Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy

Abstract

Objective: To characterize a novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy.

Design: Genomic DNA was isolated from blood and submitted for commercial testing. The identified missense mutation was confirmed in brain DNA obtained at autopsy. Genomic DNA from the brain of the proband was analyzed by comparative genome hybridization, and the coding exons of SCN9A were amplified. Quantitation studies of the mutant transcript were performed.

Setting: Children's National Medical Center and Yale University School of Medicine. PROBAND: A full-term female infant who experienced seizure onset at age 10 weeks, with progression of hemiclonic, apneic, and multifocal migrating partial seizures leading to recurrent status epilepticus and death at age 9 months.

Main outcome measures: Electroencephalographic and magnetic resonance imaging results, quantitative RNA expression, and secondary mutation test results.

Results: The heterozygous missense mutation c.C5006C>A was identified by sequencing genomic DNA from blood and was confirmed in brain DNA. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular linker of domain 4 of the SCN1A sodium channel protein Na(v)1.1. The mutant transcript is found to be expressed at levels comparable to the wild-type allele in brain RNA. No variation in copy number was detected in the chromosome region 2q24 containing SCN1A or elsewhere in the genome. No mutations were detected in the linked sodium channel gene SCN9A, which has been reported to act as a modifier of SCN1A mutations.

Conclusion: This report expands the spectrum of SCN1A epileptic channelopathies to include malignant migrating partial seizures of infancy.

Figure 1

Two separate episodes of status epilepticus with different originating hemispheres with first episode A) occurring from L Centrotemporal region on 7/7/09 and second episode B) occurring from R posterior quadrant on 7/13/09.

Figure 2

Alternating Foci of Seizures at age 9 months showing A) electrographic seizure in left centrotemporal area at 18:31:47, followed by B) onset of electrographic seizure from R centrotemporal area, 1 minute later at 18:33

Figure 3

MRI of brain at 5 months demonstrating restricted diffusion of R hippocampi

Figure 4

MRI of brain from 2 to 7 months of age demonstrating progressive atrophy, lack of myelination, and ventriculomegaly. A. MRI at 2 months of age; B. MRI at 5 months of age; C. MRI at 7 months of age. D. MR spectroscopy demonstrating equal levels of choline and NAA, suggestive of low NAA.

Figure 4

MRI of brain from 2 to 7 months of age demonstrating progressive atrophy, lack of myelination, and ventriculomegaly. A. MRI at 2 months of age; B. MRI at 5 months of age; C. MRI at 7 months of age. D. MR spectroscopy demonstrating equal levels of choline and NAA, suggestive of low NAA.

Figure 5

Patient mutation A1669E in SCN1A. A. DNA sequence from brain DNA. B. Position of mutation in the channel protein C. Evolutionary conservation of the mutated residue.

Figure 6

Quantitation of mutant and wildtype SCN1A transcripts in patient brain RNA. A. Strategy for quantitation of mutant and wildtype transcripts in heterozygous patient RNA based on the new DdeI site generated by the C>A mutation. B. Two novel DdeI products of 280 and 247 bp in the heterozgous patient. The total abundance of PCR product is similar in patient and control (− DdeI lanes). C. Capillary electrophoretic separation of the 5′ end-labeled Dde1 fragments of 528 bp (wildtype allele) and 280 bp (mutant allele) in the patient RTPCR product. D. Quantitation of the 280 and 528 bp products by calculation of peak area (2326 and 3370 arbitrary units, respectively).