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Disorders In Depth

Charcot-Marie-Tooth disease - Advanced Description of Diseases

Charcot-Marie-Tooth disease (CMT) is the eponym for non-syndromic inherited neuropathies that affect motor and sensory axons of the peripheral nervous system. It is also called Hereditary Motor and Sensory Neuropathy (HMSN), and in the older literature, Peroneal Muscular Atrophy. CMT is a common disease, with an estimated prevalence of 1/2500. Depending on which axons are affected (which differs between the forms of CMT), motor, sensory, and/or autonomic function is progressively impaired. These impairments typically begin in the longest axons and progress over time, so that affected patients have weakness, sensory loss, and/or autonomic dysfunction first in the feet and lower legs, followed by the hands. The clinical onset may be as early as infancy or childhood or as late as middle age.

The genetics of CMT is complicated. Mutations in about 50 genes cause the various forms of CMT and the closely related conditions of Hereditary Motor Neuropathy (HMN) and Hereditary Sensory and Autonomic Neuropathy (HSAN). Two further complications are that different mutations in the same gene can cause different phenotypes, and that the same phenotype can be caused by mutations different genes. A unifying principle is that both the dominantly (CMT1) and the recessively (CMT4) inherited forms of demyelinating CMT are caused by mutations in genes expressed by myelinating Schwann cells. Thus, a cell autonomous effect of the mutant gene in myelinating Schwann cells caused demyelination. Similarly, with a few potential exceptions, the dominantly (CMT2) and recessively inherited forms of axonal CMT, as well as the related conditions of HMN and HSAN, are caused by mutations in neuronally expressed genes; the mutant gene has cell autonomous effects in neurons.

Classifying Hereditary Neuropathies

Beginning with the pioneering work of Dyck and colleagues, CMT was separated into type 1 and type 2 (Shy et al., 2005). CMT1 is characterized by slowed conduction velocities in motor nerves (typically 10-40 m/s in the arms) and histological evidence of segmental demyelination and remyelination, in addition to axonal loss. These findings were extended by several groups, including Harding and Thomas (Harding and Thomas, 1980), who proposed that forearm motor conduction velocities of 38 m/s separated CMT1/HMSN I from CMT2/HMSN II. Based on their analysis of patients of known genotypes, Kennerson et al. (Kennerson et al., 2001) suggested raising the cutoff to 45 m/s, and proposed using the term, Dominant-Intermediate CMT (DI-CMT), for kindreds characterized by conduction velocities that overlapped CMT1 and CMT2.

CMT1 is more common than CMT2, and the responsible mutation can be found in a much higher proportion of patients (>95% for CMT1 vs. ~25% for CMT2). Of the 968 CMT1 probands reported by Latour et al. (Latour et al., 2006), CMT1A resulting from the PMP22 duplication is by far the most common (76%), followed by CMT1X (11%) and CMT1B (6%); CMT1C (<1%), CMT1D (<1%), and CMT1A resulting from missense mutations (some kinds are called CMT1E; <1%) are all relatively rare. CMT1 with an associated tremor is termed Roussy-Lévy syndrome; the original kindred has CMT1B, but it is more commonly associated with CMT1A (Thomas et al., 1997).

CMT3, Déjérine-Sottas Neuropathy, and Congenital Hypomyelinating Neuropathy are terms used to describe individuals with severe neuropathy with a clinically recognized onset in infancy (Congenital Hypomyelinating Neuropathy; OMIM 605253) or before three years of age (Déjérine-Sottas Neuropathy, also known as CMT3/HMSN III; OMIM 145900). Many patients ultimately require wheelchairs, but some do surprisingly well (Gabreëls-Festen, 2002). Scoliosis and hearing loss are frequent components of the clinical picture. Motor nerve conduction velocities are typically very slow (<10 m/s), with marked temporal dispersion but no conduction block. Nerves are often enlarged, and biopsies often reveal prominent “onion bulbs” (supernumerary Schwann cells that surround axons) and a complete absence of fibers containing normal/thick myelin sheaths; in most cases, axons have inappropriately thin myelin sheaths for the axonal caliber and/or are segmentally demyelinated. Historically, Déjérine-Sottas neuropathy was thought to be recessively inherited, but new, dominant mutations in MPZ and PMP22 are the commonest causes (Tyson et al., 1997; Gabreëls-Festen, 2002); rarer causes include dominant mutations of EGR2 as well as recessive mutations of MPZ, PMP22, PRX, EGR2, and FIG4. Because mutations have not been identified in some cases, other genetic causes remain to be discovered.

HSAN includes disorders that predominantly affects sensory and autonomic neurons and/or their axons. HMN includes various disorders that affect motor axons in a length-dependent manner. The apt term, “severe, early-onset axonal neuropathy”, has been proposed for the forms of CMT that fit this description (Nicholson et al., 2008), including many cases caused by dominant MFN2 mutations as well as several autosomal recessive forms of CMT2.

Please use the links in the right side menu: Each genetic disorder is discussed in groups.

Comments are based on the primary literature, as well as the following websites:

I apologize for any mistakes or unclear statements, and for not referencing more original papers. Please contact me with your questions, comments, and concerns (sscherer@mail.med.upenn.edu).

 

References

Gabreëls-Festen A (2002) Dejerine-Sottas syndrome grown to maturity: overview of genetic and morphological heterogeneity and follow-up of 25 patients. J Anat 200:341-356.

Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103:259-280.

Kennerson ML, Zhu D, Gardner RJM, Storey E, Merory J, Robertson SP, Nicholson GA (2001) Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2. Amer J Hum Genet 69:883-888.

Latour P, Gonnaud PM, Ollagnon E, Chan V, Perelman S, Stojkovic T, Stoll C, Vial C, Ziegler F, Vandenberghe A, Maire I (2006) SIMPLE mutation analysis in dominant demyelinating Charcot-Marie-Tooth disease: three novel mutations. J Peripher Nerv Syst 11:148-155.

Nicholson GA, Magdelaine C, Zhu D, Grew S, Ryan MM, Sturtz F, Vallat JM, Ouvrier RA (2008) Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations. Neurology 70:1678-1681.

Shy ME, Lupski JR, Chance PF, Klein CJ, Dyck PJ (2005) Hereditary motor and sensory neuropathies: an overview of clinical, genetic, electrophysiologic, and pathologic features. In: Peripheral Neuropathy, 4th Edition (Dyck PJ, Thomas PK, eds), pp 1623-1658. Philadelphia: Saunders.

Thomas PK, Marques W, Davis MB, Sweeney MG, King RHM, Bradley JL, Muddle JR, Tyson J, Malcolm S, Harding AE (1997) The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 120:465-478.

Tyson J, Ellis D, Fairbrother U, King RHM, Muntoni F, Jacobs J, Malcolm S, Harding AE, Thomas PK (1997) Hereditary demyelinating neuropathy of infancy - A genetically complex syndrome. Brain 120:47-63.