PMC7387725_01
(A) Baseline EEG at onset of her seizures showing a generalized atypical spike and wave discharges with a right sided predominance. (B) EEG: While maintained on propofol, seizures originated from the right hemisphere out of a burst-suppression pattern. (C,D) Intraoperative electrocorticograph. (C) Prior to resection. (D) Post right insula and right prefrontal resection and right face motor subpial transaction.
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F1
Her workup included an epilepsy protocol MRI that was normal and a 3 h video/EEG recording, which revealed a normal posterior background and fragments of generalized spike-wave discharges (GSWDs) with a right sided amplitude predominance, thought to represent an inherited EEG trait (Figure 1A). The seizures failed to respond to high dose midazolam infusion and the patient developed hemodynamic compromise on propofol with no control of the electrographic seizures that persisted despite reaching a burst-suppression on the EEG (Figure 1B). Intraoperative electrocorticography revealed nearly continuous discharges from the right centrofrontal head region (Figure 1C) that eventually nearly disappeared following a right insular and prefrontal resection along with subpial transections over the right face motor area (Figure 1D). Whole exome sequencing revealed a novel hemizygous mutation in FARS2 gene in a compound heterozygous state, with a deletion of exon 2 in one of the parent copies (confirmed by qPCR) and a Val197Met mutation in exon 2 of the second copy, confirmed by Sanger sequencing (Supplementary Figure 1).
(A) Voxel Based Morphometric (VBM) Analysis - Junction Map. (i) Axial; (ii) Coronal, and (iii) Right Sagittal cuts. Showing a suspicious lesion involving the right anterior insula with a high Z-core. (B) Intra-ictal brain MRI diffusion weighted images (DWI) showing a restricted diffusion in the cortical-subcortical area of the right frontal lobe, right insula and right thalamus.
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F2
MRI revealed a suspicious lesion in the right insula based on a high z score on the junction map (Figure 2A). Moreover, a volumetric brain analysis revealed no volume difference between the right and left gray matter structures and did not show any global atrophy or asymmetry between the two hemispheres. A repeat brain MRI showed restricted diffusion in the cortical-subcortical areas of the right frontal lobe, right insula, right thalamus and to lesser extent in the right temporal, both parietal lobes and left frontal lobe (Figure 2B).
Histological assessment of the patients' muscle biopsy. (A) Modified Gomori's Trichrome (GT) stain outline general features characterized by subsarcolemmal mitochondrial proliferation (arrowhead) and multifocal clusters of disintegrating myofibers. Succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) histoenzymatic stains illustrate normal SDH and COX activities and highlight the reactive subsarcolemmal mitochondrial proliferation (arrowhead). COX negative fibers are absent as indicated by lie COX-SDH overlay stain. (B) NADH histoenzymatic reaction demonstrate lie diffuse loss of mitochondrial network and marked mitochondrial aggregation (left) compared to an age matched control (right). Upper and lower panels represent 400-fold magnification of sections. Scale bars: 50 mum.
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F3
Histochemical assessment of oxidative enzymes, including NADH-tetrazolium reductase, succinate dehydrogenase and cytochrome c oxidase (COX), showed normal activities (Figure 3A). Reactive subsarcolemmal mitochondrial proliferation was frequently observed (Figure 3A). Mitochondrial network fragmentation with excessive mitochondrial aggregation was diffuse (Figure 3B).