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

Sanjiban Chakrabarty, Periyasamy Govindaraj, Bindu Parayil Sankaran, Madhu Nagappa, Shama Prasada Kabekkodu, Pradyumna Jayaram, Sandeep Mallya, Sekar Deepha, J. N.Jessiena Ponmalar, Hanumanthapura R. Arivinda, Angamuthu Kanikannan Meena, Rajan Kumar Jha, Sanjib Sinha, Narayanappa Gayathri, Arun B. Taly, Kumarasamy Thangaraj, Kapaettu Satyamoorthy

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
JournalJournal of Neurology
DOIs
Publication statusAccepted/In press - 2021

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

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