Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome

Abstract

Background: Mitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders. Mutations in mitochon drial DNA (mtDNA) and nuclear genome or both have been reported in mitochondrial diseases suggesting common pathophysiological pathways. Considering the clinical heterogeneity of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) phenotype including focal neurological deficits, it is important to look beyond mitochondrial gene mutation.

Methods: The clinical, histopathological, biochemical analysis for OXPHOS enzyme activity, and electron microscopic, and neuroimaging analysis was performed to diagnose 11 patients with MELAS syndrome with a multisystem presentation. In addition, whole exome sequencing (WES) and whole mitochondrial genome sequencing were performed to identify nuclear and mitochondrial mutations.

Results: Analysis of whole mtDNA sequence identified classical pathogenic mutation m.3243A > G in seven out of 11 patients. Exome sequencing identified pathogenic mutation in several nuclear genes associated with mitochondrial encephalopathy, sensorineural hearing loss, diabetes, epilepsy, seizure and cardiomyopathy (POLG, DGUOK, SUCLG2, TRNT1, LOXHD1, KCNQ1, KCNQ2, NEUROD1, MYH7) that may contribute to classical mitochondrial disease phenotype alone or in combination with m.3243A > G mutation.

Conclusion: Individuals with MELAS exhibit clinical phenotypes with varying degree of severity affecting multiple systems including auditory, visual, cardiovascular, endocrine, and nervous system. This is the first report to show that nuclear genetic factors influence the clinical outcomes/manifestations of MELAS subjects alone or in combination with m.3243A > G mutation.

Keywords: CNV; MELAS; Mutations; Nuclear genome; mtDNA.

Fig. 1

CT and MRI brain of MELAS patients with nuclear gene mutations. Axial sections of CT and MRI of brain show shifting cortical-based signal changes that do not conform any arterial territory in patient P8 (A–F). CT brain shows an ill-defined focal hypodensity in the left parietal region in 2008 (a), Brain MRI shows focal wedge-shaped hyperintensity in the left temporal region resembling an ‘infarct’ in 2010 (b, c), focal hyperintensity in the right frontal region in 2012, while the lesion seen in the left temporal region in 2010 has resolved completely (d, e) and recurrence of focal hyperintensity in the left temporal region in 2014 (f). Axial sections of MRI of brain show shifting hyperintensities involving the cortex that do not conform an arterial territory in patient P9 (g–j). Brain MRI shows focal hyperintensity in the left parieto-occipital region in September 2012 (g), focal hyperintensity in the right temporal region in November 2012 (h), focal hyperintensity in left medial temporal region in January 2013 (i) and hyperintensity in bilateral frontal region in August 2016 (j)

Fig. 2

Light and electron microscopic features of muscle biopsy from a patient negative for m.3243A > G mutation showing evidence of mitochondrial insult. a ragged red fibers (MGT); b Ragged blue fibers (SDH); c No COX-deficient fiber (COX- SDH); d Aggregates of mitochondria with altered cristae in the sub-sarcolemmal region; e, f Increased pinocytic vesicles in the endothelial cells of blood vessels