Benign familial infantile seizures (BFIS) is a clinical entity characterized by focal seizures with or without secondary generalization, occurring mostly in clusters, and usually first seen between 4 and 8 months of life. Psychomotor development is normal, and seizures usually resolve within the first year of life (1,2). Infantile seizures may be associated with other neurologic disorders such as paroxysmal dyskinesias or hemiplegic migraine (3,4) and also can occur as a nonfamilial form (1,2). BFIS is a genetically heterogenous condition with loci mapped to chromosomes 19 and 16 (5,6). Recently, mutations in the voltage-gated sodium channel α2 subunit (SCN2A) gene on chromosome 2q24 were identified in families affected by neonatal and infantile seizures (benign familial neonatal–infantile seizures; BFNIS) with typical onset before 4 months of life (7). The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS show overlapping clinical features (8).
Here we report a BFIS pedigree in which genetic analysis revealed a novel SCN2A mutation. This family showed three affected individuals over three generations, suggestive of autosomal dominant inheritance (Fig. 1A). Information from nine family members was obtained. Neonatal or febrile seizures were not reported in the family.
The proband (patient III:1) is a 11-year-old patient born at term after a normal pregnancy. At age 4 months and 23 days, while sleeping, he experienced a single afebrile episode with clonic jerking, left eye deviation, and tonic body extension, followed by apnea and cyanosis, lasting ∼2 min. A week later, a cluster of seizures with the same clinical features recurred during wakening. EEG recording in the active phase showed right parietal–occipital sharp waves. Brain MRI was unremarkable.
Developmental milestones and neurologic examination were normal. Therapy with phenobarbital (PB; 5 mg/kg/day) was started, and no further seizures occurred. At age 3 years, therapy was discontinued with no relapse.
The proband's father (patient II:2) is a 42-year-old man who experienced afebrile seizures from age 5.5 to 6 months of life. They were characterized by psychomotor arrest and staring, rapidly followed by a secondarily generalized phase. Awake and sleeping EEGs were reported as normal. He received therapy with PB that was discontinued 1 year later.
The grandfather of the proband (patient I:1), who died at age 75 years, had a cluster of seizures during the first year of life.
Mutational analysis of SCN2A was performed on genomic DNA, as described (8). A novel heterozygous mutation c.3003 T>A was found in exon 16. This mutation segregates in two available affected individuals and is not present in unaffected family members and in 90 unrelated controls. The mutation leads to the substitution of asparagine with lysine in position 1001 of the protein (p.N1001K). This residue is part of the sodium ion transport–associated domain (pfam database accession number: PF06512.1) that is located in the intracellular loop linking the second and third transmembrane segments of the protein. This 231-amino acid domain is conserved in several eukaryotic sodium channels (Fig. 1B), and its function is unknown. Interestingly, this novel variant is close to the mutation p.L1003I segregating in a family with neonatal and infantile seizures (8). Comparative analysis of different sodium channel α subunits indicates that the mutated residues are highly conserved throughout evolution, suggesting an important functional role for this domain (Fig. 1B).
The phenotype segregating in our family fits the clinical diagnosis of BFISs. All affected members experienced clusters of focal seizures with or without secondary generalization, with onset between 4 and 12 months of life. Psychomotor development seizure onset was normal in all cases. Response to AEDs and the outcome were good. In no subjects did other forms of epilepsy develop in the childhood or later in life.
BFNIS and BFIS share many clinical features: seizures are usually focal with or without secondary generalization, often occurring in a cluster over 1 day or a few days. When available, EEG reveals focal, mainly posterior, seizure onset (1,2,7,8). The typical hallmark of BFNISs is the occurrence of seizures by age 4 months (7). Conversely, in BFISs, seizure onset is between age 3 and 10 months, usually around 6 to 8 months. Molecular analysis showed that SCN2A mutations could be present in families with typical BFNISs and in families with onset after the age of 4 months (8).
We report a novel SCN2A mutation in a family with typical features of BFIS. Additional families with benign familial infantile seizures should be investigated to corroborate that these two types of benign familial seizures may share the same genetic abnormality.