Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes

Yoshihiro Hiramatsu ,Akihiro Hashiguchi,Shinichi Morishita,Kei Murayama,Mikiya Suzuki,Youji Suzuki,Yujiro Higuchi,Akinobu Yoshimura ,Fumihito Nozaki,Masamitsu Yamaguchi,Yuki Yamamoto,Naoko Matsui,Jun‐Hui Yuan ,Jun Mitsui,Yuji Okamoto,Takatsune Kumada ,Masaki Tanaka,Masahiro Ando,Ichizo Nishino,Yoshitsugu Miyazaki ,Shoji Tsuji,Hiroyuki Ishiura,Eiji Matsuura,Hiroshi Takashima

doi:10.1007/s00415-022-11026-w

Abstract

Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot–Marie–Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.

Highlights

Peripheral neuropathy has various causes, one of which is mitochondrial abnormalities
Mitochondrial disorders associated with defects in mitochondrial DNA maintenance and replication or defects in the respiratory chain complex are often associated with peripheral neuropathy [2]
Through whole-exome sequencing (WES) data, we examined a large cohort of Japanese patients with clinically suspected hereditary peripheral neuropathy patients to determine the presence of variants in a panel of mitochondrial-related nuclear genes

Summary

Introduction

Peripheral neuropathy has various causes, one of which is mitochondrial abnormalities. Mitochondrial-related nuclear genes, such as MFN2 and GDAP1 that are involved in mitochondrial dynamics, are major causes of Charcot–Marie–Tooth disease (CMT) [1, 2], the most common subtype of hereditary peripheral neuropathy. In MFN2, known as CMT2A and HMSN6A, phenotypes may cause optic atrophy, and in GDAP1, they may cause vocal cord paresis [2] so the spectrum of CMT has considerably broadened and multisystem involvement is frequently observed similar to other disorders caused by mutations in mitochondrial DNA (mtDNA) or mitochondria-related nuclear genes. Through whole-exome sequencing (WES) data, we examined a large cohort of Japanese patients with clinically suspected hereditary peripheral neuropathy patients to determine the presence of variants in a panel of mitochondrial-related nuclear genes

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Results

Conclusion