Penetrance

Penetrance appears to be incomplete .

Source: GeneReviews — "SLC6A1-Related Neurodevelopmental Disorder"

Diagnostic Criteria

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

Source: GeneReviews — "SLC6A1-Related Neurodevelopmental Disorder"

Differential Diagnosis

The phenotypic features associated with SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) are not sufficiently specific to diagnose this condition clinically; all disorders with intellectual disability and/or seizures without other distinctive findings should be considered in the differential diagnosis. See OMIM Phenotypic Series: • Autosomal Dominant Intellectual Developmental Disorder • Autosomal Recessive Intellectual Developmental Disorder • Nonsyndromic X-Linked Intellectual Developmental Disorder • Syndromic X-Linked Intellectual Developmental Disorder • Developmental and Epileptic Encephalopathy SLC6A1-NDD shares phenotypic similarities, including developmental delay, epilepsy, and autism spectrum disorder, with the disorders listed in . In particular, Rett syndrome may be considered in individuals with developmental regression, and Angelman syndrome may be considered in those with intermittent rhythmic delta activity on their EEG. Finally, sodium channelopathies (SCN1A, SCN2A, SCN8A) and GABAA receptor-related epilepsies (GABRA1, GABRB2, GABRB3, GABRG2) also have a broad phenotypic spectrum that includes epilepsy, developmental delay, and autism spectrum disorder. Table 3. Selected Genes of Interest in the Differential Diagnosis of SLC6A1-Related Neurodevelopmental Disorder

Management Guidelines

No clinical practice guidelines for SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with SLC6A1-NDD, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with SLC6A1-Related Neurodevelopmental Disorder

Clinical Guidance

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.

Source: GeneReviews — "SLC6A1-Related Neurodevelopmental Disorder"

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.

Source: GeneReviews — "SLC6A1-Related Neurodevelopmental Disorder"

Surveillance Guidelines

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

Table 6.

Recommended Surveillance for Individuals with SLC6A1-Related Neurodevelopmental Disorder

System/Concern | Evaluation | Frequency

Development

| • Monitor developmental progress educational needs.

• Physical medicine OT/PT assessment of mobility self-help skills

| At each visit

Neurologic

| • Monitor those w/seizures as clinically indicated.

• Assess for new manifestations such as seizures, changes in tone, movement disorders.

Psychiatric/

Behavioral

| Behavioral assessment for findings suggestive of ASD, ADHD, aggression, self-injury, anxiety, /or sleep disturbances

Gastrointestinal

| Monitor for constipation or diarrhea.

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "SLC6A1-Related Neurodevelopmental Disorder"