SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders

AI Summary

SCN8A-related disorders span from severe developmental and epileptic encephalopathy to benign familial infantile epilepsy, with variable intellectual disability and common movement disorders.
Diagnosis requires a heterozygous pathogenic SCN8A variant identified by molecular genetic testing in a proband with compatible clinical features.
Management includes sodium channel blocker therapy for many early onset cases, aggressive seizure control, SUDEP counselling, and multidisciplinary supportive care.

TL;DR (AI Generated)

Epilepsy phenotypes include developmental and epileptic encephalopathy (DEE) associated with severe developmental delays and usually pharmacoresistant epilepsy with multiple seizure types; mild-to-moderate developmental and epileptic encephalopathy (mild/modDEE) with partially treatable epilepsy; benign familial infantile epilepsy (BFIE, or self-limited familial infantile epilepsy, SeLFIE), with typically normal cognition and medically treatable seizures; neurodevelopmental delays with generalized epilepsy (NDDwGE); and neurodevelopmental disorder without epilepsy (NDDwoE) with mild-to-moderate intellectual disability (though it can be severe in ~10% of affected individuals).

MANAGEMENT: Targeted therapies: Sodium channel blockers represent targeted therapies for some SCN8A-related epilepsy phenotypes, including SCN8A-BFIE, SCN8A-mild/modDEE, and SCN8A-DEE with onset in the first year of life.

Each child of an individual with SCN8A-related epilepsy and/or neurodevelopmental disorders has a 50% chance of inheriting the SCN8A pathogenic variant.

Basic summary

2016 Aug 25 [updated 2026 Nov 17]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026.

ABSTRACT

CLINICAL CHARACTERISTICS: SCN8A-related epilepsy and/or neurodevelopmental disorders (SCN8A-E/NDD) encompass a spectrum of phenotypes. Epilepsy phenotypes include developmental and epileptic encephalopathy (DEE) associated with severe developmental delays and usually pharmacoresistant epilepsy with multiple seizure types; mild-to-moderate developmental and epileptic encephalopathy (mild/modDEE) with partially treatable epilepsy; benign familial infantile epilepsy (BFIE, or self-limited familial infantile epilepsy, SeLFIE), with typically normal cognition and medically treatable seizures; neurodevelopmental delays with generalized epilepsy (NDDwGE); and neurodevelopmental disorder without epilepsy (NDDwoE) with mild-to-moderate intellectual disability (though it can be severe in ~10% of affected individuals). Hypotonia and movement disorders including dystonia, ataxia, and choreoathetosis are common in some phenotypes. Sudden unexpected death in epilepsy (SUDEP) has been reported.

DIAGNOSIS/TESTING: The diagnosis of SCN8A-E/NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in SCN8A identified by molecular genetic testing.

MANAGEMENT: Targeted therapies: Sodium channel blockers represent targeted therapies for some SCN8A-related epilepsy phenotypes, including SCN8A-BFIE, SCN8A-mild/modDEE, and SCN8A-DEE with onset in the first year of life. Oxcarbazepine and carbamazepine are considered first-line treatments for these early-onset epilepsy phenotypes as well. Valproate, ethosuximide, or lamotrigine have been favored for later-onset SCN8A-NDDwGE.

Supportive care: Seizure control should be managed by a pediatric neurologist with expertise in epilepsy management who is ideally familiar with the pharmacotherapy for SCN8A-related epilepsy. Vigorous attempts to control seizures are warranted, and counseling on SUDEP risk is recommended. Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields.

Surveillance: Periodic evaluations for neurologic, developmental, musculoskeletal, and/or behavioral complications. Monitoring with EEG and other modalities such as video EEG telemetry or ambulatory EEG when new or different seizure types are suspected. Because of the increased risk of SUDEP, monitoring of seizures in individuals at higher risk, including those with generalized tonic-clonic seizures and/or nighttime seizures, is warranted. Assessment of sleep issues over time is recommended.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those who are at risk for developing seizures. This typically entails targeted molecular genetic testing for the known pathogenic variant(s) in the family.

Pregnancy management: Pregnant women should receive counseling regarding the risks and benefits of using anti-seizure medications during pregnancy; the advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily; the effects of pregnancy on anti-seizure medication metabolism; and the effect of pregnancy on maternal seizure control.

Agents/circumstances to avoid: Several families have reported worsening of seizures with levetiracetam.

GENETIC COUNSELING: SCN8A-E/NDD are inherited in an autosomal dominant manner. Individuals with more severe SCN8A-related phenotypes are more likely to have a de novo pathogenic variant than individuals with milder SCN8A-related phenotypes. Each child of an individual with SCN8A-related epilepsy and/or neurodevelopmental disorders has a 50% chance of inheriting the SCN8A pathogenic variant. Once the SCN8A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

PMID:27559564 | Bookshelf:NBK379665

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