Review article
Hereditary motor and sensory neuropathies or Charcot–Marie–Tooth diseases: An update

https://doi.org/10.1016/j.jns.2014.10.013Get rights and content

Highlights

  • Considerable genetic heterogeneity in Charcot–Marie–Tooth disease

  • Interest of clinical and pathological specific features to target genetic testing

  • Simplified classification of autosomal recessive forms proposed (AR CMT1, AR CMT2)

  • Mitochondrial abnormalities in AR CMT1A nerve biopsy newly demonstrated

  • Ongoing new therapeutic trial in CMT1A, for potential curative treatment

Abstract

Hereditary motor and sensory neuropathies (HMSN) or Charcot–Marie–Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C …), we propose a simplified classification such as AR CMT1 (A, B, C …), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment.

Introduction

Hereditary peripheral neuropathies (HPN) include hereditary motor and sensory neuropathies (HMSN), hereditary motor neuropathies (HMN) and hereditary sensory neuropathies (HSN) or hereditary sensory and autonomic neuropathies (HSAN). Despite this heterogeneity, HPN are a group of disorders that share characteristic clinical phenotypes that manifest as a peripheral neuropathy with a chronic progressive course. The most frequent entity, HMSN, also known by the eponym Charcot–Marie–Tooth disease (CMT), is a heterogeneous group of disorders which can be classified on the basis of their clinical, neurophysiological, genetic and pathological features.

Charcot–Marie–Tooth diseases are the most common degenerative disorders of the peripheral nervous system and the frequency of its different subtypes varies within distinct populations. Two major subtypes, demyelinating (CMT1 or HMSN I) and axonal (CMT2 or HMSN II), can be distinguished by electrophysiological and nerve biopsy studies [1], [2], [3].

CMT1 and CMT2 are usually inherited as an autosomal dominant (AD) trait, but autosomal recessive (AR) and X-linked inheritance had also been reported [4], [5], [6]. In Western Europe, North America and Japan, the dominant forms are more frequently found [7]. In other countries, such as those in the Mediterranean basin that shows a high prevalence of consanguineous marriages, autosomal recessive inheritance may account for more than 30 to 50% of all forms [8].

Since the identification of the 1.4-Mb duplication of chromosome 17 containing the peripheral myelin protein 22 gene (PMP22), which is the cause of the most frequent form of CMT1 [9], [10], there has been much progress in the understanding of the molecular basis for many forms of CMT such that more than 75 genes have been identified. Moreover, the diversity of cellular and molecular functions of the CMT proteins encoded by these genes has led to more insights in the pathophysiology of the disease and the cellular biology of the peripheral nervous system. Indeed, the knowledge of the multiple CMT forms and particularly the new issues in the field in the last five years for which this review aims, should lead to an accurate clinical diagnosis and management of these conditions.

Section snippets

Classical CMT phenotype and CMT classification

Most cases of CMT are slowly progressive disorders that usually present in the second decade, although earlier or later initial presentations may occur depending on the underlying genetic abnormalities. The classical phenotype includes steppage gait, moderate distal sensory deficit, and distal lower amyotrophy giving an aspect of “jambes de coq” or an inverted champagne bottle. A similar pattern of atrophy with mild or moderate sensory deficits in the hands occurs more lately in the course of

Autosomal dominant CMT (AD CMT)

Autosomal dominant CMT are the most frequent forms of CMT in most European and North-American countries.

AD CMT1 is the most common form, such that it accounts for more than 80% of patients with CMT attending an inherited neuropathy clinic [15], [16]. Most patients with AD CMT1 have the classical CMT phenotype. Median MNCVs are below 38 m/s and neuropathological features include a significant reduction of myelinated axons and “onion bulbs” which are composed of several layers of basal lamina,

Improved diagnosis by the use of new molecular techniques

In the near future, the development and the routine use of new molecular techniques, such as DNA arrays or whole genome and exome sequencing, should improve the diagnostic approach of such genetically heterogeneous diseases. In fact, next generation sequencing (NGS) techniques could allow testing of all known CMT genes for several patients in a single experiment with a high depth of sequencing, now considering it to be the most efficient method of genetic testing in CMT [46], [47], [48]. The

Therapeutic perspectives

Like for any chronic neuromuscular disorder, physical therapy and associated rehabilitative measures remain mandatory in patients with CMT diseases. The prescription of ankle–foot orthoses and/or special shoes is recommended for patients with the classical CMT phenotype. Moderate exercise training and stretching to avoid osteo-articular complications are generally well tolerated. Patients with limb and vertebral deformities often need corrective orthopedic surgeries. Medication for pain,

Conclusion

Genetic testing has greatly expanded the clinical and genetic spectra of the inherited motor and sensory neuropathies. Patients formerly classified as simply Charcot–Marie–Tooth disease patients may now be classified into many subtypes. Nonetheless, more than 80% of patients with CMT in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1.

Although new molecular techniques that can assess numerous genes simultaneously are available (e.g., DNA arrays, whole

Conflict of interest

All the authors have no conflict of interest.

Acknowledgments

We are grateful to Algiers University and the Ministry of Health and Population (Algeria) for all their invaluable support.

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