Clinical characteristics: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE 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 comorbidity, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.
Diagnosis/testing: The diagnosis of ADNFLE is established in a proband who has suggestive clinical findings combined with a family history that is positive for other affected individuals and/or by the identification of a heterozygous pathogenic variant in CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH on molecular genetic testing.
Management: Treatment of manifestations: Carbamazepine is associated with remission in about 70% of individuals, often in relatively low doses. Individuals with ADNFLE associated with the CHRNA4 pathogenic variant p.Ser284Leu are more responsive to zonisamide than carbamazepine. Resistance to AEDs, present in about 30% of affected individuals, requires a trial of all appropriate AEDs. Adjunctive fenofibrate therapy or vagal nerve stimulation may be considered for individuals resistant to AEDs.
Surveillance: Reevaluation of EEGs at regular intervals to monitor disease progression.
Evaluation of relatives at risk: A medical history from relatives at risk can identify those with ADNFLE so that treatment can be initiated promptly.
Pregnancy management: Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.
Genetic counseling: ADNFLE is inherited in an autosomal dominant manner. Most individuals diagnosed with ADNFLE have an affected parent. The proportion of cases caused by de novo pathogenic variants is unknown, as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. Penetrance is estimated at 70% and the risk to each offspring of inheriting the pathogenic variant is 50%; thus, the chance that the offspring will manifest ADNFLE is (50% x 70% =) 35%. Prenatal testing for pregnancies at increased risk is possible.
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