Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy

CLINICAL CHARACTERISTICS

Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is a seizure disorder characterized by clusters of nocturnal motor seizures that are often stereotyped and brief (<2 minutes). They vary from simple arousals from sleep to dramatic, often hyperkinetic events with tonic or dystonic features. Affected individuals may experience an aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Age of onset ranges from infancy to adulthood. About 80% of individuals develop ADSHE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidities, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent.

DIAGNOSIS/TESTING: The diagnosis of ADSHE is established in a proband who has suggestive clinical findings and a family history consistent with autosomal dominant inheritance and/or a heterozygous pathogenic variant in , , , , , , , , , or identified by molecular genetic testing.

MANAGEMENT

Many anti-seizure medications (ASM) may be effective. Carbamazepine is associated with remission in about 70% of individuals, often in relatively low doses. Individuals with ADSHE associated with the pathogenic variant p.Ser284Leu are more responsive to zonisamide than carbamazepine. -related ADSHE is difficult to treat but may be treatable using quinidine based on limited data. Resistance to ASM is present in about 30% of affected individuals and typically requires a trial of all appropriate ASM. Adjunctive fenofibrate therapy or vagal nerve stimulation may be considered in individuals resistant to standard ASM. : Reevaluation of EEGs at regular intervals to monitor disease progression, as well as assessment for changes in seizure semiology, changes in tone, and movement disorders; monitoring of developmental progress and educational needs. A medical history from relatives at risk can identify those with ADSHE so that treatment can be initiated promptly. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

GENETIC COUNSELING

ADSHE, by definition, is inherited in an autosomal dominant manner. Most individuals diagnosed with ADSHE have an affected parent. Each child of an individual with ADSHE has a 50% chance of inheriting the ADSHE-related pathogenic variant; the chance that the offspring will manifest ADSHE is (50% x 70% =) 35%, assuming penetrance of 70%. If the ADSHE-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.