Review article
Charcot–Marie–Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2

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Abstract

Charcot–Marie–Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), includes two main subtypes of CMT1/HMSN I (demyelinating), and CMT2/HMSN II (axonal). Further heterogeneity has been demonstrated by genetic molecular studies, with at least four responsible genes for CMT1. As for CMT2, a mutation in the neurofilament-light (NF-L) gene has been identified in a single family, and other CMT2 loci have been mapped. We propose a clinical classification of the CMT2 phenotypes, and review the features of the identified CMT2 genotypes. The following main subtypes of CMT2 are considered in the phenotype classification: classical CMT2, the variants of CMT2 showing atypical features that may represent either variance in the classical CMT2 phenotype or separate entities; CMT2 plus, i.e. complex forms with involvement of additional neural structures. The recognized CMT2 genotypes include: CMT2A (mapped to chromosome 1p35–36); CMT2B (3q13–22); CMT2C (with vocal cord paresis); CMT2D (7p14); CMT2E, related to a mutation in the NF-L gene on chromosome 8p21; proximal CMT2, or HMSN P (3q13.1); CMT2 with MPZ mutations; autosomal recessive CMT2 (1q21.2–q21.3); agenesis of the corpus callosum with sensorimotor neuronopathy (15q13–q15); CMT2 X-linked with deafness and mental retardation (Xq24–q26). The identified genotypes may correspond to previously described clinical subtypes of CMT2. In particular, classical CMT2 presents in association with NF-L gene mutation, in the only CMT2 family with known gene mutation, and in CMT2A patients. However, the features of classical CMT2 have been paradoxically reported also in families with MPZ mutation, and conversely several CMT2 families are not linked to the known CMT2 loci. Further cloning of the CMT2 genes will ultimately shed light on the pathogenic mechanism(s) implicated in the process of axonal degeneration, shared by the different CMT2 genotypes.

Introduction

The heterogeneity of the syndrome of peroneal muscular atrophy described by Charcot and Marie in Paris, and Tooth in London, in 1886, was initially demonstrated by Dyck and Lambert [1] who differentiated, on the basis of neurophysiological and neuropathological studies, the two main types of hereditary motor and sensory neuropathy (HMSN), type I (demyelinating) and type II (axonal), also called Charcot–Marie–Tooth disease type 1 (CMT1) and type 2 (CMT2). The term of HMSN tends to be used in a clinical setting, whereas CMT should designate genetically defined entities but tends to be used thoroughly and currently is the preferred denomination. Other subtypes were subsequently added, including complex forms with additional features [2] and Déjerine–Sottas syndrome, or HMSN III, a severe phenotype characterised by infantile onset, autosomal recessive inheritance, very low nerve conduction velocities with hypomyelination, and elevated protein concentration in the cerebrospinal fluid [3]. Genetic molecular studies have shown genetic heterogeneity within the main subtypes [4], [5], leading to the identification of three genes responsible for autosomal dominant CMT1: the peripheral myelin protein 22 (PMP22) gene for the common form of CMT1A [6], with duplication [7] or, rarely, mutation within 17p11.2; the myelin protein zero (MPZ) gene in the 1q22.23 region (CMT1B) [8]; and the human early growth response 2 (EGR2) gene on chromosome 10q21.1–q22.1 (CMT1C) [9]. Mutations in the PMP22 [10], MPZ [11], and EGR2 genes [12] are also responsible for Déjerine–Sottas syndrome. The PMP22 gene is also involved in hereditary neuropathy with liability to pressure palsies [13], which is due to deletion or, rarely, mutation in the 17p11.2 region. Demyelinating subtypes with autosomal recessive inheritance have been mapped to chromosome 8q13–21.1 [14], 11q23 [15], 5q23–q33 [16], and 8q24 [17], with a known mutation in the gene encoding myotubularin-related protein-2 (MTMR2) [15]. In addition, sibs homozygous for a PMP22 mutation [18], as well as for a EGR2 [9] and a MPZ mutation [19] have been reported: thus, mutations in the same genes responsible for autosomal dominant CMT1 may be implicated in autosomal recessive forms, further complicating the genetic classification. Mutations in the gap junction protein connexin 32 gene (Cx32) at the X chromosome, Xq13, are associated with the sex-linked dominant form (CMTX) [20]. The NCVs in male CMTX patients tend to be in the CMT1 range, whereas the findings in female carriers are those of an axonal neuropathy [21].

CMT2 is defined by the neurophysiological features of chronic axonal neuropathy, with nerve biopsy findings of chronic axonal atrophy and regeneration, and possibly rudimental onion bulbs, in the clinical setting of a hereditary syndrome of peroneal muscular atrophy [2], [22]. Neurophysiological study is characterized by normal or slightly reduced motor and sensory nerve conduction velocities (NCV) and decreased amplitudes of evoked motor and sensory nerve responses; conventional cut-off values of 75% of the lower limit for motor NCV have been proposed to differentiate CMT2 from CMT1, corresponding to 38 m/s for the motor median nerve [22], [23]. Neurophysiological studies also differentiate CMT2 from distal hereditary motor neuropathy, or spinal CMT, another phenotype of peroneal muscular atrophy characterized by normal sensory NCV and EMG findings suggesting chronic motoneuronal involvement [22], [24], with identified loci on chromosomes 12q24 [25] and 7p [26].

CMT2 seems to be less common than CMT1 [27], but it may be underdiagnosed, especially in sporadic cases, as neurophysiological features of axonopathy are not so distinctive as demyelination in CMT1, and genetic diagnostic tests are not available. All CMT types combined have a prevalence of 20–40:100,000 [27], [28], however the prevalence of CMT2 is much lower than CMT1, e.g., 12:100,000 in Cantabria (Northern Spain) [29] and 3.9:100,000 in Sweden [30] According to Ionasescu [27], CMT2 families represent 18.9% of CMT families in Iowa.

Genetic heterogeneity of CMT2 emerged from linkage studies [4], [5], and recently a CMT2 gene has been identified on chromosome 8p21, in the region of the neurofilament-light (NF-L) gene [31]. We review the known CMT2 phenotypes, proposing a clinical classification, as a possible basis for future genetic classification. We also review the features of the identified CMT2 genotypes, addressing the genotype–phenotype correlations.

Section snippets

Phenotypic classification of CMT2

Although a few loci for CMT2 have been mapped, classification of CMT2 is necessarily based, at present, mainly on clinical features.

The following main subtypes of CMT2 are considered: classical CMT2; the variants of CMT2 showing atypical features that may represent either variance in the CMT2 phenotype or separate entities; CMT2 plus, with involvement of additional neural structures (Table 1). This classification provisionally includes some recessive forms, although it has been recently

CMT2 genotypes

A specific gene mutation has been individuated [31], and other loci [4], [5] have been associated by linkage with genetic axonal neuropathies consistent with CMT2 phenotypes (Table 1). On the other hand, linkage studies excluded all known loci in several CMT2 families [22], [74], so the present genotypic classification of CMT2 based on the mapped CMT2 loci is largely incomplete.

CMT genes, demyelination versus axonal degeneration, and clinical phenotype

The heterogeneity of CMT challenges the concept of CMT as a clinical syndrome, as CMT includes demyelinating neuropathies caused by various genes that are expressed in myelinating Schwann cells, and axonal neuropathies likely caused by genes expressed by peripheral nervous system (PNS) neurons. With regard to CMT1, a unifying terminology seems justified because different genetic defects converge in a final common pathway of derangement of myelin formation and maintenance [4], [94]. The state of

Conclusions

In spite of genetic heterogeneity, the various genotypes of CMT1 and CMT2 may share some pathogenic mechanisms [96], and clinical problems are basically the same in most subtypes of CMT [101], thus the concept of CMT as a syndrome will probably survive the advances in molecular genetics. As axonal degeneration rather than demyelination seems to be the major cause of disability not only in CMT2 but also in CMT1 [97], [98], common therapeutic strategy, aimed at preventing and treating axonal

Acknowledgements

This work was supported in part by a grant from the Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST).

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