Clinical characteristics.

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is characterized by mild-to-severe developmental delay and/or intellectual disability, hypotonia, epilepsy, movement disorders (e.g., tremor, stereotypies, ataxia), and neurobehavioral and/or psychiatric manifestations (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, anxiety, and/or sleep disturbances). Language skills, particularly expressive language, are often more significantly affected than motor development. Developmental regression has been reported. Gastrointestinal manifestations (e.g., constipation, diarrhea) are also common.

Diagnosis/testing.

The diagnosis of SLC6A1-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in SLC6A1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental and educational support; anti-seizure medications are often needed to control seizures; behavioral strategies and/or neuropharmacologic interventions for psychiatric, behavioral, and/or sleep disorders; standard treatments for bowel dysfunction; family support and care coordination.

Surveillance: Assess at each visit developmental and behavioral issues, new seizures and/or changes in seizures, movement disorders, constipation or diarrhea, and family needs.

Agents/circumstances to avoid: Individuals with SLC6A1-NDD have intolerable behavioral side effects with levetiracetam at higher rates than reported in the general population. If behavioral side effects are experienced with levetiracetam, alternative anti-seizure medications should be considered.

Genetic counseling.

SLC6A1-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with SLC6A1-NDD inherited a pathogenic variant from a heterozygous parent. Each child of an individual with SLC6A1-NDD has a 50% chance of inheriting the pathogenic variant. Once the SLC6A1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) should be considered in individuals with the following clinical findings.

Clinical findings

• Mild-to-severe developmental delay (DD) and/or intellectual disability (ID)
• Generalized hypotonia of infancy
• Epilepsy including absence or atypical absence seizures, epilepsy with myoclonic-atonic seizures, generalized tonic-clonic seizures
• Movement disorders such as tremor, stereotypies, and ataxia
• Autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, anxiety, and/or sleep disturbances

Family history. Because SLC6A1-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Occasionally, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of SLC6A1-NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in SLC6A1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this section is understood to include any likely pathogenic variant. (2) Identification of a heterozygous SLC6A1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with DD or an older individual with ID may begin with chromosomal microarray analysis (CMA); however, this is unlikely to identify an individual with SLC6A1-NDD. Most individuals with SLC6A1-NDD have small SLC6A1 single-nucleotide variants or indels that can be identified on a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of SLC6A1) is rarely useful and typically NOT recommended.

• An epilepsy multigene panel that includes SLC6A1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an epilepsy multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing epilepsy whereas some multigene panels may not. Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is characterized by developmental delay, epilepsy, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Many individuals also have hypotonia, intermittent tremor or ataxia, and sleep disturbances [Johannesen et al 2018, Goodspeed et al 2020, Bain et al 2022]. To date, more than 100 individuals have been identified with a pathogenic variant in SLC6A1 [Goodspeed et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) is the most prevalent clinical feature, but it can vary from mild to severe among affected individuals. Many children with SLC6A1-NDD come to medical attention with hypotonia and delayed motor and language milestones within the first year of life (range: 3 months to 2 years).

Hypotonia is typically mild to moderate. Individuals typically sit by age nine months (range: 5-13 months) and walk by age 19 months (range: 11-33 months).

Language development is often more delayed than motor development. Children with SLC6A1-NDD often babble around age 14 months (range: 6-36 months), say their first word by age 25 months (range: 10-52 months), and use phrased speech by age 34 months (range: 23-54 months). Some individuals, however, never use words or phrases, and receptive communication is often better than expressive communication [Bain et al 2022].

Some children with SLC6A1-NDD have developmental regression that is either episodic, with recovery of skills, or followed by a plateau in development [Goodspeed et al 2020]. Regression may involve a loss of language skills, impairment in motor skills, or loss of social and adaptive skills. Factors that contribute to developmental regression are not currently known.

Intellectual disability (ID). Approximately one third of individuals will have ID; severity varies from mild to severe. Many of those who do not meet the criteria for ID will have a specific learning disorder such as dyslexia or dysgraphia [Johannesen et al 2018, Goodspeed et al 2020, Bain et al 2022].

Other neurodevelopmental manifestations. Approximately one third of individuals have autism spectrum disorder, and 10%-20% have attention-deficit/hyperactivity disorder. Children are often described as being interested in their peers, but struggle to maintain friendships and have restricted interests, repetitive speech or behavior patterns, and sensory-seeking or avoidant behaviors.

Epilepsy. Several seizure phenotypes have been reported in individuals with SLC6A1-NDD:

• Early-onset absence epilepsy / childhood absence epilepsy. Absence and atypical absence seizures are the most prevalent seizure semiology in individuals with SLC6A1-NDD. EEG features include 2-4 Hz spike and wave discharges, exacerbated by hyperventilation, and intermittent rhythmic delta activity, especially in the occipital region. Staring spells present across a broad age range, from age four to 60 months, though not all staring events will have an ictal EEG correlate in this disorder.
• Myoclonic and atonic seizures (including Doose syndrome). Myoclonic seizures are typically noted around age two years, but atonic events can be seen as early as age 12 months [Carvill et al 2015].
• Developmental and epileptic encephalopathy (DEE). Some individuals with more severe developmental delay may be classified as DEE. These individuals often have generalized or multifocal independent spike-wave discharges and background slowing on EEG and may meet criteria for Lennox-Gastaut syndrome.
• Focal epilepsy. Fewer than 10% of individuals with SLC6A1-NDD have focal-onset seizures with focal epileptiform discharges on EEG.

Movement disorders. Approximately half of individuals with SLC6A1-NDD have abnormal movements. These are often described as tremors of the upper extremities with fine motor activities or lower-extremity tremor with activity. Ataxic gait patterns with impaired balance have been reported in some children. Many also have motor stereotypies, including a tendency to clench their fists, stiffen their arms, and stare at their hands in infancy.

Behavioral issues are common in individuals with SLC6A1-NDD and likely have a significant contribution to the burden of disease. Aggression and irritability have been reported, often described as yelling or screaming and hitting themselves or caretakers. Repetitive behaviors and speech can sometimes be interpreted as a manifestation of anxiety. Sleep disturbances are also common and described as difficulty falling asleep or staying asleep. Challenging behaviors often increase in intensity when strict bedtime routines are not maintained.

Gastrointestinal issues. Some individuals with SLC6A1-NDD have abnormal bowel habits, but these can vary between constipation and chronic diarrhea. Many with autism spectrum disorder also have restrictive eating habits.

Other

• Growth. Abnormalities of growth (short stature) or head circumference are rare [Mermer et al 2022].
• Neuroimaging. Individuals with SLC6A1-NDD do not have distinctive features on brain imaging. Nonspecific white matter changes or other incidental findings such as arachnoid cysts have been identified.
• Facial features. No consistent dysmorphic features have been identified. If present, dysmorphic features are nonspecific.
• Psychiatric features. A small number of adults with an SLC6A1 pathogenic variant have been diagnosed with schizophrenia [Goodspeed et al 2020].

Prognosis. It is unknown whether life expectancy in individuals with SLC6A1-NDD is reduced. Some individuals inherited an SLC6A1 pathogenic variant from a parent with a variable phenotype (e.g., epilepsy, learning disability, behavior disorder) [Johannesen et al 2018], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified to date. However, ongoing studies suggest that the level of GAT-1 function (see Molecular Genetics) may correlate with disease severity, such that those with lower residual GAT-1 function have the most severe manifestations of SLC6A1-NDD [Mermer et al 2022].

Penetrance

Penetrance appears to be incomplete [Poliquin et al 2021].

Prevalence

SLC6A1-NDD is rare. Fewer than 500 individuals have been reported worldwide, with an estimated incidence of 2.65 in 100,000 births [López-Rivera et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SLC6A1-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 6 are recommended.

Agents/Circumstances to Avoid

Given the high prevalence of challenging behaviors in individuals with SLC6A1-NDD, levetiracetam should be used with caution. Individuals with SLC6A1-NDD have intolerable behavioral side effects with levetiracetam at higher rates than reported in the general population.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

There are therapies for SLC6A1-NDD in development. To date, one clinical trial is assessing the safety and efficacy of 4-phenylbutyrate in individuals with SLC6A1-NDD (NCT04937062).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• The majority of individuals reported to date with SLC6A1-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo SLC6A1 pathogenic variant [Goodspeed et al 2020].
• Rarely, individuals diagnosed with SLC6A1-NDD inherited an SLC6A1 pathogenic variant from a heterozygous parent. Phenotypic variability may be observed in these families, such as a heterozygous parent who experienced learning disabilities.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for an SLC6A1 pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with SLC6A1-NDD may appear to be negative because of reduced penetrance or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Affected sibs often display similar phenotypes although clinical variability may be observed between heterozygous family members.
• If the SLC6A1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with SLC6A1-NDD has a 50% chance of inheriting the SLC6A1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the SLC6A1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC6A1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SLC6A1 encodes the sodium- and chloride-dependent GABA transporter 1 (GAT-1), which is responsible for the reuptake of GABA into presynaptic neurons and glia. GABA is the principal inhibitory neurotransmitter that counterbalances neuronal excitation in the brain. The exact mechanism of molecular pathology is not yet fully understood; however, it is known that disruption of this inhibitory balance can result in seizures [Carvill et al 2015, Goodspeed et al 2020].

Mechanism of disease causation. Loss of function

Author Notes

Dr Goodspeed and Dr Johannesen are actively involved in clinical research regarding individuals with SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD). They would be happy to communicate with persons who have any questions regarding the diagnosis of SLC6A1-NDD or other considerations.

Contact Dr Lal, Dr Goodspeed, Dr Johannesen, or Dr Kang to inquire about review of SLC6A1 variants of uncertain significance.

Acknowledgments

The authors would like to acknowledge the support of the SLC6A1 Connect patient advocacy group, a champion for this disorder. They would also like to acknowledge all the patients and families who have generously given their time and stories to help us learn more about this rare neurodevelopmental disorder.

Revision History

• 9 February 2023 (sw) Review posted live
• 15 October 2018 (kg) Original submission

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