-Related Disorders

CLINICAL CHARACTERISTICS

-related disorders include self-limited familial neonatal epilepsy (SLFNE) and self-limited familial infantile epilepsy (SLFIE), seizure disorders that occur in children who typically have normal psychomotor development. An additional -related neurodevelopmental disorder (NDD) with and without epilepsy has also been described. In -SLFNE, seizures begin in an otherwise healthy infant between age days two and eight of life and spontaneously disappear within the first year of life. Seizures are generally brief, lasting one to two minutes. Seizure types include tonic or apneic episodes and focal clonic activity, with or without autonomic changes. Motor activity may be confined to one body part, migrate to other regions, or generalize. Infants are normal between seizures and feed normally. In -SLFIE, seizures start in the first year of life beyond the neonatal period and disappear after age one to two years. Seizures are generally brief, lasting two minutes; they appear as daily repeated clusters. Seizure types are usually focal, but can also include generalized, causing diffuse hypertonia with jerks of the limbs, head deviation, or motor arrest with unconsciousness and cyanosis. Infants are normal between seizures and psychomotor development is usually normal. In -NDD, individuals present with intellectual disability with or without seizures and/or cortical visual impairment. As little clinical information on these individuals is available, the clinical presentation of -NDD remains to be defined.

DIAGNOSIS/TESTING: The diagnosis of a -related disorder is established in a proband with suggestive findings and at least one heterozygous pathogenic variant in identified by molecular genetic testing. Rarely, affected individuals have biallelic pathogenic variants in .

MANAGEMENT

The seizures of -SLFNE are generally controlled with anti-seizure medications (ASMs) including phenobarbital and phenytoin or carbamazepine, usually withdrawn at age three to six months. The seizures of -SLFIE are usually completely controlled with adequate doses of phenobarbital, carbamazepine, or valproate. In rare instances of seizure recurrence, the starting dose of ASM is often low. ASMs are usually withdrawn after one to three years. -NDD is managed using standard evaluations, therapies, and educational support tailored to the individual's needs. In children with -SLFNE, EEGs at onset and age three, 12, and 24 months are recommended; the EEG at 24 months should be normal. In children with -SLFIE, EEGs at onset and age 12, 24, and 36 months are recommended; the EEG at 36 months should be normal. The management of a pregnant woman with a pathogenic variant is the same as that for any other pregnant woman with a seizure disorder or at increased risk for a seizure disorder: (1) no ASM is required if the woman has been seizure-free or if the woman has no history of seizures; and (2) ASM may be continued for epilepsy that is active during pregnancy.

GENETIC COUNSELING

-SLFNE and -SLFIE are inherited in an autosomal dominant manner; most individuals have an affected parent, or a parent known to have been symptomatic in infancy. -NDD typically occurs as an autosomal dominant disorder caused by a pathogenic variant. Rarely, NDD is caused by biallelic pathogenic variants and inherited in an autosomal recessive manner. Each child of an individual with -SLFNE, -SLFIE, or autosomal dominant NDD has a 50% chance of inheriting the pathogenic variant. If both parents of a child with autosomal recessive NDD are known to be heterozygous for a pathogenic variant, each sib of an affected individual has a 25% chance of being affected at conception, a 50% chance of being an asymptomatic carrier, and a 25% of being asymptomatic and not a carrier. Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.