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. 2013 May;54(5):e81-5.
doi: 10.1111/epi.12137. Epub 2013 Mar 28.

Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings

Marlin Touma  1 , Mugdha Joshi, Meghan C Connolly, P Ellen Grant, Anne R Hansen, Omar Khwaja, Gerard T Berry, Hannah C Kinney, Annapurna Poduri, Pankaj B Agrawal
Affiliations

Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings

Marlin Touma et al. Epilepsia. 2013 May.

Abstract

Mutations in SCN2A gene cause a variety of epilepsy syndromes. We report a novel SCN2A-associated epilepsy phenotype in monozygotic twins with tonic seizures soon after birth and a suppression-burst electroencephalography (EEG) pattern. We reviewed the medical records, EEG tracings, magnetic resonance imaging (MRI), and neuropathologic findings, and performed whole genome sequencing (WGS) on Twin B's DNA and Sanger sequencing (SS) on candidate gene mutations. Extensive neurometabolic evaluation and early neuroimaging studies were normal. Twin A died of an iatrogenic cause at 2 weeks of life. His neuropathologic examination was remarkable for dentate-olivary dysplasia and granule cell dispersion of the dentate gyrus. Twin B became seizure free at 8 months and was off antiepileptic drugs by 2 years. His brain MRI, normal at 2 months, revealed evolving brainstem and basal ganglia abnormalities at 8 and 15 months that resolved by 20 months. At 2.5 years, Twin B demonstrated significant developmental delay. Twin B's WGS revealed a heterozygous variant c.788C>T predicted to cause p.Ala263Val change in SCN2A and confirmed to be de novo in both twins by SS. In conclusion, we have identified a de novo SCN2A mutation as the etiology for Ohtahara syndrome in monozygotic twins associated with a unique dentate-olivary dysplasia in the deceased twin.

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Figures

Figure 1
Figure 1
EEG and MRI findings in affected twins, pedigree and sequencing results for SCN2A mutation. (A) EEG for twin A at 2 weeks of age showed background suppression with bursts lasting 1–2 seconds of high-voltage (100–150uV) sharp activity. (B) The EEG for Twin B at 2 weeks of age showed a similar pattern. (C) At 4 weeks age, EEG shows a similar pattern as 2 weeks but with more discontinuous background and asynchronous suppression. (D) The EEG pattern improved further at 10 weeks of age. Pedigree (E) with proband Twin B indicated by an arrow, and Sanger sequencing of genomic PCR products illustrating the alteration c.788C>T in the Twins A and B (F). MRI findings in Twin B on axial diffusion weighted (G,I,K,M) and axial T2 Turbo Spin Echo (TSE) (H,J,L,N) images. (G–H) MRI at 2 mo of age showed no diffusion or T2 signal abnormalities, MRI reported as normal. (I–J) MRI at 8 mo revealed symmetric bright signal due to decreased diffusion (arrows) on diffusion weighted imaging (DWI) (I) and abnormal increased T2 signal within the globus pallidus, thalami on axial T2 images (J). (K–L) MRI at 15 months age revealed similar findings as I–J although less bright signal (arrows) on DWI (K). (M–N) MRI at 20 months shows interval resolution of decreased diffusion (M) and T2 signal abnormalities (N).
Figure 2
Figure 2
Histopathological findings of the inferior olive, dentate nucleus of the cerebellum, cerebellar cortex and dentate gyrus of the hippocampus in Twin A. Comparison of the principal inferior olive in an age-related control (A) to Twin A (B) with SCN2A mutation; there is increased anomalous folding of the laminae in Twin A (B). Abbreviation: PYR, pyramidal tract. Scale bar=1000 microns. Comparison of the dentate nucleus of the cerebellum in an age-related control (C) to Twin A (D), indicating the segmentation of the nucleus into disconnected islands (arrows) in the latter (D), ×20. There are no histological abnormalities of the cerebellar cortex in Twin A (E) x10. The Purkinje cells are intact (arrows). Abbreviations: BV, blood vessel; ML, molecular layer; IGL, internal granular layer; PC, Purkinje cell (arrows); WM, white matter. There is focal duplication of the dentate gyrus (arrow) in Twin A (F), ×20.
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