The Pathological Features of Common Hereditary Mitochondrial Dynamics Neuropathy.

Rui Wu,Zhaoxia Wang,Hui Wang,Yun Yuan,He Lv

doi:10.3389/fnins.2021.705277

Abstract

ObjectivesMitofusin 2 and ganglioside-induced differentiation-associated protein 1 are two main mitochondrial dynamics-related proteins. Dysfunction of these two proteins leads to different subtypes of Charcot–Marie–Tooth disease type 2A (CMT2A) and CMT2K. This study aims to report the pathological difference between CMT2A and CMT2K in a large cohort.MethodsThirty patients with molecularly confirmed CMT2A and nine with CMT2K were identified by next-generation sequencing. Sural nerve biopsies were performed in 29 patients.ResultsThe patients with both diseases showed length-dependent neuropathy with distal weakness, sensory loss, and no deep tendon reflex. Optic neuropathy appeared in 3/30 (10%) patients with CMT2A. Tendon contracture appeared in 4/9 (50.0%) patients with CMT2K. Sural biopsy revealed the loss of both myelinated and unmyelinated nerve fibers. Closely packed, irregularly oriented neurofilaments were observed in axons of unmyelinated nerve fibers in both diseases. Another important finding was the ubiquitous presence of smaller, rounded, and fragmented mitochondria in CMT2A and elongated mitochondria in CMT2K in the myelinated and unmyelinated axons.ConclusionThis study confirmed large diversity in phenotypes between CMT2A and CMT2K. Mitochondrial dynamics-related variations can induce different mitochondrial morphological changes and neurofilament accumulation in axons.

Highlights

Charcot–Marie–Tooth disease (CMT), known as hereditary motor and sensory neuropathy, is the most common type of hereditary peripheral neuropathy with an incidence of about 1/2,500 (Lerat et al, 2019; Tao et al, 2019)
In a total of 160 patients clinically suspected of CMTs, we found 30 patients with the Mitofusin 2 (MFN2) prevalence rate of 18.8% (75% of CMT2s) and ganglioside-induced differentiationassociated protein 1 (GDAP1) prevalence rate of 5.6% (21.4% of CMT2s)
A variety of proteins are involved in this process, and the main ones related to CMT are fusion-related MFN2 and fission-related GDAP1

Summary

Introduction

Charcot–Marie–Tooth disease (CMT), known as hereditary motor and sensory neuropathy, is the most common type of hereditary peripheral neuropathy with an incidence of about 1/2,500 (Lerat et al, 2019; Tao et al, 2019). Variations related to mitochondrial dynamics, including mitochondrial fusion, fission, transport, and mitophagy, are the leading causes of axonal CMT2 (Pareyson et al, 2015; Minaidou et al, 2019; Sancho et al, 2019). Fusion and fission have a certain dilution effect on the mitochondrial genome variations and play an important role in maintaining the integrity of the respiratory chain and cell energy metabolism (El-Hattab et al, 2017). This process disorder can lead to the accumulation of defective mtDNA in the neuron. The impaired transport and uneven distribution of mitochondria result in energy insufficiency especially in the terminal of the long axons and causes axonal damage (Misko et al, 2012; Pareyson et al, 2013)

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