Charcot-Marie-Tooth disease

Last update: December 6, 2018

Recommended panel testing at Breda Genetics for this condition:

Charcot-Marie-Tooth neuropathy (AARS, ABHD12, AIFM1, ARHGEF10, ATP1A1, ATP7A, BAG3, BSCL2, CNTNAP1, COA7, COX6A1, DCTN1, DCTN2, DGAT2, DHTKD1, DNAJB2, DNM2, DNMT1, DRP2, DYNC1H1, EGR2, FGD4, FIG4, GARS, GDAP1, GJB1, GNB4, HARS, HINT1, HK1, HSPB1, HSPB3, HSPB8, IGHMBP2, INF2, JPH1, KARS, KIF1B, KIF5A, LITAF, LMNA, LRSAM1, MARS, MCM3AP, MED25, MFN2, MME, MORC2, MPV17, MPZ, MTMR2, NAGLU, NDRG1, NEFH, NEFL, PDK3, PLEKHG5, PMP22, PRPS1, PRX, PTRH2, RAB7A, SBF1, SBF2, SCO2, SETX, SGPL1, SH3TC2, SIGMAR1, SPG11, SPTLC1, TRIM2, TRPV4, VCP, WARS, YARS)

Summary

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogenous group of disorders characterized by chronic motor and sensory neuropathy due to progressive degeneration of peripheral nerves.

Detailed clinical description

Affected individuals usually become symptomatic between the ages of 5 and 15 years, manifesting symmetric, slowly progressive distal motor neuropathy of the limbs. Patients initially present with difficulty walking due to progressive weakness and atrophy of the distal leg muscles, resulting in foot drop and steppage gait. Other features include progressive foot deformity (pes cavus), weak ankle dorsiflexion, and depressed tendon reflexes. Weakness of the hand muscles usually occurs later in the course of the disease. Muscle weakness is often associated to loss of sensation in the hands and feet. Severity is highly variable, with some mutation-positive individuals being asymptomatic until adult life.

CMT is the most common inherited disorder of the peripheral nervous system, with an estimated prevalence of 1 in 2,500 individuals.

The traditional classification was based on clinical and neurophysiological evidence (i.e. nerve conduction velocity, NCV), and mode of inheritance. On the basis of NCV studies, CMT neuropathy was classified as demyelinating (CMT1, NVS < 35m/s), axonal (CMT2, NCV >45m/s), and dominant intermediate (DI-CMT NCV 35-45 m/s). In general, individuals with axonal neuropathy tend to be less disabled and have less sensory loss than individuals with demyelinating neuropathy. However, due to extensive clinical overlap of neuropathy phenotypes and modes of inheritance, this historical classification has been recently revised with the proposal of a gene-based classification.

Due to the high similarity of CMT with distal hereditary motor neuronopathies and distal spinal muscular atrophy, it has been suggested that these disorders should not be classified as separate entities.

Molecular genetics

The most common molecular defect leading to CMT is a duplication of 1.5 Mb at 17p11.2 encopassing the whole PMP22 gene. The deletion of the same region causes a distinct syndrome known as hereditary neuropathy with liability to pressure palsies.

Currently, mutations in more than 80 genes have been associated to CMT disease. Autosomal dominant, autosomal recessive, and X-linked forms have been described. The full list of genes currently associated to CMT is included in the Charcot-Marie-Tooth panel available at Breda Genetics.

Differential diagnosis

CMT disease may show clinical overlap with other disorders, in which distal neuropathy may be a presenting feature. These include:

–  multisystemic disorders with neuropathy, such as metachromatic leukodystrophy, or oculocerebrorenal syndrome of Lowe. In these disorders other clinical features not present in classic CMT disease are predominant (e.g. intellectual disability, cognitive deterioration, epilepsy, etc), thus suggesting a different diagnosis;

–  other hereditary neuropathies: for instance, Friedreich ataxia, which may include sensory loss, visual defects, scoliosis, and cardiomyopathy; adrenoleukodystrophy, characterized by sphincter and sexual dysfunction, and adrenal insufficiency; Refsum disease, characterized by early-onset retinitis pigmentosa;

–  hereditary sensory neuropathies, with or without autonomic involvement, characterized by progressively reduced sensation to pain, temperature and touch (see “Hereditary sensory and autonomic neuropathies” card);

–  distal myopathies, in which NCV is normal and muscle biopsy shows myopathic changes. Examples include Nonaka myopathy or Miyoshi early-adult-onset myopathy.

Recommended testing strategy

As PMP22 duplication accounts for about 50% of all CMT cases, it is recommended to proceed with PMP22 gene deletion/duplication testing as first-tier screening in affected individuals (recommneded testing at Breda Genetics: MLPA GENE: PMP22). The next step consists in analyzing a panel of genes that have been associated to CMT by means of next generation sequencing. Breda Genetics offers CMT genes in panels based on either mendeliome, exome or full genome sequencing. If the panel is negative, one may proceed to an add-on panel to test the genes included in the differential diagnosis or to the upgrade of the analysis of all data from exome or genome sequencing.

Recommended panel testing at Breda Genetics for this condition:

Charcot-Marie-Tooth neuropathy (AARS, ABHD12, AIFM1, ARHGEF10, ATP1A1, ATP7A, BAG3, BSCL2, CNTNAP1, COA7, COX6A1, DCTN1, DCTN2, DGAT2, DHTKD1, DNAJB2, DNM2, DNMT1, DRP2, DYNC1H1, EGR2, FGD4, FIG4, GARS, GDAP1, GJB1, GNB4, HARS, HINT1, HK1, HSPB1, HSPB3, HSPB8, IGHMBP2, INF2, JPH1, KARS, KIF1B, KIF5A, LITAF, LMNA, LRSAM1, MARS, MCM3AP, MED25, MFN2, MME, MORC2, MPV17, MPZ, MTMR2, NAGLU, NDRG1, NEFH, NEFL, PDK3, PLEKHG5, PMP22, PRPS1, PRX, PTRH2, RAB7A, SBF1, SBF2, SCO2, SETX, SGPL1, SH3TC2, SIGMAR1, SPG11, SPTLC1, TRIM2, TRPV4, VCP, WARS, YARS)

References:

Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. Bird TD. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 1998 Sep 28 [updated 2018 Jun 28]. PMID: 20301532

Updating the classification of inherited neuropathies: Results of an international survey. Magy L, Mathis S, Le Masson G, Goizet C, Tazir M, Vallat JM. Neurology. 2018 Mar 6;90(10):e870-e876. PMID: 29429969

Genetic heterogeneity of motor neuropathies. Bansagi B, Griffin H, Whittaker RG, Antoniadi T, Evangelista T, Miller J, Greenslade M, Forester N, Duff J, Bradshaw A, Kleinle S, Boczonadi V, Steele H, Ramesh V, Franko E, Pyle A, Lochmüller H, Chinnery PF, Horvath R. Neurology. 2017 Mar 28;88(13):1226-1234. PMID: 28251916

Hereditary neuropathies: An update. Stojkovic T. Rev Neurol (Paris). 2016 Dec;172(12):775-778. PMID: 27866730

Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease. Cornett KM, Menezes MP, Bray P, Halaki M, Shy RR, Yum SW, Estilow T, Moroni I, Foscan M, Pagliano E, Pareyson D, Laurá M, Bhandari T, Muntoni F, Reilly MM, Finkel RS, Sowden J, Eichinger KJ, Herrmann DN, Shy ME, Burns J; Inherited Neuropathies Consortium. JAMA Neurol. 2016 Jun 1;73(6):645-51. PMID: 27043305 

Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease. Cornett KM, Menezes MP, Bray P, Halaki M, Shy RR, Yum SW, Estilow T, Moroni I, Foscan M, Pagliano E, Pareyson D, Laurá M, Bhandari T, Muntoni F, Reilly MM, Finkel RS, Sowden J, Eichinger KJ, Herrmann DN, Shy ME, Burns J; Inherited Neuropathies Consortium. JAMA Neurol. 2016 Jun 1;73(6):645-51. PMID: 28796392

Chaperonopathies: Spotlight on Hereditary Motor Neuropathies. Lupo V, Aguado C, Knecht E, Espinós C. Front Mol Biosci. 2016 Dec 14;3:81. PMID: 28018906

OMIM: 118220118200

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