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 CABP4, CHRNA4, CHRNA2, CHRNB2, CRH, DEPDC5, KCNT1, NPRL2, NPRL3, or STX1B identified by molecular genetic testing.

Management: Treatment of manifestations: 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 CHRNA4 pathogenic variant p.Ser284Leu are more responsive to zonisamide than carbamazepine. KCNT1-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.

Surveillance: 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.

Evaluation of relatives at risk: A medical history from relatives at risk can identify those with ADSHE so that treatment can be initiated promptly.

Pregnancy management: 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.