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

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

doi:10.1007/s00415-020-10390-9

Abstract

BackgroundMitochondrial 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.MethodsThe 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.ResultsAnalysis 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.ConclusionIndividuals 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.

Highlights

Defective mitochondrial function contributes to childhood and adult neurometabolic disorders affecting multiple organs with a projected global prevalence of 1 in 5000 [1]
We looked at the control of nuclear gene mutations on the clinical expression of m.3243A > G and found patient P2 harbor variants in two genes namely LOXHD1 (p.Leu1564Phe, p.Arg685His) and NEUROD1 (p.Glu59Gln) which is reported to be associated with non-syndromic hearing loss and maturity-onset diabetes, respectively
We have performed whole exome sequencing (WES) of 11 MELAS patients and identified pathogenic mutation in nuclear encoded genes associated with mitochondrial encephalopathy (POLG, DGUOK, SUCLG2, TRNT1), sensorineural hearing loss, seizures, epileptic encephalopathy, and cardiomyopathy (LOXHD1, KCNQ1, KCNQ2 and MYH7)

Summary

Introduction

Defective mitochondrial function contributes to childhood and adult neurometabolic disorders affecting multiple organs with a projected global prevalence of 1 in 5000 [1]. MELAS is a clinically complex early onset multi-organ mitochondrial disorder with diverse phenotype and varying degree of severity [9, 10] These patients clinically present with encephalomyopathy, lactic acidosis, and stroke-like episodes and show evidence of ragged red fibers (RRF) on muscle biopsy. 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

Objectives

Methods

Results

Discussion

Conclusion