-Related Epilepsy and/or Neurodevelopmental Disorders

CLINICAL CHARACTERISTICS

-related epilepsy and/or neurodevelopmental disorders encompasses 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, or intermediate epilepsy) with partially treatable epilepsy; self-limited familial infantile epilepsy (SeLFIE, also known as benign familial infantile epilepsy or BFIE) with 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 in some affected individuals.

DIAGNOSIS/TESTING: The diagnosis of -related epilepsy and/or neurodevelopmental disorders is established in a proband with suggestive findings and a heterozygous pathogenic variant in identified by molecular genetic testing.

MANAGEMENT

Several studies suggest a favorable response to sodium channel blockers in the -related epilepsy phenotypes of -DEE, -mild/modDEE, and -SeLFIE. Seizure control should be managed by a pediatric neurologist with expertise in epilepsy management who is familiar with the pharmacotherapy for -related epilepsy and aware of how it differs from treatment of similar disorders. Vigorous attempts to control seizures are warranted. Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields. Periodic evaluations for neurologic, cognitive, and/or behavioral deterioration; 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 seizures in individuals at higher risk, including those with generalized tonic-clonic seizures and/or nighttime seizures, is warranted. 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. 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. Several families report worsening of seizures with levetiracetam.

GENETIC COUNSELING

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