SCN1A Seizure Disorders

Clinical characteristics: SCN1A seizure disorders encompass a spectrum that ranges from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome are often associated with cognitive decline. Less commonly observed phenotypes include myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, infantile spasms, epilepsy with focal seizures, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A seizure disorders can vary even within the same family.

Diagnosis/testing: The diagnosis of an SCN1A seizure disorder is established in a proband by identification of a heterozygous pathogenic variant in SCN1A by molecular genetic testing.

Management: Treatment of manifestations: Care is best provided by a physician (e.g., pediatric epileptologist) familiar with the pharmacotherapy for this disorder. Seizure control is critical to prevent permanent injury and death. Anti-seizure medication (ASM): clobazam (can be used for treatment of seizures in Lennox-Gastaut syndrome); stiripentol, benzodiazepines, cannabidiol, topiramate, levetiracetam, valproic acid, and ethosuximide. Levetiracetam is often effective, but may make seizures worse in some individuals. Phenobarbital is effective but poorly tolerated because of its effects on cognition. Use of the ketogenic diet to decrease seizure frequency has been beneficial in some affected individuals. Parents are advised to take a CPR course. Routine seizure and personal safety education is indicated.

Prevention of secondary complications: Use of protective helmets by individuals with atonic seizures or myoclonic-astatic epilepsy. Good sleep hygiene should be encouraged. Persons with epilepsy should be made aware of motor vehicle driving laws.

Surveillance: Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration; EEG monitoring for new or different seizure types; polysomnography should be considered if obstructive or central sleep apnea is suspected.

Agents/circumstances to avoid: ASMs: carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic seizures; phenytoin, which can induce choreoathetosis; rufinamide may exacerbate seizures as well; acetaminophen, which is hepatotoxic. Activities in which a sudden loss of consciousness could lead to injury or death (e.g., bathing, swimming, driving, or working/playing at heights). Sleep deprivation, which can exacerbate seizures, should be avoided.

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

Genetic counseling: SCN1A seizure disorders are inherited in an autosomal dominant manner. A proband with an SCN1A seizure disorder may have an inherited or a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants varies by phenotype: the percentage of probands with an SCN1A seizure disorder and an affected parent decreases as the severity of the phenotype in the proband increases; thus, most SCN1A-related severe myoclonic epilepsy in infancy (SCN1A-SMEI) and ICE-GTC are the result of a de novo pathogenic variant. Each child of an individual with an SCN1A seizure disorder has a 50% chance of inheriting the pathogenic variant; however, the risk of developing seizures is less than 100% because of reduced penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.