KCNT1-Related Epilepsy

Excerpt

Clinical characteristics: KCNT1-related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

1. EIMFS is characterized by seizures, typically focal and asynchronous, beginning in the first six months of life with associated developmental plateau or regression. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures are intractable to multiple anticonvulsants and progress to become nearly continuous by age six to nine months.

2. ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features. Individuals with KCNT1-related ADNFLE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems than individuals with ADNFLE resulting from other causes.

Less common seizure phenotypes in individuals with KCNT1-related epilepsy include West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy and/or leukoencephalopathy, focal epilepsy, and multifocal epilepsy. Additional neurologic features include hypotonia, microcephaly developing by age 12 months, strabismus, profound developmental delay, and additional movement disorders. Other systemic manifestations including pulmonary hemorrhage caused by prominent systemic-to-pulmonary collateral arteries or cardiac arrhythmia have been reported.

Diagnosis/testing: The diagnosis of KCNT1-related epilepsy is established in a proband with intractable epilepsy and a heterozygous pathogenic variant in KCNT1 identified by molecular genetic testing.

Management: Treatment of manifestations: KCNT1-related epilepsy is often refractory to conventional anticonvulsants; stiripentol, benzodiazepines, levetiracetam, and the ketogenic diet have all been well tolerated with limited success; quinidine has been used as an off-label anticonvulsant with success in some individuals; in rare cases of pulmonary hemorrhage as a result of systemic pulmonary collaterals, embolization has been recommended; developmental support is appropriate.

Surveillance: EEG at intervals determined by seizure frequency and progression, for evaluation of new involuntary movements or unexplained, paroxysmal changes in vital signs, or following adjustments to an anticonvulsant regimen; monitoring of development.

Agents/circumstances to avoid: For individuals with ADNFLE, activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights).

Pregnancy management: For women with ADNFLE, a discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

Genetic counseling: KCNT1-related epilepsy is inherited in an autosomal dominant manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a de novo KCNT1 pathogenic variant. The proportion of cases caused by a de novo pathogenic variant varies by phenotype. All individuals diagnosed with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) have the disorder as the result of a de novo pathogenic variant or an inherited variant from an unaffected parent with somatic and/or germline mosaicism. Some individuals diagnosed with KCNT1-related autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have an affected parent. Each child of an individual with KCNT1-related epilepsy has a 50% chance of inheriting the pathogenic variant, and intrafamilial clinical variability and reduced penetrance have been reported. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant in the family is known.