SLC6A1-related Neurodevelopmental Disorder

Disease Overview

Summary 

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is a rare genetic condition that affects brain development and function. It can impact learning, language, behavior, movement, and seizure control. Symptoms vary widely from person to person.  

The most common features of SLC6AI-NDD include:  

• Developmental delays

• Speech and language difficulties (language impairment) 

• Behavioral challenges 

• Epilepsy (seizures), which often begin in early childhood, typically between ages 3 and 7 

Some people with SLC6A1-NDD never develop seizures, while others may lose skills or see regression (or worsening) of abilities around the time seizures begin.  

Seizures can occur in different forms. The most common types include: 

• Absence seizures (brief staring spells) 

• Myoclonic seizures (sudden muscle jerks) 

• Atonic seizures (sudden loss of muscle tone, sometimes causing falls) 

Behavioral and emotional challenges are also common. Many affected people show features of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), difficulties with emotional regulation, or sleep problems. Movement and coordination issues, such as tremors or balance problems, are also frequently reported. Severity can vary considerably, from mild learning differences to more complex developmental and behavioral needs. 

SLC6A1-NDD is caused by a change (variant) in one copy of the SLC6A1 gene. This gene provides instructions for making a protein called GABA transporter 1 (GAT-1).  

GAT-1 plays an important role in the brain by helping regulate GABA, the brain’s main calming chemical messenger. GABA helps prevent excessive electrical activity in the brain. When GAT-1 does not work properly, brain signaling becomes disrupted, which affects brain development and can lead to seizures.  

This condition is autosomal dominant, meaning that having one non-working copy of the gene inherited from one parent is enough to cause the disorder. 

• An affected parent has a 50% chance of passing the condition on to each child. 

• Males and females are affected equally. 

Most reported cases occur de novo, meaning the genetic change happened for the first time in the affected person and was not inherited from either parent.  

There is currently no cure or targeted treatment. Care focuses on managing seizures, supporting development, and addressing behavioral and/or learning needs through therapies and educational support. Research is ongoing, including work on gene-based therapies and other precision approaches aimed at restoring GAT-1 function. 

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Synonyms

• SLC6A1-related myoclonic-atonic epilepsy (MAE)
• SLC6A1 epileptic encephalopathy
• SLC6A1 haploinsufficiency / loss of function
• GAT1 deficiency
• SLC6A1-related disorders
• SLC6A1-Related Disorder
• SLC6A1 Deficiency Disorder
• SLC6A1-related neurodevelopmental disorder
• SLC6A1-NDD

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Signs & Symptoms

People affected with SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) have signs and symptoms that affect development, learning, behavior, and the nervous system. Symptoms vary widely from person to person, and the full range of symptoms is still being defined as more individuals are diagnosed. The features most often reported include:1  

• Developmental delay (seen in over 90% of affected persons), meaning children reach milestones such as sitting, walking, and talking later than expected 

• Motor delays, with most children sitting between 5-13 months and walking between 11-33 months 

• Speech and language delay, often more affected than motor development (movement) 

• • First words usually appear around age 2. 

• • Some children may never speak. 

• • Understanding language is often stronger than spoken language 

• Intellectual disability (ID), ranging from mild (more common) to severe (seen in about one-third of the affected people) 

• • Cognitive impairment was noted in nearly all affected children studied (97%) in the largest study. 

• Developmental regression, meaning that some children temporarily lose skills in areas such as language, social interaction, or motor abilities 

• Behavioral and social features, such as: 

• • Autism spectrum disorder (ASD), including repetitive behaviors, strong interests, sensitivity to sensory input, and difficulty with social interaction despite interest in peers  

• • Attention-deficit/hyperactivity disorder (ADHD), which occurs in about 15% of the affected children 

• • Other behavioral challenges such as irritability, aggression, anxiety, and emotional regulation difficulties 

• • Sleep problems (including trouble falling or staying asleep), which are common and can significantly affect daily life 

• Epilepsy (which occurs in roughly 85% of the people) is one of the defining features of SLC6A1-NDD, usually starting around 3.7 years of age 

• • About 25% of children had normal cognitive development before seizures began; however, in the studies, nearly half experienced some decline in cognitive skills after epilepsy onset. 

• • Common seizure types include: 

• • • Absence seizures (brief staring spells in which a child “spaces out” and becomes unresponsive; the most common type of seizures) 

• • • Myoclonic seizures (sudden, brief muscle jerks) 

• • • Atonic seizures (sudden loss of muscle tone, sometimes causing falls) 

• • • Myoclonic-atonic epilepsy (Doose syndrome), a specific epilepsy pattern involving both myoclonic and atonic seizures (was identified in about 47% of children in one study) 

• • • Focal seizures, which start in one area of the brain (fewer than 10%) 

• • • EEG (electroencephalography) testing that measures electrical activity in the brain often shows irregular or abnormal brain wave patterns (generalized spike-and-wave patterns at 2.5-3.5 Hz) 

• • • • A few people develop a pattern known as electrical status epilepticus during sleep, which can affect learning and behavior. 

• Movement and coordination problems (in about 40–50% of the affected people) which may include: 

• • Tremor, especially during fine motor tasks like writing or picking up small objects 

• • Ataxia (unsteady movement and poor balance; 21% of children affected) 

• • Repetitive movements (motor stereotypies) such as hand-clenching or arm stiffening, often in infancy 

• Low muscle tone (hypotonia), which is common in infancy and often improves with age 

Additional features may include: 

• Gastrointestinal issues such as constipation, diarrhea, or restrictive (selective) eating habits  

• Growth differences or unusual head size are uncommon 

• Brain MRI scans are usually normal or show only minor, non-specific changes 

• Rare psychiatric conditions (such as schizophrenia) have been reported in a small number of adults. 

No consistent facial characteristics have been identified. 

Life expectancy is not known to be reduced. Some adults with mild symptoms have passed the condition on to their children, showing that survival into adulthood is possible. Many adults with this condition may not yet be recognized due to limited access to genetic testing in past decades.1 

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Causes

The SLC6A1 gene provides instructions for making a protein called GABA transporter 1 (GAT-1). This protein plays a key role in controlling how nerve cells communicate in the brain. 

GAT-1’s main job is to clear GABA from the space between nerve cells after it has been released. GABA is the brain’s main inhibitory neurotransmitter, meaning it helps slow down or calm brain activity and prevents excessive electrical signaling. By removing GABA after it has done its job, GAT-1 helps keep brain signaling balanced.  

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is an autosomal dominant genetic condition. This means it is caused by a change (variant) in one copy of the SLC6A1 gene that prevents the gene from working properly. The non-working gene may be inherited from either parent or may arise for the first time in the affected individual. When a parent carries the variant, there is a 50% chance of passing it on in each pregnancy, and males and females are affected equally. Notably, almost all SLC6A1 variants reported to date are de novo, meaning they were not inherited from either parent and appeared for the first time in the affected individual. 

In SLC6A1-NDD, having only one working copy of the SLC6A1 gene is not enough to maintain normal brain function. Research since the first report of this condition in 2015 has shown that SLC6A1-related disorders are caused by haploinsufficiency.3-6 Haploinsufficiency means that having only one functioning copy of the gene is not enough to maintain normal brain function.  

The genetic variants identified in people with SLC6A1-NDD most often: 2,3 

• Stop the protein from being made at all (protein-truncating variants), or 

• Alter critical parts of the protein involved in GABA binding or transport across the cell membrane.2 

As a result, the amount of working GAT-1 protein in the brain is reduced. 

Laboratory studies have shown that some altered GAT-1 proteins do not fold correctly. These misfolded proteins can become trapped inside the cell in a structure called the endoplasmic reticulum (ER) and are then broken down before they can reach the cell surface, where GAT-1 normally functions. This further reduces GABA transport activity.  

When GAT-1 function is reduced, GABA is not cleared normally, and inhibitory signaling in the brain becomes disrupted. Rather than producing a stabilizing or calming effect, this imbalance leads to neuronal hyperexcitability, meaning brain cells are more likely to fire excessively. This hyperexcitability is a key driver of seizures in people with SLC6A1-NDD. 

This understanding is supported by studies in both humans and mice. In mouse models where the SLC6A1 gene was removed (GAT-1 knockout mice) or chemically blocked, the animals develop spontaneous abnormal electrical brain activity called spike-wave discharges, which are typical of absence seizures. Absence seizures are brief episodes of staring and unresponsiveness and are one of the most common seizure types in individuals with SLC6A1-related disorders. In addition, laboratory studies using human genetic variants have shown that SLC6A1 changes associated with epilepsy reduce the ability of GAT-1 to transport GABA effectively.  

GABA signaling is not only critical for controlling seizures but also for normal brain development, especially early in life. Disrupted GABA signaling affects: 

• Neuronal maturation and migration (how brain cells develop and move to the correct locations). 

• Synaptogenesis (the formation of synapses, or connections between nerve cells). 

• Neurite outgrowth (the growth of nerve cell extensions that allow cells to communicate).  

Because these processes occur during key developmental windows, reduced GAT-1 function can lead to long-term effects on learning, behavior, movement, and cognition.  

SLCA1 is most active in the brain, particularly in GABA-producing nerve cells (GABAergic neurons) and in astrocytes, which are support cells that help regulate brain signaling. Dysfunction in both cell types likely contributes to the wide range of neurological and developmental features seen in SLC6A1-NDD. 

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Affected populations

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is extremely rare. Fewer than 500 individuals worldwide have been reported as of 2025, with an estimated incidence of 2.65 per 100,000 births.1,8   

People have been identified across various ethnic backgrounds, mainly in the U.S., Canada, and European countries. Because the SLC6A1 gene was not routinely included in diagnostic sequencing (a type of genetic testing) until recently, it is likely that many more patients will be reported with inclusion of this gene, on gene panels moving forward. 

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Disorders with Similar Symptoms

The clinical features of SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) are not specific enough to make the diagnosis on physical examination alone. Any condition that includes intellectual disability and/or seizures without other defining features must be considered.1 

SLC6A1-NDD overlaps with many disorders that also present with developmental delay, epilepsy, and/or autism spectrum disorder. 1 Because of this overlap, genetic testing is required to confirm the diagnosis. 

Certain conditions are especially important to consider, depending on the person’s presentation:  

• Rett syndrome when developmental regression is present (meaning a child loses previously acquired skills).1 

• Angelman syndrome when EEG shows intermittent rhythmic delta activity, a specific EEG pattern that can point clinicians toward that diagnosis.1 

In addition, there are many known infantile epileptic encephalopathies caused by variants in a wide range of genes. These conditions can show overlapping characteristics (phenotypes) with SLC6A1-NDD, including seizures, developmental delays, and intellectual disability. 

Examples of disorders that may be discussed in differential diagnosis include: 9 

• Postural orthostatic tachycardia syndrome, caused by variants in the SLC6A2 gene. 

• SLC6A3-related dopamine transporter deficiency syndrome, caused by variants in the SLC6A3 gene.   

• Hyperekplexia 3, caused by variants in the SLC6A5 gene. 

• Creatine transporter deficiency caused by variants in the SLC6A8 gene. 

• Atypical glycine encephalopathy caused by variants in the SLC6A9 gene.  

• Generalized epilepsy with febrile seizures plus type 2 caused by variants in the SCN1A gene. 

These conditions are associated with a broad spectrum of neurodevelopmental disorders, and many can involve epilepsy and intellectual disability. Because symptoms overlap, clinicians typically rely on a combination of a patient’s medical history, EEG findings – and most importantly – genetic testing to distinguish among them.   

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Diagnosis

A clinical exam or medical history alone is not enough to confirm the diagnosis of SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD). Diagnosis requires a genetic test.  

Several types of genetic tests may be used, depending on the available resources: 

• Whole genome and whole exome sequencing, which looks at nearly all of a person’s DNA 

• Whole exome sequencing, which looks at the parts of DNA that contain instructions for making proteins  

• Targeted gene panel testing, which examines a selected group of genes known to be linked to epilepsy or neurodevelopmental conditions 

Targeted gene panels are often used because they are faster, less expensive, and more likely to be covered by insurance. The SLC6A1 gene is included in many current epilepsy-focused gene panels.  

No matter which testing method is used, changes found in the SLC6A1 gene must be interpreted carefully. Genetic specialists follow guidelines from the American College of Medical Genetics and Genomics (ACMG) to determine whether a genetic change is diseases-causing.10 These guidelines use a five-level classification system:   

• Pathogenic 

• Likely pathogenic 

• Variant of uncertain significance 

• Likely benign 

• Benign 

This careful interpretation helps ensure that the diagnosis is accurate. 

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Standard Therapies

Treatment
There are no formal clinical treatment guidelines for SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD). When a child is diagnosed, care usually begins with a series of evaluations to better understand their individual strengths, challenges, and needs. This often includes developmental testing that looks at motor skills, learning, and language, as well as neurological assessment to check for seizures or changes in development. A brain MRI (magnetic resonance imaging) or EEG (electroencephalogram) may be recommended in certain situations.1 

Children may also be evaluated by physical and occupational therapists to understand movement, coordination, daily living skills, and whether they would benefit from specific therapies or adaptive equipment.  

Behavioral and emotional concerns are commonly assessed as well. These may include:   

• Autism-related traits 

• Attention difficulties 

• Anxiety 

• Aggression 

• Sleep problems  

Additional assessments may address:  

• Feeding issues and nutrition 

• Gastrointestinal concerns such as constipation or diarrhea 

Even though hearing problems are not expected with this condition, hearing testing is recommended for any child with language delay to rule out contributing factors. 

Families are usually offered a meeting with genetics professionals such as genetic counselors to discuss what the diagnosis means for the child and their family.1 

Treatment focuses on supporting development, improving quality of life, and preventing or reducing complications.  

Seizures are managed with anti-seizure medications chosen by a neurologist, although none has been shown to work specifically for this disorder.1 Valproic acid as been suggested to help some individuals, possibly by increasing the GABA concentration in the human brain.11 Levetiracetam, is used with caution because it can cause challenging behavioral side effects in some people with this condition. 

Behavioral challenges are addressed through therapy and, when needed, medication.  

Sleep problems are addressed with good sleep routines (sleep-hygiene strategies) and sometimes medicines like melatonin.  

Constipation or diarrhea is treated using standard approaches.  

Families often need help coordinating medical care, therapies, equipment, and appointments, and many benefit from social workers, case managers, and/or community resources, including respite care or adaptive recreational and sports programs.1 

As children grow, their developmental and educational needs are reviewed regularly. Early-intervention services help babies and toddlers build communication, motor, and learning skills.1 School-aged children may receive special education services or accommodations tailored to their needs. 

Because needs change over time, ongoing monitoring is important. Doctors and therapists check developmental progress, seizure activity, behavior, bowel habits, mobility, and sleep at routine visits. Families’ support needs are reviewed and revisited as part of ongoing care as well.  

Research on new treatments for SLC6A1-NDD is ongoing, 

• A clinical trial is currently studying 4-phenylbutyrate, a medication that may help improve GAT-1 function. Families interested in research participation can talk with their care team about available studies.1  

• A recent report of a small group of six children with SLC6A1-NDD, presenting with drug-resistant seizures noted that the medication acetazolamide (ACZ) led to seizure freedom in three children and a 50–90% reduction in the others. They also had improvements in coordination (ataxia), behavior, and social and school functioning were also reported.12 

Children with SLC6A1-NDD often have difficulty with changes in routine, limited awareness of danger, and social difficulties that can lead to isolation. These issues can place significant strain on family relationships.  

Caregivers may also experience social isolation, as the demands of care leave little time for their own relationships and support systems. For this reason, support for caregivers – including counseling, peer support, and respite services – is an important part of comprehensive care.13 

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Clinical Trials and Studies

Research on new treatments is continuing, including a clinical trial studying a medication called 4-phenylbutyrate. Families who are interested in participating in research can talk with their care team about available studies.1 

The patient advocacy organization SLC6A1 Connect is partnering with Dr. Steven Gray at UT Southwestern to develop a gene replacement therapy to treat people with SLC6A1 variants. This approach uses an adeno-associated virus (AAV) to deliver a functional copy of the SLC6A1 gene to the brain. In mouse models, AAV9-based delivery restored GAT-1 function, improved abnormal EEG patterns, and corrected several behavioral and cognitive abnormalities.14  

Building on these results, the program has moved into a first-in-human Phase I/II clinical trial designed to evaluate safety and early signs of benefit. Although the approach is still investigational, it represents a significant step toward a targeted therapy for SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD).  

Researchers at Nationwide Children’s Hospital developed an experimental gene therapy for SLC6A1-NDD that delivers a healthy copy of the SLC6A1 gene directly to the brain using an adeno-associated virus (AAV). After testing multiple versions in animal studies to find the safest and most effective approach, the team received FDA approval to begin human testing. In September 2025, the first child received this therapy, and doctors will monitor safety and potential benefits over the months and years ahead.15  

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. 

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: 

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected] 

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/ 

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/ 

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/ 

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References

1. Goodspeed K, Demarest S, Johannesen K, et al. SLC6A1-Related Neurodevelopmental Disorder. 2023 Feb 9. In: Adam MP, Bick S, Mirzaa GM, et al., editors.GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK589173/ 
2. GoodspeedK, Pérez-Palma E, Iqbal S, et al. Current knowledge of SLC6A1-related neurodevelopmental disorders. *Brain Commun.* 2020;2(2):fcaa170. doi:10.1093/braincomms/fcaa170 
3. Scimemi, A. Structure, function, and plasticity of GABA transporters. Frontiers in Cellular Neuroscience 2014; 8: 161.
4. Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536: 285-291.
5. Carvill GL, McMahon JM, Schneider A, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. AJHG 2015; 96: 808-815.
6. Amberger JS, Bocchini CA,SchiettecatteF, Scott AF, and Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM), an online catalog of human genes and genetic disorders. Nucleic Acids Research 2015; 43: D789-798. 
7. Johannesen KM, Gardella E,LinnankiviT, et al. Defining the phenotypic spectrum of SLC6A1 mutations. Epilepsia 2018;59: 389-402. 
8. Mattison KA, Butler KM, Inglis GAS, et al. SLC6A1 variantsidentifiedin epilepsy patients reduce gamma-aminobutyric acid transport. Epilepsia 2018;59: e135-e141. 
9. LandrumMJ, Lee JM, Benson M, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Research 2016; 44, D862-868. 
10. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 2015;17: 405-424.
11. ChateauvieuxS, Morceau F, Dicato M, and Diederich M. Molecular and therapeutic potential and toxicity of valproic acid. Journal of Biomedicine & Biotechnology 2010; Published online Jul 29. 
12. MelikishviliG, Dulac O, Koniashvili O, et al. Adjunctive acetazolamide for drug-resistant seizures in SLC6A1-related neurodevelopmental disorder: An exploratory case series. Epilepsia Open. Published online October 23, 2025. doi:10.1002/epi4.70155 
13. Goodspeed K, Mosca LR, Weitzel NC, et al. A draft conceptual model of SLC6A1 neurodevelopmental disorder. FrontNeurosci. 2023;16:1026065. Published 2023 Jan 19. doi:10.3389/fnins.2022.1026065. 
14. Guo W, Rioux M,Shaffo F, et al. AAV9/SLC6A1 gene therapy rescues abnormal EEG patterns and cognitive behavioral deficiencies in Slc6a1-/- mice. J Clin Invest. 2024;135(3):e Published 2024 Nov 26. doi:10.1172/JCI182235 
15. Miller A. Setting theStagethe Next Era of Gene Therapy for Ultrarare Disease.  December 04, 2025 Available at: https://pediatricsnationwide.org/2025/12/04/setting-the-stage-the-next-era-of-gene-therapy-for-ultrarare-disease/   Accessed on 12/13/2025. 

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