Review articleHereditary motor and sensory neuropathies or Charcot–Marie–Tooth diseases: An update
Graphical abstract
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.
References (55)
- et al.
DNA duplication associated with Charcot–Marie–Tooth disease type 1A
Cell
(1991) - et al.
Duplication in chromosome 17p11.2 in Charcot–Marie–Tooth neuropathy type 1a (CMT 1a)
Neuromuscul Disord
(1991) - et al.
Charcot–Marie–Tooth disease: frequency of genetic subtypes in a German neuromuscular center population
Neuromuscul Disord
(2013) - et al.
Charcot–Marie–Tooth disease: an overview of genotypes, phenotypes, and clinical management strategies
PMR
(2014) - et al.
Cowchock syndrome is associated with a mutation in apoptosis-inducing factor
Am J Hum Genet
(2012) - et al.
Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy
Am J Hum Genet
(2010) - et al.
Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster
Neuromuscul Disord
(2008) - et al.
N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom
Am J Hum Genet
(2000) - et al.
A second locus for an axonal form of autosomal recessive Charcot–Marie–Tooth disease maps to chromosome 19q13.3
Am J Hum Genet
(2001) - et al.
Randomised double-blind controlled trial of ascorbic acid in Charcot–Marie–Tooth type 1A (CMT-TRIAAL/CMT-TRAUK)
Lancet Neurol
(2011)
Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. Neurologic, genetic, and electrophysiological findings in hereditary polyneuropathies
Arch Neurol
Motor nerve conduction velocity in peroneal muscular atrophy: evidence for genetic heterogeneity
J Neurol Neurosurg Psychiatry
The clinical features of hereditary motor and sensory neuropathy types I and II
Brain
Autosomal recessive forms of hereditary motor and sensory neuropathy
J Neurol Neurosurg Psychiatry
Connexin mutations in X-linked Charcot–Marie–Tooth disease
Science
X-linked Charcot–Marie–Tooth disease with connexin 32 mutations: clinical and electrophysiologic study
Neurology
Genetics of neuropathies
Semin Neurol
Autosomal-recessive forms of demyelinating Charcot–Marie–Tooth disease
Neuromolecular Med
Reliability of the CMT neuropathy score (second version) in Charcot–Marie–Tooth disease
J Peripher Nerv Syst
Autosomal recessive forms of Charcot–Marie–Tooth disease
Bull Acad Natl Med
A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy
Ann Neurol
The various Charcot–Marie–Tooth diseases
Curr Opin Neurol
Charcot–Marie–Tooth disease subtypes and genetic testing strategies
Ann Neurol
Charcot–Marie–Tooth disease: frequency of genetic subtypes and guidelines for genetic testing
J Neurol Neurosurg Psychiatry
Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons
Genes for hereditary sensory and autonomic neuropathies: a genotype–phenotype correlation
Brain
Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort
J Neurol
Cited by (72)
Pain Phenotypes in Rare Musculoskeletal and Neuromuscular Diseases
2021, Neuroscience and Biobehavioral ReviewsNeuronal structure in aging: Cytoskeleton in health and disease
2021, Assessments, Treatments and Modeling in Aging and Neurological Disease: The Neuroscience of AgingAn altered lipid metabolism characterizes Charcot-Marie-Tooth type 2B peripheral neuropathy
2020, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsCitation Excerpt :The CMT type 2B (CMT2B) form is a dominant, axonal form of the disease, caused by 5 missense mutations (p.L129F, p.K157N, p.N161T/I and p.V162M) in the RAB7A gene, which encodes a GTPase of the RAB family [9–12]. The CMT2B peripheral neuropathy is characterized by prominent sensory loss, progressive distal weakness leading to atrophy, reduced tendon reflexes and normal or near-normal nerve conduction velocities [6,13,14]. CMT2B is also characterized by foot deformities and high frequency of ulcers and infections leading to toe and foot amputations and, for this reason, it is also classified as an ulcero-mutilating neuropathy [6,13,14].