1. Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome
- Author
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Angamuthu K. Meena, Sanjiban Chakrabarty, Sandeep Mallya, Hanumanthapura R. Arivinda, Madhu Nagappa, Kumarasamy Thangaraj, Sekar Deepha, Bindu Parayil Sankaran, Shama Prasada Kabekkodu, Narayanappa Gayathri, Pradyumna Jayaram, Arun B Taly, Periyasamy Govindaraj, J.N. Jessiena Ponmalar, Kapaettu Satyamoorthy, Sanjib Sinha, and Rajan Kumar Jha
- Subjects
0301 basic medicine ,Mitochondrial DNA ,Mitochondrial disease ,CNV ,DGUOK ,medicine.disease_cause ,MELAS syndrome ,DNA, Mitochondrial ,03 medical and health sciences ,0302 clinical medicine ,Mitochondrial Encephalomyopathies ,MELAS Syndrome ,medicine ,Humans ,Exome sequencing ,Genetics ,Mutation ,Original Communication ,mtDNA ,business.industry ,Nuclear genome ,medicine.disease ,Stroke ,Genes, Mitochondrial ,030104 developmental biology ,Neurology ,Lactic acidosis ,MELAS ,Acidosis, Lactic ,MYH7 ,Neurology (clinical) ,business ,Mutations ,030217 neurology & neurosurgery - 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.
- Published
- 2021
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