Elsevier

Neuroscience Letters

Volume 596, 2 June 2015, Pages 14-26
Neuroscience Letters

Review
Demyelinating CMT–what’s known, what’s new and what’s in store?

https://doi.org/10.1016/j.neulet.2015.01.059Get rights and content

Highlights

  • Charcot–Marie–Tooth disease is common affecting 1 in 2500 people.

  • Demyelination is observed in two major groups – CMT1 and CMT4.

  • CMT1A remains the most commonly described CMT across all populations.

  • CMT4 is typically severe with early onset and associated features, such as scoliosis.

  • Recent molecular advances have improved our understanding of demyelinating CMT.

Abstract

Inherited neuropathies known collectively as Charcot–Marie–Tooth disease are one of the most common inherited neurological conditions affecting ∼1 in 2500 people. A heterogenous disorder, CMT is divided into subtypes based on the pattern of inheritance and also by neurophysiological studies. Despite the clinical similarities among patients with demyelinating CMT, it is recognized that this group of disorders is both genetically and phenotypically heterogenous.

Understanding the pathogenesis of these disorders requires an intimate knowledge of normal myelin development and homeostasis. Improvements in genetic testing techniques over the last 20 years have contributed majorly to the identification of specific genes, proteins, and molecular pathways that are providing the basis for understanding the disease processes and developing rational approaches to therapy.

Introduction

Named after the three physicians who initially characterized this disorder in the late 19th century Charcot–Marie–Tooth disease (CMT) is the most common inherited neurological condition with a prevalence of around 1:2500 [1], [2], [3]. This group of neuropathies is also referred to as hereditary motor and sensory neuropathies, hereditary motor neuropathies, or hereditary sensory and autonomic neuropathies depending on the clinical manifestation. A heterogenous disorder, CMT is divided into subtypes based on the pattern of inheritance and also by neurophysiological studies (Table 1). Subtypes include AD demyelinating (CMT1), AD axonal (CMT2), AR (CMT4), and X-linked (CMTX) [4]. CMT1 typically has slow nerve conduction velocities (less than 38 m/s in the upper extremities) and pathological evidence of a hypertrophic demyelinating neuropathy whereas, CMT2 has relatively normal nerve conduction velocities with evidence of axonal degeneration [5]. Neurophysiology studies have also identified another group, CMT intermediate, with nerve conduction demonstrating intermediate velocities (less than and greater than 38 m/s). The discovery of causal genes has led to the modification of the classification of CMT further to now include the gene. The groups e.g., CMT1, CMT2, and CMTX, as outlined in Table 1 remain, but letters have been added to incorporate the specific gene that causes the disorder. Each type of CMT is now subdivided according to the specific genetic cause of the neuropathy (see Table 2). For example, the most common form of CMT1, termed CMT1A, is caused by a duplication of a fragment of chromosome 17 containing the peripheral myelin protein 22-kD (PMP22) gene while CMT1B is caused by mutations in the myelin protein zero (MPZ) gene [6], [7]. Currently mutations in more than 80 genes have been identified as causes of inherited neuropathies. Prevalence studies suggest that a genetic diagnosis is reached in approximately 65% of all CMT patients. Approximately 90% of these genetically stratified patients will have a mutation in one of four genes: PMP22, GJB1, MPZ, and MFN2 [8], [9], [10] and therefore, these four subtypes are well represented in treatment development approaches. Despite advances in genetic testing however, ∼35% of all CMT patients remain without a molecular diagnosis.

The clinical hallmarks of CMT include distal muscle weakness and wasting, loss of proprioception and pinprick sensation and a classical steppage gait with foot deformities, such as pes planus or cavus (see Fig. 1). The age of onset can vary from infancy to late adulthood with clinical severity ranging from mild to severe. A minority of CMT patients have a more severe phenotype with delayed motor milestones and onset in infancy, termed Déjèrine–Sottas neuropathy. Especially severe cases are classified as congenital hypomyelination if myelination appears to be disrupted during embryologic development. Many of these patients have de novo autosomal dominant disorders, and the term Déjèrine–Sottas neuropathy is now currently used primarily to denote severe early-onset clinical phenotypes regardless of the inheritance pattern.

This review will focus on the demyelinating group of CMTs. We will discuss the biological background and recent advances in diagnosis and molecular understanding that further contribute to the discovery of the pathogenic processes at play in demyelinating CMT. We will also discuss evolving treatment strategies in this particular group of inherited neuropathies.

Section snippets

Biological background of schwann cells and myelination

Most peripheral nerves are mixed sensory and motor axons that are ensheathed along their length by Schwann cells (see Fig. 2). Schwann cells that establish a one-to-one association with an axon initiate the program of myelination and become myelinating Schwann cells [11]. In contrast Schwann cells that do not establish this relationship with an axon do not activate the program of myelin gene expression and become non-myelinating Schwann cells [12]. Typically myelinating Schwann cells surround

Conclusion

The study of genetic demyelinating neuropathy together with the sequential description of new genetic causes of the demyelinating CMTs has contributed majorly to the understanding of myelin development and maintenance. Investigating CMT has led to the description of several key genes and proteins together with the functional relevance of many others. This evolving knowledge is providing a sound basis for developing treatment strategies in some of the commoner demyelinating inherited

Acknowlegements

Our work is supported by grants including INC RDCRC (U54NS065712) supported by NINDS/ORDRS, NCATS, and R01NS075764 from NINDS. We also receive research grants from the Muscular Dystrophy Association (MDA) and Charcot Marie Tooth Association (CMTA).

References (147)

  • M. Khajavi et al.

    Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy

    Am. J. Hum. Genet.

    (2007)
  • M. Pennuto et al.

    Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot–Marie–Tooth 1B mice

    Neuron

    (2008)
  • M. Russo et al.

    Variable phenotypes are associated with PMP22 missense mutations

    Neuromuscular Disord.

    (2011)
  • I.V. Mersiyanova et al.

    A new variant of Charcot–Marie–Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene

    Am. J. Hum. Genet.

    (2000)
  • P.F. Chance et al.

    DNA deletion associated with hereditary neuropathy with liability to pressure palsies

    Cell

    (1993)
  • S.M. Murphy et al.

    X inactivation in females with X-linked Charcot–Marie–Tooth disease

    Neuromuscular Disord.

    (2012)
  • K.A. Kleopa et al.

    How do mutations in GJB1 cause X-linked Charcot–Marie–Tooth disease?

    Brain Res.

    (2012)
  • C.K. Abrams et al.

    Mutations in Connexin 32: the molecular and biophysical bases for the X-linked form of Charcot–Marie–Tooth disease

    Brain Res. – Brain Res. Rev.

    (2000)
  • C. Siskind et al.

    Persistent CNS dysfunction in a boy with CMT1X

    J. Neurol. Sci.

    (2009)
  • H. Skre

    Genetic and clinical aspects of Charcot–Marie–Tooth’s disease

    Clin. Genet.

    (1974)
  • J.M.P. Charcot

    Sur une forme particulaire d’atrophie musculaire progressive souvent familial debutant par les pieds et les jamber et atteingnant plus tard les mains

    Rev. Med.

    (1886)
  • H. Tooth

    The Peroneal Type of Progressive Muscular Atrophy

    (1886)
  • A.E. Harding et al.

    Genetic aspects of hereditary motor and sensory neuropathy (types I and II)

    J. Med. Genet.

    (1980)
  • A.E. Harding et al.

    The clinical features of hereditary motor and sensory neuropathy types I and II

    Brain

    (1980)
  • K. Hayasaka et al.

    Charcot–Marie–Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene

    Nat. Genet.

    (1993)
  • P. Latour et al.

    SIMPLE mutation analysis in dominant demyelinating Charcot–Marie–Tooth disease: three novel mutations

    J. Peripheral Nerv. Syst.

    (2006)
  • A.S. Saporta et al.

    Charcot–Marie–Tooth disease subtypes and genetic testing strategies

    Ann. Neurol.

    (2011)
  • S.M. Murphy et al.

    Charcot–Marie–Tooth disease: frequency of genetic subtypes and guidelines for genetic testing

    J. Neurol. Neurosurg. Psychiatry

    (2012)
  • S.S. Scherer

    The biology and pathobiology of Schwann cells

    Curr. Opin. Neurol.

    (1997)
  • R. Mirsky et al.

    Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation

    J. Peripheral Nerv. Syst.

    (2008)
  • K.R. Jessen et al.

    The origin and development of glial cells in peripheral nerves

    Nat. Rev. Neurosci.

    (2005)
  • C. Birchmeier et al.

    Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation

    GLIA

    (2008)
  • G.V. Michailov et al.

    Axonal neuregulin-1 regulates myelin sheath thickness

    Science

    (2004)
  • A.N. Garratt et al.

    A dual role of erbB2 in myelination and in expansion of the schwann cell precursor pool

    J. Cell Biol.

    (2000)
  • L. Decker et al.

    Peripheral myelin maintenance is a dynamic process requiring constant Krox20 expression

    J. Neurosci.

    (2006)
  • K. Hirata et al.

    Myelin phagocytosis by macrophages and nonmacrophages during Wallerian degeneration

    Microsc. Res. Tech.

    (2002)
  • A. Woodhoo et al.

    Schwann cell precursors: a favourable cell for myelin repair in the Central Nervous System

    Brain

    (2007)
  • A. Woodhoo et al.

    Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity

    Nat. Neurosci.

    (2009)
  • E.J. Arroyo et al.

    On the molecular architecture of myelinated fibers

    Histochem. Cell Biol.

    (2000)
  • A. Niemann et al.

    Pathomechanisms of mutant proteins in Charcot–Marie–Tooth disease

    NeuroMol. Med.

    (2006)
  • M.A. Saporta et al.

    MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot–Marie–Tooth disease type 1B

    Brain

    (2012)
  • I.P. Blair et al.

    Prevalence and origin of de novo duplications in Charcot–Marie–Tooth disease type 1A: first report of a de novo duplication with a maternal origin

    Am. J. Hum. Genet.

    (1996)
  • I. Katona et al.

    PMP22 expression in dermal nerve myelin from patients with CMT1A

    Brain

    (2009)
  • S.W. Jang et al.

    Identification of drug modulators targeting gene-dosage disease CMT1A

    ACS Chem. Biol. [Electron. Resour.]

    (2012)
  • E.A. Jones et al.

    Regulation of the PMP22 gene through an intronic enhancer

    J. Neurosci.

    (2011)
  • Y.K. Shin et al.

    Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib-induced peripheral neuropathy

    Glia

    (2011)
  • E. Nelis et al.

    Estimation of the mutation frequencies in Charcot–Marie–Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study

    Eur. J. Hum. Genet.

    (1996)
  • D. D’Urso et al.

    Protein zero of peripheral nerve myelin: biosynthesis, membrane insertion, and evidence for homotypic interaction

    Neuron

    (1990)
  • M.T. Filbin et al.

    Role of myelin P0 protein as a homophilic adhesion molecule

    Nature

    (1990)
  • M.E. Shy et al.

    Phenotypic clustering in MPZ mutations

    Brain

    (2004)
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