Charcot-Marie-Tooth Hereditary Neuropathy Overview

[CMT]

Clinical Manifestations

Charcot-Marie-Tooth (CMT) hereditary neuropathy (also called hereditary motor/sensory neuropathy [HMSN]) results from involvement of peripheral nerves that can affect the motor system and/or the sensory system. Individuals with CMT experience symmetric, slowly progressive distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands. Pes cavus foot deformity is common.

Although usually described as "painless," the neuropathy of CMT can be painful [Carter et al 1998].

Other findings can include hearing loss and hip dysplasia, which may be an under-recognized manifestation of CMT [McGann & Gurd 2002].

Establishing the Diagnosis of CMT

Progressive weakness of the distal muscles in the feet and/or hands is evident on medical history.

Individuals with typical CMT have high-arched feet, weak ankle dorsiflexion, thin distal muscles, depressed tendon reflexes, and distal sensory loss.

Electrophysiologic studies (electromyography [EMG] and nerve conduction velocity [NCV]), when carefully done, are almost always abnormal [Carter et al 2004, Pareyson et al 2006a].

Sural nerve biopsy is not routinely performed, but is occasionally helpful in establishing the diagnosis of CMT hereditary neuropathy because relatively characteristic lesions are found in CMT1, leprosy, vasculitis, and amyloid neuropathy [Schroder 2006].

Differential Diagnosis of CMT

Causes of acquired peripheral neuropathy include alcoholism, vitamin B12 deficiency, thyroid disease, diabetes mellitus, HIV infection, vasculitis, leprosy, neurosyphilis, amyloid deposition associated with chronic inflammation, occult neoplasm, heavy metal intoxication, and inflammatory and immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP).

Blindness, seizures, dementia, and mental retardation are not part of the CMT hereditary neuropathy phenotype and suggest a different diagnosis.

Autosomal dominant disorders with neuropathy

• Familial brachial plexus neuropathy (hereditary neuralgic amyotrophy). Affected individuals have sudden onset of pain and weakness in the shoulder or upper arm associated with distal and/or proximal weakness and atrophy of the upper extremity. Associated sensory loss may occur. Onset frequently occurs in childhood but can occur at any age. Partial or full recovery is typical. The syndrome may recur in the same or opposite limb and occasionally in the lower extremity. In some families, associated clinical features include short stature, ocular hypotelorism, cleft palate, epicanthal folds, facial asymmetry, and partial syndactyly [Jeannet et al 2001]. Mutations in the SEPT9 gene are causative [Kuhlenbaumer et al 2005].

• Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by the acute onset of recurrent, painless, focal sensorimotor neuropathy in a single nerve [Kumar et al 2002]. Deletion of one PMP22 gene is causative.

• Amyloid neuropathies, including transthyretin-associated amyloidosis, result in progressive accumulation of amyloid protein in peripheral nerves [Lynch & Chance 1997].

Autosomal recessive disorders with neuropathy

• Refsum disease

• Metachromatic leukodystrophy

• Krabbe disease

X-linked recessive disorders with neuropathy

• Adrenomyeloneuropathy

• Pelizaeus-Merzbacher disease

• Lowe syndrome

Hereditary ataxias with neuropathy. Friedreich ataxia may present with sensory loss, depressed tendon reflexes, and high-arched feet.

Other hereditary ataxias sometimes have an associated peripheral neuropathy (see Ataxia Overview).

Hereditary motor neuropathies (HMN) are associated with distal weakness without sensory loss [Irobi et al 2004, Auer-Grumbach et al 2005].

CMT syndrome with spasticity. Some individuals with distal muscle atrophy and weakness may have signs of spasticity with brisk tendon reflexes and/or Babinski responses. This set of findings has been called HMSN V and sometimes overlaps with hereditary motor neuropathy (HMN).

One type is associated with mutations in BSCL2 (see BSCL2-Related Neurologic Disorders) and another with mutations in SPG20, the gene encoding spartin (see Troyer Syndrome.

See also Hereditary Spastic Paraplegia Overview.

Hereditary sensory neuropathies (HSN). Several autosomal dominant axonal neuropathies have primarily sensory symptoms (one family is described as having "burning feet syndrome" [Stogbauer et al 1999]), and are classified as hereditary sensory neuropathies (HSNs) [Auer-Grumbach et al 2003]. Distal weakness may also occur.

Distal myopathies. See Table 1.

Mitochondrial disorders associated with peripheral neuropathy

• NARP (neuropathy, ataxia, and retinitis pigmentosa): A mitochondrial disorder caused by mutations in mitochondrial DNA (mtDNA)

• MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) [Said et al 2005].

See also Mitochondrial Disorders Overview.

Prevalence

Charcot-Marie-Tooth (CMT) hereditary neuropathy is the most common genetic cause of neuropathy. Prevalence is about 1:3,300.

Approximately 20% of all individuals presenting to neuromuscular clinics with a chronic peripheral neuropathy have CMT1A.

Single-Gene Causes

The classification used in this GeneReview is based on inheritance patterns and molecular genetics (see Table 2). However, classification is especially difficult when different mutations in a single gene are associated with both autosomal dominant and autosomal recessive inheritance, and/or both axonal and demyelinating neuropathy.

Vance [2000] suggested a similar classification system that differs slightly, with CMT3 referring to axonal presentations that are autosomal recessive and CMT4 referring to demyelinating presentations that are autosomal recessive.

Other valid classification systems may emphasize electrophysiologic characteristics such as nerve conduction velocities or pathologic findings.

The molecular genetics of CMT has been reviewed by Carter et al [2004], Houlden & Reilly [2006], Kleopa & Scherer [2006], and Nicholson [2006], and the molecular pathogenesis has been reviewed by Bernard et al [2006] and Zuchner & Vance [2006].

Charcot Marie Tooth Type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity (typically 5-30 meters per second; normal: >40-45 m/s). It is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually become symptomatic between ages five and 25 years. Fewer than 5% of individuals become wheelchair dependent. Life span is not shortened.

The six subtypes of CMT1 are clinically indistinguishable and are designated solely on molecular findings [Saifi et al 2003] (Table 3).

Table 3. CMT1: Molecular Genetics

Locus Name	Proportion of CMT1	Gene Symbol	Protein Product	Test Availability
CMT1A	70%-80%	PMP22	Peripheral myelin protein 22	Clinical
CMT1B	5%-10%	MPZ	Myelin P0 protein	Clinical
CMT1C	Unknown	LITAF	Lipopolysaccharide-induced tumor necrosis factor-alpha factor	Clinical
CMT1D	Unknown	EGR2	Early growth response protein 2	Clinical
CMT1E	Unknown	PMP22	Peripheral myelin protein 22	Clinical
CMT1F/2E	Unknown	NEFL	Neurofilament light polypeptide	Clinical

Charcot Marie Tooth Type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy. Nerve conduction velocities are usually within the normal range; however, occasionally they fall in the low-normal or mildly abnormal range (35-48 m/s). Peripheral nerves are not enlarged or hypertrophic.

CMT2 shows extensive clinical overlap with CMT1; however, in general, individuals with CMT2 tend to be less disabled and have less sensory loss than individuals with CMT1. A threshold of 38 m/s for median motor nerve conduction is often used clinically to distinguish CMT1 from CMT2.

CMTX1 may present with a relatively axonal form of CMT that may be confused with CMT2.

The fifteen subtypes of CMT2 are similar clinically and are distinguished by molecular genetic findings (Table 4).

Table 4. CMT2: Molecular Genetics

Locus Name	Proportion of CMT2	Gene Symbol	Chromosomal Locus 1	Protein Product	Test Availability
CMT2A1	Unknown 2	KIF1B		Kinesin-like protein KIF1B	Clinical
CMT2A2		MFN2		Mitofusin-2	Clinical
CMT2B		RAB7		Ras-related protein Rab-7	Clinical
CMT2B1		LMNA		Lamin A/C	Clinical
CMT2B2		Unknown	19q13.3	Unknown	Research only
CMT2C		Unknown	12q23-q24	Unknown
CMT2D		GARS		Glycyl-tRNA synthetase	Clinical
CMT2E/1F		NEFL	8p21	Neurofilament light polypeptide	Clinical
CMT2F		HSPB1		Heat-shock protein beta-1	Clinical
CMT2G		Unknown	12q12-q13	Unknown	Research only
CMT2H			Unknown
CMT2I		MPZ		Myelin P0 protein	Clinical
CMT2J					Clinical
CMT2K		GDAP1		Ganglioside-induced differentiation-associated protein-1	Clinical
CMT2L		HSPB8		Heat-shock protein beta-8	Clinical

1. Chromosomal locus included only when gene is unknown

2. The frequencies of the various types of CMT2 are unknown and no single type is known to predominate [Timmerman et al 1996, Saifi et al 2003].

Autosomal Dominant Intermediate CMT

Autosomal dominant intermediate CMT (DI-CMT) (Table 5) is characterized by a relatively typical CMT phenotype with clinical and pathologic evidence of both abnormal myelin and axonopathy. Nerve conduction velocities (NCVs) overlap those observed in CMT1 and CMT2 [Nicholson & Myers 2006]. Motor NCVs usually range between 25 and 50 m/sec.

Charcot-Marie-Tooth type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies. It is distinguished from other forms of CMT by autosomal recessive inheritance (see Table 6). Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity.

Note: The term Dejerine-Sottas syndrome (DSS) was originally described as a severe demyelinating neuropathy of infancy and childhood associated with very slow NCV, elevated CSF protein, marked clinical weakness, and hypertrophic nerves with onion bulb formation. Inheritance of DSS was assumed to be autosomal recessive. Subsequently, individuals with this clinical diagnosis have had various types of autosomal recessive CMT (CMT4) and have been heterozygous for point mutations in genes associated with CMT1 including: PMP22 (CMT1A), MPZ (CMT1B), and EGR2 (CMT1D) [Boerkoel et al 2001a, Boerkoel et al 2001b].

Although the term DSS is still sometimes used to indicate a clinical phenotype, it does not imply an inheritance pattern or a specific genetic defect [Parman et al 2004].

Table 6. CMT 4: Molecular Genetics

Locus Name	Proportion of CMT4	Gene Symbol	Protein Product	Test Availability
CMT4A	Unknown	GDAP1	Ganglioside-induced differentiation-associated protein 1	Clinical
CMT4B1		MTMR2	Myotubularin-related protein 2	Research only
CMT4B2		SBF2	Myotubularin-related protein 13
CMT4C		SH3TC2	SH3 domain and tetratricopeptide repeats-containing protein 2	Clinical
CMT4D		NDRG1	Protein NDRG1	Clinical
CMT4E 1		EGR2	Early growth response protein 2	Clinical
CMT4F 1		PRX	Periaxin	Clinical
CMT4H		FGD4	FYVE, RhoGEF and PH domain-containing protein 4	Clinical
CMT4J		FIG4	Phosphatidylinositol 3, 5 biphosphate	Research only

1. Tentative name

X-Linked CMT

Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is characterized by a moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families (see Table 7).

Four other forms of hereditary neuropathy have been linked to the X chromosome. None of the genes has been identified. Associated findings are [Huttner et al 2006]:

• CMTX2. Mental retardation [Ionasescu et al 1991, Ionasescu et al 1992]

• CMTX3. Spasticity and pyramidal tract signs [Ionasescu et al 1991, Ionasescu et al 1992, Huttner et al 2006]

• CMTX4 (Cowchock syndrome). Deafness and mental retardation [Cowchock et al 1985, Priest et al 1995]

• CMTX5 with deafness and optic neuropathy maps to Xq22-q24 [Kim et al 2005]. Mutations in PRPS1 (p.Glu43Asp, p.Met115Thr) have been found in two American/European and Korean families. The gene encodes ribose-phosphate pyrophosphokinase 1, an enzyme critical for nucleotide biosynthesis [Kim et al 2007].

Table 7. CMTX: Molecular Genetics

Disease Name	Proportion of X-Linked CMT	Gene Symbol	Chromosomal Locus 1	Protein Product	Test Availability
CMTX1	90%	GJB1		Gap junction beta-1 protein (connexin 32)	Clinical
CMTX2	Unknown		Xp22.2		Research only
CMTX3			Xq26
CMTX4/Cowchock syndrome			Xq24-q26.1
CMTX5		PRPS1		Ribose-phosphate pyrophosphokinase 1	Clinical

1. Chromosomal locus included only when gene is unknown.

Mode of Inheritance

Charcot-Marie-Tooth (CMT) hereditary neuropathy may be transmitted in an autosomal dominant, autosomal recessive, or X-linked dominant manner depending on the genetic subtype in a family.

Risk to Family Members — Autosomal Dominant

Parents of a proband

• Most individuals diagnosed as having autosomal dominant CMT have an affected parent, although occasionally the family history is negative.

• Family history may appear to be negative because of failure to recognize CMT in family members, early death of the parent before the onset of symptoms, late onset in an affected parent, or reduced penetrance of the mutant allele in an asymptomatic parent.

Sibs of a proband

• The risk to sibs depends on the genetic status of the proband's parent.

• If one of the proband's parents has a mutant allele, the risk to the sibs of inheriting the mutant allele is 50%.

Offspring of a proband. Individuals with autosomal dominant CMT have a 50% chance of transmitting the mutant allele to each child.

Risk to Family Members — Autosomal Recessive

Parents of a proband

• The parents are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation.

• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

• Heterozygotes are asymptomatic.

Offspring of a proband. All of the offspring are obligate carriers.

Risk to Family Members — X-Linked

Parents of a proband

• Women who have an affected son and another affected male relative are obligate heterozygotes.

• If pedigree analysis reveals that an affected male represents a simplex case (a male with no family history of CMT), several possibilities regarding his mother's carrier status need to be considered:

  • He has a de novo disease-causing mutation and his mother is not a carrier;

  • His mother has a de novo disease-causing mutation either a) as a "germline mutation" (i.e., occurring at the time of her conception and thus present in every cell of her body; or b) as "germline mosaicism" (i.e., present in some of her germ cells only);

  • His maternal grandmother has a de novo disease-causing mutation.

Sibs of a proband

• The risk to sibs depends upon the genetic status of the proband's mother.

• A female who is a carrier has a 50% chance of transmitting the disease-causing mutation with each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation may or may not be affected.

• If the mother is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. All the daughters of an affected male inherit the mutation and may or may not have symptoms; none of his sons will be affected.

Other family members of proband. The proband's maternal aunts and their offspring may be at risk of being carriers.

Empiric Risks to Family Members

Empiric data regarding recurrence risk are not available for genetic counseling of individuals who represent simplex cases (i.e., single occurrences in a family) in which no disease-causing mutation is identified.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal or X-linked dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (i.e., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. One study found that many individuals with CMT give themselves high disability ratings and 36% would choose not to have children [Pfeiffer et al 2001]. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of asymptomatic adult relatives who are at risk of developing CMT is possible after direct DNA testing has identified the specific gene mutation in an affected relative. Such testing should be performed in the context of formal genetic counseling.

Testing of asymptomatic at-risk children is discouraged. See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents (Genetic Testing; pdf).

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only or the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for some types of CMT is possible by analysis of DNA extracted from cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15-18 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed. For laboratories offering prenatal testing search by disease in the GeneTests Laboratory Directory or see .

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal diagnosis of (typically) adult-onset diseases are uncommon. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate [Bernard et al 2002].

Preimplantation genetic diagnosis (PGD) for some forms of CMT has been reported [Sharapova et al 2004] and may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Treatment of Manifestations

Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Carter et al 2004, Grandis & Shy 2005]. Quality of life has been measured and compared among various groups of individuals with Charcot-Marie-Tooth (CMT) [Vinci et al 2005a].

Special shoes, including those with good ankle support, may be needed. Affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking.

Orthopedic surgery may be required to correct severe pes cavus deformity [Guyton & Mann 2000, Guyton 2006].

Some individuals require forearm crutches or canes for gait stability, but fewer than 5% of individuals need wheelchairs.

Exercise is encouraged within the individual's capability and many individuals remain physically active.

The cause of any pain should be identified as accurately as possible [Padua et al 2006].

• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [Carter et al 1998].

• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.

Surgery is sometimes required for hip dysplasia [Chan et al 2006].

Modafinil has been used to treat fatigue [Carter et al 2006].

Prevention of Secondary Complications

Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable, as well as gripping exercises for hand weakness [Vinci et al 2005b].

Agents/Circumstances to Avoid

Drugs and medications such as vincristine, taxol, cisplatin, isoniazid, and nitrofurantoin that are known to cause nerve damage should be avoided [Graf et al 1996, Chaudhry et al 2003, Weimer & Podwall 2006].

Obesity is to be avoided because it makes walking more difficult.

Therapies Under Investigation

Dyck et al [1982], Ginsberg et al [2004], and Carvalho et al [2005] have described a few individuals with CMT1 and sudden deterioration in whom treatment with steroids (prednisone) or IVIg has produced variable levels of improvement. Nerve biopsy has shown lymphocytic infiltration. One such family had a specific MPZ gene mutation (p.Ile99Thr) [Donaghy et al 2000].

Sahenk et al [2003] are studying the effects of neurotrophin-3 on individuals with CMT1A.

Passage et al [2004] reported benefit from ascorbic acid (vitamin C) in a mouse model of CMT1. A multicenter study is underway [Pareyson et al 2006b].

Sereda et al [2003] and Meyer zu Horste et al [2007] used a progesterone antagonist to improve neuropathy in a transgenic rat model of CMT1A.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Persistent weakness of hands and/or feet have important career and employment implications. Anticipatory counseling is appropriate.

Night splints have not improved ankle range of motion [Refshauge et al 2006].

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Suggested Reading

Revision History

• 16 April 2009 (tb) Revision: sequence analysis available clinically for CMT4H; CMT4J added

• 24 July 2008 (tb) Revision: causal gene (PRPS1) for CMTX5 identified

• 31 August 2007 (me) Comprehensive update posted to live Web site

• 19 June 2006 (cd) Revision: family history evaluation strategy

• 3 February 2006 (tb) Revision: mutations in YARS cause DI-CMTC

• 30 December 2005 (cd) Revision: testing for CMT2B clinically available

• 20 December 2005 (tb) Revision: SEPT9 mutations identified in individuals with familial brachial plexus neuropathy; changes to Differential Diagnosis

• 27 April 2005 (me) Comprehensive update posted to live Web site

• 9 September 2004 (tb) Revision: test availability

• 21 June 2004 (tb,cd) Revision: LITAF and MFN2 added

• 11 May 2004 (me) Author revisions

• 24 March 2004 (cd) Revision: CMT4A

• 22 December 2003 (tb,bp) Revision

• 23 October 2003 (cd) Revision: change in test availability

• 12 August 2003 (tb) Revision: CMT4 molecular genetics

• 29 May 2003 (td) Author revisions

• 24 April 2003 (tb) Author revisions

• 28 March 2003 (me) Comprehensive update posted to live Web site

• 10 May 2002 (tb) Author revisions

• 12 September 2001 (tb) Author revisions

• 20 June 2001 (me) Comprehensive update posted to live Web site

• 15 May 2000 (tb) Author revisions

• 14 January 2000 (tb) Author revisions

• 31 August 1999 (tb) Author revisions

• 18 June 1999 (tb) Author revisions

• 8 April 1999 (tb) Author revisions

• 5 March 1999 (tb) Author revisions

• 12 October 1998 (tb) Author revisions

• 28 September 1998 (pb) Overview posted to live Web site

• April 1996 (tb) Original submission