SCN3A- Related Neurodevelopmental Disorder

Clinical characteristics: SCN3A-related neurodevelopmental disorder (SCN3A-ND) encompasses a spectrum of clinical severity associated with epilepsy and/or brain malformation. Affected individuals may have (a) developmental and epileptic encephalopathy (DEE) (i.e., intractable seizures with developmental delays associated with ongoing epileptiform EEG activity) with or without malformations of cortical development; or (b) malformations of cortical development with or without mild focal epilepsy. Some degree of early childhood developmental delay is seen in all affected individuals; the severity varies widely, ranging from isolated speech delay to severe developmental delay. Infantile hypotonia is common but may be mild or absent in those without DEE. In those with DEE, seizure onset is typically in the first six to 12 months of life. A variety of seizure types have been described. Seizures remain intractable to multiple anti-seizure medications in approximately 50% of individuals with DEE without malformations of cortical development (MCD) and in 90% of individuals with DEE and MCD. Seizures may be absent or infrequent in those without DEE. Brain MRI findings range from normal to showing thinning or hypoplasia of the corpus callosum, to various malformations of cortical development. Autonomic dysregulation, oromotor dysfunction leading to the need for gastrostomy tube placement, progressive microcephaly, hyperkinetic movement disorder, and cortical visual impairment can also be seen in those with DEE.

Diagnosis/testing: The diagnosis of SCN3A-related neurodevelopmental disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in SCN3A identified by molecular genetic testing.

Management: Treatment of manifestations: Empiric treatment of seizures with standard anti-seizure medications (no specific anti-seizure medication has been shown to be more efficacious than another); feeding therapy and consideration of gastrostomy tube placement in those with dysphagia; standard treatment for developmental delay / intellectual disability, spasticity, hyperkinetic movements, autonomic dysfunction, and central visual impairment.

Surveillance: At each visit: measurement of growth parameters; evaluation for signs/symptoms of a movement disorder or autonomic dysfunction; monitor for new seizures or changes in seizures; assessment of developmental progress, educational needs, behavioral issues, mobility and self-help skills; annual ophthalmology evaluation to assess for visual impairment.

Agents/circumstances to avoid: There is no evidence that specific anti-seizure medications can worsen seizures associated with SCN3A-ND. There is no evidence that sleep deprivation or fever exacerbate seizures associated with SCN3A-ND.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early treatment.

Pregnancy management: Use of anti-seizure medication during pregnancy reduces the risk for mortality during pregnancy, but exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). The risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

Genetic counseling: SCN3A-ND is inherited in an autosomal dominant manner. The majority of probands diagnosed with SCN3A-ND have the disorder as the result of a de novo pathogenic variant. If a parent of the proband is affected and/or is known to have the SCN3A pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the SCN3A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.