SLC6A1-Related Neurodevelopmental Disorder

Excerpt

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.