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. 2018 Jun;83(6):1133-1146.
doi: 10.1002/ana.25243. Epub 2018 May 16.

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

Melodie R Winawer  1   2 , Nicole G Griffin  3 , Jorge Samanamud  4 , Evan H Baugh  3 , Dinesh Rathakrishnan  1 , Senthilmurugan Ramalingam  5 , David Zagzag  6   7 , Catherine A Schevon  2 , Patricia Dugan  8 , Manu Hegde  9 , Sameer A Sheth  10 , Guy M McKhann  10 , Werner K Doyle  7 , Gerald A Grant  11 , Brenda E Porter  12 , Mohamad A Mikati  13   14 , Carrie R Muh  15 , Colin D Malone  3 , Ann Marie R Bergin  16   17 , Jurriaan M Peters  16   17 , Danielle K McBrian  18 , Alison M Pack  2 , Cigdem I Akman  18 , Christopher M LaCoursiere  19 , Katherine M Keever  20 , Joseph R Madsen  21 , Edward Yang  22 , Hart G W Lidov  23 , Catherine Shain  19 , Andrew S Allen  24 , Peter D Canoll  25 , Peter B Crino  5 , Annapurna H Poduri  16   17   19   26 , Erin L Heinzen  3   25
Affiliations

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

Melodie R Winawer et al. Ann Neurol. 2018 Jun.

Abstract

Objective: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD.

Methods: We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD.

Results: We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen.

Interpretation: We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

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Conflict of interest statement

POTENTIAL CONFLICTS OF INTEREST

Dr. Sheth reports personal fees from Boston Scientific, personal fees from Medtronic.

Figures

Figure 1
Figure 1
Variant allele frequency across all available specimens as detected with digital droplet PCR (Cases 1,2,3, and 5) or next-generation sequencing (Case 4). Data are presented mean +/− standard deviation. Case 1 (two separate surgeries): two specimens (1 and 2) were collected from a right frontal resection within the supplementary motor area, and 5 specimens (3, 4, 5, 6, and 7) were collected from the right frontal premotor region anterior to the precentral sulcus. Case 2: two specimens were collected from a parietal precuneate and posterior two thirds cingulate resection. Case 3: Two specimens were collected from a right posterior temporal-occipital resection. Case 4: A temporal lobe specimen was collected as part of a functional hemispherectomy. Case 5: A frontal lobe specimen was collected as part of a right frontal resection.
Figure 2
Figure 2
Representative brain MR images from patients with somatic mutations in SLC35A2: Case 1 (A, E, I, M), Case 2 (B, F, J, N), Case 3 (C,G), Case 4 (K,O), and Case 5 (D, H, L, P). Axial T2 (A–D, K) and coronal T2 (E–H, L) images demonstrated grossly normal cerebral volume and preserved size of the hippocampi in all 5 subjects, allowing for some minimal prominence of the lateral ventricles and variant underrotation of the left hippocampus in Case 1 (E). For subjects Case 1, Case 2, and Case 3, there was no evidence of a malformation of cortical malformation apart from a tiny probable right frontal periventricular gray matter heterotopion in Case 1 (arrows in axial and sagittal T1 weighted images, I and M). For Cases 1, 2, and 3 there was also no evidence of a significant parenchymal injury or a metabolic/neurodegenerative condition, apart from nonspecific findings which were not thought to be related to seizure: an incidental left caudo-thalamic groove germinolytic cyst in Case 1 (asterisk in A); punctate mineralization versus hemosiderin deposition in the left temporo-parietal cortex of Case 2 (arrow in susceptibility weighted imaging, J); and some minimal cerebellar vermis volume loss in Case 3 (arrow sagittal T1 series, N). By comparison, subjects Case 4 and Case 5 demonstrated moderate to extensive parenchymal signal abnormality. In Case 4, T2 weighted imaging demonstrated diffuse haziness of the cerebral white matter concentrated in the right-greater-than-left frontotemporal lobes and right forceps minor (outlined by arrowheads in axial and coronal T2 weighted sequences, K and O). This pattern was consistent with cortical dysplasia and brain dysmyelination/gliosis; cortical dysplasia was thought unlikely to solely explain the findings given extent of signal abnormality, and tumor was thought unlikely given lack of mass effect. While T1 and T2 weighted imaging appeared grossly normal for subject Case 5, volumetric FLAIR imaging demonstrated loss of gray-white matter differentiation throughout the lower half of the right frontal lobe (arrowheads in coronal volumetric FLAIR, P; corresponding image slice on coronal T2, L). Although lacking a transmantle sign specific for cortical dysplasia, the regional blurring of gray-white matter differentiation in Case 5 was most suggestive of a focal cortical dysplasia; however, regional dysmyelination/gliosis could conceivably also have this appearance.
Figure 3
Figure 3
Representative histopathological findings from the surgical specimens. Immunoperoxidase stains for the neuronal marker NeuN (brown) were performed to assess the cytoarchitecture of the resected cortex. Left panel (case 2) shows prominent radial arrangement of neurons with numerous microcolumns containing more than 8 tightly aligned neurons, characteristic of FCD type 1A. The middle panel (case 1) and right panel (case 5) show normal cortical architecture and reactive changes with patchy neuronal loss. Scale bars = 200 microns.
Figure 4
Figure 4
No evidence for mTOR pathway activation in any of the five SLC35A2-associated cases. Cresyl violet staining (A) and NeuN immunoreactivity (B) in case 5 show normal laminar cytoarchitecture. There are scattered cortical neurons labeled with P-S6 antibodies in representative sections of cases 1, 4, 5, (D, E, F, respectively) associated with somatic SLC35A2 variants. The distribution and P-S6 labeling intensity in three cases was similar to that seen in control cortex from an unaffected individual (C). Scale bar = 300 microns.
Figure 5
Figure 5
Novel and previously reported rare functional variation in SLC35A2. Somatic mutations identified in this study are shown in red, those previously implicated in congenital disorders of glycosylation are shown in green, and those previously implicated in epileptic encephalopathies in blue. Six Polyphen2 probably damaging ultra-rare missense mutations identified in gnomAD in the canonical transcript are shown in yellow.
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