Seizures, Benign Familial Infantile, 5

A number sign (#) is used with this entry because of evidence that benign familial infantile seizures-5 (BFIS5) is caused by heterozygous mutation in the SCN8A gene (600702) on chromosome 12q13.

Heterozygous mutation in the SCN8A gene can also cause the more severe disorder EIEE13 (614558).

Description

Benign familial infantile seizures-5 (BFIS5) is an autosomal dominant neurologic disorder characterized by onset of afebrile seizures during infancy. In most cases, the seizures remit by age 2 years, although some patients may have single or a few seizures later in childhood. The seizures respond well to treatment with sodium channel blockers, and patients have normal subsequent psychomotor development. Some patients may develop paroxysmal kinesigenic dyskinesia around puberty (summary by Gardella et al., 2016 and Anand et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of benign familial infantile seizures, see BFIS1 (601764).

Clinical Features

Gardella et al. (2016) reported 16 individuals from 3 unrelated families with a benign seizure disorder beginning in most patients between 6 and 12 months of age. Only 1 patient had later onset of seizures at age 7 years. Most seizures were generalized tonic-clonic, and some were focal with impaired consciousness. The seizures were well-controlled and remitted in almost all patients by 14 months of age. Four patients had single seizures later in childhood or in their teens, and 1 had several additional seizures during young adulthood. Five patients from 2 families also developed paroxysmal kinesigenic dyskinesia with shivering or dystonia around puberty. Gardella et al. (2016) noted that the dyskinesia was reminiscent of 'infantile convulsions and paroxysmal choreoathetosis' (ICCA; 602066), caused by mutation in the PRRT2 gene (614386). All patients had normal cognitive function and normal neurologic examinations, except for 1 child who had a mild learning disability. Brain imaging was normal in all 6 patients who underwent imaging. Video-EEG of 1 of the patients with dyskinesia suggested focal cortical impairment.

Anand et al. (2016) reported a father and son with BFIS5. The son, who was the proband, was a 16-month-old Caucasian boy who presented with afebrile seizures at 5 months of age. Brain imaging was normal. The seizures were responsive to carbamazepine treatment, and he had normal psychomotor development. His 42-year-old father presented with seizures at age 4 months, and he has remained seizure-free on sodium valproate. He had normal psychomotor development and cognition. Anand et al. (2016) noted that both patients responded well to sodium channel blockers, which is the precise treatment for SCN8A epilepsy.

Inheritance

The transmission pattern of BFIS5 in the families reported by Gardella et al. (2016) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In 16 patients from 3 unrelated families with BFIS5, Gardella et al. (2016) identified the same heterozygous missense mutation in the SCN8A gene (E1483K; 600702.0010). The mutation in 2 families was found by exome sequencing; the mutation segregated with the disorder in all families. Linkage analysis excluded a founder effect. Although functional studies of the mutation were not performed, Gardella et al. (2016) postulated that it caused a small gain-of-function effect resulting from impaired channel inactivation.

In a father and son with BFIS5, Anand et al. (2016) identified a heterozygous missense mutation in the SCN8A gene (N1877S; 600702.0011). Functional studies of the variant were not performed, but Anand et al. (2016) noted that the same variant has been identified in patients with a more severe disorder, including developmental delay, epileptic encephalopathy, and intellectual disability (EIEE13). The benign phenotype in the father and son suggested that they may carry additional variants in other genes that offer a protective effect. Sanger sequencing excluded somatic mosaicism for the SCN8A mutation in the father.