Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan.

Hajime Tanabe,Hiroyuki Ishiura,Jun Mitsui,Yu Kono,Eiji Matsuura,Shoji Tsuji,Yujiro Higuchi,Satoshi Nozuma,Hiroshi Takashima,Satoshi Ishihara,Kengo Maeda,Shosaburo Yanamoto,Hiroshi Kida,Yoko Sunami,Yuri Asano,Jiro Fukae,Mitsuya Morita,Yuji Okamoto,Norito Kokubun,Jun‐Hui Yuan,Akihiro Hashiguchi,Ryotaro Takashima,Y Ishigaki ,Akinobu Yoshimura

doi:10.1111/jns.12252

Abstract

Mutations in small heat shock protein beta‐1 (HspB1) have been linked to Charcot‐Marie‐Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole‐exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1‐related disorders.

Highlights

Charcot-Marie-Tooth (CMT) disease is a common, clinically and genetically heterogeneous group of hereditary neuropathies
The following seven known heterozygous mutations were identified in 12 patients: T151I, P39L, R140G, R127W, S135C, K141Q, and P182A (Fig. 2A)
To clarify the presence of a sex difference, we reviewed the literature for patients with inherited peripheral neuropathies (IPNs) caused by HSPB1 mutations, which revealed a comparable male predominance (67 males vs. 26 females, despite the comparable numbers of non-affected male and female carriers (73 vs. 78, respectively; Table 3)

Summary

Introduction

Charcot-Marie-Tooth (CMT) disease is a common, clinically and genetically heterogeneous group of hereditary neuropathies. More than 80 CMT disease-causing genes have been identified. Another inherited peripheral neuropathy (IPN), distal hereditary motor neuropathy (HMN), resembles CMT but is a pure motor neuron disease with no or mild sensory nervous system involvement. Mutations in HSPB1 were shown to be associated with CMT type 2F (CMT2F, OMIM 602195) with autosomal dominant or recessive inheritance and HMN type 2B (HMN2B, OMIM 608634) with minimal sensory involvement. Since 2004, more than 40 families with CMT2F/HMN2B due to missense and rarely nonsense or frameshift mutations in HSPB1 have been reported (Evgrafov et al, 2004)

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