MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load

Yi Shiau Ng,Efstathia Chronopoulou,Doug M Turnbull,Charlotte L Alston,Surita Meldau,Emma L Blakely,Michael G Hanna,Imelda Hughes,Helen Mundy,Catherine Feeney,Ailian Du,Robert Mcfarland,Patrick F Chinnery,Smaragda Kamakari,Akira Ohtake,Robert W Taylor,Takafumi Sakakibara,Gillian Riordan,Kei Murayama,Yasushi Okazaki,Philippa D Hepplewhite,Akira Sudo,Andrew M Schaefer,Nichola Z Lax,Richard J Rodenburg,Germaine Pierre,Steven A Hardy,Paul Maddison,Christiaan G J Saris ,Georgia Antonakou Chrousos ,Andrew A M Morris ,Mike Champion ,Robert D S Pitceathly ,Gráinne Gorman

doi:10.1016/j.ebiom.2018.02.010

Abstract

Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months−37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C.

Highlights

Defects in oxidative phosphorylation (OXPHOS) are an important cause of human morbidity and mortality, with complex I (NADH-ubiquinone oxidoreductase) deficiency recognized as the most commonly observed oxidative phosphorylation system (OXPHOS) defect (Rodenburg, 2016)
Neuropathological studies of two patients manifesting with Leigh syndrome (LS)/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094TNC
Mediated respiratory failure or apnoea was documented in nine patients (38%) with LS, including an adult patient who presented at the age of 22 years (Patient 10)

Summary

Introduction

Defects in oxidative phosphorylation (OXPHOS) are an important cause of human morbidity and mortality, with complex I (NADH-ubiquinone oxidoreductase) deficiency recognized as the most commonly observed OXPHOS defect (Rodenburg, 2016). Complex I (NADH: ubiquinone oxidoreductase) is the largest component of the oxidative phosphorylation system (OXPHOS) composed of 45 subunits that, in supercomplex formation with respiratory chain complexes III and IV, drives the generation of a transmembrane protein gradient powering adenosine triphosphate (ATP) synthesis. The limited understanding of the natural history of disease caused by such mutations presents significant challenges in clinical practice, in relation to pre-symptomatic genetic testing of at-risk family relatives. We have studied the neuropathological changes in two patients with LS/MELAS overlap syndrome, to fully elucidate the spectrum of m.13094TNC-related mitochondrial disease and to offer guidance on management and genetic counseling

Methods

Results

Conclusion