Funded by the NIH  •  Developed at the University of Washington, Seattle

Charcot-Marie-Tooth Hereditary Neuropathy Overview

[CMT]

Summary

Disease characteristics. Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy. The affected individual typically has distal muscle weakness and atrophy often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet.

Diagnosis/testing. The genetic neuropathies need to be distinguished from the many causes of acquired (non-genetic) neuropathies. Clinical diagnosis is based on family history and characteristic findings on physical examination, EMG/NCV testing, and occasionally sural nerve biopsy. At least 40 different genes/loci are associated with CMT. Molecular genetic testing is available on a clinical basis for some types of CMT.

Management.  Treatment of manifestations: management by a multidisciplinary team of neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists; special shoes and/or ankle/foot orthoses (AFOs) to correct foot drop and aid walking; gripping exercises for hand weakness; orthopedic surgery as needed for severe pes cavus deformity and hip dysplasia; acetaminophen or nonsteroidal anti-inflammatory agents for musculoskeletal pain; tricyclic antidepressants, carbamazepine or gabafpentin for neuropathic pain. Prevention of secondary complications: daily heel cord stretching exercises. Agents/circumstances to avoid: drugs and medications such as vincristine, taxol, cisplatin, isoniazid, and nitrofurantoin that are known to cause nerve damage; obesity as it makes walking more difficult.

Genetic counseling. CMT hereditary neuropathy syndrome can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of  inheritance in each family, and results of molecular genetic testing. Prenatal  testing for pregnancies at increased risk is possible for some types of CMT if the disease-causing mutation(s) in the family is/are known.

Definition

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, Scaioli et al 2006].

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].

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.

Causes

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), Kleopa & Scherer (2006), Houlden & Reilly (2006), and Nicholson (2006), and the molecular pathogenesis has been reviewed by Zuchner & Vance (2006) and Bernard et al (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, Takashima, Bacino et al 2001 ; Boerkoel, Takashima, Stankiewicz et al 2001].

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 CMT4D NDRG1 Protein NDRG1 Clinical CMT4E  1 EGR2 Early growth response protein 2 Clinical CMT4F  1 PRX Periaxin Clinical

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. Deafness and optic neuropathy [Kim et al 2005]

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 Xq21.3-q24

1. Chromosomal locus included only when gene is unknown

Evaluation Strategy

Establishing the specific cause of Charcot-Marie-Tooth (CMT) hereditary neuropathy for a given individual involves a medical history, physical examination, neurologic examination, and nerve conduction and EMG testing, as well as a detailed family history and the use of molecular genetic testing when available.

Family history.  A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or through review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Individuals with CMT may have a negative family history for many reasons, including mild subclinical expression in other family members, autosomal recessive inheritance, or a de novo (new) mutation for a dominant gene.

• About one-third of individuals with identifiable point mutations in PMP22, GJB1, or MPZ causing the CMT hereditary neuropathy phenotype have de novo mutations, and thus present as simplex cases (i.e., a single occurrence in a family) [Boerkoel et al 2002].
• PMP22 duplications (which are much more common than point mutations) occur as de novo mutations in about 10%-20% of people with CMT1 [Blair et al 1996 , Bort et al 1997].

Physical examination.  In individuals who have no family history of neuropathy, the first step is to exclude acquired causes of neuropathy by standard neurologic evaluation (see Differential Diagnosis).

Distal weakness, sensory loss, depressed tendon reflexes, and foot deformity are commonly (but not always) present.

In CMT1, the most common CMT subtype, NCVs are very slow and peripheral nerves may be palpably enlarged. This is not true of CMT2 or CMTX.

Molecular genetic testing.  Molecular genetic testing is presently available on a clinical basis for mutations in numerous genes associated with similar phenotypes. (see Table 3 , Table 4 , Table 5 , Table 6 , Table 7). Note: Failure to identify a disease-causing mutation in a proband does not rule out a diagnosis of CMT since undetected mutations in other genes may be causative.

The following testing strategy may provide the most efficient and cost-effective approach to testing [Saifi et al 2003 , Klein & Dyck 2005 , Szigeti et al 2006]. However, it should be noted that some clinical laboratories may group tests into 'panels', which may be less expensive than sequential testing of individual genes if more than two or three genes are analyzed.

Positive family history

• In families with at least two-generation involvement, known male-to-male transmission, and slow NCV, testing for the PMP22 duplication (CMT1A) should be obtained first, and then, if normal, followed by testing of MPZ (CMT1B).
• In families with at least two-generation involvement and slow NCV, but without male-to-male transmission, molecular genetic testing of PMP22 (CMT1A), MPZ (CMT1B), LITAF (CMT1C), and GJB1 (CMTX) should be performed sequentially.
• In families with probable X-linked inheritance of the CMT phenotype, molecular genetic testing of GJB1 (CMTX) is appropriate to confirm the diagnosis.
• In individuals with the CMT2 phenotype, MFN2 can be tested first followed by testing of MPZ and GJB1.
• Families with early-onset CMT in which only sibs are affected may have autosomal recessive CMT and can be tested for mutations in GDAP1, EGR2, and PDX.

Negative family history

• Molecular genetic testing of PMP22dup (CMT1A), MPZ (CMT1B), and GJB1 (CMTX) should all be performed on males and females who have no family history of neuropathy because de novo duplications of the 17p11 region occur often, giving rise to CMT1A, and because females who have a GJB1 mutation causing CMTX1 may be asymptomatic.
• Early-onset severe CMT may be caused by point mutations in PMP22 (CMT1A), GDAP1 (CMT4A), EGR2 (CMT4E), or PDX (CMT4F).

CMT1 phenotype.   In more than 90% of individuals with a CMT1 phenotype a mutation is found in one of three genes (PMP22dup, MPZ, GJB1) [Szigeti et al 2006].

Testing for rare causes of CMT.  Mutations in EGR2 (CMT1D, CMT4E), NFL (CMT2E), HSPB1 (CMT2F), GDAP1 (CMT4A), and PDX (CMT4F), and point mutations in PMP22 are rare causes of the CMT phenotype. When tests for the more common forms of CMT are negative, the physician must decide if searching for rarer types of CMT justifies the cost. Such testing, often considered in the context of genetic counseling, may be useful in clarifying prognosis and risk to other family members.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

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 upon 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., present 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).

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 DNA Banking for a list of laboratories offering this service.

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 about ten to 12 weeks' gestation or amniocentesis usually performed at about 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 .

Management

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, Serrao et al 2005].

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, Villa et al 2005].

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, Schenone et al 2006].

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.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents
  
  
• National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders

Literature Cited

• Auer-Grumbach M, De Jonghe P, Verhoeven K, Timmerman V, Wagner K, Hartung HP, Nicholson GA (2003) Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review. Arch Neurol 60:329-34 [Medline]
  
  
• Auer-Grumbach M, Schlotter-Weigel B, Lochmuller H, Strobl-Wildemann G, Auer-Grumbach P, Fischer R, Offenbacher H, Zwick EB, Robl T, Hartl G, Hartung HP, Wagner K, Windpassinger C (2005) Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol 57:415-24 [Medline]
  
  
• Bernard R, Boyer A, Negre P, Malzac P, Latour P, Vandenberghe A, Philip N, Levy N (2002) Prenatal detection of the 17p11.2 duplication in Charcot-Marie-Tooth disease type 1A: necessity of a multidisciplinary approach for heterogeneous disorders. Eur J Hum Genet 10:297-302 [Medline]
  
  
• Bernard R, De Sandre-Giovannoli A, Delague V, Levy N (2006) Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies. Neuromolecular Med 8:87-106 [Medline]
  
  
• Blair IP, Nash J, Gordon MJ, Nicholson GA (1996) 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 58:472-6 [Medline]
  
  
• Boerkoel CF, Takashima H, Bacino CA, Daentl D, Lupski JR (2001) EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy. Neurogenetics 3:153-7 [Medline]
  
  
• Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K, Russo P, Kennedy S, Teebi AS, Scavina M, Williams LL, Mancias P, Butler IJ, Krajewski K, Shy M, Lupski JR (2002) Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol 51:190-201 [Medline]
  
  
• Boerkoel CF, Takashima H, Stankiewicz P, Garcia CA, Leber SM, Rhee-Morris L, Lupski JR (2001) Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am J Hum Genet 68:325-33 [Medline]
  
  
• Bort S, Martinez F, Palau F (1997) Prevalence and parental origin of de novo 1.5-Mb duplication in Charcot-Marie-Tooth disease type 1A. Am J Hum Genet 60:230-3 [Medline]
  
  
• Carter GT, England JD, Chance PF (2004) Charcot-Marie-Tooth disease: electrophysiology, molecular genetics and clinical management. IDrugs 7:151-9 [Medline]
  
  
• Carter GT, Han JJ, Mayadev A, Weiss MD (2006) Modafinil reduces fatigue in Charcot-Marie-Tooth disease type 1A: a case series. Am J Hosp Palliat Care 23:412-6 [Medline]
  
  
• Carter GT, Jensen MP, Galer BS, Kraft GH, Crabtree LD, Beardsley RM, Abresch RT, Bird TD (1998) Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil 79:1560-4 [Medline]
  
  
• Carvalho AA, Vital A, Ferrer X, Latour P, Lagueny A, Brechenmacher C, Vital C (2005) Charcot-Marie-Tooth disease type 1A: clinicopathological correlations in 24 patients. J Peripher Nerv Syst 10:85-92 [Medline]
  
  
• Chan G, Bowen JR, Kumar SJ (2006) Evaluation and treatment of hip dysplasia in Charcot-Marie-Tooth disease. Orthop Clin North Am 37:203-9 [Medline]
  
  
• Chaudhry V, Chaudhry M, Crawford TO, Simmons-O'Brien E, Griffin JW (2003) Toxic neuropathy in patients with pre-existing neuropathy. Neurology 60:337-40 [Medline]
  
  
• Cowchock FS, Duckett SW, Streletz LJ, Graziani LJ, Jackson LG (1985) X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder. Am J Med Genet 20:307-15 [Medline]
  
  
• De Jonghe P, Timmerman V, Nelis E, Martin JJ, Van Broeckhoven C (1997) Charcot-Marie-Tooth disease and related peripheral neuropathies. J Peripher Nerv Syst 2:370-87 [Medline]
  
  
• Donaghy M, Sisodiya SM, Kennett R, McDonald B, Haites N, Bell C (2000) Steroid responsive polyneuropathy in a family with a novel myelin protein zero mutation. J Neurol Neurosurg Psychiatry 69:799-805 [Medline]
  
  
• Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH (1982) Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc 57:239-46 [Medline]
  
  
• Ginsberg L, Malik O, Kenton AR, Sharp D, Muddle JR, Davis MB, Winer JB, Orrell RW, King RH (2004) Coexistent hereditary and inflammatory neuropathy. Brain 127:193-202 [Medline]
  
  
• Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD (1996) Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer 77:1356-62 [Medline]
  
  
• Grandis M and Shy ME (2005) Current Therapy for Charcot-Marie-Tooth Disease. Curr Treat Options Neurol 7:23-31 [Medline]
  
  
• Guyton GP (2006) Current concepts review: orthopaedic aspects of Charcot-Marie-Tooth disease. Foot Ankle Int 27:1003-10 [Medline]
  
  
• Guyton GP and Mann RA (2000) The pathogenesis and surgical management of foot deformity in Charcot- Marie-Tooth disease. Foot Ankle Clin 5:317-26 [Medline]
  
  
• Houlden H and Reilly MM (2006) Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease. Neuromolecular Med 8:43-62 [Medline]
  
  
• Huttner IG, Kennerson ML, Reddel SW, Radovanovic D, Nicholson GA (2006) Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease. Neurology 67:2016-21 [Medline]
  
  
• Ionasescu VV, Trofatter J, Haines JL, Summers AM, Ionasescu R, Searby C (1991) Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy. Am J Hum Genet 48:1075-83 [Medline]
  
  
• Ionasescu VV, Trofatter J, Haines JL, Summers AM, Ionasescu R, Searby C (1992) X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve 15:368-73 [Medline]
  
  
• Irobi J, De Jonghe P, Timmerman V (2004) Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet 13 Spec No 2:R195-202 [Medline]
  
  
• Jeannet PY, Watts GD, Bird TD, Chance PF (2001) Craniofacial and cutaneous findings expand the phenotype of hereditary neuralgic amyotrophy. Neurology 57:1963-8 [Medline]
  
  
• Jordanova A, Irobi J, Thomas FP, Van Dijck P, Meerschaert K, Dewil M, Dierick I, Jacobs A, De Vriendt E, Guergueltcheva V, Rao CV, Tournev I, Gondim FA, D'Hooghe M, Van Gerwen V, Callaerts P, Van Den Bosch L, Timmermans JP, Robberecht W, Gettemans J, Thevelein JM, De Jonghe P, Kremensky I, Timmerman V (2006) Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nat Genet 38:197-202 [Medline]
  
  
• Jordanova A, Thomas FP, Guergueltcheva V, Tournev I, Gondim FA, Ishpekova B, De Vriendt E, Jacobs A, Litvinenko I, Ivanova N, Buzhov B, De Jonghe P, Kremensky I, Timmerman V (2003) Dominant Intermediate Charcot-Marie-Tooth Type C Maps to Chromosome 1p34-p35. Am J Hum Genet 73:1423-30 [Medline]
  
  
• Keller MP and Chance PF (1999) Inherited neuropathies: from gene to disease. Brain Pathol 9:327-41 [Medline]
  
  
• Kennerson ML, Zhu D, Gardner RJ, Storey E, Merory J, Robertson SP, Nicholson GA (2001) Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2. Am J Hum Genet 69:883-8 [Medline]
  
  
• Kim HJ, Hong SH, Ki CS, Kim BJ, Shim JS, Cho SH, Park JH, Kim JW (2005) A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology 64:1964-7 [Medline]
  
  
• Klein CJ and Dyck PJ (2005) Genetic testing in inherited peripheral neuropathies. J Peripher Nerv Syst 10:77-84 [Medline]
  
  
• Kleopa KA and Scherer SS (2006) Molecular genetics of X-linked Charcot-Marie-Tooth disease. Neuromolecular Med 8:107-22 [Medline]
  
  
• Kuhlenbaumer G, Hannibal MC, Nelis E, Schirmacher A, Verpoorten N, Meuleman J, Watts GD, De Vriendt E, Young P, Stogbauer F, Halfter H, Irobi J, Goossens D, Del-Favero J, Betz BG, Hor H, Kurlemann G, Bird TD, Airaksinen E, Mononen T, Serradell AP, Prats JM, Van Broeckhoven C, De Jonghe P, Timmerman V, Ringelstein EB, Chance PF (2005) Mutations in SEPT9 cause hereditary neuralgic amyotrophy. Nat Genet 37:1044-6 [Medline]
  
  
• Kumar N, Muley S, Pakiam A, Parry GJ (2002) Phenotypic variability leads to under-recognition of HNPP. J Clin Neuromusc Dis 3:106-112
  
  
• Lynch DR and Chance PF (1997) Inherited peripheral neuropathies. The Neurologist 3:279-92
  
  
• McGann R and Gurd A (2002) The association between Charcot-Marie-Tooth disease and developmental dysplasia of the hip. Orthopedics 25:337-9 [Medline]
  
  
• Meyer zu Horste G, Prukop T, Liebetanz D, Mobius W, Nave KA, Sereda MW (2007) Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathy. Ann Neurol 61:61-72 [Medline]
  
  
• Nelis E, Timmerman V, De Jonghe P, Van Broeckhoven C, Rautenstrauss B (1999) Molecular genetics and biology of inherited peripheral neuropathies: a fast-moving field. Neurogenetics 2:137-48 [Medline]
  
  
• Nicholson G and Myers S (2006) Intermediate forms of Charcot-Marie-Tooth neuropathy: a review. Neuromolecular Med 8:123-30 [Medline]
  
  
• Nicholson GA (2006) The dominantly inherited motor and sensory neuropathies: clinical and molecular advances. Muscle Nerve 33:589-97 [Medline]
  
  
• Padua L, Aprile I, Cavallaro T, Commodari I, La Torre G, Pareyson D, Quattrone A, Rizzuto N, Vita G, Tonali P, Schenone A, Italian CMT QoL Study Group (2006) Variables influencing quality of life and disability in Charcot Marie Tooth (CMT) patients: Italian multicentre study. Neurol Sci 27:417-23 [Medline]
  
  
• Pareyson D, Scaioli V, Laura M (2006) Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med 8:3-22 [Medline]
  
  
• Pareyson D, Schenone A, Fabrizi GM, Santoro L, Padua L, Quattrone A, Vita G, Gemignani F, Visioli F, Solari A, CMT-TRIAAL Group (2006) A multicenter, randomized, double-blind, placebo-controlled trial of long-term ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL): the study protocol [EudraCT no.: 2006-000032-27]. Pharmacol Res 54:436-41 [Medline]
  
  
• Parman Y, Battaloglu E, Baris I, Bilir B, Poyraz M, Bissar-Tadmouri N, Williams A, Ammar N, Nelis E, Timmerman V, De Jonghe P, Necefov A, Deymeer F, Serdaroglu P, Brophy PJ, Said G (2004) Clinicopathological and genetic study of early-onset demyelinating neuropathy. Brain 127:2540-50 [Medline]
  
  
• Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J, Thirion X, Robaglia-Schlupp A, Pellissier JF, Fontes M (2004) Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med 10:396-401 [Medline]
  
  
• Pfeiffer G, Wicklein EM, Ratusinski T, Schmitt L, Kunze K (2001) Disability and quality of life in Charcot-Marie-Tooth disease type 1. J Neurol Neurosurg Psychiatry 70:548-50 [Medline]
  
  
• Priest JM, Fischbeck KH, Nouri N, Keats BJ (1995) A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq24-q26. Genomics 29:409-12 [Medline]
  
  
• Refshauge KM, Raymond J, Nicholson G, van den Dolder PA (2006) Night splinting does not increase ankle range of motion in people with Charcot-Marie-Tooth disease: a randomised, cross-over trial. Aust J Physiother 52:193-9 [Medline]
  
  
• Sahenk Z, Nagaraja HN, McCracken BS, King WM, Freimer ML, Cedarbaum JM, Mendell HR (2003) Neurotrophin-3 treatment promotes nerve regeneration and improvements in sensory function in patients with CMT1A. Ann Neurol 54(Suppl 7):S19
  
  
• Said G, Lacroix C, Plante-Bordeneuve V, Messing B, Slama A, Crenn P, Nivelon-Chevallier A, Bedenne L, Soichot P, Manceau E, Rigaud D, Guiochon-Mantel A, Matuchansky C (2005) Clinicopathological aspects of the neuropathy of neurogastrointestinal encephalomyopathy (MNGIE) in four patients including two with a Charcot-Marie-Tooth presentation. J Neurol. 2005 Mar 7; [Epub ahead of print] [Medline]
  
  
• Saifi GM, Szigeti K, Snipes GJ, Garcia CA, Lupski JR (2003) Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies. J Investig Med 51:261-83 [Medline]
  
  
• Schroder JM (2006) Neuropathology of Charcot-Marie-Tooth and related disorders. Neuromolecular Med 8:23-42 [Medline]
  
  
• Sereda MW, Meyer zu Horste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med 9:1533-7 [Medline]
  
  
• Sharapova T, Rechitsky S, Verlinsky Y (2004) Preimplantation genetic diagnosis (PGD) for three types of Charcot-Marie-Tooth (CMT) disease. Am J Hum Genet S75:A2806
  
  
• Stogbauer F, Young P, Kuhlenbaumer G, Kiefer R, Timmerman V, Ringelstein EB, Wang JF, Schroder JM, Van Broeckhoven C, Weis J (1999) Autosomal dominant burning feet syndrome. J Neurol Neurosurg Psychiatry 67:78-81 [Medline]
  
  
• Szigeti K, Nelis E, Lupski JR (2006) Molecular diagnostics of Charcot-Marie-Tooth disease and related peripheral neuropathies. Neuromolecular Med 8:243-54 [Medline]
  
  
• Timmerman V, De Jonghe P, Spoelders P, Simokovic S, Lofgren A, Nelis E, Vance J, Martin JJ, Van Broeckhoven C (1996) Linkage and mutation analysis of Charcot-Marie-Tooth neuropathy type 2 families with chromosomes 1p35-p36 and Xq13. Neurology 46:1311-8 [Medline]
  
  
• Udd B and Griggs R (2001) Distal myopathies. Curr Opin Neurol 14:561-6 [Medline]
  
  
• Vance JM (2000) The many faces of Charcot-Marie-Tooth disease. Arch Neurol 57:638-40 [Medline]
  
  
• Verhoeven K, Villanova M, Rossi A, Malandrini A, De Jonghe P, Timmerman V (2001) Localization of the gene for the intermediate form of Charcot-Marie- Tooth to chromosome 10q24.1-q25.1. Am J Hum Genet 69:889-94 [Medline]
  
  
• Vinci P, Serrao M, Millul A, Deidda A, De Santis F, Capici S, Martini D, Pierelli F, Santilli V (2005) Quality of life in patients with Charcot-Marie-Tooth disease. Neurology 65:922-4 [Medline]
  
  
• Vinci P, Villa LM, Castagnoli L, Marconi C, Lattanzi A, Manini MP, Calicchio ML, Vitangeli L, Di Gianvito P, Perelli SL, Martini D (2005) Handgrip impairment in Charcot-Marie-Tooth disease. Eura Medicophys 41:131-4 [Medline]
  
  
• Weimer LH and Podwall D (2006) Medication-induced exacerbation of neuropathy in Charcot Marie Tooth disease. J Neurol Sci 242:47-54 [Medline]
  
  
• Zuchner S, Noureddine M, Kennerson M, Verhoeven K, Claeys K, De Jonghe P, Merory J, Oliveira SA, Speer MC, Stenger JE, Walizada G, Zhu D, Pericak-Vance MA, Nicholson G, Timmerman V, Vance JM (2005) Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat Genet 37:289-94 [Medline]
  
  
• Zuchner S and Vance JM (2006) Mechanisms of disease: a molecular genetic update on hereditary axonal neuropathies. Nat Clin Pract Neurol 2:45-53 [Medline]
  
  

Suggested Readings

• Lupski JR and Garcia CA (revised 2002) Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 227. www.ommbid.com
  
  

Author Information