Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome
Open Access
- 23 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Zeitschrift für Neurologie
- Vol. 268 (6), 2192-2207
- https://doi.org/10.1007/s00415-020-10390-9
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
Funding Information
- Science and Engineering Research Board (PDF/2016/001625)
- Manipal Academy of Higher Education, Manipal
This publication has 60 references indexed in Scilit:
- POLG1 mutations and stroke like episodes: a distinct clinical entity rather than an atypical MELAS syndromeBMC Neurology, 2013
- Acute mitochondrial encephalopathy reflects neuronal energy failure irrespective of which genome the genetic defect affectsBrain, 2012
- Integrative Genomics Viewer (IGV): high-performance genomics data visualization and explorationBriefings in Bioinformatics, 2012
- CCA addition to tRNA: Implications for tRNA quality controlIUBMB Life, 2010
- MELAS ASSOCIATED WITH MUTATIONS IN THE POLG1 GENENeurology, 2007
- A novel mutation in the mitochondrial tRNASer(AGY) gene associated with mitochondrial myopathy, encephalopathy, and complex I deficiencyJournal of Medical Genetics, 2006
- Mutations of the mitochondrial ND1 gene as a cause of MELASJournal of Medical Genetics, 2004
- Minimum birth prevalence of mitochondrial respiratory chain disorders in childrenBrain, 2003
- The Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episode Syndrome-associated Human Mitochondrial tRNALeu(UUR) Mutation Causes Aminoacylation Deficiency and Concomitant Reduced Association of mRNA with RibosomesOnline Journal of Public Health Informatics, 2000
- Sequence and organization of the human mitochondrial genomeNature, 1981