Novel SCN8A mutation in a girl with refractory seizures and autistic features

Sir, A 4-year-old girl presented with speech delay and refractory seizures. She had no adverse perinatal events, had normal motor milestones, and could speak only a few bisyllables. She had seizures since 4 months of age. Initially, she had generalized tonic–clonic seizures (2–3 episodes/week) and required multiple anticonvulsant drugs (phenytoin, valproate, lamotrigine, clobazam, and levetiracetam). After 14 months of age, she experienced nocturnal tonic seizures (2–3 times/week) and atypical absences (2–3/day), which continued until her admission to our hospital. The seizures were only occasionally associated with fever. In addition to having seizures, she had autistic features (Childhood Autism Rating Scale score of 32). Her physical examination was unremarkable. Magnetic resonance imaging (MRI) of the brain was normal. Interictal electroencephalogram (EEG) showed a slow background activity with right frontopolar spike-wave discharges. Karyotype, array comparative genomic hybridization, plasma acylcarnitine profile, and urine organic acids were normal. Next generation sequencing for epilepsy genes [Table 1] revealed a novel pathogenic heterozygous missense mutation (c.4214C>A; p. Ala1405Asp) in the exon 22 of the SCN8A gene. Both the parents were negative for this variant. She was again started on phenytoin with resolution of tonic seizures, persistence of atypical absences, and appearance of daily head-drops. She was started on modified Atkins diet. However, it had to be stopped after 25 days in view of poor compliance and oral acceptance by the child. Behavioural therapy was initiated and genetic counselling was done.Table 1: Next Generation Sequencing for epilepsy gene panelMutations in SCN8A, encoding one of the main voltage-gated sodium channel subunits (Nav1.6) in the brain, have been recently described in patients with severe epilepsy and the phenotype is still evolving.[1,2] Seventeen patients with de novo heterozygous mutations of SCN8A were recently reported.[2] The phenotype comprised variable intellectual disability, drug-refractory epilepsy, autistic features, and prominent motor manifestations (hypotonia, dystonia, hyperreflexia, and ataxia). The mean age at the onset of seizures was 5 months and the reported seizure types included focal, tonic, clonic, myoclonic, atypical absence seizures, epileptic spasms, and febrile seizures. Thus, the genetic testing for SCN8A should be considered in children with unclassified severe epilepsy. This may have a therapeutic implication. Four patients with a missense SCN8A mutation and epilepsy were reported to have a remarkably good response on high doses of phenytoin, and loss of seizure control when the phenytoin medication was reduced.[3] Our patient showed resolution of tonic seizures with phenytoin; however, the other seizure types were unaffected. Due to the recent advances in targeted next-generation sequencing panels for epileptic encephalopathy/epilepsy, the diagnostic yield for an underlying genetic abnormality has increased in patients with epileptic encephalopathy. The diagnostic yields have been reported to be between 10 and 48.5% in the literature for the 35 to 265 gene panels.[4] This technique has helped us to achieve a diagnosis in the present case. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.