ReviewDemyelinating CMT–what’s known, what’s new and what’s in store?
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)
- et al.
DNA duplication associated with Charcot–Marie–Tooth disease type 1A
Cell
(1991) - et al.
Schwann cell development, differentiation and myelination
Curr. Opin. Neurobiol.
(1996) - et al.
Neuregulin-1 type III determines the ensheathment fate of axons
Neuron
(2005) - et al.
EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression
Neuron
(2001) Polarized domains of myelinated axons
Neuron
(2003)- et al.
Hereditary motor and sensory neuropathies: understanding molecular pathogenesis could lead to future treatment strategies
Biochim. Biophys. Acta
(2015) - et al.
The hereditary motor and sensory neuropathies: an overview of the clinical, genetic, electrophysiologic and pathlogic features
- et al.
Myelin synthesis in the peripheral nervous system
Prog. Neurobiol.
(2000) - et al.
Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin
Neuron
(1996) - et al.
Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants
Am. J. Hum. Genet.
(2005)
Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy
Am. J. Hum. Genet.
Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot–Marie–Tooth 1B mice
Neuron
Variable phenotypes are associated with PMP22 missense mutations
Neuromuscular Disord.
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.
DNA deletion associated with hereditary neuropathy with liability to pressure palsies
Cell
X inactivation in females with X-linked Charcot–Marie–Tooth disease
Neuromuscular Disord.
How do mutations in GJB1 cause X-linked Charcot–Marie–Tooth disease?
Brain Res.
Mutations in Connexin 32: the molecular and biophysical bases for the X-linked form of Charcot–Marie–Tooth disease
Brain Res. – Brain Res. Rev.
Persistent CNS dysfunction in a boy with CMT1X
J. Neurol. Sci.
Genetic and clinical aspects of Charcot–Marie–Tooth’s disease
Clin. Genet.
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.
The Peroneal Type of Progressive Muscular Atrophy
Genetic aspects of hereditary motor and sensory neuropathy (types I and II)
J. Med. Genet.
The clinical features of hereditary motor and sensory neuropathy types I and II
Brain
Charcot–Marie–Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene
Nat. Genet.
SIMPLE mutation analysis in dominant demyelinating Charcot–Marie–Tooth disease: three novel mutations
J. Peripheral Nerv. Syst.
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
The biology and pathobiology of Schwann cells
Curr. Opin. Neurol.
Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation
J. Peripheral Nerv. Syst.
The origin and development of glial cells in peripheral nerves
Nat. Rev. Neurosci.
Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation
GLIA
Axonal neuregulin-1 regulates myelin sheath thickness
Science
A dual role of erbB2 in myelination and in expansion of the schwann cell precursor pool
J. Cell Biol.
Peripheral myelin maintenance is a dynamic process requiring constant Krox20 expression
J. Neurosci.
Myelin phagocytosis by macrophages and nonmacrophages during Wallerian degeneration
Microsc. Res. Tech.
Schwann cell precursors: a favourable cell for myelin repair in the Central Nervous System
Brain
Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity
Nat. Neurosci.
On the molecular architecture of myelinated fibers
Histochem. Cell Biol.
Pathomechanisms of mutant proteins in Charcot–Marie–Tooth disease
NeuroMol. Med.
MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot–Marie–Tooth disease type 1B
Brain
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.
PMP22 expression in dermal nerve myelin from patients with CMT1A
Brain
Identification of drug modulators targeting gene-dosage disease CMT1A
ACS Chem. Biol. [Electron. Resour.]
Regulation of the PMP22 gene through an intronic enhancer
J. Neurosci.
Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib-induced peripheral neuropathy
Glia
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.
Protein zero of peripheral nerve myelin: biosynthesis, membrane insertion, and evidence for homotypic interaction
Neuron
Role of myelin P0 protein as a homophilic adhesion molecule
Nature
Phenotypic clustering in MPZ mutations
Brain
Cited by (47)
How T118M peripheral myelin protein 22 predisposes humans to Charcot–Marie–Tooth disease
2023, Journal of Biological ChemistryMechanisms and Treatments in Demyelinating CMT
2021, NeurotherapeuticsNew evidence for secondary axonal degeneration in demyelinating neuropathies
2021, Neuroscience LettersCitation Excerpt :Several EGR2 point mutations have been identified and they are predominantly localized to one of the three zinc finger domains of the protein which confer DNA binding [73,194]. Patient histological and electrophysiological evaluation reveals myelin deficits including loss of myelinated fibers, myelin sheaths ranging from thin to nearly absent, de- and remyelination, variable onion bulb formation, irregularly folded myelin sheaths and slowed NCV [73] (Supplemental Table 1). EGR2 is a SC transcription factor that regulates expression of essential myelin genes (PMP22, gap junction protein beta 1 (GJB1), PRX and indirectly MPZ) and CMT1D mutations have been suggested to be pathogenic due to disrupted DNA binding and transcriptional activation [73].
Disease Progression in Charcot–Marie–Tooth Disease Related to MPZ Mutations: A Longitudinal Study
2023, Annals of NeurologyGlial TGFβ activity promotes neuron survival in peripheral nerves
2023, Journal of Cell BiologyA novel mouse model of CMT1B identifies hyperglycosylation as a new pathogenetic mechanism
2022, Human Molecular Genetics