temporal dementia with parkinsonism, REM Sleep Behavior Disorder (RBD), restless-leg syndrome (RLS), neurological symptoms and / or decreased mood. Neurological symptoms may include one or more of ataxia, hypokinesia, rigor, tremor or dystonia, central ocular motor disorders such as vertical and horizontal supranuclear saccade / gaze palsy and neuropsychological deficits such as dementia. As discussed herein, an advantage of treatment with acetyl-leucine, according to the present disclosure, is that acetyl-leucine (e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof) may be administered over a long duration of time to, for example,delay or even reverse progression of Parkinson´s disease (PD) or one or more symptoms ofParkinson´s disease (PD) in a subject as compared to typical disease progression. Treatmentduration may be, for example, about seven days or more, about two weeks or more, aboutthree weeks or more, about one month or more, about six weeks or more, about seven weeks or more, or about two months or more. In one embodiment, it is about three months ormore, about four months or more, about five months or more or about six months or more.The treatment duration may be about 1 year or more, about 2 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. The treatment duration may be the life-time of the patient. Any and all combinations of dosage form, dose amount, dosing schedule and treatment duration are envisaged and encompassed by the invention. In one embodiment, the dose is from about 4 g to about 10 g per day, taken across one, two, or three administrations per day, for a treatment duration of about two months or more. In another embodiment, the dose is more than 4 g but no more than 5 g per day, taken across one, two, or three administrations per day, for a treatment duration of about six months or more. The dosage form may be a solid oral dosage form, notably tablets. The pharmaceutical composition may be used as a monotherapy (e.g., use of the active agentalone) for treating Parkinson´s disease (PD) in a subject. Alternatively, the pharmaceuticalcomposition may be used as an adjunct to, or in combination with, other known therapies,e.g., for treating Parkinson´s disease (PD) in a subject. Parkinson´s disease (PD) may, butneed not, be associated with lysosomal dysfunction (e.g., lysosomal storage defect). Major symptoms of Parkinson's Disease (PD) include rigidity, tremor, and slow movement. There are other diseases in which these symptoms are prevalent. These diseases, and PD itself, fall under the umbrella term Parkinsonism. PD can be referred to as Primary Parkinsonism. Other examples of Parkinsonisms include: Multiple System Atrophy; Progressive Supranuclear Palsy; Normal pressure hydrocephalus; and Vascular or arteriosclerotic parkinsonism. Those diseases that can be classed as Parkinsonisms, but are not PD, can also be referred to as “Parkinson-Plus Syndromes”. Unlike PD patients, individuals with Parkinson-Plus Syndromes do not respond to L-Dopa. The term “parkinsonism” as used herein may refer to a motor syndrome whose main symptoms are tremor at rest, stiffness, slowing of movement and postural instability. Parkinsoniansyndromes can be divided into four subtypes, according to their origin: primary or idiopathic;secondary or acquired; hereditary parkinsonism; and Parkinson plus syndromes or multiple system degeneration. In one embodiment, the parkinsonism is a Parkinson plus syndrome or multiple system degeneration. In one embodiment, the parkinsonism is vascular (arteriosclerotic) Parkinsonism, lower- body Parkinsonism, Multiple System Atrophy with predominant parkinsonism (MSA-P), Multiple System Atrophy with cerebellar features (MSA-C; Sporadic olivopontocerebellar atrophy (OPCA)), Shy–Drager syndrome, Progressive Supranuclear Palsy (Steele- Richardson-Olszewski syndrome), Lewy body dementia, Pick's disease, or frontotemporal dementia and parkinsonism linked to chromosome 17.In one embodiment, the acetyl-leucine (e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof), or a pharmaceutically acceptable salt thereof, treats gait deterioration, increased propensity to falls, and / or speech deterioration associated with fronto-temporal dementia with parkinsonism. For example, the acetyl-leucine, or a pharmaceutically acceptable salt thereof, may reduce the severity of or eliminate, or delay orreverse the progression of gait deterioration, increased propensity to falls, and / or speechdeterioration associated with fronto-temporal dementia with parkinsonism.In one embodiment, the acetyl-leucine (e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof), or a pharmaceutically acceptable salt thereof, treats increased propensity to falls and / or gait deterioration associated with corticobasal-degeneration-syndrome. For example, the acetyl-leucine, or a pharmaceutically acceptablesalt thereof, may reduce the severity of or eliminate, or delay or reverse the progression of increased propensity to falls and / or gait deterioration associated with corticobasal- degeneration-syndrome.There is also provided a method of treating Parkinson´s disease (PD) or one or moresymptoms of Parkinson´s disease (PD) in a subject in need thereof, the method comprisingadministering a therapeutically effective amount of acetyl-leucine, or a pharmaceuticallyacceptable salt thereof, to the subject. A “therapeutically effective amount” of an agent is any amount which, when administered to a subject, is the amount of agent that is needed to produce the desired effect, which, for thepresent disclosure, a therapeutic effect. The dose may be determined according to variousparameters, such as the specific form of acetyl-leucine used; the age, weight and condition of the patient to be treated; the type of the disease; the route of administration; and the required regimen. A physician will be able to determine the required route of administration and dosage for any particular patient. For example, a daily dose may be from about 10 to about 225 mg per kg, from about 10 to about 150 mg per kg, or from about 10 to about 100 mg per kg of body weight.Also disclosed is a kit for treating Parkinson´s disease (PD) in a subject, comprising a meansfor diagnosing or prognosing the disease / disorder, and acetyl-leucine or a pharmaceutically acceptable salt thereof.The means for diagnosing or prognosing Parkinson´s disease (PD) may include a specificbinding agent, probe, primer, pair or combination of primers, an enzyme or antibody, including an antibody fragment, which is capable of detecting or aiding in the detection of Parkinson´s disease (PD), as defined herein. The kit may comprise LysoTracker®, which is a fluorescent marker and is commercially-available from both Invitrogen and also Lonza. The LysoTracker®may be blue, blue-white, yellow, green or red. The kit also comprises acetyl-leucine or a pharmaceutically acceptable salt thereof, as defined herein. The kit may further comprise buffers or aqueous solutions. The kit may further comprise instructions for using the acetyl-leucine or a pharmaceutically acceptable saltthereof in a method of the invention.In a further embodiment, there is disclosed acetyl-leucine (e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof), or a pharmaceutically acceptable salt thereof, for use in a method of providing neuroprotection in a subject in need thereof (e.g., asubject having Parkinson´s disease (PD)). “Neuroprotection” and its cognates, as used herein, refer to prevention, a slowing in, and / or a reversed progression of neurodegeneration, including, but not limited to, progressive loss of neuronal structure, progressive loss of neuronal function, and / or progressive neuronal death.Providing neuroprotection may result in reducing the severity of Parkinson´s disease (PD) orreducing the severity of or eliminating one or more existing symptoms associated withParkinson´s disease (PD), delaying progression of Parkinson´s disease (PD) or one or moresymptoms of Parkinson´s disease (PD) over time as compared to typical disease progression,and / or reversing progression of Parkinson´s disease (PD) or one or more symptoms ofParkinson´s disease (PD) over time. The time over which neuroprotection is provided maycoincide with the duration of treatment as described herein. The treatment may provide neuroprotection over a duration of, for example, about seven days or more, about two weeks or more, about three weeks or more, about one month or more, about six weeks or more, about seven weeks or more or about two months or more. The treatment may provide neuroprotection over a duration of, for example, about three months or more, about four months or more, about five months or more or about six months or more. It may provide neuroprotection over a duration of, for example, about 1 year or more, about 2 years or more, about 3 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. The treatment may provide neuroprotection over the lifetime of the patient. In another embodiment, a method of providing neuroprotection in a subject in need thereof(e.g., a subject having Parkinson´s disease (PD)) comprises administering a therapeuticallyeffective amount of acetyl-leucine, or a pharmaceutically acceptable salt thereof, to thesubject.Also disclosed is a kit for providing neuroprotection in a subject in need thereof (e.g., asubject having PD), the kit comprising a means for diagnosing or prognosing thedisease / disorder, and acetyl-leucine or a pharmaceutically acceptable salt thereof. The present disclosure further includes the use of acetyl-leucine, or a pharmaceutically acceptable salt thereof, as a neuroprotective agent in a subject in need thereof (e.g., a subjecthaving Parkinson´s disease (PD)). In one embodiment the subject has been diagnosed withPD. All of the features described herein (including any accompanying claims, abstract and drawings), and / or all of the steps of any method so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Examples The invention will now be explained in further detail in the following Examples, whichdemonstrate the utility of acetyl-leucine in treating Parkinson´s disease (PD) in a subject andproviding neuroprotection in said subject. Example 1In Vivo Mouse Study - MethodsMouse Model This study made use of an authentic mouse model of NPC, the Npc1− / −(BALB / cNctr-Npc1m1N / J) mouse, which is null for the NPC1 protein and displays all the hallmarks of theclinical disease (Loftus, 1997). This mutant strain arose spontaneously and has a lifespan in the range of 10–14 weeks and therefore has a course of disease more acute that the vast majority of patients. The mutant mouse has been exploited successfully, not only for determining the ontogeny of disease and underlying pathogenic mechanisms, but also for the evaluation of experimental therapies. Analyses using these mice have been undertaken at the whole animal, cellular, and molecular levels (Baudry, 2003; Smith, 2009; Cologna, 2014; Cologna, 2012). It is the most intensively studied animal model of NPC. Prior to about 4–5 weeks of age Npc1− / −mice have no discernible behavioural indication of disease that distinguishes them from wild-type littermates. First indications of behavioural deficits, such as tremor and ataxic gait, appear by weeks 5–6; by weeks 7–8 defects in motor coordination become more apparent, and by 9–10 weeks ataxia is advanced and accompanied by increased loss in weight and poor coat condition as feeding and drinking becomes difficult (humane end point applied) (Smith, 2009). Wild-type (Npc1+ / +) littermates were used as a control. Treatment ProtocolA group of Npc1− / − mice and a group of Npc1+ / + mice were treated with 0.1 g / kg acetyl-DL-leucine, provided mixed in the mouse chow, from weaning (three weeks of age). Separate groups of Npc1− / −and Npc1+ / +mice were left untreated, as controls. Coat ConditionThe coat condition of Npc1− / − mice, with and without acetyl-DL-leucine treatment, wascompared by simple observation of the mice at nine weeks of age. Weight Data Animals were weighed twice a week. Weights were averaged (mean) across all mice in each group and compared. Gait Analysis Gait analysis was performed on mice at eight weeks of age using a CatWalk®15.0 system according to manufacturer’s instructions (Noldus, Nottingham, UK). Five runs were recorded per animal. CatWalk®parameters measured were: 1. Stand Mean: average duration (s) of paws in contact with glass plate;2. Step Cycle: duration (s) between two consecutive contacts of the same paw;3. Duty Cycle: percentage of time paws in contact with plate compared with time tocomplete a step cycle; 4. Step Sequence (AB): percentage of time spent walking in LF-RH-RF-LH alternatingpattern (LF: left front; RH: right hind; RF: right front; LH left hind); 5. Cadence: step per seconds in a trial;6. Diagonal Support: percentage of time with simultaneous contact of diagonal pawswith the glass plate (RF&LH or RH&LF). Motor Function Analysis Motor function analysis was performed on mice at eight and nine weeks of age using an Open Field Activity Monitor according to manufacturer’s instructions (Linton Instruments, Amlogger Software). Each mouse was placed in a plastic cage with bedding and analysed for five minutes. Rears were counted manually. Motor function parameters measured were: 1. Centre Rearing: mice rearing on hind legs unsupported;2. Rearing: mice rearing on hind legs with and without the support of cage walls;3. Activity: regular movement of the animal including walks;4. Front to Back (FR) count: movement of the animal from front to back of the cage;5. Active Time: duration (s / min) of activeness regardless of movement;6. Mobile Time: duration (s / min) of mobility;7. Rearing Time: duration of any rearing.Results Coat Condition Figure 1 B shows an untreated Npc1− / −age matched littermate. Npc1− / −mice were observed as having poor coat condition at nine weeks of age, as feeding and drinking had become difficult (see Figure 1B).In distinct contrast, Figure 1A shows an Npc1− / − mouse treated with acetyl-DL- leucine fromweaning. Npc1− / − mice treated with acetyl-DL-leucine had a smooth and glossy coat,reminiscent of wild-type (Npc1+ / +) littermates (see Figure 1A). Weight Data As can be seen in Figure 2A, wild-type (Npc1+ / +) mice progressively put on weight for theduration of the study, i.e. from three weeks to 10 weeks of age. Further, Figure 2A shows themean weight per group of mice at each point in time (Npc1− / −untreated, n = 1; Npc1− / −acetyl- DL-leucine 0.1 g / kg, n = 3; Npc1+ / +untreated, n = 3; Npc1+ / +acetyl-DL-leucine 0.1 g / kg, n = 2).Treatment with acetyl-DL-leucine had no significant effect on this weight gain.Npc1− / −mice initially put on weight, largely in the same manner as Npc1+ / +controls. However, the Npc1− / −mice then began to lose weight from six weeks of age. At the end of the study (10 weeks of age), the mice weighed nearly as little as at just four weeks of age.Treatment with acetyl-DL-leucine delayed these weight loss symptoms by two weekscompared to the untreated group.A comparison of the weight changes in Npc1− / − mice, with and without acetyl-DL-leucinetreatment, is shown in Figure 2B. In particular, Figure 2 B shows the change in weight (%)per group of mice at each point in time, for the Npc1− / −mice only. The beneficial effect ofacetyl-DL-leucine treatment in delaying weight loss is clearly evident from this Figure.Gait Analysis The results of the gait analysis are shown in Figure 3. Diagonal support, cadence and stepsequence data are shown in Figures 3A - 3C, respectively. Figures 3D and 3E show front paw(FP) data (stand mean and step cycle in Figure 3D; duty cycle in Figure 3E). Figures 3F and3G show hind paw (HP) data (stand mean and step cycle in Figure 3F; duty cycle in Figure3G). Data are presented as mean ^ SEM. n=3 for Npc1+ / + untreated, n=2 for Npc1+ / + treated,n=1 for Npc1− / −untreated (hence no statistical analysis performed), n=3 for Npc1− / −treated. The first bar in each graph shows the gait properties of wild-type (Npc1+ / +) mice. The second bar in each graph shows the gait properties of wild-type (Npc1+ / +) mice treated with acetyl-DL-leucine. There was no significant difference in gait properties between these mice and their untreated littermates. The third bar in each graph shows the gait properties of an Npc1− / −mouse. On the whole, this mouse showed poor gait compared to Npc1+ / +mice. The mouse spent extremely little time, if any, in diagonal support (Figure 3A) or step sequence (Figure 3C), and its hind paw function in stand mean (Figure 3F) and duty cycle (Figure 3G) were also drastically hindered.The fourth bar in each graph shows the gait properties of Npc1− / − mice treated with acetyl-DL-leucine. These mice demonstrated significantly improved gait compared to their untreated littermates. In fact, they showed similar gait properties to Npc1+ / +mice. Motor Function Analysis Analysis at eight weeks of age revealed no difference in motor function properties between Npc1− / −and wild-type (Npc1+ / +) mice (data not shown). By nine weeks of age, however, defects in motor coordination had become apparent. The results of the motor function analysis at nine weeks are shown in Figure 4. Centrerearing, activity, rearing and front to back (FR) count are shown in Figures 4A - 4D,respectively. Active time, mobile time, rearing time and total manual rearing count areshown in Figures 4E - 4H, respectively. Data are presented as mean ^ SEM. n=3 for Npc1+ / +untreated, n=2 for Npc1+ / +treated, n=1 for Npc1− / −untreated (hence no statistical analysis performed), n=3 for Npc1− / −treated. The first bar in each graph shows the motor function properties of wild-type (Npc1+ / +) mice. The second bar in each graph shows the motor function properties of wild-type (Npc1+ / +)mice treated with acetyl-DL-leucine. There was no significant difference in motor functionproperties between these mice and their untreated littermates. The third bar in each graph shows the motor function properties of an Npc1− / −mouse. On the whole, this mouse showed poor motor function compared to Npc1+ / +mice. The mouse spent extremely little time, if any, rearing (panel H), particularly on its hind legs unsupported (panel A). The fourth bar in each graph shows the motor function properties of Npc1− / −mice treatedwith acetyl-DL-leucine. These mice demonstrated significantly improved motor functioncompared to their untreated littermates. In fact, they showed similar motor function properties to Npc1+ / +mice. LifespanIt was also observed that treatment of the Npc1- / - mouse with acetyl-DL-leucine (0.1 g / kgfrom 3 weeks of age) is associated with a statistically significant increase in lifespan (Figure 5). This data further indicates the effect of acetyl-leucine in delaying the onset of the disease. Conclusion Where Npc1− / −mice had discernible indication of disease that distinguished them from wild-type littermates from 5-6 weeks of age, Npc1− / − littermates treated with acetyl-DL-leucinefrom weaning did not display such symptoms until two or more weeks later. Treatment ofNpc1− / − mice with acetyl-DL-leucine delayed onset and progression of NPC symptoms andshowed evidence of neuroprotection.It is reasonable to expect that, as acetyl-DL-leucine provided general neuroprotection, thatthe results observed in NPC will also be observed in other neurodegenerative disorders, and neurodegenerative disorders that are associated with defects in lysosomal storage. Example 2 Methods A fibroblast cell line from an NPC patient was treated for 3 days with N-acetyl-DL-leucine (1 mM) and relative lysosomal volume was quantified via LysoTracker, a fluorescent dye that accumulates in acidic organelles. Increased LysoTracker fluorescence is indicative of an increase in lysosomal size and / or number, and is a hallmark of NPC cells. In addition, fibroblasts derived from Niemann-Pick A (NPA), Mucolipidosis Type II (MLII), Mucopolysaccharidosis Type IIIB (MPS IIIB), Aspartylglucosaminuria, Mucolipidosis Type IIIA (MLIIIA), and Mucopolysaccharidosis Type VII (MPS VII) patients were treated with acetyl-DL-Leucine (1 mM) for 6 days and lysosomal volume was quantified via LysoTracker. Results Treatment of fibroblasts derived from an NPC patient of mild clinical severity with 1 mM N- acetyl-DL-leucine was associated with a significant decrease in LysoTracker fluorescence, indicative of reduced lysosomal volume over time (Figure 6A). These findings were replicated in fibroblasts obtained from additional NPC patients of variable clinical severity that were treated with 1 mM N-acetyl-DL-leucine for 72 hours (Figure 6B). Fibroblasts derived from NPA, and MLII, MPS IIIB, Aspartylglucosaminuria, MLIIIA, and MPS VII patients were observed to have elevated LysoTracker fluorescence levels relative to age-matched wild-type controls (Figures 6C-6H). This is indicative of an expanded lysosome occurring as a result of lipid storage compared to fibroblasts from healthy individuals. Treatment with acetyl-leucine was associated with a statistically significant reduction in LysoTracker fluorescence toward control level in both the NPA, and MLII, and MPS IIIB fibroblasts relative to untreated NPA, and MLII, and MPS IIIB fibroblasts, respectively (Figures 6C-6E), and was associated with a trend in reducing LysoTracker fluorescence toward control level in the aspartylglucosaminuria, MLIIIA, and MPS VII fibroblasts relative to untreated aspartylglucosaminuria, MLIIIA, and MPS VII fibroblasts, respectively (Figures 6F-6H). The reduction in LysoTracker fluorescence was indicative of a decrease in lysosomalvolume (Figures 6C-6H and 6D). Data presented in Figures 6A - 6D show the results after 6days of the treatment for each cell line, respectively with 1 mM acetyl-leucine, with lysosomal volume expressed as fold change relative to untreated wild-type fibroblasts. The asterisks (* / ****) indicates a p-values of ( <0.05 / 0.001) versus untreated disease fibroblasts. Conclusion N-acetyl-DL-leucine treatment was associated with the rectification of disturbed lysosomal storage by reducing lysosomal volume and thus acetyl-leucine directly corrected a phenotype of these lysosomal storage disorders. These diseases represent different classes of LSDs, and thus these results further support utility of acetyl-leucine’s effect against a broad range of lysosomal storage disorders. Example 3 Sandhoff disease is a disorder which may result from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the beta-subunit of beta-hexosaminidase. As a result of this, GM2 ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS). This study made use of a mouse model of Sandhoff disease, the Hexb− / −mouse, as described in Jeyakumar et al. (Jeyakumar, M. et al. (1999) Proc. Natl. Acad. Sci. USA 96: 6388-6393). Wild-type (Hexb+ / +) mice were used as controls. Lifespan Treatment with acetyl-DL-Leucine was associated with a statistically significant increase inthe lifespan of the Sandhoff mouse (Figure 7A). In Figure 7A, acetyl-leucine-treated micewere treated with 0.1 g / kg acetyl-leucine from 3 weeks of age. The asterisks (*) indicates a p- value of <0.05 vs untreated Sandhoff mice. Data is average of n=6 mice per group. Without treatment, the median survival time of Sandhoff mice was 112 days. Treatment with acetyl-leucine (0.1 g / kg body weight since 3 weeks of age) increased the median lifespan to 120days. Motor function Treatment of Sandhoff mice with acetyl-leucine gave rise to improvements in motor function as indicated by bar crossing and step cycle studies. Bar crossing test The bar crossing test is a method for assessing motor function in mice in which the mouse is placed hanging from the centre of a horizontal bar by its front limbs. A wild-type mouse with normal motor function will be able to engage its hind limbs and thereby move to one of the platforms at either end of the bar, and in doing so complete the test. An untreated Sandhoff mouse is able to complete the test up until around 11 weeks of age. After this point motor function and hind-limb mobility / engagement have deteriorated to the point to which the mouse cannot complete the test, and will drop from the bar onto the padded surface below. Treatment of the Sandhoff mouse model with acetyl-DL-leucine (0.1 g / kg body weight from 3 weeks of age) was associated with improved motor function and hind-limb mobility / engagement as assessed via the bar-crossing test (Figure 7B). In Figure 7 B, acetyl- leucine treatment of 0.1 g / kg body weight was provided from 3 weeks of age. The acetyl- leucine treated Sandhoff mice retained the ability to complete the test up to 13 weeks of age (inclusive). Data shown is the mean of 6 mice per group. The treated Sandhoff mice retained the ability to complete the test up to 13 weeks of age (inclusive). Step cycle Step cycle is the length of time taken during locomotion by a limb from the time it leaves the ground until it leaves the ground on the next occasion. Step cycle time was assessed at 12 weeks of age in untreated and acetyl-leucine treated Sandhoff model mice. Acetyl-leucine treatment constituted 0.1g / kg body weight acetyl- leucine from 3 weeks of age. Treatment of the Sandhoff mouse model with acetyl-leucine was associated with significantly faster front step cycle times (p<0.05 vs untreated SH mouse), significantly faster hind step cycle times (p<0.01 vs untreated SH mouse) and significantly faster average step cycle times (p<0.001 vs untreated SH mouse) (Figure 7C). In Figure 7 C, Acetyl-leucine treatment of 0.1 g / kg body weight was provided from 3 weeks of age. Front step cycle refers to the mouse’s front limbs, hind step cycle to the mouse’s rear limbs, and average step cycle takes into account all of the mouse’s limbs. The asterisks (* / ** / ***) indicate p-values of\<0.05 / 0.01 / 0.001 versus untreated Sandhoff mouse. Data shown is mean ± Stdev.Thus, acetyl-leucine treatment was associated with a faster step cycle in the Sandhoff mouse model, which may indicate improvement in motor function. Conclusions These studies demonstrate that acetyl-leucine treatment of a mouse model of Sandhoff disease may give rise to improvements in motor function as assessed by two independent experiments, as well as significantly increased lifespan. Example 4 GM2 gangliosidoses are a group of lysosomal storage disorders arising from defects in β- hexosaminidase activity. The group encompasses Tay-Sachs disease, Sandhoff disease, and the AB variant of Tay-Sachs disease. Fibroblasts derived from GM2 patients (Tay-Sachs disease, Sandhoff disease, and the AB variant of Tay-Sachs disease) and healthy controls were treated with acetyl-DL-leucine (1 mM for 6 days) prior to extraction and quantification of glycosphingolipid (GSL) levels via high performance liquid chromatography (HPLC). In the absence of treatment, fibroblasts derived from all 3 varieties of GM2 gangliosidosis demonstrated elevated GSL levels when compared to untreated wild-type controls. In all 3 cases, treatment with acetyl-DL-leucine (1 mM for 6 days) was associated with a reduction in GSL storage. In the case of Tay-Sachs disease, this decrease was statistically significant (p<0.05). In the case of Sandhoff disease and the AB variant of Tay-Sachs, there was a trendtowards decreased GSL levels associated with treatment. Data presented in Figures 8A – 8Cshow the results of the treatment for each cell line, respectively, with GSL levels adjusted for protein content and expressed as fold change relative to levels in untreated wild-type fibroblasts. Example 5 Patient 1 The patient in this case study was a 28 year-old male who was genetically diagnosed with Tay-Sachs disease and who exhibited dysarthrophonia, tremor, ataxia of stance and gait, paraparesis and muscle atrophies. In particular, the patient was not able to stand or walk, could do single steps with strong support, and had distinct postural instability, ocular movement disorder, dysphagia and dysarthria, and mild cognitive function disorder. First symptoms were observed at the age of 16 years. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 15.5 / 40. In addition, results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): 21.6 s MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 48.3 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 44.9 s MW PATA Word Test: 20 Montreal Cognitive Assessment (MoCA): 18 / 30 Video of the patient was also recorded for later comparison. The day following this examination, the patient was started on therapy with acetyl-leucine, at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week onwards. After one month and four months, respectively, the patient was re-examined while continuing treatment. After one month, the patient had improved fine motor skills and reduced hand tremor, for example while eating or drinking. Walking was not markedly changed. After four months, the patient was in stable condition with slightly improved cognitive function but had deterioration of stance, gait and fine motor function. The patient’s SARA scores and results from the patient’s SCAFI analyses are shown below compared to baseline. Baseline After one month withAfter 4 months with acetyl-DL-leucine acetyl-DL-leucine SARA 15.5 / 40 15.5 / 40 17 / 408MWT 21.6 sec 7 sec 25.49 sec9HPTD 48.3 sec 45.9 sec 48.67 sec9HPTND 44.9 sec 40.1 sec 47.09 secPATA 20 22 21MoCA 18 / 30 21 / 30 22 / 30Table 1. Patient Evaluation ParametersOverall, the patient exhibited an improvement in symptoms following acetyl-leucine treatment. Patient 2 The patient in this case study was a 32 year-old female who was genetically diagnosed with Tay-Sachs disease and who exhibited ataxia of stance and gait, fine motor impairment, paraparesis of lower extremities, and muscle atrophies. In particular, walking was notpossible without support, and the patient suffered from dysphagia and speech disorder,ocular movement disorder, and mild cognitive function disorder. First symptoms were observed at the age of 7 years. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 10.5 / 40. In addition, results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): 12.5 s MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 21.5 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 35.5 s MW PATA Word Test: 18 Montreal Cognitive Assessment (MoCA): 21 / 30 Video of the patient was also recorded for later comparison. The day of the examination, the patient was started on therapy with acetyl-leucine at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week onwards. After one month, the patient was re-examined while continuing treatment and showed increased enunciation, improved postural stability, and enhanced cognitive function. Stance and gait were possible without support. The patient’s SARA score and results from the patient’s SCAFI analysis are shown below compared to baseline. Baselin After one month with acetyl-DL- e leucine SARA 10.5 / 40 5 / 408MWT 12.5 sec 9.55 sec9HPTD 21.5 sec 34.97 sec9HPTND 35.5 sec 39.34 secPATA 18 17MoCA 21 / 30 25 / 30Table 2. Patient Evaluation ParametersPatient 3 The patient in this case study was an 8 year-old male who was genetically diagnosed with Tay-Sachs disease and who had epileptic cramps (tonic-clonic, about 10 seconds, self- limiting) almost every day before falling asleep, ocular movement disorder, anarthria, distinct problems in cognitive function and concentration (neurological examination was not possible), was not able to stand or walk by himself, and was very limited in daily activities (eating, washing or dressing himself was not possible). First symptoms were observed at the age of 9 months. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 36 / 40, a mRDS score of 18 / 24, a EQ-5D-5L visual scale of 50, and a 8MWT of 18.1 (only with strong support). The patient was started on therapy with acetyl-leucine at a dose of 1.5 g per day for the first week, followed by a dose of 3 g per day for the second week onwards. After one month, the patient was re-examined while continuing treatment and showed increased fine motor skills (was able to grab small things), increased motivation (tried more often to walk by himself), improved postural stability, gait and stance, and could speak single words. The patient’s SARA, mRDS, EQ-5D-5L visual scale, and 8MWT scores are shown below compared to baseline. Baseline After one month on acetyl-DL-leucine SARA 36 / 40 33 / 40mRDS 18 / 24 16 / 24EQ-5D-5L visual50 60scale8MWT 18.1 (only with strong11.75 (with support of one arm) support)Table 3. Patient Evaluation ParametersExample 6 The patient in this case study was a 13 year-old male who was genetically diagnosed with GM1 Gangliosidosis and who was not able to stand or walk by himself, was very limited indaily activities (eating, washing, dressing himself was not possible), and had ocularmovement disorder, anarthria, and distinct problems in cognitive function and concentration (neurological examination was not possible). First symptoms were observed at the age of 2 years. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 35 / 40, a mRDS score of 15, and a EQ-5D- 5L visual scale of 50. The patient was started on therapy with acetyl-leucine at a dose of 1.5 g per day for the first week, followed by a dose of 3 g per day for the second week onwards. After one month, the patient was re-examined while continuing treatment and showed a stable general condition, increased gait (more fluent), and stable stance in natural position. The patient’s SARA, mRDS, and EQ-5D-5L visual scale scores are shown below compared to baseline. Baseline After one month on acetyl-DL-leucineSARA 35 / 40 35 / 40mRDS 15 16EQ-5D-5L visual50 60scaleTable 4. Patient Evaluation ParametersExample 7 Patient 1 The patient in this case study was a 73 year-old male who had previously been diagnosed with amyotrophic lateral sclerosis (ALS). The patient’s symptomatology was characterised by progredient dysarthria (nasal and slurred speech) and weakness of the right dorsiflexor with consequent foot drop over the course of the previous three years. Clinically, the patient showed bulbar speech, a 3 / 5 paresis of the right foot-dorsiflexors and big toe-lift, generalised exaggerated reflexes and spastic tone increase of the right lower limb. EMG showed spontaneous activity and cMRT did not show any pathology. The patient was started on medication with Riluzol around the time of ALS diagnosis. However, the clinical symptomatology remained unchanged. The patient was then started on therapy with acetyl-DL-leucine, at a dose of 3 gram per day for the first week, then a dose of 5 gram per day for the second week onwards. The results were documented by video. After 15 days of treatment, a medical examination was conducted in which the patient reported significant improvement of speech. The patient was able to speak more fluently and was able to modulate his voice better compared to pre-medication (which was documented by video). After a further 20 days, a further medical examination was conducted in which the patient reported further improvement of speech. In addition, the patient reported improvement of gait. The paresis of the right foot-dorsiflexors and consequently the foot drop had improved dramatically and were clinically hardly detectable. In addition, the patient reported an improvement in sleep: falling asleep much quicker, sleeping longer and feeling clearly more rested in the morning. The patient continued on the treatment for approximately another 30 days. About 7 days after the patient stopped treatment, a medical examination was conducted in which the patient reported no further subjective improvement of either speech or paresis of the right dorsiflexor. Sleep had also deterioriated. After about 1-2 additional weeks off the acetyl- leucine treatment, the patient reported deterioration of speech. The patient resumedtreatment at that time and, about two months later, reported stable symptomatology.Compared to the at the time when acetyl-leucine treatment was first initiated, a slight deterioration of speech could be observed. As the patient had not observed any improvement of speech, the patient asked to stop the medication. Approximately 2-3 weeks later, the patient again reported deterioration of speech after discontinuation of acetyl-DL-leucine treatment. The patient resumed treatment and reported improved symptomatology, in particular speech. Overall, the patient exhibited an improvement in symptoms following acetyl-leucine treatment. Patient 2 The patient in this case study was a 74 old male who had been previously diagnosed with ALS. The patient’s symptomatology was characterised by progredient dysarthria (nasal and slurred speech) and concomitant dysphagia, and weakness while walking for over a year, and a paresis of the left upper limb for approximately four months. EMG had shown generalised polyphasic activity and chronic neurogenic impairment in the bulbar, cervical and lumbar segment. Clinical examination of the patient showed severe dysarthria, hypomotility of the tongue, 2 / 5-3 / 5 paresis of the left arm with impairment of fine motor skills, generalised exaggerated reflexes and fasciculations. Medication with Riluzol had been started one month earlier. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then a dose of 5 g per day for the second week onwards. After approximately 2 months, the patient was re-examined and he reported progredient deterioration of the motor function of the left hand, but a discrete improvement of walking. In addition, swallowing functions have remained stable. Patient 3 The patient in this case study was a 66 year old male who had been previously diagnosed with ALS. The patient’s symptomatology was characterized by progredient weakness and atrophy of both proximal upper extremities, slight impairment of fine motor skills, and generalized fasciculations and cramps. EMG had shown pathologic spontaneous activity and chronic neurogenic change, MRT of the brain and cervical column did not show any pathology . Medication with Riluzol was started. About two months later, a clinical examination showed a 3 / 5 to 4 / 5 paresis of both shoulders and proximal arms and a slowing of fine motor scills, generalized fasciculations, and normal reflexes. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then a dose of 5 g per day for the second week onwards. After one month, the patient did not report improvement of symptomatology, with no improvement of muscle force of upper limbs. Medication with acetyl-DL-leucine was suspended and the patient was asked to report worsening of symptomatology. Patient 4 The patient in this case study was a 66 year old male who had been diagnosed with ALS. The patient’s symptomatology was characterized by progressive weakness and atrophy of both proximal upper extremities, slight impairment of fine motor skills, and generalized fasciculations and cramps. EMG showed pathologic spontaneous activity and chronicneurogenic change. MRT of the brain and cervical column did not show any pathology.Treatment with riluzole was started. A clinical examination showed a 3 / 5 to 4 / 5 paresis of both shoulders and proximal arms, a slowing of fine motor scills, generalized fasciculations, and normal reflexes, and an ALS-FRS score of 44 / 48. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then a dose of 5 g per day for the second week onwards. After about one month, the patient reported subjective improvement of dysphagia and less hypersalivation. His relatives reported improved and more vital facial expression. Weakness of limbs was unchanged. Therapy was suspended and, 10 days later, the patient reported worsening of symptomatology, particularly subjective deterioration of dysphagia and hypersalivation. The patient resumed continuous treatment. The patient was re-evaluated about 8 weeks later and symptomatology remained stable. The patient’s ALS-FRS score was 43 / 48. Compared to symptomatology around the time of diagnosis, there was only a slight progression of weakness of gait and upper limbs. Example 8 Acetyl-leucine treatment was demonstrated to give rise to improvements in 3 patients who had been diagnosed with multisystemic atrophy cerebellar type (MSA-C). Patient 1 Patient 1 in this case study was a female in her late 50s who had shown progressive ataxia with speech problems and walking problems for the previous three years. Clinical examination of the patient revealed central cerebellar ocular motor signs, moderate dysarthrophonia, mild limb ataxia, and moderate ataxia of stance and gait. Furthermore, aMRI of the patient showed atrophy of the cerebellum and the brainstem, in particular of thepons and mesencephalon. The patient was accordingly diagnosed as having MSA-C. The patient was started on treatment with acetyl-DL-leucine, at a dose of 5 g per day (2 g upon waking, 1.5 g prior to lunch and 1.5 g prior to the evening meal). After one week of treatment the patient already showed a significant improvement in speech. Patient 2 The patient in this case study was a 77 year-old male who had been diagnosed with MSA-C. The patient’s symptomatology was characterised by progressive difficulties of walking and insecure gait with a tendency to fall (the patient fell approximately 10 times a month). The patient exhibited dizziness, hypokinetic-rigid syndrome, saccadic eye movements, dysmetria in the coordination test, and autonomic dysfunction, for example erectile dysfunction, orthostatic hypotension and incomplete bladder emptying over the course of the last four years. Before treatment was commenced, the patient’s symptoms remained unchanged over at least a three-month period. The patient was started on treatment with acetyl-DL-leucine at a dose of 3 gram per day for the first week, followed by a dose of up to 5 gram per day. After 3 weeks of treatment, a further examination was carried out. The patient and his wife reported significant improvement of gait: the patient walks more securely and the falls completely stopped. In addition, dizziness experienced by the patient substantially improved. The patient was instructed to stop the medication and after one week the patient reported a deterioration of gait and dizziness. The patient reported feeling more insecure walking, with a strong tendency to fall. The patient was then instructed to restart the medication, which he continued for a further 40 days and then again stopped. During clinical examination 7 days after stopping the medication, the patient confirmed progressive deterioration of gait and dizziness two days after stopping the treatment, and a very strong tendency to fall 5 days after stopping the treatment. The patient subsequently returned to continuous treatment. Patient 3 The patient in this case study was a 76 year-old male who had been diagnosed with oligosymptomatic MSA-C. The patient’s symptomatology was characterised by progressive difficulties in walking and insecure gait (without falls), as well as dizziness. Clinically, the patient showed saccadic eye movement and dysmetria in the coordination tests. cMRI showed an atrophy of the mesencephalon, and FDG-PET of the brain showed areduced metabolism of the striatum and cerebellum. The patient’s posturography test resultswere pathological with a high tendency to fall. Before treatment was commenced, the patient’s clinical symptomatology remained unchanged over at least a one-year period. Gait analysis was performed, which showed atactic gait, and reduced speed and increased track width compared to the normal range, and fluctuations of gait. The patient was thenstarted on treatment with acetyl-DL-leucine at a dose of 3 gram per day for the first week,followed by a dose of 5 gram per day for the second week onwards. After one month of treatment, a further examination was carried out. Gait analysis showed an improvement of gait speed, and reductions of track width and gait fluctuations. Shortly after After 27 days Normal range (± commencing of treatment SD) treatment Speed (cm / sec) 72 106 110.81 (18.33)Max. speed (cm / sec)183 208 158.30 (22.66)Cadence (steps / minute)101 113 109.19 (12.75)Track width (cm) 16.8 14.6 9.06 (1.94)Step cycle length (cm)87 113 121.81 (11.52)Double stance (%) 32.5 27.3 20.73 (2.55) Coefficient of variation (temporal)3.3 3.1 1.94 (0.85)Functional Gait Assessment21 / 30 20 / 30 24.9 (3.6)Table 5. Gait analysis parameters.The patient was instructed to stop the medication and he reported progressive deterioration of gait and dizziness approximately two to three weeks after stopping the medication. The patient subsequently returned to continuous treatment and symptomatology re- improved. Treatment was again suspended and the patient was evaluated three weeks later.The patient reported deterioration of symptoms, especially dizziness. Gait analysis showedan increased gait width comparable to pre-therapy status: After 20 days of re-suspending treatment Speed (cm / sec) 106Max. speed (cm / sec) 197Cadence (steps / minute) 112Track width (cm) 17.5Step cycle length (cm) 115Double stance (%) 27.1Coefficient of variation (temporal) 2.5Functional Gait Assessment 22 / 30Table 6. Gait analysis parameters.Example 9 The patient in this case study was a 59 year-old male with progredient personality change characterised by apathy, lethargy and indifference. In addition, the patient showed a mainlyleft-side hypokinetic-rigid syndrome with impairment of fine motor skills and reducedresonation of left arm. Furthermore, the patient showed generalised bradykinesia and gait disorder with small steps and 2-3 falls per month. The patient also shows slurred speech and cognitive deficits concerning psychomotoric slowing and reduced semantic word fluency. The patient was diagnosed with frontotemporal dementia with parkinsonism and Datscan revealed a reduction of dopamine receptors supporting the diagnosis. FDG-PET of the brain showed a mainly frontal reduced metabolism. The patient exhibited little improvement during treatment with L-Dopa and Ropinirol. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 gram per day for one week, then a dose of 5 gram per day for 4 weeks. After approximately one month of acetyl-leucine treatment, medication was stopped and the patient was re-examined 13 days later. The patient and his wife and daughter reported a significant improvement of gait under therapy with acetyl-leucine and in addition the patient’s falls stopped. The patient alsoexhibited an improvement of speech, which was less slurred, more comprehensible andsubjectively much more controlled. After suspension of treatment the symptoms worsened. Example 10 The patient in this case study was a 75 year-old male with progressive insecure gait disorder and dizziness leading to backward falls. In addition, the patient presented a mainly left-sided hypokinetic-rigid syndrome with apraxia and alien-limb phenomenon. The patient was diagnosed with corticobasal syndrome. A Datscan revealed a reduction of dopamine-receptors and an MRI showed an atrophic motorcortex of the right hemisphere supporting the diagnosis. The patient exhibited no improvement during treatment with L-Dopa. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. Gait analysis was performed before treatment commenced. After 20 days of acetyl-leucine treatment, the patient was re-examined. An improvement of dizziness symptoms and significant reduction in the frequency of falls was noted. Before After 20 days Mean (± SD) treatment of treatment Speed (cm / sec) 63 92 110.81 (18.33)Max. speed (cm / sec) 131 152 158.30 (22.66)Cadence (steps / minute)90 106 109.19 (12.75)Track width (cm) 12.1 12.3 9,06 (1.94)Step cycle length (cm) 84 104 121.81 (11.52)Double stance (%) 29.8 26.6 20.73 (2.55)Coefficient of variation (temporal)3.9 3.4 1.94 (0.85)Functional Gait Assessment13 / 30 18 / 30 24.9 (3.6)Table 7. Gait analysis parameters.There was an objective improvement in gait analysis parameters, for example in speed, maximal speed, cadence and reduced double stance (Table 2 and Figure 9). After 8 weeks of acetyl-leucine treatment, medication was stopped and the patient was re- examined 6 days later. The patient reported an increase of dizziness symptoms two days after suspension of treatment (the sensation of being drunk). The patient subsequently returned to continuous treatment. Example 11 Patient 1 The patient in this case study was a 76 year-old female with dizziness, which mainly occurred while walking. No falls were reported. The patient also exhibited gait disorder with small steps and generalised bradykinesia and vertical gaze palsy with impairment of fine motor skills. The patient was diagnosed with progressive supranuclear palsy. Datscan revealed a reduction of dopamine-receptors and FDG-PET of the brain showed a mainly frontal reduced metabolism, supporting the diagnosis. The patient exhibited little improvement during treatment with L-Dopa. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for one week, then a dose of 5 g per day for 4 weeks. After 27 days of acetyl-leucine treatment, medication was stopped and the patient was re-examined 60 days later. The patient reported a significant reduction of dizziness and slight improvement of gait under therapy with acetyl-leucine. After suspension of treatment, the symptoms worsened. The patient was re-examined about two months later and reported a stable symptomatology of underlying progressive supranuclear palsy; there was no clinical progression. The PSPRS Score remained stable, and the reduction of dizziness was still significant. Patient 2The patient in this case study was a 66 year-old female with symmetric hypokinetic-rigidsyndrome, gait disorder with insecure and small steps (strong tendency to fall) and vertical gaze palsy with impairment of fine motor skills. The patient was diagnosed with progressive supranuclear palsy. Datscan revealed a reduction of dopamine-receptors and FDG-PET of the brain showed a mainly frontal reduced metabolism, supporting the diagnosis. There was no levodopa response. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. Gait analysis was performed before treatment commenced. After 17 days of treatment, medication was stopped and the patient was re-examined 4 days later. The patient reported no significant improvement of gait or hypokinetic rigid syndrome. -BeforeAfter 17 days of Normal values (± SD) treatment treatment speed (cm / sec) 51 68 119.12 (17.27)Max. speed (cm / sec) 123 98 176.78 (19.10)cadence (steps / minute) 93 99 113.06 (10.38)Track width (cm) 10.3 9.3 9.49 (3.56)Step cycle length (cm) 66 82 126.71 (13.06)Double stance (%) 34.5 28.6 20.35 (3.21)Coefficient of variation (temporal)8.5 6.6 1.76 (0.73)Functional Gait Assessment 15 / 30 15 / 30 27.1 (2.3)Table 8. Gait analysis parameters.The patient was reevaluated about two months later and reported no deterioration ofsymptoms after stopping medication. Patient 3The patient in this case study was a 56 year-old male with symmetric hypokinetic-rigidsyndrome, insecure and history of falls and vertical gaze palsy with impairment of fine motor skills. The patient was diagnosed with progressive supranuclear palsy. Datscan revealed a reduction of dopamine-receptors and FDG-PET of the brain showed a frontomesial and parietotemporal reduced metabolism, supporting the diagnosis. There was no levodopa response. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. Gait analysis was performed before treatment commenced. After 17 days of treatment, medication was stopped and the patient was re-examined 4 days later. The patient reported no significant improvement of gait or hypokinetic rigid syndrome. -BeforeAfter 17 days of Normal values (± SD) treatment treatment speed (cm / sec) 103 120 125.34 (20.66)Max. speed (cm / sec) 163 194 180.07 (26.57)cadence (steps / minute) 106 112 115.27 (12,02)Track width (cm) 15.5 15.1 9.12 (2.97)Step cycle length (cm) 118 129 130.34 (13.01)Double stance (%) 25.8 24.3 19.65 (2.75)Coefficient of variation (temporal)3.6 3.1 1.77 (1.04)Functional Gait Assessment 28 / 30 27 / 30 28.4 (1.6)Table 9. Gait analysis parameters.The patient was reevaluated about two months later and reported no deterioration of symptoms after stopping medication. Patient 4 The patient in this case study was a 76 year-old male with progredient gait disorder, insecure and small steps (strong tendency to fall), camptocormia, slow and hypometric saccades, blepharospasmus and impairment of fine motor skills. The patient was diagnosed with progressive supranuclear palsy. MRI showed discreet atrophy of the mid brain (Mickey Mouse sign). There was a slight levodopa response. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. Gait analysis was performed before treatment commenced.After three weeks of treatment, medication was stopped and the patient was re-examined.The patient reported gait with increased subjective security and with reduced frequency of falls. Gait analysis showed improvement of gait with increased speed, max. speed, and step cycle length and reduction of track width, double stance and coefficient of variation. Before After 3 weeks of Normal values (± SD) treatment treatment speed (cm / sec) 39 65 110.81 (18.33)Max. speed (cm / sec) 70 93 158.30 (22.66)cadence (steps / minute) 109 125 109.19 (12.75)Track width (cm) 15.4 13.6 9.06 (1.94)Step cycle length (cm) 43 63 121.81 (11.52)Double stance (%) 45.4 36 20.73 (2.55) Coefficient of variation 6.8 (temporal) 8.2 1.94 (0.85) Functional Gait 14 / 30 Assessment 24.9 (3.6)Table 10. Gait analysis parameters.After three months without medication, the patient reported a progression of hypokinetic- rigid syndrome. Gait worsened, with more frequent falls. Example 12 Patient 1 The patient in this case study was a 42 year-old male engineer who had suffered from dizziness and postural imbalance for almost one year. The patient was diagnosed with downbeat nystagmus: the patient was severely impaired by blurred vision (oscillopsia) due to the nystagmus, and experienced difficulties while reading and writing. The patient’s visual acuity was: right 0.75, left 0.67, binocular 0.83, and the downbeat nystagmus was documented by video-oculography. The patient also exhibited increased body sway, which was documented by posturography. Treatment with 4-aminopyridine (Fampyra, 10 mg twice daily) for four weeks did not give rise to any benefit.The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day (1 gupon waking, 1 g prior to lunch and 1 g prior to the evening meal) for one week, then a dose of 5 gram per day (2 g upon waking, 1.5 g prior to lunch and 1.5 g prior to the evening meal). After 10 days, the patient reported significant benefit and that the effect developed slowly. The patient continued with this treatment dosage, and no side-effects resulted. A temporary suspension of the medication led to a considerable deterioration. The patient was re-examined approximately 14 weeks after starting acetyl-leucine treatment, during which the patient reported to be very happy with the benefit. The patient’s reading and writing were much better, because of reduced oscillopsia: the image of the visual surrounding was stable. The patient was able to suppress the nystagmus by visual fixation. In addition, the patient’s spatial orientation was improved. Clinical examination by two independent examiners revealed a reduction of the nystagmus and video-oculography showed that the patient could suppress the nystagmus by visual fixation. The patient’s visual acuity was: right 0.83, left 1.0, binocular 1. Posturography demonstrated a reduction of postural sway. Overall, this case study demonstrates improvement in the patient’s symptoms for this indication. Patient 2 The patient in this case study was diagnosed with downbeat nystagmus. The patient showed postural imbalance and dizziness. The patient did not benefit from Fampyra®. The patient began taking acetyl-DL-leucine (3 g / day for the first week; 5 g / day thereafter) and subsequently showed improvement of gait, with the ability to walk much longer distances (one hour), and improved alertness. The patient’s downbeat nystagmus also improved (documented by video-oculography). The patient could partially suppress the nystagmus by visual fixation, as evaluated using a target center (dot presented in the center of a display for 30 seconds, Figure 13A) and in complete darkness using goggles covered with special glasses for 45 seconds (Figure 13B). The results (median of slow phase velocity, SPV) were as follows: Target Center—horizontal: -0.02 ° / s, vertical: 2.41 ° / s; Complete Darkness— horizontal: 0.05 ° / s, vertical: 3.27 ° / s (Figure 13C). The patient was able to minimize eye movements while fixating, as shown in Figure 13A. Gait analysis showed an increase of self-chosen velocity from 56 to 85 cm / sec and maximal gait velocity from 122 to 155 cm / sec. Medication was then suspended. About one month after stopping acetyl-DL-leucine treatment, the patient’s symptomatology worsened. Gait analysis showed a decrease of self-chosen velocity from 85 to 72 cm / sec and maximal gait velocity from 155 to 113 cm / sec. Example 13 Patient 1 The patient in this case study was a 70 year-old female with mainly right sided hypokinetic- rigid syndrome and tremor, antecollis, frequent falls, orthostatic dysfunction and urge incontinence. The patient was diagnosed with with multiple system atrophy Parkinson type (MSA-P). Datscan revealed a mainly left sided reduction of dopamine-receptors and FDG-PET of the brain showed a mainly parieto-occipital reduced metabolism. There was a discreet Levodopa response (100 / 25mg 3 x daily). The patient began taking acetyl-DL-leucine (3 g / day for the first week; 5 g / day thereafter). After 3 weeks on acetyl-DL-leucine, the patient was evaluated and reported no significant improvement of gait, reduction of falls or improved hypokinetic rigid-syndrome. Medication was stopped. 6 weeks later the patient did not report deterioration of symptoms after stopping medication. Patient 2 The patient in this case study was a 78 year-old male diagnosed with multiple system atrophy Parkinson type (MSA-P). The patient’s symptomatology was characterized by a progressive hypokinetic-rigid syndrome, orthostatic dysfunction and consecutive dizziness and balance disorder. The patient showed saccadic eye movement and symmetric rigor of both upper limbs. Balancing on an imaginary tightrope was associated with insecureness and loss ofbalance. FDG-PET of the brain showed a reduced metabolism of both parietal and occipitalcortex, suggestive for Lewy-Body-Dementia. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. The patient was examined before initiation of treatment and showed the clinical symptomatology described above, with very pronounced insecure gait and dizziness. After one month of treatment, medication was stopped and the patient was evaluated. The patient reported subjective improvement of dizziness and clinical examination showed improved balancing on an imaginary tightrope, which the patient performed without any difficulties compared to the prior examination. Gait analysis was performed. After one month without medication, the patient reported stable symptomatology. No worsening of dizziness or insecurity of gait was reported. Gait analysis was performed. After two months without medication, a gait analysis was performed and showed reduction of velocity of gait, reduction of step length and worsening of FGA-Score. The patient reported aworsening of general symptomatology, including progressive weakness of legs and increasedinsecureness of gait. After 1 month After 1 month After 2 Normal values of treatment without months (± SD) treatment without treatment speed (cm / sec) 109 114 94 110.81 (18.33)Max. speed (cm / sec) 214 196 177 158.30 (22.66)cadence (steps / 1minute) 10909 106109.19 (12.75) Track width (cm) 3.8 2.3 3.4 9.06 (1.94)Step cycle length126 107(cm) 120 121.81 (11.52) Double stance (%) 25.6 22.5 26.7 20.73 (2.55)Coefficient of1.7 2.1variation (temporal) 2.7 1.94 (0.85) Functional Gait25 / 30 22 / 30Assessment 24 / 30 24.9 (3.6)Table 11. Gait analysis parameters.Patient 3 The patient in this case study was a 78 year-old male diagnosed with multiple system atrophy Parkinson type (MSA-P). The patient’s symptomatology was characterized by progressive hypokinetic-rigid syndrome, urinary incontinence, incipient cognitive dysfunction, and gait disorder with small steps and 2-3 falls per month. Cognitive deficits were characterized by psychomotoric slowing and intermittent mental confusion. Datscan revealed a reduction of dopamine-receptors, which supported the diagnosis. FDG-PET of the brain showed a mainly striatal reduced metabolism. Levodopa therapy was suspended due to side effects. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. The patient evaluated after one month on acetyl-DL-leucine. The patient’s wife reported a significant improvement of cognitive function. Episodes of mental confusion completely disappeared. The patient’s cognitive structure seemed much clearer and straighter. There was no improvement of gait function. The patient’s wife supported continuing the medication. Example 14 The patient in this case study was a 45-year-old male diagnosed with spinocerebellar ataxia 28 (SCA 28). Genetic testing showed a known pathogenic variant in AFG3L2. The patient’s symptomatology was characterized by progressive cerebellar syndrome since the age of 30, characterized by slurred speech, unstable gait, balance disorder and dizziness. The patient’s father and grandmother suffered from a similar symptomatology. The patient showed saccadic eye movements and dysmetria in the coordination tests, ataxic gait, slurred speech, exaggerated reflexes of the lower limbs, spasticity of the lower limbs and a positive Babinski sign on the left. cMRI showed a marked atrophy of the cerebellum. The patient was started on treatment with acetyl-DL-leucine at a dose of 5 g per day. A gait analysis was performed before treatment commenced. After about one month of treatment, medication was stopped and the patient was evaluated. The patient reported an improvement of the symptomatology, in particular reduced dizziness (almost vanished), and a more stable gait. The patient reported that he no longer walked like a robot and could climb the stairs without using the banisters. A gait analysis was performed, which showed an improvement of parameters. Before After treatment Standard values (± SD) treatment for one month Self-chosen speed (cm / sec)101 118 126.61 (21.43)Maximum speed (cm / sec) 188 201 182.94 (25.37)Cadence (steps / minute) 100 105 115.52 (9.36)Track width (cm) 14.5 11.7 9.43 (2.27)Step cycle length (cm) 122 135 131.55 (17.98)Double stance (%) 24.9 23.8 18.76 (3.46)Coefficient of variation (temporal)4.1 2.1 1.88 (0.79)Functional Gait Assessment24 / 30 23 / 30 28.9 (1.5)Table 12. Gait analysis parameters.Example 15 Patients 1 & 2 The patients in this case study were 2 female siblings, 24 (Patient 1) and 19 (Patient 2) years old, respectively. The patients suffer from ataxia telangiectasia. Patient 1 showed delayed developmental milestones. The patient did not walk until 2 years of age and had progression of cerebellar ataxia signs and symptoms, seizures, together with generalized, distal pronounced hypertonia and telangiectasias on the eyes, ears, and chest. Diagnosis was established at the age of 9 years. Patient 1’s ocular motor function showed downbeat-nystagmus with gaze straight-ahead and in the gaze to the left greater than right, gaze-holding nystagmus upward, vertical and horizontal saccadic smooth pursuit, and hypometric saccades horizontally and vertically, with restricted motility upward. Before treatment was commenced, examination of Patient 1 indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 22 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): 21.8 s MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 90.2 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 125.8 s MW PATA Word Test: 12.5 Visual analog scale (as evaluated by the patient): 99 Results from video-oculography were: Slow phase velocity of the gaze-Horizontal Verticalholding nystagmusCentrum 0.54 6.9Vpravo -1.16 6.2Vľavo 12.2 12.6Nadol -0.14 6.9Nahor -0.39 5.95Table 13. Video-oculography parameters.Patient 1 began treatment with acetyl-DL-leucine (5 g / day) following examination. After one month of treatment, the patient was re-evaluated. Caregivers reported an improvement of speech and gait. The patient herself did not perceive any change. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 15.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): 18.5 s MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 77.9 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 101.3 s MW PATA Word Test: 13 Visual analog scale (as evaluated by the patient): 85 Results from video-oculography were: Slow phase velocity of the gaze-Horizontal Verticalholding nystagmusCenter 0.4 4.77Right -0.95 4.83Left 8.2 8.85Down -0.44 5.29Up 0.72 2.67Table 14. Video-oculography parameters.Patient 1’s SARA and SCAFI subsets improved after treatment, and video-oculography showed significant improvement of fixation stability and decrease of intensity of downbeat- nystagmus. Patient 2 showed delayed developmental milestones, seizure at the age of 1, generalized hypotonia, contractures of low extremities with pes equinovarus bilaterally, areflexia, acute lymphoblastic leukemia at the age of 3 years, slightly enlarged spleen, hypercholesterolemia, hypochromatic microcytic anemia, pigmental naevi, and vitiligo. First symptoms were noticed by the patient’s parents at the age of 15 months. Patient 2’s ocular motor function showed square wave jerks, gaze-holding nystagmus left greater than right with vertical component, downbeat-nystagmus, saccadic smooth pursuit, vertical gaze palsy upward greater than downward, and impaired convergence. Before treatment was commenced, examination of Patient 2 indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 28.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): not able to perform without support MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 300 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 299.2 s MW PATA Word Test: 13.5 Visual analog scale (as evaluated by the patient): 45 Results from video-oculography were: Slow phase velocity of the gaze-Horizontal Verticalholding nystagmusCenter -2 6.18Right -3.97 7.6Left -0.24 9.49Down -2.86 5.58Up -1.11 4.97Table 15. Video-oculography parameters.Patient 2 began treatment with acetyl-DL-leucine (5 g / day) following examination. After one month of treatment, the patient was re-evaluated. Caregivers reported an improvement of fine motor function, hand tremor, and speech. The patient herself did not perceive any benefit. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 23.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): not able to perform without support MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 300 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 300 s MW PATA Word Test: 14 Visual analog scale (as evaluated by the patient): 80 Results from video-oculography were: Slow phase velocity of the gaze-Horizontal Verticalholding nystagmusCenter -1.45 5.6Right -3.45 6.56Left 3.58 7Down -2.5 4.69Up -0.51 3.15Table 16. Video-oculography parameters.Video-oculography showed improvement of fixation stability and significant improvement of downbeat-nystagmus intensity in Patient 2. Patient 3 The patient in this case study was a 19 year old female suffering from ataxia telangiectasia from early childhood, having: -Delayed motor development, cerebellar ataxia signs and symptoms, pronounced axial hypotonia with acral hypertonia, severe contractures of feet with orthopedic deformities pes equinus et transversoplanus bilaterally and was thus confined to wheelchair, dysdiadochokinesis, and areflexia of low extremities with decreased proprioceptive perception; and -Non-Hodgkin lymphoma, polymorphism MTHFR (C677T), lymphangioma of the lower lip, cholecystolithiasis, dilated cardiomyopathy, pigmental naevi, thoraco- lumbar kyphoscoliosis, and scleral teleangiectasias on both eyes. The patient’s ocular motor function showed gaze-holding nystagmus to the right and to the left, saccadic eye movements, slow saccades to all directions, especially horizontally, pathological vestibulo-ocular reflex with corrective catch-up saccades, and pathological visual-fixation suppression of the vestibulo-ocular reflex. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 23 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): not able to perform MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 150 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 161.6 s MW PATA Word Test: 14 Visual analog scale (as evaluated by the patient): 80 Results from video-oculography were: Slow phase velocity of the gaze- Horizontal Vertical holding nystagmus [° / s]Center 3 -1.5Right -0.4 -1Left 7.3 2.5Down 2.4 -0.2Table 17. Video-oculography parameters.The patient began treatment with acetyl-DL-leucine (5 g / day) about six months after the examination. After slightly over 7 months of treatment, the patient was re-evaluated. Caregivers and patient reported general improvement of well-being, without clearer specification. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 21.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): not able to perform MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 124.5s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 147.5 s MW PATA Word Test: 10 Visual analog scale (as evaluated by the patient): 80 Results from video-oculography were: Slow phase velocity of the gaze-Horizontal Verticalholding nystagmus [° / s]Center -0.1 0.4Right -4.2 1.7Left 1.7 0.1Down -0.6 1.2Table 18. Video-oculography parameters.The patient showed slight improvement of SARA and SCAFI subset 9HPT, and significant improvement of fixation stability and decrease of intensity of gaze-holding nystagmus at all positions. Patient 4 The patient in this case study was a 15 year-old female suffering from ataxia telangiectasiafrom 4-years of age. From 7-years of age, the patient showed severe cerebellar ataxia signsand symptoms, fine motor impairment, muscular hypotonia with areflexia, muscular atrophy, and plantar flexion with discrete contractures. The patient was confined to a wheelchair, but was able to walk with constant support. The patient had severe hemolytic anemia, hypogammaglobulinemia, telangiectasias on the scleras and chest, Secondary Cushing syndrome due to corticosteroid intake, and was suspected of having CNS Non- Hodgkin lymphoma. The patient’s ocular motor function showed slow deviation of the eyes upward, left beating nystagmus in the central position, gaze-holding nystagmus in all directions, horizontally with downbeating component, startle with sudden head movement. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 23.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): not able to perform MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 124.5 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 52.3 s MW PATA Word Test: 14 Visual analog scale (as evaluated by the patient): 70 Results from video-oculography were: Slow phase velocity of the gaze- Horizontal Vertical holding nystagmus [° / s]Center -0.6 1.76Right 3.7 -0.1Left -6 0.6Down 5.7 2.7Table 19. Video-oculography parameters.The patient began treatment with acetyl-DL-leucine (5 g / day) following the examination. After slightly over 1 month of treatment, the patient was re-evaluated. The patient and her mother reported improvement in handwriting, especially due to decreased hand tremor and fine motor function. The patient also reported that drinking was easier and no longer needed a straw. Family members described improvement of gait, with increased stability and needing less support. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 18.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): not able to perform MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 93.5 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 101.7 s MW PATA Word Test: 15.5 Visual analog scale (as evaluated by the patient): 70 Results from video-oculography were: Slow phase velocity of the gaze-Horizontal Verticalholding nystagmus [° / s]Center -0.2 4.8Right -1 0.3Left -0.8 1.9Down -0.7 -2.3Table 20. Video-oculography parameters.The patient showed improvement of SARA and SCAFI subset 9HPT of the dominant hand. Video-oculography showed general improvement of fixation stability and decrease of intensity of spontaneous and gaze-holding nystagmus at all positions. Patient 5 The patient in this case study was a 10 year-old boy suffering from ataxia telangiectasia from his early childhood, having: -Delayed psychomotor development, instable walking at 14 months with increasedincidence of falls, severe cerebellar ataxia signs and symptoms, dysarthria and dyslalia, fine motor impairment, infrequent head tremor, slow psychomotor tempo, hypotonia with muscular atrophy and hyporeflexia, anteflexia of the head with kyphosis in the thoracal area, pedes transversoplani, scapullae allatae, parasomnia with pavor nocturnus, and autism; and -Significant immunosuppression, telangiectasias on the soft palate, scleras, incontinence, and asthenic habitus. The patient was confined to a wheelchair but was able to perform a few steps with strong constant support. The patient’s ocular motor function showed oculomotor apraxia with pronounced head anteflexia, head and eye movement “en bloc” when looking to the right and left, vertical gaze palsy with slow vertical saccades and saccadic smooth pursuit, slow horizontal saccades to the left, saccade palsy to the right, restricted eye motility, especially vertically, and fixation instability in all positions. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 24.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): not able to walk without constant support MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 102.7 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 116.8 s MW PATA Word Test: 6 Visual analog scale (as evaluated by the patient): 90 Results from video-oculography were: Slow-phase velocity (SPV) of fixation and gaze-holding nystagmus, [° / s] Horizontal Vertical Center 0.96 1.53Right 0.21 2Left 2.1 3.64Down 0.71 3.91Up 0.31 1.69Table 21. Video-oculography parameters.The patient began treatment with acetyl-DL-leucine (5 g / day) following examination. After about 1 month of treatment, the patient was re-evaluated. The patient’s mother described a significant improvement of stability of the gait; prior to the therapy, he was constantly falling backward and had to be partially “transported”. On medication, he was able to walk with only holding the caregiver´s hand. Fine motor function, the intensity of hand tremor, and body holding improved. Improvement of fine motor function was reflected in daily activities, such as eating and drinking independently. The patient gained 1.5 kg and had a better appetite. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 20.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): not able to walk without support MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 103.6 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 88.8 s MW PATA Word Test: 7.5 Visual analog scale (as evaluated by the patient): 80 Results from video-oculography were: Slow-phase velocity (SPV) of fixation and gaze-holding nystagmus, [° / s] Horizontal Vertical Center 0.79 3.54Right 1.17 2.36Left 1.22 2.53Down 0.62 1.08Up 0.33 1.71Table 22. Video-oculography parameters. After almost 7 months of treatment, the patient was again re-evaluated. The patient’s mother described significantly more stable gait; this finding remained constant from the first evaluation after treatment. The patient had improved concentration and speech. The patient could stand up on his own and was generally more independent with daily activities. The patient gained another 3 kg with improved appetite and showed improved strength. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 17.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): 15.3 s (holding of the hand) MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 92.4 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 98.3 s MW PATA Word Test: 11 Visual analog scale (as evaluated by the patient): 100 The patient was re-evaluated after slightly over a year of treatment and showed improved social interaction, activity, and agility. The patient’s parents reported improvement of incontinence. The patient developed a repeatedly occuring frontal localized pain with vomiting in the morning. Based on family history, it was suspected that the localized pain may be due to infantile migraine. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 16.5 / 40. Results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): 13.9 s (able to walk by himself, mother held hand) MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 95.6 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 127.6 s MW PATA Word Test: 14.5 Visual analog scale (as evaluated by the patient): 95 On treatment with acetyl-DL-leucine, the patient showed improved SARA and SCAFI subtests, increased quality of life, generally improved fixation stability and decrease ofintensity of spontaneous and gaze-holding nystagmus, especially in the vertical plane (after 1month). Patient 6 The patient in this case study was a 10 year-old female suffering from ataxia telangiectasia who had ataxic gait and stance, fine motor function disorder with hand tremor, dysphagia and speech disorder, ocular movement disorder, and problems with cognitive function and concentration. First symptoms were observed at the age of one year. After baseline examination, the patient started acetyl-DL-leucine treatment at 1.5 g / day for the first week and at 3 g / day for the second week onwards. The patient was evaluated after one month and six months of treatment, respectively. After one month of treatment, the patient showed increased fine motor skills with reduced hand tremor, improved postural stability and gait, increased enunciation, and increased self-confidence. After six months of treatment, the patient had stable general conditions, stable gait and stance, and improved handwriting. The patient, however, was suffering from anxiety, which would be expected to negatively influence the response. The patient’s SARA and SCAFI scores at each evaluation are shown below. Baseline After one month of acetyl-After six months of acetyl- DL-leucine treatment DL-leucine treatment SARA 11 / 40 8.5 / 40 11 / 408MWT 8.95 sec 8.45 sec 7.53 sec9HPTD 85.38 sec 81.95 sec 136.27 sec9HPTND 71.2 sec 70.39 sec 80.32 secPATA 14.5 15.5 13Table 23. Patient Evaluation parameters.Example 16 The patient in this case study was a female in her early 60s who was genetically diagnosed with Spinocerebellar Ataxia (SCA) 1. Before treatment, the patient had severe problems with speaking and swallowing, tremor of both arms, spasticity and moderate ataxia of stance and gait. The patient also had problems sleeping. Three weeks on medication with acetyl-DL-leucine (5 g / day), all symptoms significantly improved, as further demonstrated by clinical examination, including spasticity and impairment of ocular motor function. Three months later the medication was stopped. After two weeks, the intensity of the signs and symptoms were the same as before therapy. Treatment was started again, and the patienthas remained, and continues, on the treatment after over two years, on the same dosagewithout any side-effects. The patient’s daughter reported considerable progression of the disease over time with a persisting symptomatic effect, yet observed, anecdotally, that there was long-term symptomatic efficacy from treatment. Example 17 The patient in this case study was a 70 year-old female with insecure gait and frequent falls, visual hallucinations at night, REM-sleep disorder. The patient had symmetric hypokinetic- rigid syndrome with impairment of fine motor skills and fluctuations in attention and awareness. The patient was diagnosed with Lewy Body dementia. FDG-PET of the brain showed a synaptic dysfunction in the parietal and occipital lobe and DATscan showed a degeneration of presynaptic dopamine transporter, supporting the diagnosis. Treatment with Levodopa 100 mg 4 x daily and Quetiapin 25mg at night improved the symptomatology. The patient started taking acetyl-leucine (3 g / day for one week; 5 g / day thereafter) and was evaluated after four weeks. The patient reported increased fatigue and a deterioration of balance and speech. Medication was reduced to 3 g / day, and the patient was instructed to stop medication about two weeks later. The patient was re-evaluated about one month after ceasing medication and did not report improvement of symptomatology with the decreased dose and no deterioration of symptoms after stopping medication. -After 1 week onAfter 4 weeks on Normal value (± SD) acetyl-DL-leucine acetyl-DL-leucine speed (cm / sec) 55 56 119.12 (17,27)Max. speed (cm / sec) 92 74 176,78 (19,10)cadence (steps / minute) 81 85 113.06 (10,38)Track width (cm) 4.6 6.7 9,49 (3,56)Step cycle length (cm) 81 79 126.71 (13.06)Double stance (%) 36.1 38.7 20,35 (3,21)Coefficient of variation (temporal)9.1 8.8 1.76 (0.73)Functional Gait Assessment 11 / 30 27.1 (2.3)Table 24. Gait parameters.Example 18 In this case study, four patients (male siblings) suffered from, and were later diagnosed with, ataxia with oculomotor apraxia type 4. The older three siblings were 12, 11, and 10 years of age, respectively, at the time of disease onset. Prior to commencing treatment with acetyl- DL-leucine, by the age of 15 / 16 years, the three older siblings walked with an expedient, as reported by the patients’ mother. The older siblings began treatment with acetyl-leucine at 25, 23, and 19 years of age, respectively, and have been on the treatment for approximately four years. No long-term clinical data is available for these three patients. The youngest sibling was 11 years old at the time of onset. He began treatment with acetyl- DL-leucine at the age of 13. While on treatment, the youngest sibling did not walk with an expedient until nearly 18 years of age, as reported by the patient’s mother. The patient’s mother also reported that the youngest sibling had improved fine motor skills and improved speech at each age compared to his older siblings. No long-term clinical data is available for the youngest sibling. Example 19 An NPC patient’s severity may be quantified by assigning a clinical severity score (CSS),which assesses various parameters of the disease and gives each parameter a score out of 5(higher score = greater severity). See Yanjanin et al., “Linear Clinical Progression, Independent of Age of Onset, in Niemann–Pick Disease, Type C,” Am J Med Genet Part B 153B:132–140. In an untreated patient, one can typically predict how the CSS will change over time in an individual, as disease progression appears to be linear. For example, if Patient A moves from a CSS of 8 to a CSS of 12 between month 0 and month 12, it can be predicted that by month 36, the patient will have a CSS of 20. The annual severity increment score (ASIS) quantities the annual rate of change in the CSS, calculated by dividing the CSS of a patient by the patient’s age. For example, if untreated Patient B had a CSS of 8 at two years of age, the patient’s ASIS would be 4. Each year, the patient would be expected to progress by 4 CSS points, such that at 4 years of age, the patient’s CSS would be 16. If therapeutic intervention slowed or arrested disease progression, one would expect the patient to have a smaller ASIS score after such therapy than at baseline. Ten NPC patients were administered acetyl-leucine at 4.5 g / day over long durations. A CSS was determined at baseline, and at various time points, for eye movement, ambulation, speech, swallow, fine motor skills, cognition, memory, and seizures. An overall CSS was calculated at baseline and at each such time point by adding the individual CSS values for each parameter (eye movement, ambulation, etc.). The number of days post-initiation of therapy at which CSS was assessed was different for each patient, as shown in Table 25.Patient I.D Baseline (days) Time Point 2 (days) Time Point 3 (days) Time Point 4 (days)1 0 126 2312 0 119 200 2973 0 91 2404 0 107 1965 0 78 238 4146 0 184 238 4147 0 81 1658 0 90 2179 0 400 64410 0 83Table 25. Days post-initiation of acetyl-leucine administration at which CSS was assessedTables 26-34 below show each CSS for overall, eye movement, ambulation, speech, swallow, fine motor skills, cognition, memory, and seizures, respectively. Clinical Severity Score (CSS) Patient I.D Baseline Time Point 2 Time Point 3 Time Point 41 11 11 102 33 33 33 333 13 12 114 13 13 105 12 12 12 126 21 23 21 217 19 19 198 13 12 119 22 22 2110 14 11Table 26. CSS overall.Clinical Severity Score (CSS) Patient I.D Baseline Time Point 2 Time Point 3 Time Point 41 3 3 32 3 3 3 33 3 3 34 2 2 25 3 3 3 36 3 3 3 37 3 3 38 3 3 29 3 3 310 3 3Table 27. CSS eye movement.Clinical Severity Score (CSS) Patient I.D Baseline Time Point 2 Time Point 3 Time Point 41 2 2 12 5 5 5 53 1 1 14 2 2 15 1 1 1 16 2 4 2 27 2 2 28 1 1 19 2 2 210 2 2Table 28. CSS ambulation.Clinical Severity Score (CSS) Patient I.D Baseline Time Point 2 Time Point 3 Time Point 41 1 1 12 2 2 2 23 1 1 14 2 2 15 1 1 1 16 2 2 2 27 1 1 18 1 1 19 2 2 210 1 1Table 29. CSS speech.Clinical Severity Score (CSS) Patient I.D Baseline Time Point 2 Time Point 3 Time Point 41 0 0 02 4 4 4 43 2 2 24 2 2 25 2 2 2 26 3 3 3 37 3 3 38 2 2 29 3 3 310 2 2Table 30. CSS swallow.Clinical Severity Score (CSS) Patient I.D Baseline Time Point 2 Time Point 3 Time Point 41 1 1 12 5 5 5 53 2 1 14 1 1 15 1 1 1 16 4 4 4 47 2 2 28 2 1 19 4 4 410 1 1Table 31. CSS fine motor skills.Clinical Severity Score (CSS) Patient I.D Baseline Time Point 2 Time Point 3 Time Point 41 3 3 32 5 5 5 53 3 3 34 3 3 35 3 3 3 36 4 4 4 47 4 4 48 3 3 39 4 4 410 3 2Table 32. CSS cognition.Clinical Severity Score (CSS) Patient I.D Baseline Time Point 2 Time Point 3 Time Point 41 1 1 12 4 4 4 43 1 1 04 1 1 05 1 1 1 16 3 3 3 37 4 4 48 1 1 19 4 4 310 2 0Table 33. CSS memory.Clinical Severity Score (CSS) Patient I.D Baseline Time Point 2 Time Point 3 Time Point 41 0 0 02 5 5 5 53 0 0 04 0 0 05 0 0 0 06 0 0 0 07 0 0 08 0 0 09 0 0 010 0 0Table 34. CSS seizures.The ASIS at baseline and each time point was calculated using each patient’s CSS and age at the time of assessment. The overall ASIS for each patient at each time point is shown below in Table 35. Annual Severity Increment Scores (ASIS) Baseline Time Point 2 Time Point 3 Time Point 40.381371618 0.376864272 0.3392624931.94125463 1.904748736 1.880675612 1.8526360280.65 0.592617631 0.532504970.481909063 0.476731928 0.3634690020.433188377 0.429874461 0.423232908 0.4161602730.561964246 0.607297766 0.552333117 0.5454206070.536675431 0.533334614 0.5299137140.486750384 0.445200609 0.4029031290.738624874 0.71243018 0.6656469670.595597228 0.406038403Table 35. ASIS overall.As shown in Table 26 and Figure 10A, none of the ten patients showed an overall increase in CSS over the course of the experiment. Patient 6 showed an increased CSS between baseline and time point 2, but returned to baseline by time point 3 and remained there at time point 4. Four of the ten patients (Patients 2, 5, 6, and 7) had a constant CSS over the course of the experiment, indicating that the disease did not progress in these individuals. Six of the ten patients (Patients 1, 3, 4, 8, 9, and 10) showed a reduction in CSS over the course of the experiment, indicating that the disease did not progress and actually became less severe. Improvements were seen in different subscores: Patient 1: ambulation; Patient 3: fine motor skills; Patient 4: ambulation and speech; Patient 8: eye movement and fine motor skills; Patient 9: memory; Patient 10: cognition. Data presented in Figures 11A-11J show the CSS subscores for each patient, respectively, in the form of a bar graph. As shown in Table 35 and Figures 10B, all ten patients showed a reduction in ASIS during treatment relative to ASIS at baseline. In Patients 2, 5, 6, and 7, CSS remained the samewhile age increased, resulting in a small reduction in ASIS. In Patients 1, 3, 4, 8, 9, and 10,the reduction in ASIS was larger due to CSS decreasing while age increased. Example 20 The Niemann-Pick Disease Type C (NPC) mouse model shares a number of pathological features with Alzheimer’s disease (AD) as described herein. Wild type NPC1- / -mice were treated with acetyl-dl-leucine (0.1 g / kg body weight daily) from 3 weeks of age. Mice were sacrificed at 8 weeks of age. Levels of amyloid precursor protein C-terminal fragments (APP- CTFs) were evaluated relative to total amyloid precursor protein (APP) levels in the cerebellum for wild type, untreated wild type NPC1- / -mice, and AL-treated wild type NPC1- / -mice. Levels of microtubule-associated protein 1A / 1B-light chain 3- phosphatidylethanolamine conjugate (LC3-II) were also evaluated relative to levels of tubulin loading control for wild type, untreated wild type NPC1- / -mice, and AL-treated wild type NPC1- / -mice. The APP-CTF data is shown in Figure 12A. The data replicated the previously noted accumulation of APP-CTFs in the NPC1 mouse brain. Treatment with acetyl-dl-leucine was associated with lowering of APP-CTFs. The LC3-II data is shown in Figure 12B. The data replicated the previously noted accumulation of LC3-II in the NPC1 mouse brain. Treatment with acetyl-dl-leucine was associated with a lowering of LC3-II, indicative of a partial restoration of autophagic flux. Conclusion Acetyl-leucine treatment was associated with an improvement in AD pathology in the NPC1 mouse brain. Example 21 NPC Chinese Hamster Ovary (CHO) cells were treated in vitro for 72 hours with 1 mM of acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, DL-leucine, L-leucine, and D-leucine, respectively. Relative lysosomal volume was quantified via LysoTracker. The NPC CHO cells were observed to have elevated LysoTracker fluorescence levels relative to wild-type controls, which is indicative of increased lysosomal volume of the diseased phenotype. Treatment of the NPC CHO cells with each of acetyl-DL-leucine, acetyl-L-leucine, acetyl-D- leucine, DL-leucine, L-leucine, and D-leucine significantly reduced lysosomal volume in the cells. Data presented in Figure 14 show the results for each treatment, with lysosomal volume expressed as fold change relative to untreated wild-type fibroblasts. The asterisks (**) indicate a p-value of <0.01 versus untreated NPC1-null.The data shows that leucine and acetyl-leucine demonstrated similar activity in vitro andwere both associated with the rectification of disturbed lysosomal storage by reducing lysosomal volume and thus directly corrected a phenotype of lysosomal storage disorders. Example 22 Patient 1The patient in this case study was a 55-year-old female showing proximal weakness of thelower limb. She had a flexor paresis of the head slowly progressive since age 42 and had been diagnosed (genetically confirmed) with myotonic dystrophy type 2. Upon consultation at age 55, she reported no sensory symptoms but complained of a restless leg syndrome at night and during resting periods of the day, occuring over the course of the last two years. Pre- treatment with dopamine agonist were without symptom relief. Serum creatine kinaseactivity was only mildly elevated at up to 400 IU / L. The patient was evaluated using the RLSdiagnostic index (RLS-DI) (see Walters et al., Sleep Med 2003;4(2):121-132; ). The patient’sInternational Restless Legs Syndrome Rating Scale score (IRLS) was 36, and thus a severeRLS was diagnosed. The patient was started on therapy with acetyl-DL-leucine at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week onwards.Within 14 days on acetyl-DL-leucine, the IRLS dropped to 26, and after another 5 weeks, theIRLS declined to 9. Interruption of 4 weeks of the treatment after week 12 of the treatmentincreased the IRLS to 28. Re-introduction of the treatment re-declined the score to 8 after 2weeks. Continuation of treatment over more than 22 weeks stabilized the IRLS score at 8. Patient 2The patient in this case study was a 72-year-old female showing proximal weakness of thelower limb. She had a flexor paresis of the head slowly progressive since age 48 and had been diagnosed (genetically confirmed) with myotonic dystrophy type 215 years ago. Upon consultation at age 72, she reported no sensory symptoms but complained of a restless leg syndrome at night and during resting periods of the day, occurring over the course of the last eight years. Pre-treatment with dopamine agonist, L-dopa, pregabaline, and opiods were without sustained symptom relief. Serum creatine kinase activity was mildly elevated at 300 IU / L. Iron measurements and all additional lab investigations were normal. The patient wasevaluated using the RLS-DI and the patient’s IRLS was 32, and thus a moderate to severeRLS was diagnosed. The patient was started on therapy with acetyl-DL-leucine at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week onwards.Within 14 days on acetyl-DL-leucine, the IRLS dropped to 22, and after another 5 weeks, theIRLS declined to 7. Continuation of treatment over more than 28 weeks stabilized the IRLSscore at 8. Patient 3The patient in this case study was a 73-year-old male showing mild proximal weakness of theupper and lower limbs slowly progressive since age 50. The patient had been diagnosed (genetically confirmed) with McArdle myopathy about 16 years ago. Upon consultation atage 73, he reported no sensory symptoms but complained about a severe fatigue and reducedstamina. The patient further reported a restless leg syndrome at night and during resting periods of the day, occurring over the course of the last 12 years. Pre-treatment with dopamine agonist, L-dopa, pregabaline were without sustained symptom relief. Serumcreatine kinase activity was mildly elevated at 200 IU / L; however, the patient had 5 episodesof rhabdomyolysis during the past 20 years. Repeated iron measurements and all additional lab investigations were normal. The patient was evaluated using the RLS-DI and thepatient’s IRLS was 34, and thus a severe RLS was diagnosed. The patient was started ontherapy with acetyl-DL-leucine at a dose of 3 g per day for the first week, followed by a doseof 5 g per day for the second week onwards. Within 21 days on acetyl-DL-leucine, the IRLSdropped to 20, and after another 10 weeks, the IRLS declined to 10. Continuation oftreatment over more than 30 weeks stabilized the IRLS score at 10. In addition, the patient’sfatigue declined (Fatigue Severit Scale: 9 (minimum) to 63 (maximum)) from 53 to 28. Example 23The patient in this case study was a male 79 year-old subject, who suffered from REM SleepBehavior Disorder (RBD), hypokinetic type with intestinal hypokinetic disorder and RestlessLegs Syndrome (RLS). The patient was diagnosed with Parkinson’s disease.Patient suffered from the RBD in combination with the RLS since 2003, which was severeand considered to be a 10 on a scale from 1 – 10 before treatment with Acetyl-DL-leucine(AL). The patient began treatment with AL in March 2021, and received AL at a dosage of1500 mg at noon, and 3500 mg at night, resulting in a total daily dosage of 5 g AL.Within 2-3 weeks, significant and dramatic improvements could be detected. In contrast tothe state before AL therapy, patient under AL therapy was able to fall sleep immediatelywithout interruption, and had improvement of dreams for more than 6 months, including nocrying during night and no traumatic falling out of the bed combined with head injury. Patient also reported improvement of bladder incontinence. No adverse side effects were present. After administration of acetyl-leucine, the symptoms of Parkinson’s disease (PD) improvedsignificantly (the patient reported an “improvement of about 70%”). The evaluated andobserved improvements after 6 weeks treatment with acetyl-leucine included patient´s gaitand mobility, fluidity of patient´s arm movements, constipation (as a symptom ofParkinson’s disease), cognitive function, alertness and mood. The severity of PD symptomscan be measured with any suitable known scale, e.g. UPDRS. ConclusionAcetyl-leucine treatment was associated with a drastic improvement in PD symptoms.Example 24The patient in this case study was a male 83 year-old subject, who was diagnosed with earlyParkinson´s disease one year prior to starting therapy with acetyl-DL-leucine (AL) at a totaldaily dosage of 5 g AL. After 4 weeks, the subject noticed an improvement of his constipation.Constipation frequently occurs in PD patients due to improper functioning of the autonomicnervous system, and is a nonmotor symptom in the early stages of PD. Conclusion Acetyl-leucine treatment was associated with a improvement in early PD symptoms. Example 25 The patient in this case study was a 63 year-old female subject, who was diagnosed with Parkinson´s disease (PD) and under treatment regimen of 300 mg / day L-DOPA. After none year of the diagnosis and L-DOPA treatment, the patient was started on a therapy with acetyl-DL-leucine (AL) at a total daily dosage of 5 g AL per day. Patient suffered mainly from hypomimia, bradykinesia and rigor more on left, slight tremor more on the left.During treatment with acetyl-leucine, PD symptoms were stable for 22 months and treatmentis ongoing. There was also no need to increase the dosage of L-Dopa over this period of time.Acetyl-leucine was well tolerated. Patient under continuous treatment. ConclusionAcetyl-leucine treatment was associated with an improvement in PD symptoms.Example 26The patient in this case study was a 69 year-old male subject, who was diagnosed withParkinson´s disease in 2019, with the main symptoms being hypokinesia and rigor bilaterally, more pronounced on the left, moderate tremor. Patient was treated with L-DOPA since 2022 and due to increasing severity of PD symptoms, the dosage of L-DOPA wasincreased to 1000 mg L-DOPA per day. Treatment with acetyl-DL-leucine (AL) at a totaldaily dosage of 5 g AL per day began at the beginning of 2024. After six weeks of treatment the dosage of L-Dopa could be reduced to 600 mg per day because of the symptomatic effects. His hyokinesia and tremor improved even with a lower dosage of of L-Dopa. Further, his spouse noticed an improvement of his mood, alertness and night sleep. Since Summer 2024 the condition is stable with no further deterioration. Acetyl-leucine was well tolerated. Patient is under continuous treatment. ConclusionAcetyl-leucine treatment was associated with drastic improvements in PD symptomsincluding less dependency on L-DOPA. Example 27The patient in this case study was a 80 year-old male subject, who was diagnosed in 2015with Parkinson´s disease, slowly progressive with the main symptoms being hypokinesia ofarms and legs, gait impairment, decreased mobility, and a symmetrical mild tremor of bothhands. Patient received L-DOPA since 2015 with slowly increasing dosage, beginning 50 mgL-DOPA twice per day, which was increased to 700 mg / d L-DOPA. The patient receivedAcetyl-DL-leucine (5 g / d) since the beginning of 2022. His condition is stable, i.e., the L- Dopa dosage had not to be increased (still on 700 mg / d). After the initiation of the treatment with Acetyl-DL-leucine his mobility, hypokinesia of arms and legs, gait impairment andmobility increased, according to the patient by 50%. The patient is much more active, and hissleeping problems improved. Further, his depression – one of the leading symptoms duringthe course of the disease – also improved. Patient´s quality of life improved. Acetyl-leucinewas well tolerated. Patient under continuous treatment. ConclusionAcetyl-leucine treatment was associated with drastic improvements in PD symptoms,including mobility, sleep problems and depression.Example 28 The patient in this case study was a 85 year-old male subject, who was diagnosed withParkinson´s disease in 2023 and suffered mainly from tremor dominating, right side. Patientreceived 400 mg / d L-DOPA after the diagnosis was made. Treatment with Acetyl-leucine (5 g / d) commenced in summer 2024. Since then, hiscondition is stable (further deterioration was prevented) and his tremor improved. Acetyl-leucine was well tolerated. Patient under continuous treatment. ConclusionAcetyl-leucine treatment was associated with drastic improvements in PD symptoms.Example 29The patient in this case study was a 83 year-old male subject, who was diagnosed withParkinson´s disease in July 2024. Symptoms began in 2023 on the left side with reduced armmovements and slight tremor. Patient received 300 mg / d L-DOPA to treat his tremordominating on the right side. Co-therapy with acetyl-DL-leucine (AL) was started inNovember 2024 at a total daily dosage of 5 g AL. As of January 2025, patient reportedgeneral improvement of his movement disorder, including improvement in arm movements,hypokinesia, tremor and sleep quality, resulting in an overall improvement of quality of life.Acetyl-leucine has been well tolerated. Patient under continuous treatment. ConclusionAcetyl-leucine treatment was associated with drastic improvements in PD symptoms.Example 30The patient in this case study was a 85 year-old male subject, whose symptoms ofhypokinesia and gait disorder began at the beginning of 2023, and were slowly progressive.He was diagnosed with Parkinson´s disease in November 2024. Since then, the patientreceived L-Dopa at a dosage of 300 mg per day plus Acetyl-Leucine 4 g / day (Acetyl-L-Leucine; Aqneursa, individual off-label use). After two months of treatment, a significantimprovement of all symptoms, including improved coordination of the arms, improved walking and general mood, were reported. Patient was very satisfied with state of conditions. Acetyl-leucine has been well tolerated. Patient under continuous treatment. ConclusionAcetyl-leucine treatment was associated with drastic improvements in PD symptoms.

Claims

Claims:

1. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method ofreducing the severity of, eliminate, delay or reverse the progression of Parkinson´s disease (PD) or one or more symptoms of Parkinson´s disease (PD) in a subject in need thereof, said method comprising administering a therapeutically effectiveamount of acetyl-leucine to the subject.

2. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according toclaim 1, wherein acetyl-leucine is administered to the subject for a duration chosen from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.

3. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according to anyof claims 1 to 3, wherein the symptoms of Parkinson’s Disease comprise one or more of hypokinesia, rigor, resting tremor, hyposmia, or vegetative dysfunction, cognitivedeficits, optionally wherein the cognitive deficits comprise dementia, psychiatric symptoms, optionally wherein the psychiatric symptoms are behavioural disorders, slow movement, decreased fluidity of limb movements, instable gait and mobility, constipation, gait deterioration, increased propensity to falls, speech deterioration associated with fronto-temporal dementia with parkinsonism, REM Sleep Behavior Disorder (RBD), restless-leg syndrome (RLS), neurological symptoms and / or decreased mood.

4. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according toclaim 3, wherein the neurological symptoms include one or more of ataxia,hypokinesia, rigor, tremor or dystonia, central ocular motor disorders such as vertical and horizontal supranuclear saccade / gaze palsy and neuropsychological deficits such as dementia.

5. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according to anyof claims 1 to 4, wherein the acetyl-leucine is acetyl-DL-leucine.

6. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according to anyof claims 1 to 5, wherein the acetyl-leucine has an enantiomeric excess of the L- enantiomer or the D-enantiomer.

7. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according to anyof claims 1 to 6, wherein the therapeutically effective amount ranges from 1 g to 15 g per day, from 1 g to 10 g per day, from 1.5 g to 7 g per day, from 4 g to 6 g per day, or from 4 g to 5 g per day.

8. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according claim7, wherein the therapeutically effective amount is about 5 g per day.

9. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according anyone of claims 1 to 8, wherein the acetyl-leucine, or a pharmaceutically acceptable salt thereof is administered in one dose, two doses, three doses, four doses or more per day, preferably wherein the acetyl-leucine, or a pharmaceutically acceptable salt thereof is administered in two doses per day.

10. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according to anyone of claims 1 to 9, wherein the initial administration occurs after the subject has been diagnosed with Parkinson´s disease (PD) or been found to have a genetic and / or biochemical marker of Parkinson´s disease (PD).

11. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according toclaim 10, wherein the subject has been diagnosed with PD with UPDRS, dopamine transporter (DAT) density as measured by a single photon emission computed tomography (SPECT) scan, or by fluorodeoxyglucose-positron emission tomography (FDG-PET) scan or any combination thereof.

12. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according toclaim 10, wherein the biochemical marker for Parkinson’s disease is identified by a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan, a dopamine transporter (DAT) density as measured by a single photon emission computed tomography (SPECT) scan, or any combination thereof, optionally wherein thebiochemical marker for Parkinson’s disease is identified by a EuroQol-5 Dimension-5 Levels (5Q-5D-5L) score, a Montreal Cognitive Assessment (MoCA) score, or a combination thereof.

13. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according to anyone of claims 10 to 12, wherein the administration of Acetyl-leucine, or apharmaceutically acceptable salt thereof, improves the biochemical marker and / or one or more symptoms associated with PD over time.

14. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according toclaim 13, wherein improvement of the biochemical marker comprises improvement of the biochemical marker over time compared to a control value, prevents the progression of a biochemical marker over time, and / or delays the progression of the biochemical marker over time as compared to typical disease progression.

15. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according toclaim 14, wherein improvement of the symptoms associated with PD comprises reducing one or more of the severity, frequency or occurrence of any one or more of the symptoms associated with PD compared to the severity, frequency or occurrence before treatment with acetyl-leucine, wherein the symptoms comprise hypokinesia, rigor, resting tremor, hyposmia, or vegetative dysfunction, cognitive deficits, optionally wherein the cognitive deficits comprise dementia, psychiatric symptoms, optionally wherein the psychiatric symptoms are behavioural disorders, slow movement, decreased fluidity of limb movements, instable gait and mobility, constipation, gait deterioration, increased propensity to falls, speech deterioration associated with fronto-temporal dementia with parkinsonism, REM Sleep Behavior Disorder (RBD), restless-leg syndrome (RLS), neurological symptoms and / or decreased mood.

16. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according to anyone of the preceding claims, wherein the subject receives co-treatment with L-DOPA,wherein L-DOPA is administered separately or together with Acetyl-Leucine.

17. Acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use according toclaim 16, wherein Acetyl-Leucine reduces the rate of disease progression, optionally, wherein Acetyl-Leucine stabilizes, delays or reverses the progression of Parkinson´s disease (PD) or one or more symptoms of Parkinson´s disease (PD) compared totypical PD progression with L-DOPA monotherapy.

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