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

Autor: Chakrabarty S; Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India., Govindaraj P; Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.; Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.; Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.; Institute of Bioinformatics, International Tech Park, Bangalore, India.; Manipal Academy of Higher Education, Manipal, India., Sankaran BP; Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.; Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.; Genetic Metabolic Disorders Service, Children's Hospital At Westmead, Sydney, NSW, Australia.; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Nagappa M; Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.; Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India., Kabekkodu SP; Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India., Jayaram P; Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India., Mallya S; Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India., Deepha S; Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.; Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India., Ponmalar JNJ; Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India., Arivinda HR; Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India., Meena AK; Department of Neurology, Nizam's Institute Medical Sciences (NIMS), Hyderabad, India., Jha RK; CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India., Sinha S; Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India., Gayathri N; Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.; Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India., Taly AB; Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.; Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India., Thangaraj K; CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.; Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India., Satyamoorthy K; Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India. ksatyamoorthy@manipal.edu.
Jazyk: angličtina
Zdroj: Journal of neurology [J Neurol] 2021 Jun; Vol. 268 (6), pp. 2192-2207. Date of Electronic Publication: 2021 Jan 23.
DOI: 10.1007/s00415-020-10390-9
Abstrakt: 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.
Databáze: MEDLINE
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