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

Chakrabarty, Sanjiban and Govindaraj, Periyasamy and Kabekkodu, Shama Prasada and Jayaram, Pradyumna and Mallya, Sandeep P and Kapaettu, Satyamoorthy (2021) Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke‑like episodes (MELAS) syndrome. Journal of Neurology, 268. pp. 2192-2207. ISSN 0340-5354

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Abstract

Background Mitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders.Mutations in mitochondrial 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 11patients. 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

Item Type: Article
Uncontrolled Keywords: MELAS; Mutations; Nuclear genome; mtDNA; CNV
Subjects: Life Sciences > MLSC Manipal
Depositing User: KMC Library
Date Deposited: 25 Nov 2021 08:48
Last Modified: 25 Nov 2021 08:48
URI: http://eprints.manipal.edu/id/eprint/157756

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