FARS2 Mutations: More Than Two Phenotypes? A Case Report

Abstract

FARS2, a nuclear gene, encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS). Previous reports have described two distinct phenotypes linked to FARS2 gene mutation: an early onset epileptic encephalopathy and spastic paraplegia. This report describes a distinctive phenotype of FARS2-linked, juvenile onset refractory epilepsy, caused by a hemizygous mutation in a compound heterozygous state (p.V197M and exon 2 microdeletion). A 17-year- old woman with normal development presented with a super refractory focal motor status epilepticus. Only an emergency life-saving surgery aborted her status after all therapeutic interventions, including anesthesia, failed to control her seizures. Pathological and biochemical activities on muscle biopsy showed mitochondrial proliferation with enhanced isolated activities of complexes II and IV, suggestive of a compensatory mechanism for the bioenergetic deficiency. Postoperatively, the patient started experiencing focal aware motor seizures originating from the contralateral hemisphere after being seizure free for a few months. This report suggests a third phenotypic manifestation of FARS2 gene mutation.

Keywords: FARS2; juvenile onset epilepsy; mitochondrial epilepsy; mitochondrial tRNA synthetase; refractory status epilepticus.

FIGURE 1

(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.

FIGURE 2

(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.

FIGURE 3

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 μm.