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 under-recognized manifestations of CMT [McGann & Gurd 2002].

Establishing the Diagnosis of CMT

Reviews on diagnosis include Pareyson & Marchesi [2009a], Pareyson & Marchesi [2009b], and Reilly & Shy [2009].

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 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 (with the exception of optic atrophy in CMT2A and CMTX5), seizures, dementia, and intellectual disability 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 SEPT9 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 copy of PMP22 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
• 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).
• X-linked disorders with neuropathy
  • Adrenomyeloneuropathy
  • Pelizaeus-Merzbacher disease
  • Lowe syndrome

Hereditary motor neuropathies (HMN) are associated with distal weakness without sensory loss [Irobi et al 2004, Auer-Grumbach et al 2005]. The key distinction between typical CMT and HMN is that the latter has no sensory loss.

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.

See also Hereditary Sensory Neuropathy Type I and Hereditary Sensory and Autonomic Neuropathy Type II.

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 an unclassified chronic peripheral neuropathy have CMT1A.

The prevalence of genetic subtypes differs in Japan, where there are fewer cases of CMT1A (23% of CMT1) and more cases with an unknown genetic cause [Abe et al 2011].

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. Reviews of the diagnosis and natural history include Pareyson & Marchesi [2009a], Pareyson & Marchesi [2009b], and Reilly & Shy [2009].

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], Nicholson [2006], Reilly & Shy [2009], and Pareyson & Marchesi [2009a], and the molecular pathogenesis has been reviewed by Bernard et al [2006] and Zuchner & Vance [2006]. The various genetic subtypes and their associated genes are shown in Figure 1 [Pareyson & Marchesi 2009a].

Figure

Figure 1. Different forms of Charcot-Marie-Tooth disease and associated genes

There are areas of overlap between different types of CMT. Red shading indicates the most commonly involved genes.

dHMN = distal hereditary (more...)

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 m/sec; normal: >40-45 m/sec). 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

View in own window

Locus Name	Proportion of CMT1 (excluding CMTX) 1	Gene Symbol	Protein Product	Test Availability
CMT1A	70%-80%	PMP22	Peripheral myelin protein 22	Clinical
CMT1B	10%-12%	MPZ	Myelin P0 protein	Clinical
CMT1C	~1%	LITAF	Lipopolysaccharide-induced tumor necrosis factor-alpha factor	Clinical
CMT1D	Unknown	EGR2	Early growth response protein 2	Clinical
CMT1E	~1%	PMP22	Peripheral myelin protein 22 (sequence changes)	Clinical
CMT1F/2E	Unknown	NEFL	Neurofilament light polypeptide	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Saporta et al [2011]

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/sec). 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/sec 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.

CMT2A2, the most common type of CMT2, is caused by mutations in MFN2 (reviewed in Chung et al [2006]). Known MFN2 mutations and related pathophysiology are reviewed in Cartoni & Martinou [2009].

CMT2B, caused by mutations in RAB7A, is associated with prominent sensory loss [Cogli et al 2009].

Table 4. CMT2: Molecular Genetics

View in own window

Locus Name	Proportion of CMT2 1	Gene Symbol/ Chromosomal Locus 2	Protein Product	Test Availability
CMT2A1	Unknown	KIF1B	Kinesin-like protein KIF1B	Clinical
CMT2A2	20%	MFN2	Mitofusin-2	Clinical
CMT2B	Unknown	RAB7A	Ras-related protein Rab-7	Clinical
CMT2B1	Unknown	LMNA	Lamin A/C	Clinical
CMT2B2	Unknown	MED25	Mediator of RNA polymerase II transcription subunit 25	Clinical
CMT2C	Unknown	TRPV4	Transient receptor potential cation channel subfamily V member 4	Clinical
CMT2D	3%	GARS	Glycyl-tRNA synthetase	Clinical
CMT2E/1F	4%	NEFL	Neurofilament light polypeptide	Clinical
CMT2F	Unknown	HSPB1	Heat-shock protein beta-1	Clinical
CMT2G	Unknown	12q12-q13	Unknown	Research only
CMT2H/2K	5%	GDAP1	Ganglioside-induced differentiation-associated protein-1	Clinical
CMT2I	Unknown	MPZ	Myelin P0 protein	Clinical
CMT2J	Unknown	MPZ	Myelin P0 protein	Clinical
CMT2L	Unknown	HSPB8	Heat-shock protein beta-8	Clinical
CMT2N	Unknown	AARS	Alanyl-tRNA synthetase, cytoplasmic	Clinical
CMT2O	Unknown	DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Research only
CMT2P	Unknown	LRSAM1	E3 ubiquitin-protein ligase LRSAM1	Research only

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Chromosomal locus included only when gene is unknown

2. Saporta et al [2011]

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. In the two families reported by Soong et al [2013] median motor nerve conduction velocities (MNCV) ranged from clearly slow/demyelinating (16.5-28 m/s) to normal (44-45 m/s). The family members with slow MNCV would have been classified as having CMT1.

Table 5. Autosomal Dominant Intermediate CMT: Molecular Genetics

View in own window

Locus Name	Proportion of Intermediate CMT	Gene Symbol/ Chromosomal Locus 1	Protein Product	Reference	Test Availability
DI-CMTA	Unknown	10q24.1-q25.1	Unknown	Verhoeven et al [2001]	Research only
DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB)		DNM2	Dynamin 2	Kennerson et al [2001], Zuchner et al [2005]	Clinical
YARS-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTC)		YARS	Tyrosyl-tRNA synthetase	Jordanova et al [2003], Jordanova et al [2006]	Clinical
MPZ-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTD)		MPZ	Myelin P0 protein		Clinical
GNB4-related intermediate Charcot-Marie-Tooth neuropathy		GNB4	Guanine nucleotide-binding protein subunit beta-4	Soong et al [2013]	Research only

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Chromosomal locus included only when gene is unknown

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. The autosomal recessive forms of CMT are reviewed by Bernard et al [2006] and Kabzinska et al [2008].

Note: The term Dejerine-Sottas syndrome (DSS) was originally used to describe a severe demyelinating neuropathy of infancy and childhood associated with very slow NCVs, 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

View in own window

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	Clinical
CMT4B2		SBF2	Myotubularin-related protein 13	Clinical
CMT4C		SH3TC2	SH3 domain and tetratricopeptide repeats-containing protein 2	Clinical
CMT4D		NDRG1	Protein NDRG1	Clinical
CMT4E		EGR2	Early growth response protein 2	Clinical
CMT4F		PRX	Periaxin	Clinical
CMT4H		FGD4	FYVE, RhoGEF and PH domain-containing protein 4	Clinical
CMT4J		FIG4	Phosphatidylinositol 3, 5 biphosphate	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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).

Five other forms of hereditary neuropathy have been linked to the X chromosome. The genes associated with CMTX5 and CMTX6 have been identified. Associated findings are [Huttner et al 2006]:

• CMTX2. Intellectual disability [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 intellectual disability [Cowchock et al 1985, Priest et al 1995]. Rinaldi et al [2012] identified a missense mutation (p.Glu493Val) in AIFM1 (encoding apoptosis-inducing factor 1) in a member of the original family.
• CMTX5. Deafness and optic neuropathy. CMTX5 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].
• CMTX6. Males have childhood onset of a slowly progressive motor and sensory neuropathy that is largely axonal (variable mild conduction slowing) with steppage gait and absent tendon reflexes. Carrier females may have a mild sensory motor axonal neuropathy [Kennerson et al 2013].

Kennerson et al [2010] described two families with an X-linked distal motor neuropathy similar to CMT with missense mutations in ATP7A, the same gene involved in Menkes disease.

A retrospective review of X-linked CMT in childhood has been reported [Yiu et al 2011].

Table 7. CMTX: Molecular Genetics

View in own window

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		Research only
CMTX4/Cowchock syndrome		AIFM1	Apoptosis-inducing factor 1	Research only
CMTX5		PRPS1	Ribose-phosphate pyrophosphokinase 1	Clinical
CMTX6		PDK3	Pyruvate dehydrogenase kinase isoform 3	Research only

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Chromosomal locus included when gene is unknown

Mitochondrial CMT

Mitochondrial abnormalities are known to sometimes be associated with peripheral neuropathy. Mutations in the nuclear gene MFN2 produce abnormal mitochondrial fusion/fission and resultant neuropathy (CMT2A). Mutations in the mitochondrial genome may also be associated with neuropathy, for example in NARP. Pitceathly et al [2012] have reported an axonal predominantly motor neuropathy associated with the m.9185T>C mutation in MT-ATP6.

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 parents.
• 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, in which case 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 on 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 (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• 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 of being affected.
• 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].

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 position statement on genetic testing of minors for adult-onset conditions 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.

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. 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 to 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

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, 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 .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Treatment of Manifestations

Reviews of treatment approaches to CMT are available [Carter et al 2008, Young et al 2008, Reilly & Shy 2009]. Reviews of the diagnosis, natural history and management are available [Pareyson & Marchesi 2009a, Pareyson & Marchesi 2009b].

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, Burns et al 2010]. Persistent weakness of the hands and/or feet has important career and employment implications; anticipatory counseling is appropriate.

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.

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

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

Orthopedic surgery may be required to correct severe pes cavus deformity [Guyton & Mann 2000, Guyton 2006, Casasnovas et al 2008, Ward et al 2008]. Surgery is sometimes required for hip dysplasia [Chan et al 2006].

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.

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

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

Medications that are toxic or potentially toxic to persons with CMT comprise a range of risks including:

• Definite high risk. Vinca alkaloids (Vincristine)
  • This category should be avoided by all persons with CMT, including those who are asymptomatic
• Other potential risk levels. See Table 8 or for more information click here (pdf).

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 mutation (p.Ile99Thr) [Donaghy et al 2000]. A young child with CMT1A and an inflammatory neuropathy has been reported [Marques et al 2010].

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. However, a study of 277 persons with CMT1A found no significant effect of a daily 1.5-g dose of ascorbic acid after two years [Pareyson et al 2011]. Similar studies of smaller numbers of patients have also shown no benefit of such treatment [Micallef et al 2009, Verhamme et al 2009].

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

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

Genetics clinics, staffed by genetics professionals, provide 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.

Published Guidelines/Consensus Statements

1. 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. Available online. 1995. Accessed 3-20-13. [PMC free article: PMC1801355] [PubMed: 7485175]
2. National Society of Genetic Counselors. Policy statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 3-20-13.

Literature Cited

1. Abe A, Numakura C, Kijima K, Hayashi M, Hashimoto T, Hayasaka K. Molecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Japan. J Hum Genet. 2011 [PubMed: 21326314]
2. Auer-Grumbach M, De Jonghe P, Verhoeven K, Timmerman V, Wagner K, Hartung HP, Nicholson GA. Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review. Arch Neurol. 2003;60:329–34. [PubMed: 12633143]
3. 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. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol. 2005;57:415–24. [PubMed: 15732094]
4. Bernard R, Boyer A, Negre P, Malzac P, Latour P, Vandenberghe A, Philip N, Levy N. 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. 2002;10:297–302. [PubMed: 12082504]
5. Bernard R, De Sandre-Giovannoli A, Delague V, Levy N. Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies. Neuromolecular Med. 2006;8:87–106. [PubMed: 16775369]
6. Blair IP, Nash J, Gordon MJ, Nicholson GA. 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. 1996;58:472–6. [PMC free article: PMC1914557] [PubMed: 8644705]
7. Boerkoel CF, Takashima H, Bacino CA, Daentl D, Lupski JR. EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy. Neurogenetics. 2001a;3:153–7. [PubMed: 11523566]
8. 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. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol. 2002;51:190–201. [PubMed: 11835375]
9. Boerkoel CF, Takashima H, Stankiewicz P, Garcia CA, Leber SM, Rhee-Morris L, Lupski JR. Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am J Hum Genet. 2001b;68:325–33. [PMC free article: PMC1235266] [PubMed: 11133365]
10. Bort S, Martinez F, Palau F. Prevalence and parental origin of de novo 1.5-Mb duplication in Charcot-Marie-Tooth disease type 1A. Am J Hum Genet. 1997;60:230–3. [PMC free article: PMC1712552] [PubMed: 8981968]
11. Burns J, Ramchandren S, Ryan MM, Shy M, Ouvrier RA. Determinants of reduced health-related quality of life in pediatric inherited neuropathies. Neurology. 2010;75:726–31. [PMC free article: PMC2931653] [PubMed: 20733147]
12. Carter GT, England JD, Chance PF. Charcot-Marie-Tooth disease: electrophysiology, molecular genetics and clinical management. IDrugs. 2004;7:151–9. [PubMed: 15057660]
13. Carter GT, Han JJ, Mayadev A, Weiss MD. Modafinil reduces fatigue in Charcot-Marie-Tooth disease type 1A: a case series. Am J Hosp Palliat Care. 2006;23:412–6. [PubMed: 17060310]
14. Carter GT, Jensen MP, Galer BS, Kraft GH, Crabtree LD, Beardsley RM, Abresch RT, Bird TD. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. 1998;79:1560–4. [PubMed: 9862301]
15. Carter GT, Weiss MD, Han JJ, Chance PF, England JD. Charcot-Marie-Tooth disease. Curr Treat Options Neurol. 2008;10:94–102. [PubMed: 18334132]
16. Cartoni R, Martinou JC. Role of mitofusin 2 mutations in the physiopathology of Charcot-Marie-Tooth disease type 2A. Exp Neurol. 2009;218:268–73. [PubMed: 19427854]
17. Carvalho AA, Vital A, Ferrer X, Latour P, Lagueny A, Brechenmacher C, Vital C. Charcot-Marie-Tooth disease type 1A: clinicopathological correlations in 24 patients. J Peripher Nerv Syst. 2005;10:85–92. [PubMed: 15703022]
18. Casasnovas C, Cano LM, Albertí A, Céspedes M, Rigo G. Charcot-Marie-tooth disease. Foot Ankle. 2008;1(Spec.):350–4. [PubMed: 19825739]
19. Chan G, Bowen JR, Kumar SJ. Evaluation and treatment of hip dysplasia in Charcot-Marie-Tooth disease. Orthop Clin North Am. 2006;37:203–9. [PubMed: 16638451]
20. Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, Suh JS, Hwang JH, Kim WK, Seo BC, Kim SH, Son IH, Kim SM, Sunwoo IN, Choi BO. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain. 2006;129(Pt 8):2103–18. [PubMed: 16835246]
21. Cogli L, Piro F, Bucci C. Rab7 and the CMT2B disease. Biochem Soc Trans. 2009;37(Pt 5):1027–31. [PubMed: 19754445]
22. Cowchock FS, Duckett SW, Streletz LJ, Graziani LJ, Jackson LG. X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder. Am J Med Genet. 1985;20:307–15. [PubMed: 3856385]
23. De Jonghe P, Timmerman V, Nelis E, Martin JJ, Van Broeckhoven C. Charcot-Marie-Tooth disease and related peripheral neuropathies. J Peripher Nerv Syst. 1997;2:370–87. [PubMed: 10975746]
24. Donaghy M, Sisodiya SM, Kennett R, McDonald B, Haites N, Bell C. Steroid responsive polyneuropathy in a family with a novel myelin protein zero mutation. J Neurol Neurosurg Psychiatry. 2000;69:799–805. [PMC free article: PMC1737181] [PubMed: 11080236]
25. Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH. Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc. 1982;57:239–46. [PubMed: 7070119]
26. England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ, Cohen JA, Asbury AK, Szigeti K, Lupski JR, Latov N, Lewis RA, Low PA, Fisher MA, Herrmann DN, Howard JF, Lauria G, Miller RG, Polydefkis M, Sumner AJ. American Academy of Neurology; Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72:185–92. [PubMed: 19056666]
27. Ginsberg L, Malik O, Kenton AR, Sharp D, Muddle JR, Davis MB, Winer JB, Orrell RW, King RH. Coexistent hereditary and inflammatory neuropathy. Brain. 2004;127:193–202. [PubMed: 14607795]
28. Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. 1996;77:1356–62. [PubMed: 8608515]
29. Grandis M, Shy ME. Current Therapy for Charcot-Marie-Tooth Disease. Curr Treat Options Neurol. 2005;7:23–31. [PubMed: 15610704]
30. Guyton GP. Current concepts review: orthopaedic aspects of Charcot-Marie-Tooth disease. Foot Ankle Int. 2006;27:1003–10. [PubMed: 17144969]
31. Guyton GP, Mann RA. The pathogenesis and surgical management of foot deformity in Charcot- Marie-Tooth disease. Foot Ankle Clin. 2000;5:317–26. [PubMed: 11232233]
32. Houlden H, Reilly MM. Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:43–62. [PubMed: 16775366]
33. Huttner IG, Kennerson ML, Reddel SW, Radovanovic D, Nicholson GA. Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease. Neurology. 2006;67:2016–21. [PubMed: 17159110]
34. Ionasescu VV, Trofatter J, Haines JL, Summers AM, Ionasescu R, Searby C. Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy. Am J Hum Genet. 1991;48:1075–83. [PMC free article: PMC1683112] [PubMed: 1674639]
35. Ionasescu VV, Trofatter J, Haines JL, Summers AM, Ionasescu R, Searby C. X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve. 1992;15:368–73. [PubMed: 1557086]
36. Irobi J, De Jonghe P, Timmerman V. Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet. 2004;13(Spec No 2):R195–202. [PubMed: 15358725]
37. Jeannet PY, Watts GD, Bird TD, Chance PF. Craniofacial and cutaneous findings expand the phenotype of hereditary neuralgic amyotrophy. Neurology. 2001;57:1963–8. [PubMed: 11739810]
38. 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. Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nat Genet. 2006;38:197–202. [PubMed: 16429158]
39. 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. Dominant Intermediate Charcot-Marie-Tooth Type C Maps to Chromosome 1p34-p35. Am J Hum Genet. 2003;73:1423–30. [PMC free article: PMC1180404] [PubMed: 14606043]
40. Kabzinska D, Hausmanowa-Petrusewicz I, Kochanski A. Charcot-Marie-Tooth disorders with an autosomal recessive mode of inheritance. Clin Neuropathol. 2008;27:1–12. [PubMed: 18257469]
41. Keller MP, Chance PF. Inherited neuropathies: from gene to disease. Brain Pathol. 1999;9:327–41. [PubMed: 10219749]
42. Kennerson ML, Zhu D, Gardner RJ, Storey E, Merory J, Robertson SP, Nicholson GA. Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2. Am J Hum Genet. 2001;69:883–8. [PMC free article: PMC1226074] [PubMed: 11533912]
43. Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, Llanos RM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D, Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, Garbern JY. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet. 2010;86:343–52. [PMC free article: PMC2833394] [PubMed: 20170900]
44. Kennerson ML, Yiu EM, Chuang DT, Kidambi A, Tso SC, Ly C, Chaudhry R, Drew AP, Rance G, Delatycki MB, Züchner S, Ryan MM, Nicholson GA. A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum Mol Genet. 2013;(Jan):17. [PMC free article: PMC3596851] [PubMed: 23297365]
45. Kim HJ, Hong SH, Ki CS, Kim BJ, Shim JS, Cho SH, Park JH, Kim JW. A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology. 2005;64:1964–7. [PubMed: 15955956]
46. Kim HJ, Sohn KM, Shy ME, Krajewski KM, Hwang M, Park JH, Jang SY, Won HH, Choi BO, Hong SH, Kim BJ, Suh YL, Ki CS, Lee SY, Kim SH, Kim JW. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (CMTX5). Am J Hum Genet. 2007;81:552–8. [PMC free article: PMC1950833] [PubMed: 17701900]
47. Kleopa KA, Scherer SS. Molecular genetics of X-linked Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:107–22. [PubMed: 16775370]
48. 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. Mutations in SEPT9 cause hereditary neuralgic amyotrophy. Nat Genet. 2005;37:1044–6. [PubMed: 16186812]
49. Kumar N, Muley S, Pakiam A, Parry GJ. Phenotypic variability leads to under-recognition of HNPP. J Clin Neuromuscl Dis. 2002;3:106–112. [PubMed: 19078663]
50. Lynch DR, Chance PF. Inherited peripheral neuropathies. The Neurologist. 1997;3:279–92.
51. Marques W Jr, Funayama CA, Secchin JB, Lourenço CM, Gouvêa SP, Marques VD, Bastos PG, Barreira AA. Coexistence of two chronic neuropathies in a young child: Charcot-Marie-Tooth disease type 1A and chronic inflammatory demyelinating polyneuropathy. Muscle Nerve. 2010;42:598–600. [PubMed: 20878740]
52. McGann R, Gurd A. The association between Charcot-Marie-Tooth disease and developmental dysplasia of the hip. Orthopedics. 2002;25:337–9. [PubMed: 11918042]
53. Meyer zu Horste G, Prukop T, Liebetanz D, Mobius W, Nave KA, Sereda MW. Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathy. Ann Neurol. 2007;61:61–72. [PubMed: 17262851]
54. Micallef J, Attarian S, Dubourg O, Gonnaud PM, Hogrel JY, Stojkovic T, Bernard R, Jouve E, Pitel S, Vacherot F, Remec JF, Jomir L, Azabou E, Al-Moussawi M, Lefebvre MN, Attolini L, Yaici S, Tanesse D, Fontes M, Pouget J, Blin O. Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2009;8:1103–10. [PubMed: 19818690]
55. Nelis E, Timmerman V, De Jonghe P, Van Broeckhoven C, Rautenstrauss B. Molecular genetics and biology of inherited peripheral neuropathies: a fast-moving field. Neurogenetics. 1999;2:137–48. [PubMed: 10541586]
56. Nicholson G, Myers S. Intermediate forms of Charcot-Marie-Tooth neuropathy: a review. Neuromolecular Med. 2006;8:123–30. [PubMed: 16775371]
57. Nicholson GA. The dominantly inherited motor and sensory neuropathies: clinical and molecular advances. Muscle Nerve. 2006;33:589–97. [PubMed: 16392117]
58. Nishikawa T, Kawakami K, Kumamoto T, Tonooka S, Abe A, Hayasaka K, Okamoto Y, Kawano Y. Severe neurotoxicities in a case of Charcot-Marie-Tooth disease type 2 caused by vincristine for acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008;30:519–21. [PubMed: 18797198]
59. 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. Variables influencing quality of life and disability in Charcot Marie Tooth (CMT) patients: Italian multicentre study. Neurol Sci. 2006;27:417–23. [PubMed: 17205227]
60. Pareyson D, Scaioli V, Laura M. Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:3–22. [PubMed: 16775364]
61. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009a;8:654–67. [PubMed: 19539237]
62. Pareyson D, Marchesi C. Natural history and treatment of peripheral inherited neuropathies. Adv Exp Med Biol. 2009b;652:207–24. [PubMed: 20225028]
63. Pareyson D, Reilly MM, Schenone A, Fabrizi GM, Cavallaro T, Santoro L, Vita G, Quattrone A, Padua L, Gemignani F, Visioli F, Laurà M, Radice D, Calabrese D, Hughes RA, Solari A. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Lancet Neurol. 2011;10:320–8. [PMC free article: PMC3154498] [PubMed: 21393063]
64. 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. Clinicopathological and genetic study of early-onset demyelinating neuropathy. Brain. 2004;127:2540–50. [PubMed: 15469949]
65. Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J, Thirion X, Robaglia-Schlupp A, Pellissier JF, Fontes M. Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med. 2004;10:396–401. [PubMed: 15034573]
66. Pfeiffer G, Wicklein EM, Ratusinski T, Schmitt L, Kunze K. Disability and quality of life in Charcot-Marie-Tooth disease type 1. J Neurol Neurosurg Psychiatry. 2001;70:548–50. [PMC free article: PMC1737299] [PubMed: 11254787]
67. Pitceathly RD, Murphy SM, Cottenie E, Chalasani A, Sweeney MG, Woodward C, Mudanohwo EE, Hargreaves I, Heales S, Land J, Holton JL, Houlden H, Blake J, Champion M, Flinter F, Robb SA, Page R, Rose M, Palace J, Crowe C, Longman C, Lunn MP, Rahman S, Reilly MM, Hanna MG. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology. 2012;79:1145–54. [PMC free article: PMC3525307] [PubMed: 22933740]
68. Porter CC, Carver AE, Albano EA. Vincristine induced peripheral neuropathy potentiated by voriconazole in a patient with previously undiagnosed CMT1X. Pediatr Blood Cancer. 2009;52:298–300. [PubMed: 18837430]
69. Priest JM, Fischbeck KH, Nouri N, Keats BJ. A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq24-q26. Genomics. 1995;29:409–12. [PubMed: 8666389]
70. Refshauge KM, Raymond J, Nicholson G, van den Dolder PA. Night splinting does not increase ankle range of motion in people with Charcot-Marie-Tooth disease: a randomised, cross-over trial. Aust J Physiother. 2006;52:193–9. [PubMed: 16942454]
71. Reilly MM, Shy ME. Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry. 2009;80:1304–14. [PubMed: 19917815]
72. Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2012;91:1095–102. [PMC free article: PMC3516602] [PubMed: 23217327]
73. Sahenk Z, Nagaraja HN, McCracken BS, King WM, Freimer ML, Cedarbaum JM, Mendell HR. Neurotrophin-3 treatment promotes nerve regeneration and improvements in sensory function in patients with CMT1A. Ann Neurol. 2003;54 Suppl 7:S19.
74. Said G, Lacroix C, Planté-Bordeneuve V, Messing B, Slama A, Crenn P, Nivelon-Chevallier A, Bedenne L, Soichot P, Manceau E, Rigaud D, Guiochon-Mantel A. Clinicopathological aspects of the neuropathy of neurogastrointestinal encephalomyopathy (MNGIE) in four patients including two with a Charcot-Marie-Tooth presentation. J Neurol. 2005;252:655–62. [PubMed: 15742109]
75. Saifi GM, Szigeti K, Snipes GJ, Garcia CA, Lupski JR. Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies. J Investig Med. 2003;51:261–83. [PubMed: 14577517]
76. Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol. 2011;69:22–33. [PMC free article: PMC3058597] [PubMed: 21280073]
77. Schroder JM. Neuropathology of Charcot-Marie-Tooth and related disorders. Neuromolecular Med. 2006;8:23–42. [PubMed: 16775365]
78. Sereda MW, Meyer zu Horste G, Suter U, Uzma N, Nave KA. Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med. 2003;9:1533–7. [PubMed: 14608378]
79. Sharapova T, Rechitsky S, Verlinsky Y. Preimplantation genetic diagnosis (PGD) for three types of Charcot-Marie-Tooth (CMT) disease. Am J Hum Genet. 2004;S75:A2806.
80. Soong BW, Huang YH, Tsai PC, Huang CC, Pan HC, Lu YC, Chien HJ, Liu TT, Chang MH, Lin KP, Tu PH, Kao LS, Lee YC. Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease. Am J Hum Genet. 2013;92:422–30. [PMC free article: PMC3591844] [PubMed: 23434117]
81. Stogbauer F, Young P, Kuhlenbaumer G, Kiefer R, Timmerman V, Ringelstein EB, Wang JF, Schroder JM, Van Broeckhoven C, Weis J. Autosomal dominant burning feet syndrome. J Neurol Neurosurg Psychiatry. 1999;67:78–81. [PMC free article: PMC1736450] [PubMed: 10369826]
82. Szigeti K, Nelis E, Lupski JR. Molecular diagnostics of Charcot-Marie-Tooth disease and related peripheral neuropathies. Neuromolecular Med. 2006;8:243–54. [PubMed: 16775379]
83. Udd B, Griggs R. Distal myopathies. Curr Opin Neurol. 2001;14:561–6. [PubMed: 11562566]
84. Vance JM. The many faces of Charcot-Marie-Tooth disease. Arch Neurol. 2000;57:638–40. [PubMed: 10815126]
85. Verhoeven K, Villanova M, Rossi A, Malandrini A, De Jonghe P, Timmerman V. Localization of the gene for the intermediate form of Charcot-Marie- Tooth to chromosome 10q24.1-q25.1. Am J Hum Genet. 2001;69:889–94. [PMC free article: PMC1226075] [PubMed: 11533914]
86. Verhamme C, de Haan RJ, Vermeulen M, Baas F, de Visser M, van Schaik IN. Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double-blind, placebo-controlled phase II trial. BMC Med. 2009;7:70. [PMC free article: PMC2784478] [PubMed: 19909499]
87. Vinci P, Serrao M, Millul A, Deidda A, De Santis F, Capici S, Martini D, Pierelli F, Santilli V. Quality of life in patients with Charcot-Marie-Tooth disease. Neurology. 2005a;65:922–4. [PubMed: 16186535]
88. Vinci P, Villa LM, Castagnoli L, Marconi C, Lattanzi A, Manini MP, Calicchio ML, Vitangeli L, Di Gianvito P, Perelli SL, Martini D. Handgrip impairment in Charcot-Marie-Tooth disease. Eura Medicophys. 2005b;41:131–4. [PubMed: 16200028]
89. Ward CM, Dolan LA, Bennett DL, Morcuende JA, Cooper RR. Long-term results of reconstruction for treatment of a flexible cavovarus foot in Charcot-Marie-Tooth disease. J Bone Joint Surg Am. 2008;90:2631–42. [PMC free article: PMC2663331] [PubMed: 19047708]
90. Weimer LH, Podwall D. Medication-induced exacerbation of neuropathy in Charcot Marie Tooth disease. J Neurol Sci. 2006;242:47–54. [PubMed: 16386273]
91. Yiu EM, Geevasinga N, Nicholson GA, Fagan ER, Ryan MM, Ouvrier RA. A retrospective review of X-linked Charcot-Marie-Tooth disease in childhood. Neurology. 2011;76:461–6. [PubMed: 21282593]
92. Young P, De Jonghe P, Stögbauer F. Treatment for Charcot-Marie-Tooth disease. Cochrane Database Syst Rev. 2008;23:CD006052. [PubMed: 18254090]
93. 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. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat Genet. 2005;37:289–94. [PubMed: 15731758]
94. Zuchner S, Vance JM. Mechanisms of disease: a molecular genetic update on hereditary axonal neuropathies. Nat Clin Pract Neurol. 2006;2:45–53. [PubMed: 16932520]

Suggested Reading

1. Lupski JR, Garcia CA. Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 227. Available online. Accessed 2-5-13.
2. Nicholson G, Kennerson M, Brewer M, Gardern J, Shy M. Genotypes & sensory phenotypes in 2 new X-linked neruopathies (CMTX3 and dSMAX) and dominant CMT/HMN overlap syndromes. Adv Exp Med Biol. 2009;652:201–6. [PubMed: 20225027]
3. Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet. 2011;89:308–12. [PMC free article: PMC3155164] [PubMed: 21820100]
4. Weterman MA, Sorrentino V, Kasher PR, Jakobs ME, van Engelen BG, Fluiter K, de Wissel MB, Sizarov A, Nürnberg G, Nürnberg P, Zelcer N, Schelhaas HJ, Baas F. A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy. Hum Mol Genet. 2012;21:358–70. [PMC free article: PMC3276280] [PubMed: 22012984]

Revision History

• 28 March 2013 (tb) Revision: to include GNB4 mutations as causative of dominant intermediate Charcot-Marie-Tooth Disease [Soong et al 2013]
• 7 March 2013 (tb) Revision: to include mutations in AIFM1 as causative of CMTX4
• 14 February 2013 (tb) Revision: to include mutation in PDK3 as causative of CMTX6
• 27 September 2012 (tb) Revision: report of CMT resulting from mutation in a mitochondrial gene [Pitceathly et al 2012]
• 9 February 2012 (tb) Revision: mutations in DYNC1H1 reported to be associated with CMT2O; mutation in LRSAM1 associated with CMT2P
• 31 May 2011 (me) Comprehensive update posted live
• 16 April 2009 (tb) Revision: sequence analysis available clinically for CMT4H; CMT4J added
• 24 July 2008 (tb) Revision: 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