-Related Disorders

CLINICAL CHARACTERISTICS

-related disorders represent a continuum of overlapping neonatal epileptic phenotypes ranging from self-limited familial neonatal epilepsy (SLFNE) at the mild end to neonatal-onset developmental and epileptic encephalopathy (NEO-DEE) at the severe end. Additional, less common phenotypes consisting of neonatal encephalopathy with non-epileptic myoclonus, infantile or childhood-onset developmental and epileptic encephalopathy (DEE), and isolated intellectual disability (ID) without epilepsy have also been described. is characterized by seizures that start in otherwise healthy infants between two and eight days after term birth and spontaneously disappear between the first and the sixth to 12th month of life. There is always a seizure-free interval between birth and the onset of seizures. Seizures are characterized by sudden onset with prominent motor involvement, often accompanied by apnea and cyanosis; video EEG identifies seizures as focal onset with tonic stiffening of limb(s) and some migration during each seizure's evolution. About 30% of individuals with -SLFNE develop epileptic seizures later in life. is characterized by multiple daily seizures beginning in the first week of life that are mostly tonic, with associated focal motor and autonomic features. Seizures generally cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI can show basal ganglia hyperdensities and later MRIs may show white matter or general volume loss. Moderate-to-profound developmental impairment is present.

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

MANAGEMENT

Seizures are generally controlled with conventional anti-seizure medication (ASM), although a significant number of individuals experience seizure freedom spontaneously. Seizures may be resistant to multiple ASMs alone or in combination. Seizure freedom is more likely achieved when receiving sodium channel blockers. Individualized therapies are utilized for developmental delay and intellectual disability. EEG at age three, 12, and 24 months is appropriate. At 24 months EEG should be normal. EEG monitoring as clinically indicated.

GENETIC COUNSELING

-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with SLFNE are heterozygous for a pathogenic variant inherited from a parent. Most individuals diagnosed with -NEO-DEE have a pathogenic variant. Each child of a heterozygous individual with -SLFNE has a 50% chance of inheriting the pathogenic variant. Given the severity of the disease course, individuals with -NEO-DEE rarely reproduce. Once a pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.