Novel SCN2A mutation in a family associated with juvenile-onset myoclonus: Case report

Abstract

Rationale: The phenotypic spectrum caused by SCN2A mutations includes benign neonatal/infantile seizures, Ohtahara syndrome, infantile spasms, West syndrome, and other unclassified epileptic phenotypes. Mutations in SCN2A have been implicated in neonatal seizure cases. Here, we described a Chinese family with 2 members having juvenile-onset myoclonus and identified a novel SCN2A point mutation within this family.

Patient concerns: The 21-year-old male proband suffered from frequent myoclonus at 11 years old with subsequent progressive ataxia. His elder maternal half-sister also experienced myoclonus. Genomic DNA of the patients was extracted from the peripheral blood cells of the proband, elder maternal half-sister, parents, and uncle of the proband. Targeted next-generation sequencing was used to screen gene mutations in the proband. The potential functional effects of mutations within SCN2A were predicted In silico analyses.

Diagnoses: Genetic testing revealed a novel SCN2A variant, c.T4820C, which contains a highly conserved amino acid substitution within segment S5 (p.V1607A). This mutation was predicted to produce a dysfunctional Nav1.2 protein by Mutation Taster and Protein Variation Effect Analyzer (PROVEAN). Genotype-phenotype correlation showed an incomplete penetrance of p.V1607A.

Interventions: The proband was treated by multiple antiepileptic drugs. These included carbamazepine, oxcarbazepine, valproate, and topiramate.

Outcomes: The duration of follow up was 2 years, and the proband developed drug-resistant epilepsy.

Lessons: The case gives us the lesson that SCN2A mutation can contribute to juvenile-onset myoclonus. Our findings extend the spectrums of SCN2A mutations and the clinical features of patients with SCN2A mutations.

Figure 1

Interictal and ictal EEG features of the family with SCN2A mutation. Generalized seizure pattern was recorded when the proband received 16 Hz photic stimulation (B, blue arrow) with myoclonus (B, red arrow). The interictal EEG results of his mother and uncle showed an episodic frontal small spike sharp (D & E, green line). EEG = electroencephalogram.

Figure 2

DNA sequencing chromatographs of the SCN2A gene. (A) Nucleotide sequence in the proband (III-1), (B) the maternal half-sister of the proband (III-2), (C) the mother of the proband (II-2), (D) the uncle of the proband (II-3), and (E) the father of the proband (II-1). The heterozygous missense mutation (red arrow) c.T4820C was identified in all the family members except the father.

Figure 3

Pedigree diagram and clinical pictures of the family.

Figure 4

Topological analysis of Nav1.2. The alternation p.V1607A is located on S3 of dominant IV (A) and on extremely conserved positions in mammals (B). 3D structure of residues 1581 to 2005 of SCN2A as predicted by I-TASSER (C–E). Transmembrane segments, S3 (Orange), S4 (Peach), S5 (Blue), S6 (Purple), and pore forming area (Yellow) were marked. Previous missense mutations were highlighted in red (C). The replacement of V1607 (D) by alanine decreases the helix propensity, indicating that the helix is less stable in the mutant (E).