Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough

doi:10.1016/j.jns.2008.06.027

Journal of the Neurological Sciences

Volume 273, Issues 1–2, 15 October 2008, Pages 88-92

https://doi.org/10.1016/j.jns.2008.06.027 Get rights and content

Abstract

We studied a four-generation pedigree of a Japanese family with hereditary neuropathy to elucidate the genetic basis of this disease. Twelve members of the family were enrolled in this study. The clinical features were neurogenic muscle weakness with proximal dominancy in the lower extremities, sensory involvement, areflexia, fine postural tremors, painful muscle cramps, elevated creatine kinase levels, recurrent paroxysmal dry cough, and neurogenic bladder.

We performed a genome-wide search using genetic loci spaced at about 13 Mb intervals. Although nine chromosomes (1, 3, 4, 5, 6, 10, 17, 19, and 22) had at least one region in which the logarithm of odds (LOD) score was over 1.0, no loci fulfilled the criteria for significant evidence of linkage. Moreover, we analyzed an extra 14 markers on 3p12–q13 (the locus of hereditary motor and sensory neuropathy, proximal dominant form) and an extra five markers on 3p22–p24 (the locus of hereditary sensory neuropathy with chronic cough) and observed LOD scores of < − 3 on both 3p12–q13 and 3p22–p24. Mutation scanning of the entire coding regions of the MPZ and PMP22 genes revealed no mutations. We conclude that the disorder described here is a newly classified hereditary motor and sensory neuropathy with autosomal dominant inheritance.

Introduction

Hereditary motor and sensory neuropathy (HMSN) includes a heterogeneous group of neurodegenerative disorders characterized by progressive neuropathy [1]. Most HMSN patients show muscular weakness with distal predominance, while muscular weakness with proximal dominancy is quite rare. Causative mutations have been identified in over 20 types of HMSN with distal predominance. Two overlapping genetic loci (3q13.1 and 3p12–q13) for hereditary motor and sensory neuropathy (proximal dominant form) (HMSN-P) have been identified [2], [3], [4]. However, no causative gene for HMSN-P has yet been elucidated. We have identified a four-generation Japanese family with hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities. The atypical features present in this family, when compared to previously reported HMSN-P cases, were urinary dysfunction and recurrent paroxysmal dry cough. We performed clinical, electrophysiological, and genetic analyses of this family. We propose here the existence of a new type of HMSN-P based on results of these analyses.

Section snippets

Subjects

We studied a four-generation Japanese pedigree originating from Kumamoto prefecture, a southern province of Japan. Fig. 1 shows an extract from this pedigree. After informed consent was obtained, nine available family members and three spouses underwent a neurological examination and were blood-sampled in 2006. This study was approved by the Ethics Committees of Kurume University School of Medicine and Kyushu University, Faculty of Medicine.

Genotype analysis

We performed a genome-wide scan using 292

Phenotypic features

Autosomal dominant transmission was the most likely mode of inheritance, although male-to-male transmission was absent in the pedigree (Fig. 1). In this pedigree, five members (two men and three women) were affected, and the disease statuses of three members (III-4, IV-1, and IV-2) were undefined because of the current difficulty in evaluating symptoms. The clinical and laboratory findings in the five afflicted patients are summarized in Table 1. In the affected individuals, the age at onset

Discussion

The cardinal clinical features of the present family were as follows: 1) slow progression; 2) muscular weakness with dominancy in the proximal portion of the lower limbs; 3) sensory involvement with dominancy in the lower limbs; 4) areflexia; 5) fine postural or action tremor; 6) painful muscle cramping; 7) elevated serum creatine kinase level; 8) urinary dysfunction; and 9) recurrent paroxysmal dry cough. Painful muscle cramping started in the proximal muscles of the lower limbs, then spread

Acknowledgments

The authors thank all of the individuals for their participation in this study.

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Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough

Abstract

Introduction

Section snippets

Subjects

Genotype analysis

Phenotypic features

Discussion

Acknowledgments

Neuromuscul Disord

Am J Hum Genet

Clin Neurol Neurosurg

Findings the causes of inherited neuropathies

Arch Neurol