Acetyl leucine for treating neurodevelopmental disorders

Abstract

The present disclosure provides methods of treating a neurodevelopmental disorder (NDD) in a subject by administering a therapeutically effective amount of N-acetyl leucine.

Description

ACETYL LEUCINE FOR TREATING NEURODEVELOPMENTAL DISORDERSBACKGROUNDField

[0001] The present disclosure provides methods of treating a neurodevelopmental disorder in a subject by administering a therapeutically effective amount of N-acetyl leucine.Background

[0002] Neurodevelopmental disorders (NDDs) are characterized as disorders that influence how the brain functions and alters neurological development, causing difficulties in social, cognitive, and emotional functioning. Common NDDs include autism spectrum disorder (ASD) and attention-deficit / hyperactive disorder (ADHD). Many NDDs are not as well known or widely studied.

[0003] NDDs usually onset during early stages of development which makes them most prevalent in toddlers, children, and adolescents. But some NDDs continue to persist into adulthood, or may go undiagnosed until one is an adult.

[0004] There are not many treatment options for those suffering from NDDs and thus there is a need for effective therapeutics to treat or prevent NDDs and symptoms of NDDs.BRIEF SUMMARY

[0005] In one aspect, the present disclosure provides methods of treating or preventing a neurodevelopmental disorder, or a symptom thereof, in a subject in need thereof, the method comprising administering a therapeutically effective amount of N-acetyl leucine, e.g., N-acetyl-DL-leucine or N-acetyl-L-leucine, to the subject.

[0006] In another aspect, the present disclosure provides N-acetyl leucine, or a pharmaceutical composition thereof, for use in treating or preventing a neurodevelopmental disorder, or a symptom thereof, in a subject in need thereof.

[0007] In another aspect, the present disclosure provides the use of N-acetyl leucine for the manufacture of a medicament for treating or preventing a neurodevelopmental disorder, or a symptom thereof, in a subject in need thereof.

[0008] In some aspects, the neurodevelopmental disorder include one or more of the diseases, disorders, or syndromes listed in Table 1 A.

[0009] In some aspects, the neurodevelopmental disorder is the syndrome listed in Table IB.

[0010] In some aspects, the neurological symptoms of the neurodevelopmental disorder include one or more of the neurological symptoms listed in Table 1 A.

[0011] In some aspects, the neurological symptoms of the neurodevelopmental disorder include one or more of the neurological symptoms listed in Table IB.

[0012] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.BRIEF SUMMARY OF THE DRAWINGS

[0013] Fig. 1A is a line graph showing the morning dose and cumulative daily dose of N-acetyl-DL- leucine in MED13L-NDD Case Report # 1.

[0014] Fig. IB is a line graph showing the number of seizures for the subject of MED13L-NDD Case Report # 1.

[0015] Fig. 1C is a line graph showing sleep quality recorded as the number of hours asleep and awake during the normal nighttime sleeping period in MED13L-NDD Case Report # 1.

[0016] Fig. ID is a line graph showing daily quality of life (QOL) ratings for the subject and the caregivers in MED13L-NDD Case Report # 1. QOL ratings were reported from +5 (great day) to -5 (terrible day).

[0017] Fig. 2A is a line graph showing the morning dose and cumulative daily dose of N-acetyl-DL- leucine in MED13L-NDD Case Report # 2.

[0018] Fig. 2B is a line graph showing the number of seizures for the subject of MED13L-NDD Case Report # 2.

[0019] Fig. 2C is a line graph showing sleep quality recorded as the number of hours asleep and awake during the normal nighttime sleeping period in MED13L-NDD Case Report # 2.

[0020] Fig. 2D is a line graph showing daily quality of life (QOL) ratings for the subject and the caregivers in MED13L-NDD Case Report # 2. QOL ratings were reported from +5 (great day) to -5 (terrible day).

[0021] Fig. 3A is a line graph showing the morning dose and cumulative daily dose of N-acetyl-DL- leucine in CTNNB1-NDD Case Report # 1.

[0022] Fig. 3B is a line graph showing the number of seizures for the subject of CTNNB1-NDD Case Report # 1.

[0023] Fig. 3C is a line graph showing sleep quality recorded as the number of hours asleep and awake during the normal nighttime sleeping period in CTNNB1 -NDD Case Report # 1.

[0024] Fig. 3D is a line graph showing daily quality of life (QOL) ratings for the subject and the caregivers in CTNNB1-NDD Case Report # 1. QOL ratings were reported from +5 (great day) to -5 (terrible day).

[0025] Fig. 4A is a line graph showing the morning dose and cumulative daily dose of N-acetyl-DL- leucine in CTNNB1-NDD Case Report # 2.

[0026] Fig. 4B is a line graph showing the number of seizures for the subject of CTNNB1-NDD Case Report # 2.

[0027] Fig. 4C is a line graph showing sleep quality recorded as the number of hours asleep and awake during the normal nighttime sleeping period in CTNNB1-NDD Case Report # 2.

[0028] Fig. 4D is a line graph showing daily quality of life (QOL) ratings for the subject and the caregivers in CTNNB1-NDD Case Report # 2. QOL ratings were reported from +5 (great day) to -5 (terrible day).

[0029] Fig. 5A is a line graph showing the Total Yale Global Tics Severity Scale (YGTSS) clinical assessment of Tourette syndrome Subject # 1 (dashed line) and Subject # 2 (solid line) at baseline and during follow-ups at 3, 6, and 12 weeks. The box highlights the six- week therapy period with N-acetyl-DL- leucine (5 g / day) (referred to as "Acetyl-leucin" in the figure).

[0030] Fig. 5B is a line graph showing the YGTSS motor and vocal subscales clinical assessment of Tourette syndrome Subject # 1 (light dashed line) and Subject # 2 (bold dashed line) at baseline and during follow-ups at 3, 6, and 12 weeks. The box highlights the six-week therapy period with N-acetyl-DL-leucine (5 g / day) (referred to as "Acetyl- leucin" in the figure).

[0031] Fig. 5C is a line graph showing the Gilles de la Tourette Syndrome-Quality of Life scale (GTS-QoL) clinical assessment of Tourette syndrome Subject # 1 (dashed line) and Subject # 2 (solid line) at baseline and during follow-ups at 3, 6, and 12 weeks. The boxhighlights the six-week therapy period with N-acetyl-DL- leucine (5 g / day) (referred to as " Acetyl-leucin" in the figure).

[0032] Fig. 5D is a line graph showing the Yale-Brown Obsessive Compulsive Scale (YBOCS) clinical assessment of Tourette syndrome Subject # 1 (dashed line) and Subject # 2 (solid line) at baseline and during follow-ups at 3, 6, and 12 weeks. The box highlights the six-week therapy period with N-acetyl-DL-leucine (5 g / day) (referred to as "Acetyl- leucin" in the figure).DETAILED DESCRIPTION

[0033] 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, a laboratory animal, e.g. a mouse or rat, or may be used in other veterinary applications. In one embodiment, the subject is a human being. "Subject" and "patient" are used interchangeably.

[0034] As used herein, the singular forms "a," "an," and "the" include plural reference.

[0035] As used herein, the term "about" should be generally understood to encompass± 10% of a specified amount, frequency or value. Numerical quantities given herein are approximate unless stated otherwise, meaning that term "about" can be inferred when not expressly stated.

[0036] 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, N-acetyl leucine; and (2) putting into, taking or consuming by the patient or person himself or herself, N-acetyl leucine.

[0037] The term "N-acetyl leucine" refers to N-acetyl-DL-leucine, N-acetyl-D-leucine, and / or N-acetyl-L-leucine. Any reference to N-acetyl leucine includes pharmaceutically acceptable salts of the same, even if not expressly stated.

[0038] 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-pyrro lidin- l'-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.

[0039] N-acetyl leucine may be formulated and administered to a subject in accordance with known teachings in the art. For example, N-acetyl leucine may be formulated as a pharmaceutical composition. The pharmaceutical composition may comprise N-acetyl- DL- leucine and a pharmaceutically acceptable carrier, N-acetyl-L-leucine and a pharmaceutically acceptable carrier, or N-acetyl-D-leucine and a pharmaceutically acceptable carrier.

[0040] 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.

[0041] A "pharmaceutically acceptable carrier" as referred to herein, is any known compound or combination of known compounds, e.g., excipients, carriers, etc., 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.

[0042] In one embodiment, the pharmaceutically acceptable carrier may be a solid, and the composition may be in the form of a powder or tablet. A solid pharmaceutically acceptable carrier 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 an encapsulating material. In powders, the carrier may be a finely divided solid that is in admixture with the finely divided active agents according to the disclosure. In tablets, theactive agent may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets may, for example, contain up to 99% of the active agents. Suitable solid carriers include, for example, 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.

[0043] The carrier may include, but is not limited to, one or more excipients or diluents. Examples of such excipients are gelatin, gum arabicum, lactose, micro crystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.

[0044] In another embodiment, the pharmaceutically acceptable carrier may be a liquid. In one embodiment, the pharmaceutical composition is in the form of a solution. Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. N-acetyl leucine may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical 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 parenteral administration 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 also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurised compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0045] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, may be utilised by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous and 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.

[0046] The compositions may be administered orally in the form of a sterile solution or suspension optionally 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 composition form. 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.

[0047] Compositions 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.

[0048] N-acetyl leucine may be incorporated within a slow- or delayed-release device. Such devices may, 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 longterm treatment with N-acetyl leucine according to the present disclosure is required and which may require frequent administration, e.g. at least daily administration.

[0049] In one embodiment, the pharmaceutical composition is a solid oral dosage form, such as a tablet. In tablets, the active agent may be mixed with a vehicle, such as a pharmaceutically acceptable carrier, having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The tablets may contain up to 99% by weight of the N-acetyl leucine.

[0050] 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 active agent with conventional pharmaceutically acceptable carriers.

[0051] A tablet may be formulated as is known in the art. Tanganil®, for example, includes wheat starch, pregelatinised maize (com) starch, calcium carbonate and magnesium stearate as excipients. The same, or similar, excipients, for example, may be employed with the present disclosure.

[0052] The composition of each 700 mg Tanganil® tablet is as follows: 500 mg acetyl-DL- leucine, 88 mg wheat starch, 88 mg pregelatinised maize (com) starch, 13 mg calcium carbonate and 11 mg magnesium stearate. The same tablets, for example, may be employed in the methods of the present disclosure.

[0053] In one embodiment, N-acetyl-L-leucine is formulated as granules for oral suspension in sachet. The granules for oral suspension may also comprise isomalt and / or hypromellose. Each sachet with 1000 mg of N-acetyl-L-leucine may be formulated, for example, to be suspended in 40 mL water.

[0054] As discussed above, N-acetyl leucine may be formulated and administered as a pharmaceutical composition taking any number of different forms. For example, N-acetyl leucine may be formulated as a pharmaceutical composition to facilitate its delivery across the blood-brain barrier. As a further example, N-acetyl leucine may be formulated as a pharmaceutical composition for bypassing the blood-brain barrier. Formulations that facilitate delivery across the blood-brain barrier or that are suitable for administration in a manner that bypasses the blood-brain barrier may be used to prepare and administer N-acetyl leucine.

[0055] In one embodiment, the pharmaceutical composition, e.g., a pharmaceutical composition comprising N-acetyl-L-leucine, or salt thereof, is formulated for nanodelivery, e.g., colloidal drug-carrier systems. Suitable examples include but are not limited to liposomes, nanoparticles (e.g., polymeric, lipid and inorganic nanoparticles), nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots. See, e.g., Patel et al., "Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain," CNS Drugs 31:109-133 (2017); Kabanov et al., "New Technologies for Drug Delivery across the Blood Brain Barrier," Curr Pharm Des., 10(12): 1355-1363 (2004); Cheng et al., "Highly Stabilized Curcumin Nanoparticles Tested in an In Vitro Blood-Brain Barrier Model and in Alzheimer's Disease Tg2576 Mice," The AAPS Journal, vol. 15, no. 2, pp. 324-336 (2013); Lahde et al. "Production of L-Leucine Nanoparticles under Various Conditions Using an Aerosol Flow Reactor Method," Journal of Nanomaterials, vol. 2008, article ID 680897 (2008).

[0056] In one embodiment, the pharmaceutical composition, e.g., a pharmaceutical composition comprising acetyl-L-leucine, or salt thereof, is formulated for direct delivery to the central nervous system (CNS), such as by injection or infusion. Formulations forand methods of direct delivery to the CNS are known in the art. See, e.g., U.S. Patent No. 9,283,181. Examples of such administration include but are not limited to intranasal, intraventricular, intrathecal, intracranial, and delivery via nasal mucosal grafting.

[0057] In one embodiment, the pharmaceutical composition is formulated for (and administered by) intranasal delivery. See, e.g., Hanson et al., "Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neuro degenerative disease," BMCNeurosci. 9(Suppl 3):S5 (2008). In one embodiment, the pharmaceutical composition is formulated for (and administered by) delivery via a nasal mucosal graft. In one embodiment, the pharmaceutical composition is formulated for (and administered by) intracerebroventricular injection or infusion. In another embodiment, the pharmaceutical composition is formulated for (and administered by) intrathecal intracistemal injection or infusion. In one embodiment, the pharmaceutical composition is formulated for (and administered by) intrathecal lumbar injection or infusion.

[0058] Various techniques may be used including, without limitation, injection through a burrhole or cisternal or lumbar puncture or the like as known in the art. Various devices, whether internal (e.g., implanted) or external, may be used for delivery as known in the art, such as pumps, catheters, reservoirs, etc. In one embodiment, the administration interval is once every two weeks.

[0059] In one embodiment, the administration interval is once every month. In one embodiment, the administration interval is once every two months. In one embodiment, the administration interval is twice per month. In one embodiment, the administration interval is once every week. In one embodiment, the administration interval is twice or several times per week. In one embodiment, the administration interval is daily. In one embodiment, the administration is continuous, such as continuous infusion.

[0060] In one embodiment, the dose or amount equivalent ofN-acetyl leucine may adjusted to account for either its direct delivery to the CNS or its delivery across the blood-brain barrier.

[0061] Certain aspects, of the disclosure are directed to methods of treating or preventing a neuro developmental disorder (NDD), or a neurological symptom thereof, in a subject in need thereof, the method comprising administering a therapeutically effective amount of N-acetyl-DL- leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject

[0062] In some aspects, the N-acetyl-DL- leucine or N-acetyl-L-leucine is administered to the subject to treat the NDD. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L- leucine is administered to the subject to treat any one or more of the neurological symptoms of the NDD.

[0063] A "subject in need thereof' as used herein may be any subject who has a neurodevelopmental disorder or a symptom thereof.

[0064] As used herein, "neurodevelopmental disorder" or "NDD" refers to a condition, disease, disorder, or syndrome characterized by abnormal neuro development and / or basic biobehavioral processes, including attentional and perceptual processing, executive function, inhibitory control (e.g., sensory gating), social cognition, and communication and affiliative behaviors.

[0065] Neurodevelopmental disorders include a spectrum of disorders that can include, but are not limited to the diseases, disorders, or syndromes listed in Table 1A. Neurodevelopmental disorders include a spectrum of disorders that can include, but are not limited to the diseases, disorders, or syndromes listed in Table IB. Neurodevelopmental disorders include a spectrum of disorders that can include, but are not limited to the diseases, disorders, or syndromes listed in Table 1C.Table 1ATable IBTable 1C

[0066] In some aspects, the neurodevelopmental disorder is fragile X syndrome, down syndrome, Prader-Willi syndrome, Cri-du-Chat syndrome, Turner syndrome, developmental delay and seizures with or without movement abnormalities (DEDSM), DHDDS syndrome, Asperger syndrome, Childhood disintegrative disorder, Rett syndrome, ADHD with predominantly inattentive presentation, ADHD with predominantly hyperactive-impulsive presentation, ADHD with combined presentation, dyslexia, dyscalculia, dysgraphia, nonverbal learning disability, language disorder, speech sound disorder, childhood-onset fluency disorder, communication disorder, developmental coordination disorder, stereotypic movement disorder, Tourette syndrome, chronic motor or vocal tic disorder, transient tic disorder, spastic cerebral palsy, dyskinetic cerebral palsy, ataxic cerebral palsy, mixed cerebral palsy, Williams syndrome, tuberous sclerosis, DEPDC5-related epilepsy, phenylketonuria (PKU), Smith-Magenis syndrome, Angelman syndrome, Cornelia de Lange syndrome, Kabuki syndrome, Moebius syndrome, Sturge- Weber syndrome, Landau-Kleffner syndrome, Sanflippo syndrome, Charge syndrome, Pitt-Hopkins syndrome, 22ql l.2 Deletion syndrome, STXBP1 disorder, CDKL5 deficiency disorder, FOXG1 syndrome, PURA syndrome, ADNP syndrome, GRIN1 / 2 disorders, chromosome SP, Lesch-Nyhan syndrome, Lowe syndrome, trisomy 18 (Edwards syndrome) PACS-l-NDD, Alfi's syndrome, Joubert syndrome, Kleefstra syndrome, Lissencephaly, Mowat-Wilson syndrome, Rubinstein-Taybi syndrome, Schinzel-Giedion syndrome, Smith-Lemli-Opitz syndrome, Wolf-Hirschhorn syndrome, van der Woude syndrome, Walker-Warburg syndrome, Zellweger Spectrum disorder, Aicardi syndrome, Bohring-Opitz syndrome, Coffin-Siris syndrome, Cornelia de Lange syndrome, MeCP2 Duplication syndrome, CTNNB1 syndrome, MED13L syndrome, FOXG1 syndrome, NARS1 -related neurodevelopmental disorder, CA CNA 1A -related neurodevelopmental disorder, and / or SLC6A 1 -related neurodevelopmental disorder.

[0067] In some aspects, the N-acetyl-DL- leucine or N-acetyl-L-leucine is administered to the subject to treat fragile X syndrome, down syndrome, Prader-Willi syndrome, Cri-du- Chat syndrome, Turner syndrome, developmental delay and seizures with or without movement abnormalities (DEDSM), DHDDS syndrome, Asperger syndrome, Childhood disintegrative disorder, Rett syndrome, ADHD with predominantly inattentive presentation, ADHD with predominantly hyperactive-impulsive presentation, ADHD with combined presentation, dyslexia, dyscalculia, dysgraphia, nonverbal learning disability, language disorder, speech sound disorder, childhood-onset fluency disorder, communication disorder, developmental coordination disorder, stereotypic movement disorder, Tourette syndrome, chronic motor or vocal tic disorder, transient tic disorder, spastic cerebral palsy, dyskinetic cerebral palsy, ataxic cerebral palsy, mixed cerebral palsy, Williams syndrome, tuberous sclerosis, DEPDC5 -related epilepsy, phenylketonuria (PKU), Smith-Magenis syndrome, Angelman syndrome, Cornelia de Lange syndrome, Kabuki syndrome, Moebius syndrome, Sturge-Weber syndrome, Landau-Kleffner syndrome, Sanflippo syndrome, Charge syndrome, Pitt-Hopkins syndrome, 22ql l.2 Deletion syndrome, STXBP1 disorder, CDKL5 deficiency disorder, FOXG1 syndrome, PURA syndrome, ADNP syndrome, GRIN1 / 2 disorders, chromosome SP, Lesch -Nyhan syndrome, Lowe syndrome, trisomy 18 (Edwards syndrome) PACS-l-NDD, Alfi's syndrome, Joubert syndrome, Kleefstra syndrome, Lissencephaly, Mowat-Wilson syndrome, Rubinstein-Taybi syndrome, Schinzel-Giedion syndrome, Smith-Lemli-Opitz syndrome, Wolf-Hirschhom syndrome, van der Woude syndrome, Walker -Warburg syndrome, Zellweger Spectrum disorder, Aicardi syndrome, Bohring-Opitz syndrome, Coffin-Siris syndrome, Cornelia de Lange syndrome, MeCP2 Duplication syndrome, CTNNB1 syndrome, MED13L syndrome, FOXG1 syndrome, NARS1 -related neurodevelopmental disorder, CACNA 1A -related neurodevelopmental disorder, and / or SLC6A 1 -related neurodevelopmental disorder.

[0068] In some aspects, the N-acetyl-DL- leucine or N-acetyl-L-leucine is administered to the subject to prevent fragile X syndrome, down syndrome, Prader-Willi syndrome, Cri- du-Chat syndrome, Turner syndrome, developmental delay and seizures with or without movement abnormalities (DEDSM), DHDDS syndrome, Asperger syndrome, Childhood disintegrative disorder, Rett syndrome, ADHD with predominantly inattentive presentation, ADHD with predominantly hyperactive-impulsive presentation, ADHD withcombined presentation, dyslexia, dyscalculia, dysgraphia, nonverbal learning disability, language disorder, speech sound disorder, childhood-onset fluency disorder, communication disorder, developmental coordination disorder, stereotypic movement disorder, Tourette syndrome, chronic motor or vocal tic disorder, transient tic disorder, spastic cerebral palsy, dyskinetic cerebral palsy, ataxic cerebral palsy, mixed cerebral palsy, Williams syndrome, tuberous sclerosis, DEPDC5 -related epilepsy, phenylketonuria (PKU), Smith-Magenis syndrome, Angelman syndrome, Cornelia de Lange syndrome, Kabuki syndrome, Moebius syndrome, Sturge-Weber syndrome, Landau-Kleffher syndrome, Sanflippo syndrome, Charge syndrome, Pitt-Hopkins syndrome, 22ql l.2 Deletion syndrome, STXBP1 disorder, CDKL5 deficiency disorder, FOXG1 syndrome, PURA syndrome, ADNP syndrome, GRIN1 / 2 disorders, chromosome SP, Lesch -Nyhan syndrome, Lowe syndrome, trisomy 18 (Edwards syndrome) PACS-l-NDD, Alfi's syndrome, Joubert syndrome, Kleefstra syndrome, Lissencephaly, Mowat-Wilson syndrome, Rubinstein-Taybi syndrome, Schinzel-Giedion syndrome, Smith-Lemli-Opitz syndrome, Wolf-Hirschhom syndrome, van der Woude syndrome, Walker -Warburg syndrome, Zellweger Spectrum disorder, Aicardi syndrome, Bohring-Opitz syndrome, Coffm-Siris syndrome, Cornelia de Lange syndrome, MeCP2 Duplication syndrome, CTNNB1 syndrome, MED13L syndrome, F0XG1 syndrome, NARS1 -related neurodevelopmental disorder, CA CNA 1A -related neurodevelopmental disorder, and / or SLC6A 1 -related neurodevelopmental disorder.

[0069] In some aspects, the NDD is any one or more of the syndromes associated with intellectual disability listed in Table 1 A. In some aspects, the NDD is any one or more of the autism spectrum disorders listed in Table 1 A. In some aspects, the NDD is any one or more of the attention deficit hyperactivity disorders listed in Table 1 A. In some aspects, the NDD is any one or more of the learning disorders listed in Table 1 A. In some aspects, the NDD is any one or more of the communication disorders listed in Table 1A. In some aspects, the NDD is any one or more of the motor disorders listed in Table 1 A. In some aspects, the NDD is any one or more of the tic disorders listed in Table 1 A. In some aspects, the NDD is any one or more of the cerebral palsy disorders listed in Table 1A. In some aspects, the NDD is any one or more of the rare neurodevelopmental disorders listed in Table 1A. In some aspects, the NDD is any one or more of the rare genetic neurodevelopmental disorders listed in Table 1 A. In some aspects, the NDD is any one ormore of the ultra-rare neuro developmental disorders listed in Table 1 A. In some aspects, the NDD is any one or more of the gene mutation-related disorders listed in Table 1A. In some aspects, the NDD is any one or more of the gene mutation-related disorders listed in Table IB.

[0070] A "therapeutically effective amount" of N-acetyl leucine is any amount which, when administered to a subject, is the amount that is needed to produce the desired effect, which, for the present disclosure, can be therapeutic and / or prophylactic. The dose may be determined according to various parameters, such as the N-acetyl leucine used, e.g., N-acetyl-DL-leucine or N-acetyl-L-leucine; the age, weight and condition of the patient to be treated; 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 0.1 g to about 30 g, from about 1 g to about 15 g, or from about 3 g to about 10 g of N-acetyl leucine may be administered, e.g., as a tablet or an oral suspension.

[0071] As used herein, "treating" or "treatment" refers to any indicia of success in preventing, arresting, or ameliorating a neurodevelopmental disorder, in a subject, and / or preventing, arresting, or ameliorating any one or more symptoms of a neurodevelopmental disorder in a subject, including any objective or subjective parameter such as abatement; remission; diminishing, inhibiting, preventing, or eliminating one or more symptoms; making the neurodevelopmental disorder more tolerable to the subject; slowing in the worsening of the neurodevelopmental disorder; or improving the physical or mental wellbeing of the subject in need thereof.

[0072] The terms "treating" or "treatment" also encompasses, e.g., inducing inhibition, regression, rescue, or stasis of a neurodevelopmental disorder. For example, treatment of a subject in need of treatment for a neurodevelopmental disorder includes preventing or reducing a symptom of the neurodevelopmental disorder in the subject, inducing clinical response, preventing, inhibiting or reducing progression of a neurodevelopmental disorder, or preventing, inhibiting or reducing a complication of a neurodevelopmental disorder.

[0073] Preventing, arresting, or ameliorating a neurodevelopmental disorder, such as preventing, diminishing, inhibiting, or eliminating one or more symptoms of a neurodevelopmental disorder can be based on objective and / or subjective parameters, including, e.g., the results of genetic testing, physical examination(s), neurologicalexamination(s), and / or psychiatric evaluation(s). The success of treatment for a neurodevelopmental disorder may be measured or evaluated by, for example, comparing the severity of the neurodevelopmental disorder, or symptom thereof, before treatment with N-acetyl leucine is initiated, with the severity of the neurodevelopmental disorder, or symptom thereof, following treatment with N-acetyl leucine. For example, the severity of a neurodevelopmental disorder, or symptom thereof, may be assessed using a scale, index, rating, or score. In one embodiment, the treatment described herein improves such an assessment from a value or degree characteristic of a symptomatic subject to a value or degree characteristic of a non- symptomatic subject. In one embodiment, the treatment described herein improves such an assessment compared to a baseline. The baseline may be, for example, the subject's condition before initiating any treatment for the neurodevelopmental disorder, or symptom thereof, or before initiating treatment for the neurodevelopmental disorder, or symptom thereof, with N-acetyl leucine. Alternatively, the baseline may be, for example, the subject's condition after a certain time period on treatment for the disease. In one embodiment, treatment with N-acetyl leucine as described herein improves the subject's assessment, e.g., scale, index, rating, or score of objective and / or subjective parameters, compared to a baseline by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In one embodiment, assessment is improved by at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0074] A "neurological symptom" of a neurodevelopmental disorder includes any clinical or laboratory manifestation associated with the neurodevelopmental disorder and is not limited to what the subject can feel or observe. Neurological symptoms of a neurodevelopmental disorder include, but are not limited to, the neurological symptoms listed in Table 1 A. Neurological symptoms of a neurodevelopmental disorder include, but are not limited to, the neurological symptoms listed in Table IB. Neurological symptoms of a neurodevelopmental disorder include, but are not limited to, the neurological symptoms listed in Table 1C. In some aspects, the neurological symptom of the NDD is one or more of seizures, sleep disturbance, and / or behavior disorder.

[0075] In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of fragile X syndrome, down syndrome, Prader-Willi syndrome, Cri-du-Chat syndrome, Turner syndrome, developmental delay and seizures with or without movement abnormalities (DEDSM),DHDDS syndrome, Asperger syndrome, Childhood disintegrative disorder, Rett syndrome, ADHD with predominantly inattentive presentation, ADHD with predominantly hyperactive-impulsive presentation, ADHD with combined presentation, dyslexia, dyscalculia, dysgraphia, nonverbal learning disability, language disorder, speech sound disorder, childhood-onset fluency disorder, communication disorder, developmental coordination disorder, stereotypic movement disorder, Tourette syndrome, chronic motor or vocal tic disorder, transient tic disorder, spastic cerebral palsy, dyskinetic cerebral palsy, ataxic cerebral palsy, mixed cerebral palsy, Williams syndrome, tuberous sclerosis, DEPDC5-related epilepsy, phenylketonuria (PKU), Smith-Magenis syndrome, Angelman syndrome, Cornelia de Lange syndrome, Kabuki syndrome, Moebius syndrome, Sturge- Weber syndrome, Landau-Kleffner syndrome, Sanflippo syndrome, Charge syndrome, Pitt-Hopkins syndrome, 22ql l.2 Deletion syndrome, STXBP1 disorder, CDKL5 deficiency disorder, FOXG1 syndrome, PURA syndrome, ADNP syndrome, GRIN1 / 2 disorders, chromosome SP, Lesch-Nyhan syndrome, Lowe syndrome, trisomy 18 (Edwards syndrome) PACS-l-NDD, Alfi's syndrome, Joubert syndrome, Kleefstra syndrome, Lissencephaly, Mowat-Wilson syndrome, Rubinstein-Taybi syndrome, Schinzel-Giedion syndrome, Smith-Lemli-Opitz syndrome, Wolf-Hirschhorn syndrome, van der Woude syndrome, Walker-Warburg syndrome, Zellweger Spectrum disorder, Aicardi syndrome, Bohring-Opitz syndrome, Coffin-Siris syndrome, Cornelia de Lange syndrome, MeCP2 Duplication syndrome, CTNNB1 syndrome, MED13L syndrome, F0XG1 syndrome, NARS1 -related neuro developmental disorder, CACNA1A -related neurodevelopmental disorder, and / or SLC6A 1 -related neurodevelopmental disorder.

[0076] Certain aspects of the disclosure are directed to methods of treating a disease or disorder associated with intellectual disability, or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N- acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the N-acetyl-DL- leucine or N-acetyl-L-leucine is administered to the subject to treat a disease or disorder associated with intellectual disability. In some aspects, the N-acetyl-DL-leucine or N- acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of a disease or disorder associated with intellectual disability.

[0077] In some aspects, the disease or disorder associated with intellectual disability is selected from fragile X syndrome, down syndrome, prader-willi syndrome, cri-du-chatsyndrome, and turner syndrome. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L- leucine is administered to the subject to treat one or more of fragile X syndrome, down syndrome, prader-willi syndrome, cri-du-chat syndrome, and / or turner syndrome. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of fragile X syndrome, down syndrome, prader- willi syndrome, cri-du-chat syndrome, and / or turner syndrome.

[0078] Certain aspects of the disclosure are directed to methods of treating fragile X syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with transcriptional silencing of the FMRI gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat fragile X syndrome. In some aspects, the subject is administered the N- acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of fragile X syndrome. In some aspects, the neurological symptoms associated with fragile X syndrome include one or more of global brain atrophy and white matter abnormalities including involvement of the middle cerebellar peduncles, motor and language delays, cognitive deficits include problems with working and short term memory, executive function, and mathematic and visuospatial abilities, anxiety, mood disorders, hyperactivity, impulsivity, aggressive behavior, social anxiety, shyness, social avoidance, withdrawal, language deficits, mood lability, and / or depression.

[0079] Certain aspects of the disclosure are directed to methods of treating down syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with supernumerary chromosome 21 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat down syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L- leucine to treat one or more neurological symptoms of down syndrome. In some aspects, the neurological symptoms associated with down syndrome include one or more of alzheimer's disease like neuropathology, deficits in memory and attention, sleep apnea, epilepsy, depression and anxiety, cognitive disability, weakness in expressive language, verbal working memory, episodic memory, and / or autism spectrum disorder.

[0080] Certain aspects of the disclosure are directed to methods of treating Prader-Willi syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with absence of paternally expressed imprinted genes at 15ql l.2-ql3 by genetic testing. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat Prader-Willi syndrome. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Prader-Willi syndrome. In some aspects, the neurological symptoms associated with Prader-Willi syndrome include one or more of delayed motor development, intellectual disabilities, behavior disorders, attention deficit / hyperactivity disorder, temper tantrums, stubbornness, controlling and manipulative behavior, compulsivity, difficulty with change in routine, sleep abnormalities including rapid eye movement (REM) latency, altered sleep architecture, oxygen denaturation, central and obstructive apnea, infantile hypotonia, and / or cognitive rigidity.

[0081] Certain aspects of the disclosure are directed to methods of treating Cri-du-Chat syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject is diagnosed with deletion of variable size occurring on the short arm of chromosome 5 (5p-) by genetic testing. In some aspects, the subject is administered the N- acetyl-DL-leucine or N-acetyl-L-leucine to treat Cri-du-Chat syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Cri-du-Chat syndrome. In some aspects, the neurological symptoms associated with Cri-du-Chat syndrome include one or more of psychomotor and mental retardation, hyperactivity, self injury, repetitive movements, hypersensitivity to sounds, clumsiness, and / or obsessive attachment to objects.

[0082] Certain aspects of the disclosure are directed to methods of treating Turner syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with partial or complete monosomy-X by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Turner syndrome. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Turnersyndrome. In some aspects, the neurological symptoms associated with Turner syndrome include one or more of impaired nonverbal abilities, visual-spacial, visual-perceptual, and visual-constructional deficits, impaired executive functioning such as impaired attention and concentration, problem- solving ability, organization, working memory, behavioral control and use of goal-directed strategies, impulsivity, slower processing speed, attention deficit hyperactivity disorder (ADHD), shyness, anxiety, low self-esteem and / or depression.

[0083] Certain aspects of the disclosure are directed to methods of treating an autism spectrum disorder (ASD), or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N- acetyl-L-leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L- leucine is administered to the subject to treat an autism spectrum disorder (ASD). In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of an autism spectrum disorder (ASD).

[0084] In some aspects, the autism spectrum disorder (ASD) is selected from Asperger syndrome, childhood disintegrative disorder, and Rett syndrome. In some aspects, the N- acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat Asperger syndrome, childhood disintegrative disorder, and / or Rett syndrome. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of Asperger syndrome, childhood disintegrative disorder, and / or Rett syndrome.

[0085] Certain aspects of the disclosure are directed to methods of treating Asperger syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Asperger syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat one or more neurological symptoms of Asperger syndrome. In some aspects, the neurological symptoms associated with Asperger syndrome include one or more of obsessive-compulsive behavior, sleep disorder, Tourette syndrome, Attention Deficit Hyperactivity Disorder, anxiety disorder, communication difficulties including challenges in acquiring and comprehending language, struggle with nonverbal cues including facial expressions, eye contact, and hand movements, social disturbancesincluding lack of an instinctive understanding of social norms, emotional and behavioral neurological symptoms including resistance to change, rigid adherence to routines, repetitive and stereotyped behavior, abnormal response to sensory stimuli, exaggerated emotional responses, regulatory attention disturbances, and / or unusual eating habits.

[0086] Certain aspects of the disclosure are directed to methods of treating childhood disintegrative disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat childhood disintegrative disorder. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of childhood disintegrative disorder. In some aspects, the neurological symptoms associated with childhood disintegrative disorder includes one or more of expressive language impairments including echolalia and mutism, abnormalities in non-verbal communication including gaze avoidance and regression in gesturing, loss of motor skills including hyperkinesis and / or psychomotor regression.

[0087] Certain aspects of the disclosure are directed to methods of treating Rett syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with mutations in the MECP2 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Rett syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat one or more neurological symptoms of Rett syndrome. In some aspects, the neurological symptoms associated with Rett syndrome include one or more of early neurological regression that severely affects motor, cognitive and communication skills, often leading to microcephaly, a delay in acquiring new skills, absence of speech, emergence of autistic features, loss of purposeful manipulation skills, replaced by stereotyped hand movements, other motor abnormalities including abnormal muscle tone, ataxia and apraxia, and / or a seizure disorder.

[0088] Certain aspects of the disclosure are directed to methods of treating an attention deficit hyperactivity disorder (ADHD), or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L-leucine to the subject. In some aspects, the N-acetyl-DL-leucine orN-acetyl-L-leucine is administered to the subject to treat the attention deficit hyperactivity disorder (ADHD). In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of the attention deficit hyperactivity disorder (ADHD).

[0089] In some aspects, the attention deficit hyperactivity disorder (ADHD) is selected from ADHD with predominantly inattentive presentation, ADHD with predominantly hyperactive-impulsive presentation, and ADHD with combined presentation. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat ADHD with predominantly inattentive presentation, ADHD with predominantly hyperactive-impulsive presentation, and / or ADHD with combined presentation. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of ADHD with predominantly inattentive presentation, ADHD with predominantly hyperactive-impulsive presentation, and / or ADHD with combined presentation.

[0090] Certain aspects of the disclosure are directed to methods of treating ADHD with predominantly inattentive presentation in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat ADHD with predominantly inattentive presentation. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of ADHD with predominantly inattentive presentation. In some aspects, the neurological symptoms associated with ADHD with predominantly inattentive presentation include one or more of failing to give close attention to details, difficulty sustaining attention in tasks, not following through on instructions and failure to finish chores or duties in the workplace, difficulty in listening to instructions and organizing tasks, avoiding tasks that require sustained effort, losing things, being easily distracted, and forgetfulness in daily activities, abnormalities in executive functions including focusing and sustaining attention, deficits in working memory and / or processing speed deficits.

[0091] Certain aspects of the disclosure are directed to methods of treating ADHD with predominantly hyperactive-impulsive presentation in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject is administered the N-acetyl-DL-leucineor N-acetyl-L-leucine to treat ADHD with predominantly hyperactive-impulsive presentation. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L- leucine to treat one or more neurological symptoms of ADHD with predominantly hyperactive-impulsive presentation. In some aspects, the neurological symptoms associated with ADHD with predominantly hyperactive-impulsive presentation include one or more of move hands or feet excessively or restless when seated, cannot remain seated when they must be seated, run or jump excessively in situations or places where it is inappropriate, have trouble relaxing or playing games when it is necessary to stay still, keep permanently in motion and / or excessive talking.

[0092] Certain aspects of the disclosure are directed to methods of treating ADHD with combined presentation in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat ADHD with combined presentation. In some aspects, the subject is administered the N- acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of ADHD with combined presentation. In some aspects, the neurological symptoms associated with ADHD with combined presentation include one or more of the symptoms of ADHD with predominantly inattentive presentation and / or ADHD with predominantly hyperactive-impulsive presentation.

[0093] Certain aspects of the disclosure are directed to methods of treating a learning disorder, or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat the learning disorder. In some aspects, the N-acetyl-DL- leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of the learning disorder.

[0094] In some aspects, the learning disorder is selected from dyslexia, dyscalculia, dysgraphia, and nonverbal learning disability. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat dyslexia, dyscalculia, dysgraphia, and / or nonverbal learning disability. In some aspects, the N-acetyl-DL-leucine or N-acetyl- L-leucine is administered to the subject to treat one or more neurological symptoms of dyslexia, dyscalculia, dysgraphia, and / or nonverbal learning disability.

[0095] Certain aspects of the disclosure are directed to methods of treating dyslexia in a subject in need thereof, the method comprising a therapeutically effective amount of N- acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more alterations of DYX1 (15q21.1, DYXCI gene), DYX2 (6p22.2, KIAA0319 gene, and 6p22, DCDC2 gene), DYX3 (2pl5-16, MRPL19 and C20RF3 genes), DYX5 (3pl2-ql3, ROBO1 genes), DYX6 (18pl 1.2, MC5R, DYM, and NEDD4L genes), SPCH1 (7q31.1 and FOXP2 gene), SL14 (7q35-36, CNTNAP2 gene), and / or SLI1 (16q23-24, CM1P and ATP2C2 genes) by genetic testing. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat dyslexia. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of dyslexia. In some aspects, the neurological symptoms associated with dyslexia include one or more of difficulties with accurate and / or fluent word recognition and spelling despite adequate instruction and intelligence and intact sensory abilities.

[0096] Certain aspects of the disclosure are directed to methods of treating dyscalculia in a subject in need thereof, the method comprising a therapeutically effective amount of N- acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat dyscalculia. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of dyscalculia. In some aspects, the neurological symptoms associated with dyscalculia include one or more of impaired innate number sense, problems in quantity estimation, reduced subitizing range, inaccurate mapping and transfer of different number representations, counting difficulties, no understanding of the place- value system, impaired development of or access to the mental number line, stick to counting strategies by the usage of their fingers, often very limited retrieval, lack of understanding how to decompose difficult problems into easier ones, no understanding of calculation procedures and concepts, aberrant neural network, differences in brain activation, grey and white matter volume, and fibre connections, activation pattern less precise and main functional and structural deficits in core regions for number processing (parietal regions), other cortical and subcortical regions that contribute to numerical cognition can be affected and / or stronger recruitment of supporting areas associated withworking memory, attention, monitoring, and / or updating or finger representation might reflect compensatory mechanisms.

[0097] Certain aspects of the disclosure are directed to methods of treating dysgraphia in a subject in need thereof, the method comprising a therapeutically effective amount of N- acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat dysgraphia. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of dysgraphia. In some aspects, the neurological symptoms associated with dysgraphia include one or more of difficulty executing coordinated motor actions, and fine and gross motor disorders, resulting in clumsiness, slowness, and inaccurate motor performances deficits in postural control (hypotonia or hypertonia, immature distal control, poor static and dynamic balance, etc), sensorimotor coordination, and / or motor learning (motor planning, learning new movements, adaptation to change, etc).

[0098] Certain aspects of the disclosure are directed to methods of treating nonverbal learning disability in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat nonverbal learning disability. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of nonverbal learning disability. In some aspects, the neurological symptoms associated with nonverbal learning disability include one or more of low visuo spatial intelligence, discrepancy between verbal and visuospatial intelligence, visuo constructive and fine-motor coordination skills, visuospatial memory tasks, and / or reading better than mathematical achievement, socio emotional skills.

[0099] Certain aspects of the disclosure are directed to methods of treating a communication disorder, or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N- acetyl-L-leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L- leucine is administered to the subject to treat the communication disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of the communication disorder.

[0100] In some aspects, the learning disorder is selected from language disorder, speech sound disorder, childhood-onset fluency disorder, and social communication disorder. In some aspects, the N-acetyl-DL- leucine or N-acetyl-L- leucine is administered to the subject to treat language disorder, speech sound disorder, childhood-onset fluency disorder, and / or social communication disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L- leucine is administered to the subject to treat one or more neurological symptoms of language disorder, speech sound disorder, childhood-onset fluency disorder, and / or social communication disorder.

[0101] Certain aspects of the disclosure are directed to methods of treating language disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with one or more of deletion of the ATP2C2 gene, alteration / mutation of the CHD3 gene, alteration / mutation of the CNTNAP2 gene, alteration / mutation of the GRPN2A gene, and / or alteration of the SRPX2 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L- leucine to treat language disorder. In some aspects, the subject is administered the N- acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of language disorder. In some aspects, the neurological symptoms associated with language disorder include delayed early communication milestones (e.g., age of first word acquisition, production of two-word combinations and sentence generation).

[0102] Certain aspects of the disclosure are directed to methods of treating speech sound disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of alteration / mutation of the MON1B / SYCE1L gene, alteration / mutation of the SETD3 gene, alteration / mutation of the SETX gene, deletions of the SETD3 gene, deletion of the CCNK gene, and / or overexpression of the FI6 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat speech sound disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of speech sound disorder. In some aspects, the neurological symptoms associated with speech sound disorder include one or more of difficulties insound production, errors of articulation or phonetic structure (from poor motor abilities) and / or phonological errors (applying linguistic rules).

[0103] Certain aspects of the disclosure are directed to methods of treating childhood-onset fluency disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the SSUH2 gene and / or alteration / mutation of the FBLN7 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat childhood-onset fluency disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of childhood-onset fluency disorder. In some aspects, the neurological symptoms associated with childhood-onset fluency disorder include prolonged, blocked, and / or repeated speech sounds.

[0104] Certain aspects of the disclosure are directed to methods of treating social communication disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with duplication at 19p 13.2p 12 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat social communication disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of social communication disorder. In some aspects, the neurological symptoms associated with social communication disorder include impaired verbal and nonverbal communication for social purposes.

[0105] Certain aspects of the disclosure are directed to methods of treating a motor disorder, or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat a motor disorder. In some aspects, the N-acetyl-DL- leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of a motor disorder.

[0106] In some aspects, the motor disorder is selected from developmental coordination disorder and stereotypic movement disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat developmental coordinationdisorder and / or stereotypic movement disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of developmental coordination disorder and / or stereotypic movement disorder.

[0107] Certain aspects of the disclosure are directed to methods of treating developmental coordination disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with deletion of 22ql 1.2, deletion of 6ql4.2-ql4.3, deletion of 16p 11.2, and deletion of 6q25 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat developmental coordination disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of developmental coordination disorder. In some aspects, the neurological symptoms associated with developmental coordination disorder include one or more of poor gross motor movements, poor fine motor movements, and / or secondary neurological symptoms (academic, psychosocial, and physical difficulties).

[0108] Certain aspects of the disclosure are directed to methods of treating stereotypic movement disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat stereotypic movement disorder. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of stereotypic movement disorder. In some aspects, the neurological symptoms associated with stereotypic movement disorder include one or more of common and complex motor behaviors: pencil tapping, hair twisting, nail biting, hand flapping, waving, and / or finger wiggling.

[0109] Certain aspects of the disclosure are directed to methods of treating a Tic disorder, or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat the Tic disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl- L-leucine is administered to the subject to treat one or more neurological symptoms of the Tic disorder.

[0110] In some aspects, the Tic disorder is selected from Tourette syndrome, chronic motor or vocal tic disorder, and transient tic disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat Tourette syndrome, chronic motor or vocal tic disorder, and / or transient tic disorder. In some aspects, the N-acetyl-DL- leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of Tourette syndrome, chronic motor or vocal tic disorder, and / or transient tic disorder.

[0111] Certain aspects of the disclosure are directed to methods of treating Tourette syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alterations / mutations of the SLITRK1 gene on chromosome 13 and / or alterations / mutations of the HDC gene on chromosome 15 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat Tourette syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Tourette syndrome. In some aspects, the neurological symptoms associated with Tourette syndrome include one or more of transient or chronic motor and / or vocal tics.

[0112] Certain aspects of the disclosure are directed to methods of treating chronic motor or vocal tic disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alterations / mutations of the SLITRK1 gene on chromosome 13 and / or alterations / mutations of the HDC gene on chromosome 15 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat chronic motor or vocal tic disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of chronic motor or vocal tic disorder. In some aspects, the neurological symptoms associated with chronic motor or vocal tic disorder include one or more of chronic motor and / or vocal tics.

[0113] Certain aspects of the disclosure are directed to methods of treating transient tic disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alterations / mutations of the SLITRK1 gene onchromosome 13 and / or alterations / mutations of the HDC gene on chromosome 15 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat transient tic disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L- leucine to treat one or more neurological symptoms of transient tic disorder. In some aspects, the neurological symptoms associated with transient tic disorder include one or more of transient motor and / or vocal tics.

[0114] Certain aspects of the disclosure are directed to methods of treating a cerebral palsy disorder, or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat the cerebral palsy disorder. In some aspects, the N- acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of the cerebral palsy disorder.

[0115] In some aspects, the cerebral palsy disorder is selected from spastic cerebral palsy, dyskinetic cerebral palsy, ataxic cerebral palsy, and / or mixed cerebral palsy. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat spastic cerebral palsy, dyskinetic cerebral palsy, ataxic cerebral palsy, and / or mixed cerebral palsy. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of spastic cerebral palsy, dyskinetic cerebral palsy, ataxic cerebral palsy, and / or mixed cerebral palsy.

[0116] Certain aspects of the disclosure are directed to methods of treating spastic cerebral palsy in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of mutation of the ATL1 gene, SPG7 gene, ALDH18A1 gene, and / or SPG11 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat spastic cerebral palsy. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of spastic cerebral palsy. In some aspects, the neurological symptoms associated with spastic cerebral palsy include one or more of ataxia, paraplegia, hypertonia, seizures and / or secondary neurological symptoms (intellectual disability, dementia, muscle atrophy, extrapyramidal disturbance, peripheral neuropathy).

[0117] Certain aspects of the disclosure are directed to methods of treating dyskinetic cerebral palsy in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with mutation of the ADCY5 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat dyskinetic cerebral palsy. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of dyskinetic cerebral palsy. In some aspects, the neurological symptoms associated with dyskinetic cerebral palsy include one or more of anarthria, seizures, dystonia, and / or choreoathetosis.

[0118] Certain aspects of the disclosure are directed to methods of treating ataxic cerebral palsy in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of mutation of the KCNC3 gene, ITPR1 gene, SPTBN2 gene, and / or chromosome 9pl2-ql2 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat ataxic cerebral palsy. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat one or more neurological symptoms of ataxic cerebral palsy. In some aspects, the neurological symptoms associated with ataxic cerebral palsy include one or more of ataxia, dysarthria, and / or dysdiadochokinesis.

[0119] Certain aspects of the disclosure are directed to methods of treating mixed cerebral palsy in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of mutation of the AGAP1 gene, CTNNB1 gene, FBXO31 gene, KDM7A gene, KIF1A gene, and / or RHOB gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat mixed cerebral palsy. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of mixed cerebral palsy. In some aspects, the neurological symptoms associated with mixed cerebral palsy include one or more of dystonia and spasms, choreoathetosis and / or spasms.

[0120] Certain aspects of the disclosure are directed to methods of treating a rare neurodevelopmental disorder, or a neurological symptom thereof, in a subject in needthereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl- L-leucine is administered to the subject to treat the rare neurodevelopmental disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L- leucine is administered to the subject to treat one or more neurological symptoms of the rare neurodevelopmental disorder.

[0121] In some aspects, the rare neurodevelopmental disorder is selected from Williams syndrome, tuberous sclerosis, DEPDC5 -related epilepsy, Phenylketonuria (PKU), Smith- Magenis syndrome, Angelman syndrome, Cornelia de Lange syndrome, Kabuki syndrome, Moebius syndrome, Sturge-Weber syndrome, Landau- Kleffher syndrome, Sanfilippo syndrome, Charge syndrome, Pitt-Hopkins syndrome, 22ql l.2 Deletion syndrome, STXBP1 disorder, CDKL5 deficiency disorder, FOXG1 syndrome, PURA syndrome, ADNP syndrome, GRIN1 / 2 disorder, Chromosome 8P, Lesch-Nyhan syndrome, Lowe syndrome, Prader-Willi syndrome, Trisomy 18 (Edwards syndrome), and PACS-l-NDD. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat Williams syndrome, tuberous sclerosis, DEPDC5 -related epilepsy, Phenylketonuria (PKU), Smith-Magenis syndrome, Angelman syndrome, Cornelia de Lange syndrome, Kabuki syndrome, Moebius syndrome, Sturge-Weber syndrome, Landau-Kleffner syndrome, Sanfilippo syndrome, Charge syndrome, Pitt-Hopkins syndrome, 22ql l.2 Deletion syndrome, STXBP1 disorder, CDKL5 deficiency disorder, FOXG1 syndrome, PURA syndrome, ADNP syndrome, GRIN1 / 2 disorder, Chromosome 8P, Lesch-Nyhan syndrome, Lowe syndrome, Prader-Willi syndrome, Trisomy 18 (Edwards syndrome), and / or PACS-l-NDD. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of Williams syndrome, tuberous sclerosis, DEPDC5 -related epilepsy, Phenylketonuria (PKU), Smith-Magenis syndrome, Angelman syndrome, Cornelia de Lange syndrome, Kabuki syndrome, Moebius syndrome, Sturge-Weber syndrome, Landau-Kleffner syndrome, Sanfilippo syndrome, Charge syndrome, Pitt-Hopkins syndrome, 22ql l.2 Deletion syndrome, STXBP1 disorder, CDKL5 deficiency disorder, FOXG1 syndrome, PURA syndrome, ADNP syndrome, GRIN1 / 2 disorder, Chromosome 8P, Lesch-Nyhan syndrome, Lowe syndrome, Prader-Willi syndrome, Trisomy 18 (Edwards syndrome), and / or PACS-l-NDD.

[0122] Certain aspects of the disclosure are directed to methods of treating Williams syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with a 1.5- to 1.8-Mb deletion of the Williams-Beuren syndrome critical region (WBSCR) at 7ql l.23 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Williams syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat one or more neurological symptoms of Williams syndrome. In some aspects, the neurological symptoms associated with Williams syndrome include one or more of developmental delay (delayed walking and talking), hypotonia, intellectual disability, impairment of visuospatial construction, sleep disorders, and / or autism-like neurological symptoms.

[0123] Certain aspects of the disclosure are directed to methods of treating tuberous sclerosis in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with mutations in the TSC1 or TSC2 genes by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat tuberous sclerosis. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of tuberous sclerosis. In some aspects, the neurological symptoms associated with tuberous sclerosis include one or more of intellectual disability, autism spectrum disorder, ADHD, anxiety, depression neurological symptoms, and / or executive deficits.

[0124] Certain aspects of the disclosure are directed to methods of treating DEPDC5- related epilepsy in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the DEPDC5 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat DEPDC5 -related epilepsy. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of DEPDC5 -related epilepsy. In some aspects, the neurological symptoms associated with DEPDC5 -related epilepsy include one or more of intellectualdisability, autism spectrum disorder and / or developmental delays (however psychomotor development is usually normal)

[0125] Certain aspects of the disclosure are directed to methods of treating phenylketonuria(PKU) in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the PX / / gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL- leucine orN-acetyl-L-leucine to treat phenylketonuria (PKU). In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of phenylketonuria (PKU). In some aspects, the neurological symptoms associated with phenylketonuria (PKU) include one or more of intellectual disability, disruptive behavior, seizures, tremors, behavioral neurological symptoms associated with mood, anxiety, and / or cognition.

[0126] Certain aspects of the disclosure are directed to methods of treating Smith-Magenis syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed a deleted or mutated RAI1 gene ( 17p 11.2) by genetic testing. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat Smith-Magenis syndrome. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Smith- Magenis syndrome. In some aspects, the neurological symptoms associated with Smith- Magenis syndrome include one or more of developmental delay, intellectual disability, hypotonia, and / or oromotor dysfunction.

[0127] Certain aspects of the disclosure are directed to methods of treating Angelman syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed one or more of deletions in 5- to 7-Mb of 15ql 1.2-ql 3 and / or mutation of the UBE3A gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Angelman syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Angelman syndrome. In some aspects, the neurological symptoms associated with Angelman syndrome include one or more ofseizures, nonepileptic myoclonus, hypermotor activity, autism spectrum traits, motor delay, tremor, language delay, and / or cognitive impairment.

[0128] Certain aspects of the disclosure are directed to methods of treating Cornelia de Lange syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of alteration / mutation of the NIPBL gene, SMC1A gene, SMC3 gene, RAD21 gene, and / or HDAC8 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat Cornelia de Lange syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Cornelia de Lange syndrome. In some aspects, the neurological symptoms associated with Cornelia de Lange syndrome include one or more of intellectual disability and / or developmental delay.

[0129] Certain aspects of the disclosure are directed to methods of treating Kabuki syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of alteration / mutation of the KMT2D gene and / or KDM6A gene by genetic testing. In some aspects, the subject is administered the N- acetyl-DL-leucine or N-acetyl-L-leucine to treat Kabuki syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Kabuki syndrome. In some aspects, the neurological symptoms associated with Kabuki syndrome include one or more of Intellectual disability, developmental delays, hypotonia and / or oromotor dysfunction.

[0130] Certain aspects of the disclosure are directed to methods of treating Moebius syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of alteration / mutation of the REV3L gene, PLXND1 gene, HOXA1 gene, HOXB1 gene, and / or TUBB3 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Moebius syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Moebius syndrome. In some aspects, the neurological symptoms associated with Moebius syndrome includeone or more of intellectual disability, developmental delays, autism, ocular deformities, developmental delay, musculoskeletal malformations, neurological disorders, mental retardation, facial and abducens and / or nerve palsies.

[0131] Certain aspects of the disclosure are directed to methods of treating Sturge-Weber syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with one or more of mutation of the GNAQ gene and / or substitution of C.548G— »A on 9q21.2 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Sturge-Weber syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat one or more neurological symptoms of Sturge-Weber syndrome. In some aspects, the neurological symptoms associated with Sturge-Weber syndrome include one or more of capillary malformation, ocular vascular malformations, seizures, hemiparesis, migraine-like vascular headaches, delayed neuropsychological development, hemiplegia, visual field defects, and / or behavioral problems.

[0132] Certain aspects of the disclosure are directed to methods of treating Landau- Kleffher syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with mutation of the GRIN2A gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat Landau-Kleffner syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Landau-Kleffner syndrome. In some aspects, the neurological symptoms associated with Landau-Kleffner syndrome include one or more of verbal and / or auditory agnosia, verbal preservation, mutism, seizures, intellectual disability, and / or autism-like behavior.

[0133] Certain aspects of the disclosure are directed to methods of treating Sanfilippo syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of alteration / mutation of the SGSH gene, NAGLU gene, HGSNAT gene, and / or GNS gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Sanfilippo syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat one or more neurological symptoms of Sanfilippo syndrome. In some aspects, the neurological symptoms associated with Sanfilippo syndrome include one or more of progressive neurocognitive degeneration, language delay, abnormal behavior, autism spectrum disorder, speech loss, seizures, and / or deterioration of walking.

[0134] Certain aspects of the disclosure are directed to methods of treating Charge syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl- L-leucine to the subject. In some aspects, the subject has been diagnosed with mutation, deletion, or translocation of the CHD7 gene located on 8ql2 by genetic testing. In some aspects, the subject is administered the N- acetyl-DL-leucine or N-acetyl-L-leucine to treat Charge syndrome. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Charge syndrome. In some aspects, the neurological symptoms associated with Charge syndrome include one or more or Coloboma, cranial nerve abnormalities (e.g., facial nerve palsy), developmental delay, and / or hypothalamo- hypophyseal dysfunction.

[0135] Certain aspects of the disclosure are directed to methods of treating Pitt-Hopkins syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the TCF4 gene and / or a deletion of the chromosome region in which TCF4 is located (18q21.2) by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Pitt-Hopkins syndrome. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Pitt-Hopkins syndrome. In some aspects, the neurological symptoms associated with Pitt-Hopkins syndrome include one or more of developmental delay, intellectual disability, autism spectrum disorder neurological symptoms (e.g., impairments in communication, behavior, and social interactions), and / or seizures.

[0136] Certain aspects of the disclosure are directed to methods of treating 22ql 1.2 deletion syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with deletion on chromosome 22 at locus ql 1.2 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L- leucine to treat 22ql l.2 deletion syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of 22ql l.2 deletion syndrome. In some aspects, the neurological symptoms associated with 22ql l.2 deletion syndrome include one or more of developmental delays, speech delays, learning deficits and differences in behavior, and / or impaired psychosocial development.

[0137] Certain aspects of the disclosure are directed to methods of treating STXBP1 disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the STXBP1 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat STXBP1 disorder. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of STXBP1 disorder. In some aspects, the neurological symptoms associated with STXBP1 disorder include one or more of epileptic encephalopathy neurological symptoms, epileptic spasms, seizures, intellectual disability neurological symptoms, autistic-like neurological symptoms and behavioral problems, adaptive impairments, fine motor difficulties, tremors, hyperactivity, psychiatric problems, communication difficulties (e.g., absent speech), axial hypotonia, spastic or flaccid tetraplegia, hypomimia, bradykinesia, dystonia, dyskinesia, and / or choreo athetosis.

[0138] Certain aspects of the disclosure are directed to methods of treating CDKL5 deficiency disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the CDKL5 gene on the short arm of the X chromosome (Xp22) by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat CDKL5 deficiency disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat one or more neurological symptoms of CDKL5 deficiency disorder. In some aspects, the neurological symptoms associated with CDKL5 deficiency disorder include one or more of early-onset epilepsy (mostly drug-refractory), generalized hypotonia, psychomotor developmental disorder neurological symptoms, intellectualdisability neurological symptoms, autistic features (e.g., poor social interactions, poor eye contact), and / or hand stereotypy.

[0139] Certain aspects of the disclosure are directed to methods of treating FOXG1 syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the FOXG gene and / or frameshift, in-frame, and missense mutations at c.256dupC and / or c.460dupG in the N-domain by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat FOXG1 syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L- leucine to treat one or more neurological symptoms of FOXG1 syndrome. In some aspects, the neurological symptoms associated with FOXG1 syndrome include one or more of choreoathetosis, dystonia, orolingual / facial dyskinesias, myoclonic jerk, spams, and / or seizures.

[0140] Certain aspects of the disclosure are directed to methods of treating PURA syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the PURA gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat PURA syndrome. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of PURA syndrome. In some aspects, the neurological symptoms associated with PURA syndrome include one or more of hypotonia, impaired cognitive development, seizures, cognitive delay, apnea, hyper / hyporeflexia, atonic / myopathic face, and / or peripheral weakness.

[0141] Certain aspects of the disclosure are directed to methods of treating ADNP syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the ADNP gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat ADNP syndrome. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of ADNP syndrome. In some aspects, the neurological symptoms associated with ADNP syndrome include one or more of intellectual disability, autism spectrum disorder neurologicalsymptoms, anxiety, speech development difficulties, language development difficulties, psychomotor developmental problems, behavioral problems, sleep disturbances, social problems, and / or hypotonia.

[0142] Certain aspects of the disclosure are directed to methods of treating GRIN1 / 2 disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with de novo pathogenic variants causing excessive or insufficient NMDAR function by genetic testing. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L- leucine to treat GRIN1 / 2 disorder. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of GRIN1 / 2 disorder. In some aspects, the neurological symptoms associated with GRIN1 / 2 disorder include one or more of intellectual disability, developmental delay, autism-like features, schizophrenia, and / or epilepsy.

[0143] Certain aspects of the disclosure are directed to methods of treating chromosome 8P duplication / deletion syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with inversion, duplication, and / or deletion of chromosome 8P by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat chromosome 8P duplication / deletion syndrome. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of chromosome 8P duplication / deletion syndrome. In some aspects, the neurological symptoms associated with chromosome 8P duplication / deletion syndrome include one or more of psychomotor delay, language delay, muscle hypotonia, dysmorphic facial features, central nervous system malformations, and / or seizures.

[0144] Certain aspects of the disclosure are directed to methods of treating Lesch-Nyhan syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with an X-linked disorder caused by mutations in HPRT1 enzyme of the purine salvage pathway by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Lesch-Nyhansyndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat one or more neurological symptoms of Lesch-Nyhan syndrome. In some aspects, the neurological symptoms associated with Lesch-Nyhan syndrome include one or more of dystonia, intellectual disability, delayed motor development, choreoathetosis, and / or dystonia.

[0145] Certain aspects of the disclosure are directed to methods of treating Lowe syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with an X-linked recessive variant of the OCRL gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine orN-acetyl-L-leucine to treat Lowe syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Lowe syndrome. In some aspects, the neurological symptoms associated with Lowe syndrome include one or more of intellectual disability, hypotonia, areflexia, delayed motor development, seizure, and / or facial dysmorphisms.

[0146] Certain aspects of the disclosure are directed to methods of treating Prader-Willi syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with absence of paternally expressed imprinted genes at 15ql 1.2-ql 3 by genetic testing. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat Prader-Willi syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Prader-Willi syndrome. In some aspects, the neurological symptoms associated with Prader-Willi syndrome include one or more of delayed motor development, intellectual disabilities, behavior disorders, attention deficit / hyperactivity disorder, temper tantrums, stubbornness, controlling and manipulative behavior, compulsivity, difficulty with change in routine, sleep abnormalities including rapid eye movement (REM) latency, altered sleep architecture, oxygen denaturation, central and obstructive apnea, infantile hypotonia, and / or cognitive rigidity.

[0147] Certain aspects of the disclosure are directed to methods of treating Trisomy 18 (Edwards syndrome) in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In someaspects, the subject has been diagnosed with supernumerary Chromosome 21 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat Trisomy 18 (Edwards syndrome). In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Trisomy 18 (Edwards syndrome). In some aspects, the neurological symptoms associated with Trisomy 18 (Edwards syndrome) include one or more of psychomotor disability neurological symptoms, intellectual disability neurological symptoms, muscular tone abnormalities, and / or seizures.

[0148] Certain aspects of the disclosure are directed to methods of treating PACS-l-NDD in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the PACS1 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat PACS-l-NDD. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L- leucine to treat one or more neurological symptoms of PACS-l-NDD. In some aspects, the neurological symptoms associated with PACS-l-NDD include one or more of psychomotor disability neurological symptoms, Autism-like behaviors (temper tantrums, aggression), developmental delays, and / or hypotonia.

[0149] Certain aspects of the disclosure are directed to methods of treating a rare genetic neurodevelopmental disorder, or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl- L-leucine is administered to the subject to treat the rare genetic neurodevelopmental disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of the rare genetic neurodevelopmental disorder.

[0150] In some aspects, the rare genetic neurodevelopmental disorder is selected from Alfi's syndrome, Joubert syndrome, Kleefstra syndrome, Lissencephaly, Mowat-Wilson syndrome, Rubinstein-Taybi syndrome, Schinzel-Giedion syndrome, Smith-Lemli-Opitz syndrome, Wold-Hirschhom syndrome, Van der Woude syndrome, Walker-Warburg syndrome, and Zellweger Spectrum disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat from Alfi's syndrome, Joubertsyndrome, Kleefstra syndrome, Lissencephaly, Mowat-Wilson syndrome, Rubinstein- Taybi syndrome, Schinzel-Giedion syndrome, Smith-Lemli-Opitz syndrome, Wold- Hirschhom syndrome, Van der Woude syndrome, Walker- Warburg syndrome, and / or Zellweger Spectrum disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L- leucine is administered to the subject to treat one or more neurological symptoms of from Alfi's syndrome, Joubert syndrome, Kleefstra syndrome, Lissencephaly, Mowat-Wilson syndrome, Rubinstein-Taybi syndrome, Schinzel-Giedion syndrome, Smith-Lemli-Opitz syndrome, Wold-Hirschhom syndrome, Van der Woude syndrome, Walker-Warburg syndrome, and / or Zellweger Spectrum disorder.

[0151] Certain aspects of the disclosure are directed to methods of treating Alfi’s Syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with a missing or deleted part of the short-arm of chromosome 9 within ~4-6 Mb interval of 9p22 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L- leucine to treat Alfi’s Syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine orN-acetyl-L-leucine to treat one or more neurological symptoms of Alfi’s Syndrome. In some aspects, the neurological symptoms associated with Alfi’s Syndrome include one or more of delayed cognitive development, intellectual disability, hypertonia, hypotonia, and / or seizures.

[0152] Certain aspects of the disclosure are directed to methods of treating Joubert syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with one or more alteration / mutation of the INPP5E gene, TMEM216 gene, AHI1 gene, NPHP1 gene, CEP290 gene, TMEM67 gene, RPGRIP1L gene, ARL13B gene, CC2D2A gene, and / or the OFD1 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Joubert syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Joubert syndrome. In some aspects, the neurological symptoms associated with Joubert syndrome include one or more of hypotonia, developmental delay, and / or intellectual disability.

[0153] Certain aspects of the disclosure are directed to methods of treating Kleefstra syndrome in a subject in need thereof, the method comprising a therapeutically effectiveamount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with one or more of a deletion at 9q34.3 and / or an intragenic EHMT1 pathogenic variant by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Kleefstra syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Kleefstra syndrome. In some aspects, the neurological symptoms associated with Kleefstra syndrome include one or more of intellectual disability, expressive speech delay, sleep disturbances, autism-like social functioning, hypotonia, seizures, and / or motor dysfunction.

[0154] Certain aspects of the disclosure are directed to methods of treating Lissencephaly in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of a deletion at 17p 13.3, alteration / mutation of the LISI gene, DCX gene, and / or TUBA1A gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Lissencephaly. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Lissencephaly. In some aspects, the neurological symptoms associated with Lissencephaly include one or more of intellectual disability, neuro developmental delay, hypertonia, hypotonia, and / or seizures.

[0155] Certain aspects of the disclosure are directed to methods of treating Mowat-Wilson syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with mutation or deletion of ZEB2 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Mowat-Wilson syndrome. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Mowat- Wilson syndrome. In some aspects, the neurological symptoms associated with Mowat- Wilson syndrome include one or more of seizures, developmental delay, hypotonia, and / or behavioral impairment.

[0156] Certain aspects of the disclosure are directed to methods of treating Rubinstein- Taybi syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In someaspects, the subject has been diagnosed one or more of alteration / mutation of the CREBBP gene and / or EP300 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Rubinstein-Taybi syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Rubinstein-Taybi syndrome. In some aspects, the neurological symptoms associated with Rubinstein-Taybi syndrome include one or more of hypotonia, intellectual disability, speech delay, and / or behavioral / neurological problems (mood swings, obsessive-compulsive disorders, attention deficit, motor stereotypes, seizures, poor coordination).

[0157] Certain aspects of the disclosure are directed to methods of treating Schinzel- Giedion syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the SETBP1 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat Schinzel-Giedion syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Schinzel-Giedion syndrome. In some aspects, the neurological symptoms associated with Schinzel-Giedion syndrome include one or more of developmental delay (expressive language delay), seizures, vision impairment, and / or hearing impairment.

[0158] Certain aspects of the disclosure are directed to methods of treating Smith-Lemli- Opitz syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with missense, nonsense, insertion, deletion, and splice defect mutations of the DHCR7 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Smith-Lemli-Opitz syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat one or more neurological symptoms of Smith-Lemli-Opitz syndrome. In some aspects, the neurological symptoms associated with Smith-Lemli-Opitz syndrome include one or more of seizures, intellectual disabilities, and / or hypotonia.

[0159] Certain aspects of the disclosure are directed to methods of treating Wolf- Hirschhom syndrome in a subject in need thereof, the method comprising a therapeuticallyeffective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with deletion of the short arm of chromosome 4 (del 4p 16.3) encoding MSX1 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Wolf-Hirschhorn syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Wolf-Hirschhorn syndrome. In some aspects, the neurological symptoms associated with Wolf-Hirschhorn syndrome include one or more of growth impairment, impairment, intellectual disability, delayed psychomotor development, seizures, and / or hypotonia.

[0160] Certain aspects of the disclosure are directed to methods of treating van der Woude syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the IRF6 gene on chromosome 1 by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat van der Woude syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of van der Woude syndrome. In some aspects, the neurological symptoms associated with van der Woude syndrome include generalized cognitive defects.

[0161] Certain aspects of the disclosure are directed to methods of treating Walker- Warburg syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of alteration / mutation of the POMT1 gene, fukutin gene, FKRP gene, and / or POMT2 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Walker- Warburg syndrome. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Walker- Warburg syndrome. In some aspects, the neurological symptoms associated with Walker- Warburg syndrome include one or more of hypotonia, developmental delay with mental retardation, and / or seizures.

[0162] Certain aspects of the disclosure are directed to methods of treating Zellweger Spectrum disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In someaspects, the subject has been diagnosed with alteration / mutation in one or more of the 13 PEX genes by genetic testing. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat Zellweger Spectrum disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Zellweger Spectrum disorder. In some aspects, the neurological symptoms associated with Zellweger Spectrum disorder include one or more of hypotonia, seizures, and / or developmental delay.

[0163] Certain aspects of the disclosure are directed to methods of treating an ultra-rare neurodevelopmental disorder, or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl- L-leucine is administered to the subject to treat the ultra-rare neurodevelopmental disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of the an ultra-rare neurodevelopmental disorder.

[0164] In some aspects, the an ultra-rare neurodevelopmental disorder is selected from Aicardi syndrome, Bohring-Opitz syndrome, Coffm-Siris syndrome, Cornelia de Lange syndrome, Rett syndrome, and MeCP2 Duplication syndrome. In some aspects, the N- acetyl-DL- leucine or N-acetyl-L-leucine is administered to the subject to treat from Aicardi syndrome, Bohring-Opitz syndrome, Coffin-Siris syndrome, Cornelia de Lange syndrome, Rett syndrome, and / or MeCP2 Duplication syndrome. In some aspects, the N-acetyl-DL- leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of from Aicardi syndrome, Bohring-Opitz syndrome, Coffin-Siris syndrome, Cornelia de Lange syndrome, Rett syndrome, and / or MeCP2 Duplication syndrome.

[0165] Certain aspects of the disclosure are directed to methods of treating Aicardi syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of a gene on the X chromosome by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat Aicardi syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms ofAicardi syndrome. In some aspects, the neurological symptoms associated with Aicardi syndrome include one or more of infantile spasms, intellectual disability, and / or developmental disability.

[0166] Certain aspects of the disclosure are directed to methods of treating Bohring-Opitz syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the ASXL1 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Bohring-Opitz syndrome. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Bohring- Opitz syndrome. In some aspects, the neurological symptoms associated with Bohring- Opitz syndrome include one or more of intellectual disability, hypotonic facies, seizures, developmental delay, truncal hypotonia, and / or hypertonia of the extremities.

[0167] Certain aspects of the disclosure are directed to methods of treating Coffin-Siris syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of alteration / mutation the ARID1B gene, ARID1A gene, SMARCB1 gene, SMARCA4 gene, SMARCE1 gene, ARID2 gene, DPF2 gene, SMARCC2 gene, SOX11 gene, SOX4 gene, SMARCD1 gene, and / or BICRA gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl-L-leucine to treat Coffin-Siris syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Coffm-Siris syndrome. In some aspects, the neurological symptoms associated with Coffin-Siris syndrome include one or more of hypotonia, developmental delays, cognitive delays, intellectual disability, behavioral abnormalities (e.g., hyperactivity, aggressiveness, autistic features), seizures, and / or tics.

[0168] Certain aspects of the disclosure are directed to methods of treating Cornelia de Lange syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of alteration / mutation of the NIPBL gene, SMC1A gene, SMC3 gene, RAD21 gene, and / or HDAC8 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Cornelia de Lange syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of Cornelia de Lange syndrome. In some aspects, the neurological symptoms associated with Cornelia de Lange syndrome include one or more of intellectual disability and / or developmental delay.

[0169] Certain aspects of the disclosure are directed to methods of treating Rett syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl- L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more of alteration / mutation of the MECP2 gene, CDKL5 gene, FOXG1 gene, MEF2C gene, and / or TCF4 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat Rett syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N- acetyl- L-leucine to treat one or more neurological symptoms of Rett syndrome. In some aspects, the neurological symptoms associated with Rett syndrome include one or more of intellectual disability, motor impairment, poor communication skills, poor motor skills, and / or seizures.

[0170] Certain aspects of the disclosure are directed to methods of treating MeCP2 Duplication syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with a duplication of the MECP2 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat MeCP2 Duplication syndrome. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of MeCP2 Duplication syndrome. In some aspects, the neurological symptoms associated with MeCP2 Duplication syndrome include one or more of Intellectual disability, developmental delay, hypotonia, seizures, autistic-like behavior, and / or epilepsy.

[0171] Certain aspects of the disclosure are directed to methods of treating a gene mutation- related disorder, or a neurological symptom thereof, in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L- leucine to the subject. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat the gene mutation-related disorder. In some aspects, theN-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of the gene mutation-related disorder.

[0172] In some aspects, the an gene mutation-related disorder is selected from CTNNB1 syndrome, MED13L syndrome, FOXG1 syndrome, NARS1 -related neurodeve lopmental disorder, CACNA / ^-related neurodevelopmental disorder, and SLC6A 1 -related neurodevelopmental disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L- leucine is administered to the subject to treat from CTNNB1 syndrome, MED13L syndrome, FOXG1 syndrome, NARS1 -related neurodevelopmental disorder, CA CNA / ^-related neurodevelopmental disorder, and / or SLC6A 1 -related neurodevelopmental disorder. In some aspects, the N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat one or more neurological symptoms of from CTNNB1 syndrome, MED13L syndrome, FOXG1 syndrome, NARS1 -related neurodevelopmental disorder, CACNA1A- related neurodevelopmental disorder, and / or SLC6A 1 -related neurodevelopmental disorder.

[0173] Certain aspects of the disclosure are directed to methods of treating CTNNB1 syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the CTNNB1 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat CTNNB1 syndrome. In some aspects, the subject is administered the N- acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of CTNNB1 syndrome. In some aspects, the neurological symptoms associated with CTNNB1 syndrome include one or more of hypotonia, peripheral neuropathy, spastic diplegia, motor delay, developmental disorder and / or autism spectrum disorder.

[0174] Certain aspects of the disclosure are directed to methods of treating MED13L syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed alteration / mutation of the MED13L gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat MED13L syndrome. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of MED13L syndrome. In some aspects, the neurological symptoms associated with MED13L syndromeinclude one or more of intellectual disability, developmental disability, speech delay, autistic features, hypotonia, poor coordination, seizures, aggressive behavior, strabismus, and / or facial dysmorphism.

[0175] Certain aspects of the disclosure are directed to methods of treating FOXG1 syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the FOXG1 gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat FOXG1 syndrome. In some aspects, the subject is administered the N-acetyl-DL- leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of FOXG1 syndrome. In some aspects, the neurological symptoms associated with FOXG1 syndrome include one or more of choreoathetosis, dystonia, orolingual / facial dyskinesias, myoclonic jerk, spams, and / or seizures.

[0176] Certain aspects of the disclosure are directed to methods of treating NARS1 -related neurodevelopmental disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the NARS1 gene by genetic testing. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat A / 47?S7-related neurodevelopmental disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of NARS1 -related neurodevelopmental disorder. In some aspects, the neurological symptoms associated with NARS1 -related neurodevelopmental disorder include one or more of intellectual disability, seizures, spasticity, neuropathy, and / or ataxia.

[0177] Certain aspects of the disclosure are directed to methods of treating CACNA1A- related neurodevelopmental disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the CACNA1A gene by genetic testing. In some aspects, the subject is administered the N- acetyl-DL-leucine or N-acetyl-L-leucine to treat CA CNA / ^-related neurodevelopmental disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L-leucine to treat one or more neurological symptoms of CACNA 1A -relatedneurodevelopmental disorder. In some aspects, the neurological symptoms associated with CACNA 1A -related neurodevelopmental disorder include one or more of migraine, vertigo, ataxia, hemianopsia, tingling / numbness of the extremities, dysphasia, noro deficitis, tininitus, ataxia, dystonia, cognitive dysfunction, developmental delay, autistic -like features, and / or attention -deficit hyperactivity disorder-like features.

[0178] Certain aspects of the disclosure are directed to methods of treating SLC6A 1 -related neurodevelopmental disorder in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with alteration / mutation of the SLC6A1 gene by genetic testing. In some aspects, the subject is administered the N-acetyl- DL-leucine or N-acetyl-L-leucine to treat SLC6A / -related neurodevelopmental disorder. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of SLC6A 1 -related neurodevelopmental disorder. In some aspects, the neurological symptoms associated with SLC6A 1 -related neurodevelopmental disorder include one or more of developmental delay, hypotonia, intellectual disability, seizures, movement disorders, autism, attention deficit, developmental delay, and / or seizures.

[0179] Certain aspects of the disclosure are directed to methods of treating developmental delay and seizures with or without movement abnormalities (DEDSM) in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL-leucine or N-acetyl-L-leucine to the subject. In some aspects, the subject has been diagnosed with one or more mutations in the DHDDS gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat developmental delay and seizures with or without movement abnormalities (DEDSM). In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of developmental delay and seizures with or without movement abnormalities (DEDSM). In some aspects, the neurological symptoms associated with developmental delay and seizures with or without movement abnormalities (DEDSM) include one or more of global developmental delay, variable intellectual disability, early- onset seizures with a myoclonic component, delayed motor development, abnormal movements, ataxia, dystonia, and / or tremor.

[0180] Certain aspects of the disclosure are directed to methods of treating DHDDS syndrome in a subject in need thereof, the method comprising a therapeutically effective amount of N-acetyl-DL- leucine or N-acetyl-L- leucine to the subject. In some aspects, the subject has been diagnosed with one or more mutations in the DHDDS gene by genetic testing. In some aspects, the subject is administered the N-acetyl-DL-leucine or N-acetyl- L- leucine to treat DHDDS syndrome. In some aspects, the subject is administered the N- acetyl-DL-leucine or N-acetyl-L-leucine to treat one or more neurological symptoms of DHDDS syndrome. In some aspects, the neurological symptoms associated with DHDDS syndrome include one or more of mild to severe learning difficulties, tremor / myclonus, seizure (ranging from absence, tonic-clonic, myoclonic, atonic, myoclonic — tonic, tonic to focal), ataxia, parkinsonism, dystonia, dysarthria, autistic traits, hyperactivity / inattention, anxiety disorders, pyramidal signs, chorea, behaviour disorders, psychosis, stereotypies, and / or OCD.

[0181] In some embodiments, the subject has been diagnosed with a neuro developmental disorder by genetic testing prior to administration of N-acetyl leucine. In some aspects, the subject has been diagnosed with any one of more of the genetic mutations listed in Table 1A by genetic testing. In some aspects, the subject has been diagnosed with any one of more of the genetic mutations listed in Table IB by genetic testing. In some aspects, the subject has been diagnosed with any one of more of the genetic mutations listed in Table 1C by genetic testing.

[0182] In some aspects, the subject has been diagnosed with one or more of the following genetic mutations: transcriptional silencing of the FMRI gene, supernumary chromosome 21, absence of paternally expressed imprinted genes at 15ql l.2-ql3, deletion of variable size occurring on the short arm of chromosome 5 (5p-), partial or complete monosomy-X, deletion of the ATP2C2 gene, deletion of the SETD3 gene, deletion of the CCNK gene, overexpression of the IFI6 gene, duplication of 19pl3.2pl2, deletion of 22ql 1.2, deletion of 6ql4.2-ql4.3, deletion of 6q25, 1.5- to 1.8-Mb deletion of the Williams-Beuren syndrome critical region (WBSCR) at 7ql 1.23, deletion of the RAI1 gene, deletions in 5- to 7-Mb 15ql l.2-ql3, deletion or translocation of the CHD7 gene, deletion of the TCF4 gene, deletion on chromosome 22 at locus ql l.2, deletion of chromosome 8p, duplication of chromosome 8p, inversion of chromosome 8p, absence of paternally expressed imprinted genes at 15ql l.2-ql3, supemumary chromosome 21, Missing or deleted part of the short-arm of chromosome 9 within ~4-6 Mb interval of 9p22, deletion at 9q34.3, deletion at 17p 13.3, deletion of the ZEB2 gene, deletion of the DHCR7 gene, deletion of the short arm of chromosome 4 (del 4pl6.3) encoding MSX1, duplication of the MECP2 gene, alteration or mutation of the DHDDS gene, DYNAP2 gene, SPNS1 gene, MECP2 gene, CDKL5 gene, F0XG1 gene, MEF2C gene, TCF4 gene, DYXCI gene (15q21. 1), KIAA0319 gene (6p22.2), DCDC2 gene (6p22), MRPL19 gene (2pl5-16), C20RF3 gene (2pl5-16), ROBO1 gene (3pl2-ql3), MC5R gene (18pl l.2,), D YM gene (18pl l.2,), NEDD4L gene (18pl l.2,), F0XP2 gene (7q31.1), CNTNAP2 gene (7q35-36), CM IP gene (16q23-24), J7P2C2 gene (16q23-24), CHD3 gene, CNTNAP2 gene, GRIN2A gene, SRPX2 gene, M0N1B / SYCE1L gene, SETD3 gene, SETX gene, SSUH2 gene, FBLN7 gene, chromosome 3, chromosome 7q, chromosome 12, chromosome 19p, chromosome 19q, chromosome X, SLITRK1 gene, HDC gene, ATL1 gene, SPG7 gene, ALDH18A1 gene, SPG11 gene, ADCY5 gene, KCNC3 gene, ITPR1 gene, SPTBN2 gene, chromosome 9pl2-ql2, AGAP1 gene, CTNNB1 gene, FBX031 gene, KDM7A gene, KIF1A gene, RHOB gene, TSC1 gene, TSC2 gene, DEPDC5 gene, PAH gene, RAI1 gene, UBE3A gene, NIPBL gene, SMC1A gene, SMC3 gene, RAD21 gene, HDAC8 gene, KMT2D gene, KDM6A gene, REV3L gene, PLXND1 gene, H0XA1 gene, H0XB1 gene, TUBB3 gene, GNAQ gene, GRIN2A gene, SGSH gene, NAGLU gene, HGSNAT gene, GNS gene, CHD7 gene, TCF4 gene, STXBP1 gene, CDKL5 gene, PURA gene, ADNP gene, HPRT1 gene, OCRL gene, PACS1 gene, INPP5E gene, TMEM216 gene, AHI1 gene, NPHP1 gene, CEP290 gene, TMEM67 gene, RPGRIP1L gene, ARL13B gene, CC2D2A gene, 0FD1 gene, EHMT1 gene, LISI gene, DCX gene, TUBA1A gene, ZEB2 gene, CREBBP gene, EP300 gene, SETBP1 gene, DHCR7 gene, IRF6 gene, P0MT1 gene, fukutin gene, FKRP gene, P0MT2 gene, PEX gene, X chromosome, ASXL1 gene, ARID1B gene, ARID1A gene, SMARCB1 gene, SMARCA4 gene, SMARCE1 gene, ARID2 gene, DPF2 gene, SMARCC2 gene, SOX11 gene, SOX4 gene, SMARCD1 gene, BICRA gene, NIPBL gene, SMC1A gene, SMC3 gene, RAD21 gene, HDAC8 gene, CTNNB1 gene, MED13L gene, F0XG1 gene, NARSI gene, CACNAIA gene, and / or SLC6A1 gene.

[0183] An "alteration" or "mutation" of a gene refers to a missense, nonsense, insertion, deletion, splice defect mutation, deletion, truncation, duplication, loss-of-fimction, and / or inversion of the gene.

[0184] In another embodiment, the disclosure provides procedures of personalized medicine for subjects having a neuro developmental disorder that encompasses the selectionof treatment options with the highest likelihood of successful outcome for individual subjects. In another aspect, the disclosure relates to the use of a genetic testing to predict treatment outcome, e.g., the likelihood of favorable responses or treatment success, in subjects having neuro developmental disorder.

[0185] In another embodiment, the disclosure provides a method of selecting a subject for treatment of a neurodevelopmental disorder with N-acetyl leucine, comprising obtaining a biological sample, e.g., a blood or saliva sample, from the subject, and testing the biological sample from the subject for the presence of a pathogenic variant, i.e., a mutation in a gene. Mutations in genes can be determined by genetic testing, e.g., chromosomal microarray analysis (CMA), single gene sequencing, multigene panel testing, and / or exome sequencing.

[0186] In another embodiment, the disclosure provides methods of treating a neurodevelopmental disorder in a subject, comprising administering a therapeutically effective amount of N-acetyl leucine to the subject wherein the subject's cells contain a genetic mutation listed in Table 1A. In another embodiment, the disclosure provides methods of treating a neurodevelopmental disorder in a subject, comprising administering a therapeutically effective amount of N-acetyl leucine to the subject wherein the subject's cells contain a genetic mutation listed in Table IB. In another embodiment, the disclosure provides methods of treating a neurodevelopmental disorder in a subject, comprising administering a therapeutically effective amount of N-acetyl leucine to the subject wherein the subject's cells contain a genetic mutation listed in Table 1C.

[0187] In one embodiment, the subject is selected for treatment with N-acetyl leucine after the subject's cells have been determined to contain a genetic mutation listed in Table 1 A. In one embodiment, the subject is selected for treatment with N-acetyl leucine after the subject's cells have been determined to contain a genetic mutation listed in Table IB. In one embodiment, the subject is selected for treatment with N-acetyl leucine after the subject's cells have been determined to contain a genetic mutation listed in Table 1C.

[0188] The term "biological sample" as used herein refers to any tissue or fluid from a subject that is suitable for detecting a pathogenic variant and / or genetic mutation in a gene. Examples of useful biological samples include, but are not limited to, blood, plasma, serous fluid, cerebrospinal fluid, saliva, urine, lymph, cerebral spinal fluid, and the like. Other suitable biological samples will be familiar to those of ordinary skill in the relevant arts. Abiological sample can be analyzed for biomarker expression and / or mutation using any technique known in the art and can be obtained using techniques that are well within the scope of ordinary knowledge of a clinical practitioner. In one embodiment of the disclosure, the biological sample comprises blood cells.

[0189] Certain aspects of the disclosure are directed to methods of treating a subject having a NDD and / or the associated neurological symptoms of the NDD listed in Table 1 A, the method comprising: (a) determining whether any one or more of the genetic mutations associated with the NDD listed in Table 1A are present or absent in a biological sample taken from the subject; and (b) administering a therapeutically effective amount of N- acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject if any one or more of the genetic mutations associated with the NDD are present in the biological sample.

[0190] Certain aspects of the disclosure are directed to methods of treating a subject having a NDD and / or the associated neurological symptoms of the NDD listed in Table IB, the method comprising: (a) determining whether any one or more of the genetic mutations associated with the NDD listed in Table IB are present or absent in a biological sample taken from the subject; and (b) administering a therapeutically effective amount of N- acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject if any one or more of the genetic mutations associated with the NDD are present in the biological sample.

[0191] Certain aspects of the disclosure are directed to methods of treating a subject having a NDD and / or the associated neurological symptoms of the NDD listed in Table 1C, the method comprising: (a) determining whether any one or more of the genetic mutations associated with the NDD listed in Table 1C are present or absent in a biological sample taken from the subject; and (b) administering a therapeutically effective amount of N- acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject if any one or more of the genetic mutations associated with the NDD are present in the biological sample.

[0192] Certain aspects of the disclosure are directed to methods, comprising administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein: (a) the subject suffers from a NDD and / or theassociated neurological symptoms of the NDD listed in Table 1A; and / or (b) any one or more of the genetic mutations associated with the NDD listed in Table 1 A is present in a biological sample taken from the subject.

[0193] Certain aspects of the disclosure are directed to methods, comprising administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L- leucine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein: (a) the subject suffers from a NDD and / or the associated neurological symptoms of the NDD listed in Table IB; and / or (b) any one or more of the genetic mutations associated with the NDD listed in Table IB is present in a biological sample taken from the subject.

[0194] Certain aspects of the disclosure are directed to methods, comprising administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L- leucine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein: (a) the subject suffers from a NDD and / or the associated neurological symptoms of the NDD listed in Table 1C; and / or (b) any one or more of the genetic mutations associated with the NDD listed in Table 1C is present in a biological sample taken from the subject.

[0195] The present disclosure provides the following particular embodiments with respect to personalized medicine for subjects having a neurodeve lopmental disorder:

[0196] Embodiment I: A method of treating a subject having a neurodevelopmental disorder, the method comprising administering a therapeutically effective amount of N-acetyl leucine to the subject, wherein cells of the subject contain one or more genetic mutations listed in Table 1A.

[0197] Embodiment II: A method of treating a subject having a neurodevelopmental disorder, the method comprising administering a therapeutically effective amount of N-acetyl leucine to the subject, wherein cells of the subject contain one or more genetic mutations listed in Table IB.

[0198] Embodiment III: A method of treating a subject having a neurodevelopmental disorder, the method comprising administering a therapeutically effective amount of N-acetyl leucine to the subject, wherein cells of the subject contain one or more genetic mutations listed in Table 1C.

[0199] Embodiment IV : A method of treating a subject having a neurodevelopmental disorder, the method comprising:

[0200] (a) determining whether one or more genetic mutations listed in Table 1A are present or absent in a biological sample taken from the subject, and

[0201] (b) administering a therapeutically effective amount of N-acetyl leucine to the subject if one or more genetic mutations listed in Table 1A are present in the biological sample.

[0202] Embodiment V : A method of treating a subject having a neurodevelopmental disorder, the method comprising:

[0203] (a) determining whether one or more genetic mutations listed in Table IB are present or absent in a biological sample taken from the subject, and

[0204] (b) administering a therapeutically effective amount of N-acetyl leucine to the subject if one or more genetic mutations listed in Table IB are present in the biological sample.

[0205] Embodiment VI: A method of treating a subject having a neurodevelopmental disorder, the method comprising:

[0206] (a) determining whether one or more genetic mutations listed in Table 1C are present or absent in a biological sample taken from the subject, and

[0207] (b) administering a therapeutically effective amount of N-acetyl leucine to the subject if one or more genetic mutations listed in Table 1C are present in the biological sample.

[0208] Embodiment VII: A method for treating a neurodevelopmental disorder in a subject having one or more genetic mutations listed in Table 1 A, the method comprising administering to the subject a therapeutically effective amount of N-acetyl leucine.

[0209] Embodiment VIII: A method for treating a neurodevelopmental disorder in a subject having one or more genetic mutations listed in Table IB, the method comprising administering to the subject a therapeutically effective amount of N-acetyl leucine.

[0210] Embodiment IX: A method for treating a neurodevelopmental disorder in a subject having one or more genetic mutations listed in Table 1C, the method comprising administering to the subject a therapeutically effective amount of N-acetyl leucine.

[0211] In one embodiment, N-acetyl leucine may be administered, for example, at a dose ranging from about 500 mg to about 30 g per day or ranging from about 500 mg to about15 g per day, such as ranging from about 1.5 g to about 10 g per day, optionally by solid oral or liquid oral route, e.g., as an oral suspension. N-acetyl leucine, 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.

[0212] If a single enantiomer, i.e., N-acetyl-D-leucine or N-acetyl-L-leucine, is administered the doses may be adjusted accordingly. For instance if N-acetyl-L-leucine is administered, the dose may range from about 250 mg to about 30 g per day, range from about 250 mg to about 15 g per day, range from about 1 mg to about 10 g per day, or range from about 1 g to about 5 g per day.

[0213] In one embodiment, the administered total daily dose ranges of N-acetyl- leucine, e.g., N-acetyl-DL-leucine or N-acetyl-L-leucine, are from about 1 g to about 30 g per day, 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, from 15.1 g to about 30 g per day, 16 g to about 30 g per day, 17 g to about 30 g per day, 18 g to about 30 g per day, 19 g to about 30 g per day, or 20 g to about 30 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 from 15.1, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 25, 27, 28, or 29 g to about 30 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, the dose is about 1 g per day, about 2 g per day, about 3 g per day, about 4 g per day, about 5 g per day, about 6 g per day, about 7 g per day, about 8 g per day, about 9 g per day, about 10 g per day, about 11 g per day, about 12 g per day, about 13 g per day, about 14 g per day, or about 15 g per day. In another embodiment, the dose is about 16 g per day, about 17 g per day, about 18 g per day, about 19 g per day, or about 20 g per day. In another embodiment, the dose is about 21 g per day, about 22 g per day, about 23 g per day, about 24 g per day, about 25 g per day, about 26 g per day, about 27 g per day, about 28 g per day, about 29 g per day, or about 30 g per day. In one embodiment, these doses are administered in a solid oral dosage form, notably tablets, or as an oral suspension. In another embodiment, these doses are for acetyl-leucine when in its racemic form. Doses for acetyl-leucine when an enantiomeric excess is present may ormay not be lower, for example, around 50% lower. The above recited dose-ranges when halved are thus also explicitly encompassed by the present disclosure.

[0214] In one embodiment, the total daily dose of N-acetyl leucine may be spread across multiple administrations, i.e., administration of N-acetyl leucine may occur two, three, or more times a day to achieve the total daily dose. As an example, the required number of tablets or amount of an oral suspension to provide the total daily dose of N-acetyl- leucine may be split across two administrations (for example, in the morning and evening) or three administrations (for example, in the morning, noon, and evening). Each dose may be administered with or without food. For example, N-acetyl-L-leucine or N-acetyl-DL- 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.

[0215] Treatment duration may be, 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. In one embodiment, it is about three months or more, 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 subject.

[0216] Any and all combinations of dosage form, dose amount, dosing schedule and treatment duration are envisaged and encompassed by the disclosure. In one embodiment, the dose of N-acetyl- leucine is from about 4 g to about 15 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 dosage may also be in the form of an oral suspension.

[0217] N-acetyl-leucine may be used as a monotherapy for treating or preventing a neurodevelopmental disorder, or a symptom thereof, in a subject. Alternatively, N-acetyl- leucine may be used as an adjunct to, or in combination with, one or more therapeutic agents for treating or preventing a neurodevelopmental disorder, or a symptom thereof, in a subject. The one or more therapeutic agents include, but are not limited to, growth hormone, risperidone, aripiprazole, trofmetide, atomoxetine, guanfacine, clonidine, viloxazine, haloperidol, pimozide, aripiprazole, onabotulinumtoxin A, abo botulinumtoxin A, baclofen, diazepam, tizanidine, dantrolene, baclofen, trihexyphenidyl, L-dopa or carbidopa-levodopa, clonazepam, tetrabenazine, zolpidem, phenobarbital, phenytoin, clonazepam, valproic acid / divalproex sodium, carbamazepine, oxcarbazepine, topiramate, lamotrigine, zonisemide, lacosamide, rufinamide, clobazam, everolimus, cannabidiol, sapropterin hydrochloride, pegvaliase-pqpz, tasimelteon, ganaxolone, acetazolaminde, 4- aminopyridine, fampridine, flunarizine, and / or topiramate.

[0218] In some aspects, the additional therapeutic agent is growth hormone. In some aspects, the additional therapeutic agent is growth hormone and the subject has been diagnosed with Prader-Willi syndrome and / or Turner syndrome. In some aspects, the one or more additional therapeutic agents is risperidone and / or aripiprazole. In some aspects, the one or more additional therapeutic agents is risperidone and / or aripiprazole and the subject has been diagnosed with an autism spectrum disorder. In some aspects, the additional therapeutic agent is trofmetide. In some aspects, the additional therapeutic agent is trofmetide and the subject has been diagnosed with Rett syndrome. In some aspects, the one or more additional therapeutic agents is atomoxetine, guanfacine, clonidine, and / or viloxazine. In some aspects, the one or more additional therapeutic agents is atomoxetine, guanfacine, clonidine, and / or viloxazine and the subject has been diagnosed with an attention deficit hyperactivity disorder (ADHD). In some aspects, the one or more additional therapeutic agents is haloperidol, pimozide, and / or aripiprazole. In some aspects, the one or more additional therapeutic agents is haloperidol, pimozide, and / or aripiprazole and the subject has been diagnosed with a Tic disorder. In some aspects, the one or more additional therapeutic agents is onabotulinumtoxin A, abobotulinumtoxin A, baclofen, diazepam, tizanidine, and / or dantrolene. In some aspects, the one or more additional therapeutic agents is onabotulinumtoxin A, abobotulinumtoxin A, baclofen, diazepam, tizanidine, and / or dantrolene and the subject has been diagnosed with spastic cerebral palsy.In some aspects, the one or more additional therapeutic agents is baclofen, trihexyphenidyl, L-dopa or carbidopa-levodopa, clonazepam, tetrabenazine, and / or zolpidem. In some aspects, the one or more additional therapeutic agents is baclofen, trihexyphenidyl, L-dopa or carbidopa-levodopa, clonazepam, tetrabenazine, and / or zolpidem and the subject has been diagnosed with dyskinetic cerebral palsy. In some aspects, the one or more additional therapeutic agents is onabotulinumtoxin A, abobotulinumtoxin A, baclofen, diazepam, tizanidine, dantrolene, baclofen, trihexyphenidyl, L-dopa or carbidopa-levodopa, clonazepam, tetrabenazine, and / or zolpidem. In some aspects, the one or more additional therapeutic agents is onabotulinumtoxin A, abobotulinumtoxin A, baclofen, diazepam, tizanidine, dantrolene, baclofen, trihexyphenidyl, L-dopa or carbidopa-levodopa, clonazepam, tetrabenazine, and / or zolpidem and the subject has been diagnosed with mixed cerebral palsy. In some aspects, the one or more additional therapeutic agents is phenobarbital, phenytoin, clonazepam, valproic acid / divalproex sodium, carbamazepine, oxcarbazepine, topiramate, lamotrigine, zonisemide, lacosamide, rufinamide, clobazam, everolimus, and / or cannabidiol. In some aspects, the one or more additional therapeutic agents is phenobarbital, phenytoin, clonazepam, valproic acid / divalproex sodium, carbamazepine, oxcarbazepine, topiramate, lamotrigine, zonisemide, lacosamide, rufinamide, clobazam, everolimus, and / or cannabidiol and the subject has been diagnosed with tuberous sclerosis. In some aspects, the one or more additional therapeutic agents is sapropterin hydrochloride and / or pegvaliase-pqpz. In some aspects, the one or more additional therapeutic agents is sapropterin hydrochloride and / or pegvaliase-pqpz and the subject has been diagnosed with phenylketonuria (PKU). In some aspects, the additional therapeutic agent is tasimelteon. In some aspects, the additional therapeutic agent is tasimelteon and the subject has been diagnosed with Smith-Magenis syndrome. In some aspects, the additional therapeutic agent is ganaxolone. In some aspects, the additional therapeutic agent is ganaxolone and the subject has been diagnosed with CDKL5 deficiency disorder. In some aspects, the additional therapeutic agent is acetazolaminde, 4- aminopyridine, fampridine, flunarizine, and / or topiramate and the subject has been diagnosed with CACNA J A-related neurodevelopmental disorder.

[0219] In another embodiment, the disclosure provides a kit comprising N-acetyl-DL- leucine, or a pharmaceutically acceptable, and instructions for administering N-acetyl-DL-leucine, or a pharmaceutically acceptable to a subject having a neurodevelopmental disorder, or a symptom thereof.

[0220] In another embodiment, the disclosure provides a kit comprising N-acetyl-L- leucine, or a pharmaceutically acceptable, and instructions for administering N-acetyl-L- leucine, or a pharmaceutically acceptable to a subject having neurodevelopmental disorder, or a symptom thereof.

[0221] 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.

[0222] In another embodiment, the present disclosure provides a method of treating or preventing a neurodevelopmental disorder, in a subject in need thereof, or treating or preventing a symptom of a neurodevelopmental disorder in a subject in need thereof, the method comprising administering about 1 g to about 30 g of N-acetyl-DL-leucine to the subject per day. In another embodiment, about 2 g to about 15 g of N-acetyl-DL-leucine is administered to the subject per day. In another embodiment, about 3 g to about 10 g of N- acetyl-DL-leucine is administered is administered to the subject per day. In another embodiment, about 4 g to about 8 g of N-acetyl-DL-leucine is administered to the subject per day. In another embodiment, about 4 g to about 5 g of N-acetyl-DL-leucine is administered to the subject per day. In another embodiment, about 15 g to about 30 g of N-acetyl-DL-leucine is administered to the subject per day. In another embodiment, about 5 g of N-acetyl-DL-leucine is administered to the subject per day.

[0223] In another embodiment, the present disclosure provides a method of treating or preventing a neurodevelopmental disorder, in a subject in need thereof, or treating or preventing a symptom of a neurodevelopmental disorder in a subject in need thereof, the method comprising administering about 1 g to about 30 g of N-acetyl-L-leucine to the subject per day. In another embodiment, about 2 g to about 15 g of N-acetyl-L-leucine is administered to the subject per day. In another embodiment, about 3 g to about 10 g of N- acetyl-L-leucine is administered is administered to the subject per day. In another embodiment, about 4 g to about 8 g of N-acetyl-DL-leucine is administered to the subject per day. In another embodiment, about 4 g to about 5 g of N-acetyl-L-leucine is administered to the subject per day. In another embodiment, about 15 g to about 30 g ofN-acetyl-L-leucine is administered to the subject per day. In another embodiment, about 5 g of N-acetyl-L-leucine is administered to the subject per day.

[0224] The disclosure also provides the following particular method of treatment embodiments.

[0225] Embodiment 1. A method of treating or preventing a neurodevelopmental disorder (NDD), or a neurological symptom thereof, in a subject in need thereof, the method comprising administering a therapeutically effective amount of N-acetyl-DL- leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject.

[0226] Embodiment 2. The method of Embodiment 1, wherein the NDD is any one or more of the diseases, disorders, or syndromes listed in Table 1 A.

[0227] Embodiment 3. The method of Embodiment 1, wherein the NDD is the syndrome listed in Table IB.

[0228] Embodiment 4. The method of Embodiment 1, wherein the NDD is the syndrome listed in Table 1C.

[0229] Embodiment 5. The method of Embodiments 1 or 2, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table 1 A.

[0230] Embodiment 6. The method of Embodiments 1 or 2, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table IB.

[0231] Embodiment 7. The method of Embodiment 1, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table 1C.

[0232] Embodiment 8. The method of Embodiments 4-7, wherein the neurological symptom of the NDD is one or more of seizures, sleep disturbance, and / or behavior disorder.

[0233] Embodiment 9. The method of any one of Embodiments 1 -8, wherein administration of the N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, improves the subjects communication and / or speech.

[0234] Embodiment 10. The method of any one of Embodiments 1-9, wherein the subject has been diagnosed with any one of more of the genetic mutations listed in Table 1 A and / or Table IB by genetic testing.

[0235] Embodiment 11. The method of any one of Embodiments 1-9, wherein the subject has been diagnosed with any one of more of the genetic mutations listed in Table 1C by genetic testing.

[0236] Embodiment 12. The method of any one of Embodiments 1-11, wherein N- acetyl-DL-leucine or N-acetyl-L- leucine is administered to the subject to treat the NDD.

[0237] Embodiment 13. The method of any one of Embodiments 1-12, wherein N- acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat any one or more of the neurological symptoms of the NDD.

[0238] Embodiment 14. The method of any one of Embodiments 1-13, wherein the NDD is any one or more of the syndromes associated with intellectual disability listed in Table 1A.

[0239] Embodiment 15. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the autism spectrum disorders listed in Table 1 A.

[0240] Embodiment 16. The embodiment of any one claims 1-13, wherein the NDD is any one or more of the attention deficit hyperactivity disorders listed in Table 1 A.

[0241] Embodiment 17. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the learning disorders listed in Table 1 A.

[0242] Embodiment 18. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the communication disorders listed in Table 1 A.

[0243] Embodiment 19. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the motor disorders listed in Table 1 A.

[0244] Embodiment 20. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the tic disorders listed in Table 1 A.

[0245] Embodiment 21. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the cerebral palsy disorders listed in Table 1 A.

[0246] Embodiment 22. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the rare neurodevelopmental disorders listed in Table 1 A.

[0247] Embodiment 23. The method of any one of Embodiments 1-13, wherein the NDD is any one or more of the rare genetic neurodevelopmental disorders listed in Table 1A.

[0248] Embodiment 24. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the ultra-rare neurodevelopmental disorders listed in Table 1 A.

[0249] Embodiment 25. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the gene mutation-related disorders listed in Table 1 A.

[0250] Embodiment 26. The method of any one of Embodiments 1-13, wherein theNDD is any one or more of the gene mutation-related disorders listed in Table IB.

[0251] Embodiment 27. The method of any one of Embodiments 1 -26, wherein a total dose of about 1 g to about 30 g of N-acetyl-DL- leucine is administered to the subject per day.

[0252] Embodiment 28. The method of Embodiment 27, wherein a total dose of about1 g to about 15 g of N-acetyl-DL- leucine is administered to the subject per day.

[0253] Embodiment 29. The method of Embodiment 28, wherein a total dose of about1 g to about 10 g of N-acetyl-DL- leucine is administered to the subject per day.

[0254] Embodiment 30. The method of Embodiment 29, wherein a total dose of about1 g to about 8 g of N-acetyl-DL- leucine is administered to the subject per day.

[0255] Embodiment 31. The method of Embodiment 30, wherein a total dose of about1 g to about 5 g of N-acetyl-DL-leucine is administered to the subject per day.

[0256] Embodiment 32. The method of any one of Embodiments 27-31, wherein theN-acetyl-DL-leucine is administered once a day, twice a day, or three times a day to the subject to achieve the total daily dose.

[0257] Embodiment 33. The method of any one of Embodiments 27-32, wherein theN-acetyl-DL-leucine is administered to the subject as a tablet or as an oral suspension.

[0258] Embodiment 34. The method of any one of Embodiments 1 -25, wherein a total dose of about 1 g to about 30 g of N-acetyl-L- leucine is administered to the subject per day.

[0259] Embodiment 35. The method of Embodiment 34, wherein a total dose of about1 g to about 15 g of N-acetyl-L- leucine is administered to the subject per day.

[0260] Embodiment 36. The method of Embodiment 35, wherein a total dose of about1 g to about 10 g of N-acetyl-L- leucine is administered to the subject per day.

[0261] Embodiment 37. The method of Embodiment 36, wherein a total dose of about1 g to about 8 g of N-acetyl-L-leucine is administered to the subject per day.

[0262] Embodiment 38. The method of Embodiment 37, wherein a total dose of about1 g to about 5 g of N-acetyl-L-leucine is administered to the subject per day.

[0263] Embodiment 38. The method of any one of Embodiments 34-38, wherein theN-acetyl-L-leucine is administered once a day, twice a day, or three times a day to the subject to achieve the total daily dose.

[0264] Embodiment 40. The method of any one of Embodiments 34-38, wherein theN-acetyl-L-leucine is administered to the subject as a tablet or as an oral suspension.

[0265] Embodiment 41. The method of any one of Embodiments 1-35, wherein theN-acetyl-DL-leucine is administered to the subject in combination with one or more additional therapeutic agents.

[0266] Embodiment 43. The method of any one of Embodiments 1-25 or 31-37, wherein the N-acetyl-L-leucine is administered to the subject in combination with one or more additional therapeutic agents.

[0267] Embodiment 44. The method of Embodiments 41 or 43, wherein the one or more additional therapeutic agents comprise growth hormone, risperidone, aripiprazole, trofmetide, atomoxetine, guanfacine, clonidine, viloxazine, haloperidol, pimozide, aripiprazole, onabotulinumtoxin A, abobotulinumtoxin A, baclofen, diazepam, tizanidine, dantrolene, baclofen, trihexyphenidyl, L-dopa or carbidopa-levodopa, clonazepam, tetrabenazine, zolpidem, phenobarbital, phenytoin, clonazepam, valproic acid / divalproex sodium, carbamazepine, oxcarbazepine, topiramate, lamotrigine, zonisemide, lacosamide, rufmamide, clobazam, everolimus, cannabidiol, sapropterin hydrochloride, pegvaliase- pqpz, tasimelteon, ganaxolone, acetazolaminde, 4-aminopyridine, fampridine, flunarizine, and / or topiramate.

[0268] Embodiment 45. A kit for carrying out the method of any one of Embodiments 1-35, the kit comprising N-acetyl-DL-leucine and instructions for administering N-acetyl- DL-leucine to the subject.

[0269] Embodiment 46. A kit for carrying out the method of any one of Embodiments 1-25 or 34-40, the kit comprising N-acetyl-L-leucine and instructions for administering N- acetyl-L-leucine to the subject.

[0270] Embodiment 47. A method of treating a subject having a NDD and / or the associated neurological symptoms of the NDD listed in Table 1A, the method comprising:

[0271] (a) determining whether any one or more of the genetic mutations associated with the NDD listed in Table 1 A are present or absent in a biological sample taken from the subject; and

[0272] (b) administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L- leucine, or a pharmaceutically acceptable salt thereof, to the subject if any one or more of the genetic mutations associated with the NDD are present in the biological sample.

[0273] Embodiment 48. A method of treating a subject having a NDD and / or the associated neurological symptoms of the NDD listed in Table IB, the method comprising:

[0274] (a) determining whether any one or more of the genetic mutations associated with the NDD listed in Table IB are present or absent in a biological sample taken from the subject; and

[0275] (b) administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L- leucine, or a pharmaceutically acceptable salt thereof, to the subject if any one or more of the genetic mutations associated with the NDD are present in the biological sample.

[0276] Embodiment 49. A method of treating a subject having a NDD and / or the associated neurological symptoms of the NDD listed in Table 1C, the method comprising:

[0277] (a) determining whether any one or more of the genetic mutations associated with the NDD listed in Table 1C are present or absent in a biological sample taken from the subject; and

[0278] (b) administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L- leucine, or a pharmaceutically acceptable salt thereof, to the subject if any one or more of the genetic mutations associated with the NDD are present in the biological sample.

[0279] Embodiment 50. A method, comprising administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein:

[0280] (a) the subject suffers from a NDD and / or the associated neurological symptoms of the NDD listed in Table 1A; and / or

[0281] (b) any one or more of the genetic mutations associated with the NDD listed inTable 1 A is present in a biological sample taken from the subject.

[0282] Embodiment 51. A method, comprising administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein:

[0283] (a) the subject suffers from a NDD and / or the associated neurological symptoms of the NDD listed in Table IB; and / or

[0284] (b) any one or more of the genetic mutations associated with the NDD listed inTable IB is present in a biological sample taken from the subject.

[0285] Embodiment 52. A method, comprising administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein:

[0286] (a) the subject suffers from a NDD and / or the associated neurological symptoms of the NDD listed in Table 1C; and / or

[0287] (b) any one or more of the genetic mutations associated with the NDD listed inTable 1C is present in a biological sample taken from the subject.

[0288] The disclosure also provides the following particular use-limited product embodiments.

[0289] Embodiment 1. N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a neurodevelopmental disorder (NDD), or a neurological symptom thereof, in a subject in need thereof.

[0290] Embodiment 2. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of Embodiment 1, wherein the NDD is any one or more of the diseases, disorders, or syndromes listed in Table 1 A.

[0291] Embodiment 3. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of Embodiment 1, wherein the NDD is the syndrome listed in Table IB.

[0292] Embodiment 4. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use ofEmbodiment 1, wherein the NDD is the syndrome listed in Table 1C.

[0293] Embodiment 5. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-4, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table 1 A.

[0294] Embodiment 6. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-4, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table IB.

[0295] Embodiment 7. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-4, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table 1C.

[0296] Embodiment 8. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of Embodiments 5 or 6, wherein the neurological symptom of the NDD is one or more of seizures, sleep disturbance, and / or behavior disorder.

[0297] Embodiment 9. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-8, wherein administration of the N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, improves the subjects communication and / or speech.

[0298] Embodiment 10. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-9 wherein the subject has been diagnosed with any one of more of the genetic mutations listed in Table 1 A by genetic testing.

[0299] Embodiment 11. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-9, wherein the subject has been diagnosed with any one of more of the genetic mutations listed in Table IB by genetic testing.

[0300] Embodiment 12. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-11, wherein the subject has been diagnosed with any one of more of the genetic mutations listed in Table 1C by genetic testing.

[0301] Embodiment 13. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-12, wherein N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat the NDD.

[0302] Embodiment 13. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein N-acetyl-DL-leucine or N-acetyl-L-leucine isadministered to the subject to treat any one or more of the neurological symptoms of the NDD.

[0303] Embodiment 14. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the syndromes associated with intellectual disability listed in Table 1 A.

[0304] Embodiment 15. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the autism spectrum disorders listed in Table 1A.

[0305] Embodiment 16. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the attention deficit hyperactivity disorders listed in Table 1 A.

[0306] Embodiment 17. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the learning disorders listed in Table 1A.

[0307] Embodiment 18. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the communication disorders listed in Table 1A.

[0308] Embodiment 19. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the motor disorders listed in Table 1 A.

[0309] Embodiment 20. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the tic disorders listed in Table 1 A.

[0310] Embodiment 21. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the cerebral palsy disorders listed in Table 1A.

[0311] Embodiment 22. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the rare neurodevelopmental disorders listed in Table 1 A.

[0312] Embodiment 23. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the rare genetic neurodevelopmental disorders listed in Table 1 A.

[0313] Embodiment 24. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the ultra -rare neurodevelopmental disorders listed in Table 1 A.

[0314] Embodiment 25. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the gene mutation- related disorders listed in Table 1 A.

[0315] Embodiment 26. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-13, wherein the NDD is any one or more of the gene mutation- related disorders listed in Table IB.

[0316] Embodiment 27. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-26, wherein a total dose of about 1 g to about 30 g of N-acetyl- DL-leucine is administered to the subject per day.

[0317] Embodiment 28. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiment 27, wherein a total dose of about 1 g to about 15 g of N-acetyl- DL-leucine is administered to the subject per day.

[0318] Embodiment 29. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiment 28, wherein a total dose of about 1 g to about 10 g of N-acetyl- DL-leucine is administered to the subject per day.

[0319] Embodiment 30. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiment 29, wherein a total dose of about 1 g to about 8 g of N-acetyl-DL- leucine is administered to the subject per day.

[0320] Embodiment 31. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiment 30, wherein a total dose of about 1 g to about 5 g of N-acetyl-DL- leucine is administered to the subject per day.

[0321] Embodiment 32. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 27-31, wherein the N-acetyl-DL-leucine is administered once a day, twice a day, or three times a day to the subject to achieve the total daily dose.

[0322] Embodiment 33. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 27-32, wherein the N-acetyl-DL-leucine is administered to the subject as a tablet or as an oral suspension.

[0323] Embodiment 34. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-26, wherein a total dose of about 1 g to about 30 g of N-acetyl- L-leucine is administered to the subject per day.

[0324] Embodiment 35. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiment 34, wherein a total dose of about 1 g to about 15 g of N-acetyl-L- leucine is administered to the subject per day.

[0325] Embodiment 36. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiment 35, wherein a total dose of about 1 g to about 10 g of N-acetyl-L- leucine is administered to the subject per day.

[0326] Embodiment 37. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiment 36, wherein a total dose of about 1 g to about 8 g of N-acetyl-L- leucine is administered to the subject per day.

[0327] Embodiment 38. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiment 37, wherein a total dose of about 1 g to about 5 g of N-acetyl-L- leucine is administered to the subject per day.

[0328] Embodiment 39. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 34-38, wherein the N-acetyl-L-leucine is administered once a day, twice a day, or three times a day to the subject to achieve the total daily dose.

[0329] Embodiment 40. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 34-39, wherein the N-acetyl-L-leucine is administered to the subject as a tablet or as an oral suspension.

[0330] Embodiment 41. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-33, wherein the N-acetyl-DL-leucine is administered to the subject in combination with one or more additional therapeutic agents.

[0331] Embodiment 42. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 1-26 or 34-40, wherein the N-acetyl-L-leucine is administered to the subject in combination with one or more additional therapeutic agents.

[0332] Embodiment 43. The N-acetyl-DL-leucine or N-acetyl-L-leucine for use of any one of Embodiments 41 or 42, wherein the one or more additional therapeutic agents comprise growth hormone, risperidone, aripiprazole, trofinetide, atomoxetine, guanfacine, clonidine, viloxazine, haloperidol, pimozide, aripiprazole, onabotulinumtoxin A, abobotulinumtoxin A, baclofen, diazepam, tizanidine, dantrolene, baclofen,trihexyphenidyl, L-dopa or carbidopa-levodopa, clonazepam, tetrabenazine, zolpidem, phenobarbital, phenytoin, clonazepam, valproic acid / divalproex sodium, carbamazepine, oxcarbazepine, topiramate, lamotrigine, zonisemide, lacosamide, rufinamide, clobazam, everolimus, cannabidiol, sapropterin hydrochloride, pegvaliase-pqpz, tasimelteon, ganaxolone, acetazolaminde, 4-aminopyridine, fampridine, flunarizine, and / or topiramate.

[0333] The disclosure also provides the following particular use-limited process embodiments.

[0334] Embodiment 1. Use of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L- leucine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a neurodevelopmental disorder (NDD), or a neurological symptom thereof, in a subject in need thereof.

[0335] Embodiment 2. The use of Embodiment 1, wherein the NDD is any one or more of the diseases, disorders, or syndromes listed in Table 1 A.

[0336] Embodiment 3. The use of Embodiment 1, wherein the NDD the syndrome listed in Table IB

[0337] Embodiment 4. The use of Embodiment 1, wherein the NDD the syndrome listed in Table 1C.

[0338] Embodiment 5. The use of any one of Embodiments 1-3, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table 1 A.

[0339] Embodiment 6. The use of any one of Embodiments 1-3, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table IB.

[0340] Embodiment 7. The use of any one of Embodiments 1-3, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table 1C.

[0341] Embodiment 8. The method of Embodiment 5 or 6, wherein the neurological symptom of the NDD is one or more of seizures, sleep disturbance, and / or behavior disorder.

[0342] Embodiment 9. The method of any one of Embodiments 1-8, wherein administration of the N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof,or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, improves the subjects communication and / or speech.

[0343] Embodiment 10. The use of any one of Embodiments 1 -7, wherein the subject has been diagnosed with any one of more of the genetic mutations listed in Table 1 A by genetic testing.

[0344] Embodiment 11. The use of any one of Embodiments 1 -7, wherein the subject has been diagnosed with any one of more of the genetic mutations listed in Table IB by genetic testing.

[0345] Embodiment 12. The use of any one of Embodiments 1 -7, wherein the subject has been diagnosed with any one of more of the genetic mutations listed in Table 1C by genetic testing.

[0346] Embodiment 13. The use of any one of Embodiments 1-10, wherein N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat the NDD.

[0347] Embodiment 14. The use of any one of Embodiments 1-10, wherein N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat any one or more of the neurological symptoms of the NDD.

[0348] Embodiment 15. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the syndromes associated with intellectual disability listed in Table 1A.

[0349] Embodiment 16. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the autism spectrum disorders listed in Table 1 A.

[0350] Embodiment 17. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the attention deficit hyperactivity disorders listed in Table 1A.

[0351] Embodiment 18. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the learning disorders listed in Table 1 A.

[0352] Embodiment 19. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the communication disorders listed in Table 1 A.

[0353] Embodiment 20. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the motor disorders listed in Table 1 A.

[0354] Embodiment 21. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the tic disorders listed in Table 1 A.

[0355] Embodiment 22. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the cerebral palsy disorders listed in Table 1 A.

[0356] Embodiment 23. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the rare neurodevelopmental disorders listed in Table 1 A.

[0357] Embodiment 24. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the rare genetic neurodevelopmental disorders listed in Table 1 A.

[0358] Embodiment 25. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the ultra-rare neurodevelopmental disorders listed in Table 1 A.

[0359] Embodiment 26. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the gene mutation-related disorders listed in Table 1 A.

[0360] Embodiment 27. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the gene mutation-related disorders listed in Table IB.

[0361] Embodiment 28. The use of any one of Embodiments 1-13, wherein the NDD is any one or more of the gene mutation-related disorders listed in Table 1C.

[0362] Embodiment 29. The use of any one of Embodiments 1-27, wherein a total dose of about 1 g to about 30 g of N-acetyl-DL- leucine is administered to the subject per day.

[0363] Embodiment 30. The use of any one of Embodiment 2, wherein a total dose of about 1 g to about 15 g of N-acetyl-DL- leucine is administered to the subject per day.

[0364] Embodiment 31. The use of any one of Embodiment 30, wherein a total dose of about 1 g to about 10 g of N-acetyl-DL- leucine is administered to the subject per day.

[0365] Embodiment 32. The use of any one of Embodiment 31, wherein a total dose of about 1 g to about 8 g of N-acetyl-DL- leucine is administered to the subject per day.

[0366] Embodiment 33. The use of any one of Embodiment 32, wherein a total dose of about 1 g to about 5 g of N-acetyl-DL- leucine is administered to the subject per day.

[0367] Embodiment 34. The use of any one of Embodiments 29-33, wherein the N- acetyl-DL-leucine is administered once a day, twice a day, or three times a day to the subject to achieve the total daily dose.

[0368] Embodiment 35. The use of any one of Embodiments 29-34, wherein the N- acetyl-DL-leucine is administered to the subject as a tablet or as an oral suspension.

[0369] Embodiment 36. The use of any one of Embodiments 1-28, wherein a total dose of about 1 g to about 30 g of N-acetyl-L- leucine is administered to the subject per day.

[0370] Embodiment 37. The use of any one of Embodiment 36, wherein a total dose of about 1 g to about 15 g of N-acetyl-L- leucine is administered to the subject per day.

[0371] Embodiment 38. The use of any one of Embodiment 37, wherein a total dose of about 1 g to about 10 g of N-acetyl-L- leucine is administered to the subject per day.

[0372] Embodiment 39. The use of any one of Embodiment 38, wherein a total dose of about 1 g to about 8 g of N-acetyl-L- leucine is administered to the subject per day.

[0373] Embodiment 40. The use of any one of Embodiment 39, wherein a total dose of about 1 g to about 5 g of N-acetyl-L- leucine is administered to the subject per day.

[0374] Embodiment 41. The use of any one of Embodiments 36-40, wherein the N- acetyl-L- leucine is administered once a day, twice a day, or three times a day to the subject to achieve the total daily dose.

[0375] Embodiment 42. The use of any one of Embodiments 36-41, wherein the N- acetyl-L-leucine is administered to the subject as a tablet or as an oral suspension.

[0376] Embodiment 43. The use of any one of Embodiments 1-37, wherein theN-acetyl-DL-leucine is administered to the subject in combination with one or more additional therapeutic agents.

[0377] Embodiment 44. The use of any one of Embodiments 1-28 or 36-38, wherein the N-acetyl-L-leucine is administered to the subject in combination with one or more additional therapeutic agents.

[0378] Embodiment 45. The use of any one of Embodiments 43 or 44, wherein the one or more additional therapeutic agents comprise growth hormone, risperidone, aripiprazole, trofinetide, atomoxetine, guanfacine, clonidine, viloxazine, haloperidol, pimozide, aripiprazole, onabotulinumtoxin A, abobotulinumtoxin A, baclofen, diazepam, tizanidine, dantrolene, baclofen, trihexyphenidyl, L-dopa or carbidopa-levodopa, clonazepam, tetrabenazine, zolpidem, phenobarbital, phenytoin, clonazepam, valproic acid / divalproex sodium, carbamazepine, oxcarbazepine, topiramate, lamotrigine, zonisemide, lacosamide, rufmamide, clobazam, everolimus, cannabidiol, sapropterin hydrochloride, pegvaliase-pqpz, tasimelteon, ganaxolone, acetazolaminde, 4- aminopyridine, fampridine, flunarizine, and / or topiramate.EXAMPLESExample 1

[0379] Subjects with one or more of the neurodevelopmental disorders, diseases, or syndromes listed in Table 1 A and / or Table IB will be treated with about 1 g to about 30 g of N-acetyl-DL- leucine per day or about 1 g to about 30 g of N-acetyl-L-leucine per day and, optionally, one or more additional therapeutic agents.

[0380] Neurological symptoms of neurodevelopmental disorders will be documented prior to administration and then at defined intervals after administration of N-acetyl-DL-leucine or N-acetyl-L-leucine. Subjects and / or caregivers will keep a daily diary to record medication usage, adverse events, e.g., seizure type and frequency, sleep habits, and quality of life measures, including communication, behavior, coordination, sensory and GI issues.

[0381] The following assessments may be used to score and document the subject's neurological symptoms.Intellectual Assessment

[0382] The Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI- IV) is an individualized, standardized intelligence test for children aged from 2 years 6 months to 7 years 7 months. At ages from 2 years 6 months to 3 years 11 months, the WPPSI-IV subtests are organized as follows: 1) The Verbal Comprehensive Index (VCI) from the Receptive Vocabulary and Information subtests, 2) The Visual Spatial Index (VSI) from the Block Design and Object Assembly subtests, and 3) The Working Memory Index (WMI) from the Picture Memory and Zoo Locations subtests. One supplementary subtest - Picture Naming - is provided.

[0383] At ages from 4 years to 7 years 7 months, the WPPSI-IV subtests are organized as follows: 1) The VCI from the Information and Similarities subtests, 2) The VSI from the Block Design and Object Assembly subtests, 3) The Fluid Reasoning Index (FRI) from the Matrix Reasoning and Picture Concepts subtests, 4) The WMI from the Picture Memory and Zoo Locations subtests, and 5) The Processing Speed Index (PSI) from the Bug Search and Cancellation subtests. Five supplementary subtests - Vocabulary, Animal Coding, Comprehension, Receptive Vocabulary, and Picture Naming - are provided. The Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) is the latest version of the most frequently used intelligence test for children aged from 6 years to 16 years 11 months. TheWISC-IV core subtests produce four indexes: 1) The VCI from the Similarities, Vocabulary, and Comprehension subtests, 2) The Perceptual Reasoning Index (PRI) from the Block Design, Picture Concepts, and Matrix Reasoning subtests, 3) The WMI from the Digit Span and Coding Subtests, and 4) The PSI from the Letter-Number Sequencing and Symbol Search subtests. Five supplementary subtests - Information, Word Reasoning, Picture Completion, Arithmetic, and Cancellation - are provided to substitute for core subtests as necessary. Children with ADHD are more likely to receive low scores on the WMI and PSI. Children with high- functioning autism scored above normal on the VCI and PRI, but scored below normal on the WMI and PSI.

[0384] The Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) is an individualized, standardized intelligence test for adults and older adolescents. The WAIS- IV core subtests produce four indexes: 1) The VCI from the Similarity, Vocabulary, and Information subtests, 2) The PRI from the Block Design, Matrix Reasoning, and Visual Puzzles subtests, 3) The WMI from the Digit Span and Arithmetic subtests, and 4) The PSI from the Symbol Search and Coding subtests. Five supplementary subtests - Letter- Number Sequencing, Figure Weights, Comprehension, Cancellation, and Picture Completion - are provided. (Oh, Mi-Young, “Psychological Assessment in Neurodevelopmental Disorders," Hanyang Med Rev, 36:72-77 (2016)).Neuropsychological Assessment

[0385] The omission, commission, and latency errors of the Continuous Performance Test (CPT) are intended to measure visual / auditory sustained attention, vigilance, and impulsivity. The color-word score of the Stroop test is intended to measure response inhibition. The Trail Making Test (TMT) has two versions: 1) TMT A measures visual search and perceptual motor speed. 2) TMT B measures executive function and set shifting. The WMI of the Wechsler intelligence scales measures attention and working memory.

[0386] The Wisconsin Card Sorting Test (WCST) is the most widely used executive function test throughout the world. It measures cognitive flexibility and set shifting. Subjects are asked to sort cards based on an undisclosed sorting rule (by either shape, color, or number). They are given feedback about whether they are sorting correctly or incorrectly. Once the individual has correctly completed 10 sorts, the rule is changed without any warning or comment, and the individual is expected to shift to a new sorting set. The most relevant score is the number of perseverative responses, defined as thenumber of sorts that use an old sorting rule despite feedback that it is incorrect. (Oh, Mi- Young, "Psychological Assessment in Neurodevelpomental Disorders," Hanyang Med Rev, 36:72-77 (2016)).Adaptive Behavior Assessment

[0387] The most widely used scale to measure adaptive behavior is the Vineland Adaptive Behavior Scale (VABS). The revised edition of the VABS, the Vineland Adaptive Behavior Scale-2nd Edition (Vin-eland-II), was published in 2005. Vineland-II is available in two forms: interview and parent / caregiver rating, both forms have the same questionnaire content. For the interview form, a trained examiner interviews the child’s primary caregiver using a semi- structured interview format and measures the adaptive behaviors of the child. For the parent / caregiver rating, the child’s primary caregiver completes the questionnaire and assesses their child’s adaptive behaviors. Similar to the VABS, the Vineland-II measures adaptive functioning in 4 domains: communication, daily-living skills, socialization, and motor skills. The motor skills domain is only applicable to children under 6-years-old. A composite score of adaptive behavior is calculated as the sum of the standard scores from the 4 domains. (Oh, Mi-Young, "Psychological Assessment in Neurodevelpomental Disorders," Hanyang Med Rev, 36:72-77 (2016)).Autism Diagnostic Assessment

[0388] The Childhood Autism Rating Scale (CARS) is a 15 -item structured structured observation tool that assesses the child’s symptoms based on direct observation of the behavior. Each item is rated on a 7-point scale and the scores range from 0 to 60. To be diagnosed with ASD, the total score should be higher than 30, however, for adolescents, a lower cut-off score is suggested. The CARS was designed to measure and assess development through direct observation. The observed behavior of the children is assessed and compared to that of typically developed children at the same age. If abnormal behavior is observed, the child’s age, characteristics, frequency of the behavior, and severity of the behavior should be collected when considering a diagnosis.

[0389] The Autism Diagnostic Interview-Revised (ADI-R) is a comprehensive parentinterview tool that is used to assess symptoms of ASD. The ADI-R is administered by trained clinicians in a semi-structured interview format. Clinicians gather information through parent’s report of the child’s noticeable behavior and development. The ADI-Rquestionnaire comprises questions that distinguish ASD from other developmental disorders, and it measures the following 3 domains: social interaction, communication, and stereotyped, repetitive, and fixated behavior patterns. Additionally, the ADI-R provides algorithm scores.

[0390] The Social Communication Questionnaire (SCQ), which is based on the ADI-R, works as a parent-report screening- instrument to diagnose individuals at risk for ASD. The SCQ is a 40-item questionnaire that was revised to help parents understand without any further elaboration needed. There are two versions of the SCQ: lifetime and current. The lifetime version is typically used for distinguishing individuals who might have ASD, or for an evaluative diagnosis. The current version is more suitable to assess changes in symptoms over time. A cut-off score over 15 suggests the individual is likely to have ASD. (Oh, Mi-Young, "Psychological Assessment in Neurodevelpomental Disorders," Hanyang Med Rev, 36:72-77 (2016)).Psychiatric Comorbidities

[0391] The Child Behavior Checklist (CBCL) is widely used to assess emotional and behavioral problems during preschool, childhood, and adolescence. The CBCL is standardized in many different languages and are cost-effective when compared to interviews because the survey is completed by the primary caregivers.

[0392] The CBCL Preschool Form is intended for preschoolers between 1.5-5 years old. The primary caregiver rates the preschooler on a scale from 0 to 2 for each question. Items are scored on 3 main scales including internalizing problems, externalizing problems, and total behavior problems, and 7 sub-scales including emotional reactivity, depression / anxiety, social withdrawal, somatic symptoms, sleeping problems, attention problems, and aggressive behavior. The CBCL School-Age Form measures various emotional and behavioral problems among children and adolescents between 6-18 years old. The CBCL is conducted by the primary caregiver who rates the child or adolescent on a scale from 0 to 2 for each question. Problematic behavior syndrome is rated on 3 main- scales of internalizing, externalizing, and total behavior problems, and 8 sub-scales of social withdrawal, somatic symptom, depression / anxiety, social immaturity, logic-based problems, attention problems, aggressiveness, and rule breaking. (Oh, Mi-Young, "Psychological Assessment in Neurodevelpomental Disorders," Hanyang Med Rev, 36:72- 77 (2016)).Other Assessments

[0393] Changes in seizures, sleep, communication, behaviors, and physical abilities will be assessed before and after treatment with acetyl-leucine using a multi-question form. The ratings will also be reported on a scale from +5 (really improved) to -5 (much worse), with 0 being the same as baseline. Cumulative ratings from each category will be generated.Example 2

[0394] A patient diagnosed with CTNNB1 syndrome was administered lg N-acetyl-DL- leucine (Tanganil) twice a day. Prior to administration of N-acetyl-DL-leucine, the patient exhibited aggression, self-harm, and behavioural issues. After administration almost a complete lack of these behaviors has been noted. The patient's symptoms prior to and after administration of N-acetyl-DL-leucine is provided in Table 2.Table 2Example 3

[0395] A patient diagnosed with DHDDS was administered 5g N-acetyl-DL-leucine (Tanganil®) a day (2 g in the morning, 1.5 g at noon, 1.5 g in the evening). Six weeks after the initial administration, the patient was able to walk while being less hunched over, was not holding his hands in a fist as much, showed mildly improved concentration, had a happier mood, and showed a small improvement in tremor. Eleven weeks after the initial administration, the patient continued to show improved balance, less tremor, and overall mildly improved focus and better mood.Example 4Additional Case Reports with N-acetyl leucine

[0396] N-acetyl-DL-leucine (Tanganil®) was sourced by families from pharmacies in France. Families voluntarily followed treatment monitoring protocols and provided their results for analysis.

[0397] Families included in this report intended to evaluate the effects of N-acetyl-DL- leucine regardless of their participation in this analysis. Families voluntarily followed treatment monitoring protocols and provided their results for analysis. Identifying families intending to take N-acetyl-DL-leucine prior drug initiation allowed us to ensure we captured the full range of patient experiences and that responses were not biased to only those that observed significant improvements.

[0398] NDD symptoms were documented at baseline then at defined intervals. Caregivers completed a daily diary to record medication usage, adverse events, seizures type and frequency, sleep habits, and quality of life measures, including communication, behavior, coordination, sensory and GI issues. Daily quality of life was scored from +5 (great day) to -5 (terrible day), with 0 being the same as baseline. Caregivers then rated quality of life for the same measures at baseline, weekly for 1 month, then monthly for up to 3 months. These weekly ratings were also reported on a scale from +5 (really improved) to -5 (much worse), with 0 being the same as baseline. See, e.g. „Wright et al., J. Neurodev. Disord. 14:34(2022); Wiltrout et al., Epilepsia (2024) doi: 10. I l l 1 / epi.17913; Vlaskamp, Neurology 92: e96-el07 (2019).

[0399] Given the subjective nature of these scores which makes comparisons and aggregation problematic, in the report summaries we have collapsed the scores to a three- point scale: improved, unchanged, and worsened.

[0400] Caregivers also completed a function and behavior rating form at baseline and 3 months, including the National Institute for Children’s Health Quality (NICHQ) Vanderbilt Assessment Scale and the Nisonger Child Behavior Rating Form. Results from the assessments were scored following the respective instructions. The assessment forms were used to rate positive and problem behaviors; an increase in positive behaviors and decrease in problem behaviors indicate improved function. The preliminary results in these case studies may not include these results for patients that have not yet completed 3 months of treatment.

[0401] This example includes case reports # 1 to # 4. Case reports were generated for each patient. Throughout the report the word patient is used to describe the individual with the NDD that received the N-acetyl-DL- leucine treatment. For ease of review, consistency was maintained in data visualization across all case reports, with daily monitoring shown in the upper panel, weekly monitoring shown in the middle panel and the 3 -month ratings shown in the bottom panel. Two patients with MED13L contributed to the case reports # 1 and # 2. Two patients with CTNNB1 contributed to the case reports # 3 and # 4.MED13L-NDD Case Report # 1

[0402] A 3-year-old male (15kg) with MED13L-NDD (frameshift) was treated orally with 1-4 grams of Tanganil® daily. The patient's baseline medications included multivitamin, N-acetyl glucosamine, N-acetyl cysteine, fish oil, and Montelukast. No adjustments were made to his existing medications before initiation of treatment. Caregivers monitored the effects of drug treatment using the approach outlined above. At the time this case report was prepared, the patient had completed 13 weeks of treatment and the study is ongoing.

[0403] Caregivers used an escalating dose to 4 grams per day given in split doses twice a day, then reduced and modified dosing throughout the 13-week period (Fig. 1 A). No visible seizures were reported prior to or during treatment (Fig. IB). Duration of nighttime was variable over time but seemed unaffected by treatment (Fig. 1C). Quality of life was scored from +5 (great day) to -5 (terrible day), with 0 being the same as baseline. Quality of lifeincreased over time for the patient as well as the family, with several days of reduced QOL reported during travel or a hospital visit (Fig. ID). No adverse events were reported.

[0404] Reports from the caregivers daily diary entries and quick assessment indicate improvements in QOL were related to improved communication and physical abilities. No other reports were provided. After 13 weeks, the caregivers continue to include N-acetyl- DL-leucine in their medication regimen.MED13L-NDD Case Report # 2

[0405] A 3-year-old female with MED13L-NDD was treated orally with 1-1.5 grams of Tanganil® daily. The patient didn’t have any baseline medications. Caregivers monitored the effects of drug treatment using the approach outlined above. At the time this case report was prepared, the patient had just completed 5 weeks of treatment and the study is ongoing.

[0406] Caregivers used an escalating dose to 1.5 grams per day given in split doses twice a day (Fig. 2A). No visible seizures were reported prior to or during treatment (Fig. 2B). Duration of nighttime was variable over time but seemed unaffected by treatment (Fig. 2C). Quality of life was scored from +5 (great day) to -5 (terrible day), with 0 being the same as baseline. Quality of life increased over time for the patient as well as the family; improvements persisted over the 5 weeks of treatment (Fig. 2D). No adverse events were reported.

[0407] Reports from the caregivers’ daily diary entries indicate improvements in QOL were related to improved communication and coordination. No other reports were provided. After 5 weeks, the caregivers continue to include N-acetyl-DL-leucine in their medication regimen.CTNNB1-NDD Case Report # 1

[0408] A 7-year-old female (17 kg) with CTNNB1-NDD was treated orally with 0.5-1 gram of Tanganil® daily. The patient's baseline medications included trihexyphenidyl and levodopa / carbidopa. No adjustments were made to her existing medications before initiation of treatment. Caregivers monitored the effects of drug treatment using the approach outlined above. At the time this case report was prepared, the patient had just completed 5 weeks of acetyl- leucine treatment and the study is ongoing.

[0409] Caregivers used an escalating dose to 1 gram per day given in split doses twice a day (Fig. 3A). No visible seizures were reported prior to or during treatment (Fig. 3B).Duration of nighttime was variable over time but seemed unaffected by treatment (Fig. 3C). Quality of life was scored from +5 (great day) to -5 (terrible day), with 0 being the same as baseline. Quality of life increased over time for the patient as well as the family, with several days of reduced QOL reported for the family (Fig. 3D). No adverse events were reported.

[0410] Reports from the caregivers’ daily diary entries indicate improvements in QOL were related to improved communication and coordination. No other reports were provided.CTNNB1-NDD Case Report # 2

[0411] A 6-year-old female (32 kg) with CTNNB1-NDD (nonsense) was treated orally with 2 grams of acetyl-leucine (Tanganil®) daily. The patient did not have any baseline medications. Caregivers monitored the effects of drug treatment using the approach outlined above. At the time this case report was prepared, the patient had just completed 7 weeks of acetyl-leucine treatment and the study is ongoing.

[0412] Caregivers used a dose of 2 grams per day given in split doses twice a day (Fig. 4A). No visible seizures were reported prior to or during treatment (Fig. 4B). Duration of nighttime was variable over time but seemed unaffected by treatment (Fig. 4C). Quality of life increased for both the patient and the family (Fig. 4D). No adverse events were reported.

[0413] Reports from the caregivers’ daily diary entries indicate improvements in QOL were related to improved communication and coordination, as well as reduced behaviors. No other reports were provided. After 7 weeks caregivers continue to use N-acetyl-DL- leucine.EXAMPLE 5Treatment of Tourette Syndrome

[0414] Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder, characterized by involuntary movements and vocalizations. The disorder is prevalent into adulthood, disturbing voluntary movements or communication, and often accompanied by behavioral comorbidities. Behavioral therapy approaches are recommended as first line treatment according to the European guidelines for Tourette Syndrome and tic disorders due to their tolerability and strengthening of the patients ’ self-regulatory control. Roessner et al. , Eur Child Adolesc Psychiatry 2022; 31 (3) :425-441. doi: 10.1007 / s00787-021-01899-z. However, local accessibility is limited in many countries and the feasibility is often restricted due to low introspective ability in young age or low IQ, or due to low motivation or ability to invest time and effort required for practicing in behavioral therapy. Pharmaceutical treatments in TS include first-, second-, and third-generation antipsychotic agents as well as other agents like tiapride or clonidine. While these pharmaceutical therapies have demonstrated efficacy in treating tics, they are often associated with short - and long-term adverse effects. Alternative treatments with fewer side effects would represent a major advancement for TS patients.

[0415] Three subjects diagnosed with TS provided written informed consent for N-acetyl- DL-leucine ("AL") therapy under individual case rules in accordance with CARE guidelines and the Declaration of Helsinki. The participates were evaluated at baseline, and follow-up visits at three weeks (FU3), six weeks (FU6), and six weeks post-treatment discontinuation (FU12). The clinical evaluation included the Yale Global Tics Severity Scale (YGTSS), the Premonitory Urge for Tic Scale (PUTS), the Yale-Brown Obsessive Compulsive Scale (YBOCS), and the Gilles de la Tourette Syndrome-Quality of Life scale (GTS-QoL). The YGTSS was used as primary outcome measure, while the remaining tests were used as secondary measures. Adverse events were investigated at each follow-up visit. The results are presented as individual values, no statistical analysis was performed.

[0416] Subject # 1 (Pl), 28 years old, male, suffered from multiple motor tics since the age of 9 and additional vocal tics in the course of time. As a result of the high level of suffering caused by the tics, depressive symptoms also developed in young adulthood, which could be treated well with outpatient psychotherapy. Drug therapy trials with tiapride, aripiprazole and cannabinoids, which were used to treat the tics, did not result in a relevant reduction in tics or were not tolerated by the subject in the long term due to their side effects. At the time of the individual treatment trial AL, there was no other fixed medication and no ongoing psychotherapy.

[0417] Subject # 2 (P2), 40 years old, male, suffered from multiple motor tics and throat clearing since the age of 8. At the age of 31, the subject also developed torticollis. He also had intermittent anxiety states and difficulty falling asleep. The tics had not yet been treated with psychotherapy or medication before. At the time of the individual treatment trial, the subject was on fixed medication consisting of gabapentin 300 mg due to trigeminal neuralgia and opipramol 50 mg to treat the anxiety.

[0418] Subject # 3 (male, 20 years old) stopped the therapy after six days due to abdominal discomfort.

[0419] P 1 and P2 were treated with 5g / day AL for about six weeks. Strupp et al., J Neurol. 2013; 260(10):2556-61. https: / / doi.org / 10.1007 / s00415-013-7016-x; Oertel et al., Nat Commun. 2024; 15(1):7619. https: / / doi.org / 10.1038 / s41467-024-51502-7. No serious adverse events were observed during the study.

[0420] After six weeks of AL treatment, both treated patients experienced a reduction in YGTSS total scores: Pl improved from 62 to 55 at FU6 and further to 41 at FU12. P2 improved from 77 to 54 points at FU6, but increased to 58 at FU12. Fig. 5A and Fig. 5B. Both patients reported improvements in tic-related quality of life (GTS-QoL) by FU6 and FU12 (Pl from 51 to 46 at FU6 and 36 at FU12, P2 from 55 to 53 at FU6 and 36 at FU12). Fig. 5C. Premonitory urges, measured by PUTS, showed minimal change: Pl and P2 increased by 1 point at FU6 (from 26 and 28 points at BL), Pl then decreased to 23 at FU12, while P2 increased to 32 at FU12. Obsessive-compulsive symptoms, measured by YBOCS, improved in both patients: Pl from 17 to 11 at FU6, remaining lower at 15 at FU12; P2 from 11 to 10 at FU6, further reduced to 8 at FU12. Fig. 5D.

[0421] The two treated TS patients showed clinically meaningful improvement of tics and tic-related symptoms following short term AL treatment of six weeks. The treatment effect was reflected in three different outcome measures: i) a decline in both motor and vocal tics measured by the YGTSS; ii) a reduction of obsessive-compulsive symptoms measured by the YBOCS; and iii) an improvement of tic-related quality of life indicated by the GTS- QoL. Six weeks after discontinuation of AL we observed continuous effects of tic reduction compared to baseline.

[0422] The study has several limitations given its case-study design. The treatment period of six weeks is short for the assessment of tics that are characterized by a waxing and waning pattern. Furthermore, we cannot exclude the possibility of a placebo effect, as neither the patients nor the investigators were blinded.

[0423] In conclusion, the improvement of motor and vocal tics and the absence of severe adverse effects indicate that AL may have therapeutic potential for TS, warranting further investigation in randomized placebo-controlled trials.

[0424] It is to be understood that the foregoing embodiments and exemplifications are not intended to be limiting in any respect to the scope of the disclosure, and that the claimspresented herein are intended to encompass all embodiments and exemplifications whether or not explicitly presented herein.

[0425] All patents and publications cited herein are fully incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or preventing a neurodevelopmental disorder (NDD), or a neurological symptom thereof, in a subject in need thereof, the method comprising administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject.

2. The method of claim 1, wherein the NDD is any one or more of the diseases, disorders, or syndromes listed in Table 1 A.

3. The method of claim 1, wherein the NDD is the syndrome listed in Table IB.

4. The method of claims 1 or 2, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table 1 A.

5. The method of claims 1 or 2, wherein the neurological symptom of the NDD is any one or more of the neurological symptoms listed in Table IB.

6. The method of claim 3 or 4, wherein the neurological symptom of the NDD is one or more of seizures, sleep disturbance, and / or behavior disorder.

7. The method of any one of claims 1-6, wherein administration of the N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, improves the subject's communication and / or speech.

8. The method of any one of claims 1-7, wherein the subject has been diagnosed with any one or more of the genetic mutations listed in Table 1 A by genetic testing.

9. The method of any one of claims 1-7, wherein the subject has been diagnosed with any one or more of the genetic mutations listed in Table IB by genetic testing.

10. The method of any one of claims 1-9, wherein N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat the NDD.

11. The method of any one of claims 1 -9, wherein N-acetyl-DL-leucine or N-acetyl-L-leucine is administered to the subject to treat any one or more of the neurological symptoms of the NDD.

12. The method of any one of claims 1-11, wherein the NDD is any one or more of the syndromes associated with intellectual disability listed in Table 1 A.

13. The method of any one of claims 1-11, wherein the NDD is any one or more of the autism spectrum disorders listed in Table 1 A.

14. The method of any one claims 1-11, wherein the NDD is any one or more of the attention deficit hyperactivity disorders listed in Table 1 A.

15. The method of any one of claims 1-11, wherein the NDD is any one or more of the learning disorders listed in Table 1A.

16. The method of any one of claims 1-11, wherein the NDD is any one or more of the communication disorders listed in Table 1 A.

17. The method of any one of claims 1-11, wherein the NDD is any one or more of the motor disorders listed in Table 1A.

18. The method of any one of claims 1-11, wherein the NDD is any one or more of the tic disorders listed in Table 1A.

19. The method of any one of claims 1-11, wherein the NDD is any one or more of the cerebral palsy disorders listed in Table 1 A.

20. The method of any one of claims 1-11, wherein the NDD is any one or more of the rare neurodevelopmental disorders listed in Table 1 A.

21. The method of any one of claims 1-11, wherein the NDD is any one or more of the rare genetic neurodevelopmental disorders listed in Table 1 A.

22. The method of any one of claims 1-11, wherein the NDD is any one or more of the ultra- rare neuro developmental disorders listed in Table 1 A.

23. The method of any one of claims 1-11, wherein the NDD is any one or more of the gene mutation-related disorders listed in Table 1 A.

24. The method of any one of claims 1-8, wherein the NDD is the syndrome listed in Table IB.

25. The method of any one of claims 1-24, wherein a total dose of about 1 g to about 30 g of N-acetyl-DL-leucine is administered to the subject per day.

26. The method of claim 25, wherein a total dose of about 1 g to about 15 g of N-acetyl-DL- leucine is administered to the subject per day.

27. The method of claim 26, wherein a total dose of about 1 g to about 10 g of N-acetyl-DL- leucine is administered to the subject per day.

28. The method of claim 27, wherein a total dose of about 1 g to about 8 g of N-acetyl-DL- leucine is administered to the subject per day.

29. The method of claim 28, wherein a total dose of about 1 g to about 5 g of N-acetyl-DL- leucine is administered to the subject per day.

30. The method of any one of claims 25-29, wherein the N-acetyl-DL-leucine is administered once a day, twice a day, or three times a day to the subject to achieve the total daily dose.

31. The method of any one of claims 25-30, wherein the N-acetyl-DL-leucine is administered to the subject as a tablet or as an oral suspension.

32. The method of any one of claims 1-24, wherein a total dose of about 1 g to about 30 g of N-acetyl-L-leucine is administered to the subject per day.

33. The method of claim 32, wherein a total dose of about 1 g to about 15 g of N-acetyl-L- leucine is administered to the subject per day.

34. The method of claim 33, wherein a total dose of about 1 g to about 10 g of N-acetyl-L- leucine is administered to the subject per day.

35. The method of claim 34, wherein a total dose of about 1 g to about 8 g of N-acetyl-L- leucine is administered to the subject per day.

36. The method of claim 35, wherein a total dose of about 1 g to about 5 g of N-acetyl-L- leucine is administered to the subject per day.

37. The method of any one of claims 32-36, wherein the N-acetyl-L-leucine is administered once a day, twice a day, or three times a day to the subject to achieve the total daily dose.

38. The method of any one of claims 32-37, wherein the N-acetyl-L-leucine is administered to the subject as a tablet or as an oral suspension.

39. The method of any one of claims 1-31, wherein the N-acetyl-DL-leucine is administered to the subject in combination with one or more additional therapeutic agents.

40. The method of any one of claims 1-24 or 32-38, wherein the N-acetyl-L-leucine is administered to the subject in combination with one or more additional therapeutic agents.

41. The method of claims 39 or 40, wherein the one or more additional therapeutic agents comprise growth hormone, risperidone, aripiprazole, trofinetide, atomoxetine, guanfacine, clonidine, viloxazine, haloperidol, pimozide, aripiprazole, onabotulinumtoxin A, abobotulinumtoxin A, baclofen, diazepam, tizanidine, dantrolene, baclofen, trihexyphenidyl, L-dopa or carbidopa-levodopa, clonazepam, tetrabenazine, zolpidem, phenobarbital, phenytoin, clonazepam, valproic acid / divalproex sodium, carbamazepine, oxcarbazepine, topiramate, lamotrigine, zonisemide, lacosamide, rufinamide, clobazam, everolimus, cannabidiol, sapropterin hydrochloride, pegvaliase-pqpz, tasimelteon, ganaxolone, acetazo laminde, 4-aminopyridine, fampridine, flunarizine, and / or topiramate.

42. A kit for carrying out the method of any one of claims 1-31, the kit comprising N-acetyl- DL-leucine and instructions for administering N-acetyl-DL-leucine to the subject.

43. A kit for carrying out the method of any one of claims 1-24 or 32-38, the kit comprising N- acetyl-L-leucine and instructions for administering N-acetyl-L-leucine to the subject.

44. A method of treating a subject having a NDD and / or the associated neurological symptoms of the NDD listed in Table 1A, the method comprising:(a) determining whether any one or more of the genetic mutations associated with the NDD listed in Table 1 A are present or absent in a biological sample taken from the subject; and(b) administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject if any one or more of the genetic mutations associated with the NDD are present in the biological sample.

45. A method of treating a subject having a NDD and / or the associated neurological symptoms of the NDD listed in Table IB, the method comprising:(a) determining whether any one or more of the genetic mutations associated with the NDD listed in Table IB are present or absent in a biological sample taken from the subject; and(b) administering a therapeutically effective amount of N-acetyl-DL-leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject if any one or more of the genetic mutations associated with the NDD are present in the biological sample.

46. A method, comprising administering a therapeutically effective amount of N-acetyl-DL- leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein:(a) the subject suffers from a NDD and / or the associated neurological symptoms of the NDD listed in Table 1A; and / or(b) any one or more of the genetic mutations associated with the NDD listed in Table 1 A is present in a biological sample taken from the subject.

7. A method, comprising administering a therapeutically effective amount of N-acetyl-DL- leucine, or a pharmaceutically acceptable salt thereof, or N-acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein:(a) the subject suffers from a NDD and / or the associated neurological symptoms of the NDD listed in Table IB; and / or(b) any one or more of the genetic mutations associated with the NDD listed in Table IB is present in a biological sample taken from the subject.

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