Clinical Diagnosis

Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is diagnosed clinically in individuals with the following:

• A progressive peripheral motor and sensory neuropathy

• Nerve conduction velocities (NCVs) that are usually within the normal range (>40-45 m/s), although occasionally in a mildly abnormal range (30-40 m/s)

• EMG testing that shows evidence of an axonal neuropathy with such findings as positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses

• Greatly reduced compound motor action potentials (CMAP)

• A family history consistent with autosomal dominant inheritance

Testing

Nerve biopsy does not show the hypertrophy or onion bulb formation seen in Charcot-Marie-Tooth hereditary neuropathy type 1 (CMT1) but instead shows loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments.

Molecular Genetic Testing

Genes. Thirteen genes are known to be associated with subtypes of CMT2 [Züchner & Vance 2006b] (Table 1).

Table 1. Genes Associated with CMT2 Subtypes

View in own window

CMT2 Subtype	Gene Symbol	Reference
CMT2A1	KIF1B 1	Zhao et al [2001]
CMT2A2	MFN2 2	Verhoeven et al [2006]
CMT2B	RAB7A	Verhoeven et al [2003]
CMT2B1	LMNA	De Sandre-Giovannoli et al [2002]
CMT2B2	MED25	Leal et al [2009]
CMTC	TRPV4	Deng et al [2010], Auer-Grumbach et al [2010], Landouré et al [2010]
CMT2D	GARS
CMT2E/1F	NEFL
CMT2F	HSPB1 (HSP27)	Evgrafov et al [2004]
CMT2I/J	MPZ	Sowden et al [2005]
CMT2H/K	GDAP1	Barhoumi et al [2001], Claramunt et al [2005]
CMT2L	HSPB8 (HSP22)	Tang et al [2005]
CMT2N	AARS	McLaughlin et al [2012]
CMT2O	DYNC1H1	Weedon et al 2011
CMT2P	LRSAM1	Guersney et al [2010], Weterman et al [2012]

1. Found in one family

2. Represents approximately 20%-30% of CMT2

Other loci. Another locus for CMT2 has been mapped; no gene has yet been identified (Table 2):

Table 2. CMT2: Other Locus

View in own window

CMT2 Subtype	Chromosomal Locus	Reference
CMT2G	12q12-q13.3	Nelis et al [2004]

Clinical testing (CMT2A1, CMT2A2, CMT2B, CMT2B1, CMT2B2, CMT2C, CMT2D, CMT2E/1F, CMT2F, CMT2I/J, CMT2H/K, CMT2L, CMT2N)

• Sequence analysis. Sequence analysis of KIFB1, MFN2, RAB7A, LMNA, MED25, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8 and AARS is available on a clinical basis.

• Mutation scanning of MFN2 and MPZ is available clinically.

• Targeted mutation analysis for the p.Ala335Val mutation in MED25 is available on a clinical basis.

Table 3. Summary of Molecular Genetic Testing Used in CMT2

View in own window

Gene Symbol / Locus Name	Test Method	Mutations Detected	Proportion of CMT2 Attributed to Mutations in This Gene	Mutation Detection Frequency 1	Test Availability
KIF1B / CMT2A1	Sequence analysis	Sequence variants 2	Rare	Unknown	Clinical
MFN2 / CMT2A2	Sequence analysis and mutation scanning 3	Sequence variants 2	20%	Unknown	Clinical
RAB7A / CMT2B	Mutation scanning	Sequence variants 2	Rare	Unknown	Clinical
LMNA / CMT2B1	Sequence analysis	Sequence variants 2	Rare	Unknown	Clinical
	Deletion / duplication analysis 4	Deletions or duplications 5		Unknown
MED25 / CMT2B2	Mutation scanning of selected exons 3	Sequence variants 2	Rare	Unknown	Clinical
	Targeted mutation analysis	p.Ala335Val
TRPV4 / CMT2C	Sequence analysis	Sequence variants 2	Rare	Unknown	Clinical
GARS / CMT2D	Sequence analysis	Sequence variants 2	Rare	Unknown	Clinical
NEFL / CMT2E/1F		Sequence variants 2	Rare	Unknown	Clinical
HSPB1 / CMT2F		Sequence variants 2	Rare	Unknown	Clinical
Unknown / CMT2G	Linkage analysis		Rare	Unknown	Research only
MPZ / CMT2I/J	Sequence analysis, mutation scanning 6	Sequence variants 2	Rare	Unknown	Clinical
	Deletion / duplication analysis 4	Deletions or duplications 5		Unknown
GDAP1 / CMT2H/K	Sequence analysis	Sequence variants 2	Rare	Unknown	Clinical
HSPB8 / CMT2L	Sequence analysis	Sequence variants 2	Rare	Unknown	Clinical
AARS / CMT2N	Sequence analysis	Sequence variants 2	Rare	Unknown	Clinical
DYNC1H1 / CMT2O	Sequence analysis	Sequence variants 2	Rare		Research only
LRSAM1 / CMT2P	Sequence analysis	Sequence variants 2	Rare		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. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Selected exons for testing may vary among laboratories.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

5. No deletions or duplications have been reported involving these genes as causative of CMT2. However, newly available deletion/duplication testing methods may define mutations in individuals where prior testing by sequence analysis of the entire coding region was negative.

6. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies, although mutation scanning detection rates may vary considerably among laboratories as that method is highly dependent on details of the methodology employed.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the diagnosis of a CMT2 subtype the proband should first be tested for mutations in MFN2, MPZ, and GJB1 (encoding connexin 32) as these are the most common genes responsible for this syndrome, probably accounting for 20%-25% of cases [Züchner & Vance 2006b, Bienfait et al 2007, Saporta et al 2011].

Note: If there is male-to-male transmission in the family it is not necessary to check GJB1, an X-linked gene.

If no mutation is identified in these three genes, many neurologists do no further genetic tests because the other known genes are quite rare and many genetic causes remain to be discovered. Patients who wish to exhaust all possibilities may wish to proceed with the other clinically available tests relevant to CMT2 (e.g., NEFL, GDAP1, RAB7A, MED25, TRPV4, AARS). If the phenotype includes vocal cord paresis, molecular genetic testing of GDAP1 and TRPV4 is appropriate.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

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).

Genetically Related (Allelic) Disorders

KIF1B. CMT2A is the only phenotype known to be associated with KIF1B.

MFN2. CMT2A is the only phenotype known to be associated with MFN2.

RAB7A. CMT2B is the only phenotype known to be associated with RAB7A.

LMNA. In addition to CMT2B1, the following phenotypes are associated with pathologic or normal variations in LMNA:

• Hutchinson-Gilford progeria syndrome (HGPS or progeria)

• Autosomal dominant Emery-Dreifuss muscular dystrophy type 2 (EMD2). See Emery-Dreifuss Muscular Dystrophy (EDMD).

• Autosomal recessive Emery-Dreifuss muscular dystrophy type 2 (EMD2). See EDMD.

• Autosomal dominant familial dilated cardiomyopathy and conduction system defects (CMD1A) (see Dilated Cardiomyopathy Overview)

• Autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD)

• Autosomal dominant limb-girdle muscular dystrophy 1B (LGMD1B). See Limb-Girdle Muscular Dystrophy Overview.

• A normal allelic variant in LMNA (NM_170707.2:c.1908C>T) associated with obesity-related traits in Canadian Oji-Cree

• Autosomal recessive mandibuloacral dysplasia (MAD). A compound heterozygous mutation p.[Arg471Cys]+ [Arg527Cys] in a 28-year-old woman with mandibuloacral dysplasia, previously diagnosed as "atypical progeria," was reported [Cao & Hegele 2003].

• Atypical Werner syndrome [Chen et al 2003]

• A single case report of a male heterozygous for the mutation p.Arg133Leu with lipoatrophy, disseminated white skin papules, hypertrophic cardiomyopathy, hepatic steatosis, and insulin resistance [Caux et al 2003]

• Co-occurrence of myopathy and neuropathy [Benedetti et al 2005, Walter et al 2005]

See OMIM 150330 for additional references regarding other laminopathies.

TRPV4. In addition to CMT2C, TRPV4 has been associated with both brachyolmia and metaphyseal dysplasia [Rock et al 2008, Krakow et al 2009]

GARS. In addition to CMT2D, the other phenotype associated with mutations in GARS is hereditary motor neuropathy type 5 (HMN V) [Antonellis et al 2003].

NEFL. CMT2E/1F is the only phenotype known to be associated with mutations in NEFL.

HSPB1. CMT2F is the only phenotype known to be associated with mutations in HSPB1.

MPZ. In addition to CMT2I and CMT2J, mutations in MPZ are associated with CMT1B (see CMT1) [Senderek et al 2000].

GDAP1. In addition to CMT2H/K, autosomal recessive CMT4A is associated with mutations in GDAP1.

HSPB8. In addition to CMT2L, mutations in HSPB8 have been reported in distal hereditary motor neuropathy type 2 (dHMNII) [Irobi et al 2004b].

AARS. CMT2N is the only phenotype known to be associated with mutations in AARS.

DYNC1H1. CMT2O is the only phenotype known to be associated with mutations in DYNC1H1.

LRSAM1. CMT2P is the only phenotype known to be associated with mutations in LRSAM1.

Natural History

Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is a disorder of peripheral nerves in which the motor system is more prominently involved than the sensory system, although both are involved [Pareyson & Marchesi 2009]. The affected individual typically has slowly progressive weakness and atrophy of distal muscles in the feet and/or hands usually associated with depressed tendon reflexes and mild or no sensory loss. The clinical syndrome overlaps extensively with CMT1. With the exception of CMT2B, CMT2 tends to be less disabling and to cause less sensory loss than CMT1 [Bienfait et al 2006, Pareyson et al 2006].

Affected individuals usually become symptomatic between ages five and 25 years [Bienfait et al 2006], though onset ranges from infancy with delayed walking to after the third decade. The typical presenting symptom is weakness of the feet and ankles. The initial physical findings are depressed or absent tendon reflexes with weakness of foot dorsiflexion at the ankle.

The adult with CMT2 typically has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance) and absent tendon reflexes in the lower extremities. However, brisk tendon reflexes and extensor plantar responses have been reported as well as asymmetric muscle atrophy in up to 15% of affected individuals [Bienfait et al 2007].

Atrophy of intrinsic hand muscles is less frequently present and tendon reflexes may be intact in the upper limbs.

Proximal muscles usually remain strong. Brisk tendon reflexes and extensor plantar responses have been reported [Bienfait et al 2007].

Mild sensory deficits of position, vibration, and pain/temperature may occur in the feet or sensation may be intact. Pain, especially in the feet, is reported by about 20%-40% of affected individuals [Gemignani et al 2004]. Hearing impairment has been reported [Bienfait et al 2006].

Optic atrophy may occur in CMT2A [Züchner et al 2006].

A few individuals have vocal cord or phrenic nerve involvement resulting in difficulty with phonation or breathing [Dematteis et al 2001, Sulica et al 2001].

Restless legs and sleep apnea have been associated with CMT2 [Aboussouan et al 2007].

CMT2 is progressive over many years, but affected individuals experience long plateau periods without obvious deterioration. In some, the disease can be so mild as to go unrecognized by the affected individual and physician. The disease does not decrease life span.

CMT2 subtypes

• CMT2A (comprising CMT2A1 and CMT2A2) has a typical CMT phenotype with onset in the second or third decade of distal muscle weakness and atrophy, less severe sensory loss, and depressed tendon reflexes. NCVs fall within the normal or near-normal range, compatible with an axonal neuropathy. Clinical features of families with MFN2 mutations are described by Züchner et al [2004a] and Kijima et al [2005]. Optic atrophy may occur in CMT2A [Züchner et al 2006].

• CMT2B has prominent sensory loss with distal ulceration; controversy exists regarding its exact classification. Additional phenotype information is presented in Auer-Grumbach et al [2000], Verhoeven et al [2003], and Houlden et al [2004].

• CMT2B1 is found primarily in Algeria. Mean age of onset is 14 years (range 6-27 years); functional disability ranges from mild to severe [Tazir et al 2004].

• CMT2B2 occurred in a Costa Rican family with adult onset [Leal et al 2001, Berghoff et al 2004].

• CMT2C is associated with frequent vocal cord and phrenic nerve paralysis sometimes requiring tracheotomy [Santoro et al 2002, McEntagart et al 2005]. Mild sensory loss was noted in the individuals reported by Dyck et al [1994].

• CMT2D is characterized by predominately distal motor weakness with wasting of the hand muscles [Antonellis et al 2003].

• CMT2E/1F has been reported in several families with a progressive sensory and motor neuropathy. The full range of phenotype may overlap with the CMT1 syndrome characterized by slow NCV [Georgiou et al 2002; Jordanova et al 2003; Züchner et al 2004a]. A Belgian family had NCVs ranging from 25 to 42 m/s, overlapping both axonal and demyelinating phenotypes [De Jonghe et al 2001]. A Russian family had relatively normal NCV and hyperkeratosis [Mersiyanova et al 2000]. It is unknown if the presence of hyperkeratosis is coincidental or represents variable expressivity of the CMT2E/1F phenotype.

• CMT2F has been reported in a single Russian family with distal weakness, atrophy, and sensory loss beginning between ages 15 and 25 years. This disorder is similar to distal hereditary motor neuropathy (HMN), except that there is no sensory loss in HMN [Ismailov et al 2001, Evgrafov et al 2004, Irobi et al 2004a].

• CMT2G has been reported in a single Spanish family [Nelis et al 2004].

• CMT2H has associated pyramidal features [Barhoumi et al 2001] and CMT2K is associated with the p.Arg120Trp and Thr157Pro mutations in GDAP1 [Claramunt et al 2005]

• CMT2I has only mild slowing of NCV [Li et al 2006].

• CMT2J. The MPZ mutation p.Thr134Met is associated with an axonal neuropathy with deafness and Argyll Robertson pupils [Chapon et al 1999]. In addition, the pathologic allelic variants p.Thr134Met and p.Asp85Val have been associated with axonal neuropathy and marked sensory impairment, Adie's pupil, and deafness [Misu et al 2000].

• CMT2L has been reported in a single Chinese family, with onset between ages 15 and 33 years and normal NCV [Tang et al 2004, Tang et al 2005].

• CMT2N has been reported in two French families and in one Australian family. The recurrent loss-of-function AARS mutation p.Arg329His segregates with and results in the CMT phenotype in each of these families [Latour et al 2010, McLaughlin et al 2012].

• CMT2O has been reported in a large family with childhood onset of delayed motor milestones associated with progressive distal lower limb weakness, pes cavus, variable sensory loss, and normal nerve conductions. Occasional proximal weakness and waddling gait were noted [Weedon et al 2011].

• CMT2P has been reported in a large rural Canadian family with onset of progressive distal muscle weakness and atrophy usually starting in young adulthood [Guernsey et al 2010]. Nerve electrophysiology was consistent with an axonal neuropathy. The inheritance was autosomal recessive and associated with a homozygous single nucleotide change in an intronic consensus acceptor splicing site of LRSAM1. Weterman et al [2011] reported a three-generation Dutch family with onset in the second or third decade of slowly progressive distal weakness and atrophy with mild sensory loss and an axonal neuropathy. The disease was autosomal dominant and caused by a frameshift mutation (p.Leu708Arg fx28) in LRSAM1.

Neuropathology. The disease process is presumed to occur in the axon or cytoplasm of the anterior horn cell neuron. Anterior horn cell loss has been found in two autopsies [Schroder 2006].

In CMT2E, electron microscopy has shown giant axons with accumulation of disorganized neurofilaments [Fabrizi et al 2004].

Genotype-Phenotype Correlations

Few specific genotype-phenotype correlations are known. Considerable variability of phenotype has been observed within a family [Züchner et al 2004a].

Optic atrophy is associated with mutations in MFN2 [Verhoeven et al 2006, Züchner et al 2006].

Penetrance

Penetrance is usually nearly complete; however, some subtypes of CMT2 are associated with adult onset of symptoms.

Nomenclature

CMT2A. In addition to the pure CMT2A phenotype, optic atrophy has been reported in a number of individuals [Züchner et al 2006]; this disorder is also known as hereditary motor and sensory neuropathy VI (HMSN VI).

CMT2 with pyramidal signs, also known as hereditary motor and sensory neuropathy V (HMSN V), has been associated with MFN2 mutations [Zhu et al 2005] and with mutations in BSCL2 [Bienfait et al 2007] (see BSCL2-Related Neurologic Disorders).

CMT2C. Previously this has sometimes been called scapuloperoneal spinal muscular atrophy.

CMT2E/1F. Some individuals with mutations in NEFL, which typically cause CMT2E, may have slow NCVs, resulting in a diagnosis of CMT1F. To accommodate these two phenotypes associated with mutations in NEFL, the designation CMT2E/1F has been used.

Prevalence

The overall prevalence of hereditary neuropathies is estimated at approximately 3:10,000 population. About 30% of these individuals (1:10,000) may have CMT2. The prevalence of the various subtypes of CMT2 is unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2), the following evaluations are recommended:

• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss

• Nerve conduction velocity (NCV)

• Complete family history

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 [Grandis & Shy 2005].

The following may be indicated:

• Special shoes, including those with good ankle support

• Ankle/foot orthoses (AFO) to correct foot drop and aid walking

• Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000]

• Forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.

• Treatment of sleep apnea or restless legs [Aboussouan et al 2007]

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

Pain and depression should be treated symptomatically [Gemignani et al 2004, Padua et al 2006].

Prevention of Secondary Complications

Daily heel cord-stretching exercises are helpful in preventing Achilles' tendon shortening.

Surveillance

Gait and condition of feet should be monitored to determine need for bracing, special shoes, or surgery.

Agents/Circumstances to Avoid

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

Medications which 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 4. For more information, click here (pdf).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Career and employment choices may be influenced by persistent weakness of hands and/or feet.

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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

CMT2B1, CMT2B2, CMT2H, and CMT2K are inherited in an autosomal recessive manner; all other subtypes of Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) are inherited in an autosomal dominant manner.

CMT2P has been reported to be inherited in an autosomal recessive manner in one family and in an autosomal dominant manner in one family.

Risk to Family Members — Autosomal Dominant CMT2

Parents of a proband

• Most individuals with autosomal dominant CMT2 have an affected parent.

• A proband with autosomal dominant CMT2 may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown but likely very small.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include neurologic examination and molecular genetic testing if the mutation in the proband has been identified.

Note: Although most individuals diagnosed with autosomal dominant CMT2 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband. The risk to sibs depends on the genetic status of the proband's parents.

• If a parent has a disease-causing mutation, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. No instances of germline mosaicism have been reported, although it remains a possibility.

Offspring of a proband. Every child of an individual with autosomal dominant CMT2 has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected and/or has a disease-causing mutation, his or her family members are at risk.

Risk to Family Members — Autosomal Recessive CMT2

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual 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 risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive CMT2 are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members for CMT2B1 and CMT2K is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal 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. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made 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.

Testing of at-risk asymptomatic adults. Asymptomatic adults at risk of having inherited a mutation associated with autosomal dominant CMT2 may wish to pursue further clinical evaluation and NCV testing. No treatment is available to individuals early in the course of the disease. Thus, such testing is for personal decision making only.

Testing of at-risk asymptomatic individuals during childhood. Testing of at-risk asymptomatic individuals who are younger than age 18 years is not appropriate. 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.

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 testing for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for most subtypes of CMT2 is available by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele(s) must be identified before prenatal testing can be performed.

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

For some subtypes of CMT2, no laboratories offering prenatal testing are listed in the GeneTests™ Laboratory Directory. However, for these subtypes prenatal testing may be available for families in which a disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see testing.

Requests for prenatal testing for conditions which (like CMT2) do not affect intellect or life span are not common. Differences in perspectives 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 regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) of CMT2E has been reported [Sharapova et al 2004]. Preimplantation genetic diagnosis of other CMT2 subtypes may be available for families in which the disease-causing mutation(s) have been identified. For laboratories offering PGD, see testing.

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).

Molecular Genetic Pathogenesis

The relationship of myelin and axon pathology to the pathogenesis of CMT is discussed in detail in several reviews [Krajewski et al 2000, Berger et al 2002, Maier et al 2002, Züchner & Vance 2006a, Züchner & Vance 2006b].

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 at www.ashg.org. 1995. Accessed 2-6-12.
2. National Society of Genetic Counselors. Resolution on prenatal and childhood testing for adult-onset disorders. Available at www.nsgc.org. 1995. Accessed 2-6-12.

Literature Cited

1. Aboussouan LS, Lewis RA, Shy ME. Disorders of pulmonary function, sleep, and the upper airway in Charcot-Marie-Tooth disease. Lung. 2007;185:1–7. [PubMed: 17294338]
2. Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, Green ED. Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V. Am J Hum Genet. 2003;72:1293–9. [PMC free article: PMC1180282] [PubMed: 12690580]
3. Auer-Grumbach M, De Jonghe P, Wagner K, Verhoeven K, Hartung HP, Timmerman V. Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus. Neurology. 2000;55:1552–7. [PubMed: 11094113]
4. 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]
5. Auer-Grumbach M, Olschewski A, Papić L, Kremer H, McEntagart ME, Uhrig S, Fischer C, Fröhlich E, Bálint Z, Tang B, Strohmaier H, Lochmüller H, Schlotter-Weigel B, Senderek J, Krebs A, Dick KJ, Petty R, Longman C, Anderson NE, Padberg GW, Schelhaas HJ, van Ravenswaaij-Arts CM, Pieber TR, Crosby AH, Guelly C. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet. 2010;42:160–4. [PMC free article: PMC3272392] [PubMed: 20037588]
6. Baloh RH, Schmidt RE, Pestronk A, Milbrandt J. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci. 2007;27:422–30. [PubMed: 17215403]
7. Barhoumi C, Amouri R, Ben Hamida C, Ben Hamida M, Machghoul S, Gueddiche M, Hentati F. Linkage of a new locus for autosomal recessive axonal form of Charcot-Marie-Tooth disease to chromosome 8q21.3. Neuromuscul Disord. 2001;11:27–34. [PubMed: 11166163]
8. Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, Hentati F, Ben Hamida M, Bel S, Stenger JE, Gilbert JR, Pericak-Vance MA, Vance JM. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet. 2002;30:21–2. [PubMed: 11743579]
9. Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L, de Jong P, Brown RH. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet. 2001;27:261–2. [PubMed: 11242106]
10. Bellone E, Rodolico C, Toscano A, Di Maria E, Cassandrini D, Pizzuti A, Pigullo S, Mazzeo A, Macaione V, Girlanda P, Vita G, Ajmar F, Mandich P. A family with autosomal dominant mutilating neuropathy not linked to either Charcot-Marie-Tooth disease type 2B (CMT2B) or hereditary sensory neuropathy type I (HSN I) loci. Neuromuscul Disord. 2002;12:286–91. [PubMed: 11801401]
11. Benedetti S, Bertini E, Iannaccone S, Angelini C, Trisciani M, Toniolo D, Sferrazza B, Carrera P, Comi G, Ferrari M, Quattrini A, Previtali SC. Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathy. J Neurol Neurosurg Psychiatry. 2005;76:1019–21. [PMC free article: PMC1739728] [PubMed: 15965218]
12. Berger P, Young P, Suter U. Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics. 2002;4:1–15. [PubMed: 12030326]
13. Berghoff C, Berghoff M, Leal A, Morera B, Barrantes R, Reis A, Neundorfer B, Rautenstrauss B, Del Valle G, Heuss D. Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3. Neuromuscul Disord. 2004;14:301–6. [PubMed: 15099588]
14. Bienfait HM, Baas F, Koelman JH, de Haan RJ, van Engelen BG, Gabreels-Festen AA, Ongerboer de Visser BW, Meggouh F, Weterman MA, De Jonghe P, Timmerman V, de Visser M. Phenotype of Charcot-Marie-Tooth disease Type 2. Neurology. 2007;68:1658–67. [PubMed: 17502546]
15. Bienfait HM, Verhamme C, van Schaik IN, Koelman JH, de Visser BW, de Haan RJ, Baas F, van Engelen BG, de Visser M. Comparison of CMT1A and CMT2: similarities and differences. J Neurol. 2006;253:1572–80. [PubMed: 16941080]
16. Boyer O, Nevo F, Plaisier E, Funalot B, Gribouval O, Benoit G, Cong EH, Arrondel C, Tête MJ, Montjean R, Richard L, Karras A, Pouteil-Noble C, Balafrej L, Bonnardeaux A, Canaud G, Charasse C, Dantal J, Deschenes G, Deteix P, Dubourg O, Petiot P, Pouthier D, Leguern E, Guiochon-Mantel A, Broutin I, Gubler MC, Saunier S, Ronco P, Vallat JM, Alonso MA, Antignac C, Mollet G. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy. N Engl J Med. 2011;365:2377–88. [PubMed: 22187985]
17. Cao H, Hegele RA. LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J Hum Genet. 2003;48:271–4. [PubMed: 12768443]
18. Caux F, Dubosclard E, Lascols O, Buendia B, Chazouilleres O, Cohen A, Courvalin JC, Laroche L, Capeau J, Vigouroux C, Christin-Maitre S. A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab. 2003;88:1006–13. [PubMed: 12629077]
19. Chapon F, Latour P, Diraison P, Schaeffer S, Vandenberghe A. Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene. J Neurol Neurosurg Psychiatry. 1999;66:779–82. [PMC free article: PMC1736388] [PubMed: 10329755]
20. Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J. LMNA mutations in atypical Werner's syndrome. Lancet. 2003;362:440–5. [PubMed: 12927431]
21. Claramunt R, Pedrola L, Sevilla T, Lopez de Munain A, Berciano J, Cuesta A, Sanchez-Navarro B, Millan JM, Saifi GM, Lupski JR, Vilchez JJ, Espinos C, Palau F. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet. 2005;42:358–65. [PMC free article: PMC1736030] [PubMed: 15805163]
22. De Jonghe P, Mersivanova I, Nelis E, Del Favero J, Martin JJ, Van Broeckhoven C, Evgrafov O, Timmerman V. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E. Ann Neurol. 2001;49:245–9. [PubMed: 11220745]
23. De Sandre-Giovannoli A, Chaouch M, Kozlov S, Vallat JM, Tazir M, Kassouri N, Szepetowski P, Hammadouche T, Vandenberghe A, Stewart CL, Grid D, Levy N. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot- Marie-Tooth disorder type 2) and mouse. Am J Hum Genet. 2002;70:726–36. [PMC free article: PMC384949] [PubMed: 11799477]
24. Dematteis M, Pepin JL, Jeanmart M, Deschaux C, Labarre-Vila A, Levy P. Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study. Lancet. 2001;357:267–72. [PubMed: 11214130]
25. Deng H-X, Klein CJ, Yan J, Shi Y, Wu Y, Fecto F, Yau H-J, Yang Y, Zhai H, Siddique N, Hedley-Whyte ET, DeLong R, Martina M, Dyck PJ, Siddique T. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet. 2010;42:165–169. [PubMed: 20037587]
26. Dyck PJ, Litchy WJ, Minnerath S, Bird TD, Chance PF, Schaid DJ, Aronson AE. Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol. 1994;35:608–15. [PubMed: 8179305]
27. Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, Schagina O, Verpoorten N, Van Impe K, Fedotov V, Dadali E, Auer-Grumbach M, Windpassinger C, Wagner K, Mitrovic Z, Hilton-Jones D, Talbot K, Martin JJ, Vasserman N, Tverskaya S, Polyakov A, Liem RK, Gettemans J, Robberecht W, De Jonghe P, Timmerman V. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet. 2004;36:602–6. [PubMed: 15122254]
28. Fabrizi GM, Cavallaro T, Angiari C, Bertolasi L, Cabrini I, Ferrarini M, Rizzuto N. Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Neurology. 2004;62:1429–31. [PubMed: 15111691]
29. Gemignani F, Melli G, Alfieri S, Inglese C, Marbini A. Sensory manifestations in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2004;9:7–14. [PubMed: 14871449]
30. Georgiou DM, Zidar J, Korosec M, Middleton LT, Kyriakides T, Christodoulou K. A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family. Neurogenetics. 2002;4:93–6. [PubMed: 12481988]
31. 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(7):1356–62. [PubMed: 8608515]
32. Grandis M, Shy ME. Current therapy for Charcot-Marie-Tooth disease. Curr Treat Options Neurol. 2005;7:23–31. [PubMed: 15610704]
33. Guernsey DL, Jiang H, Bedard K, Evans SC, Ferguson M, Matsuoka M, Macgillivray C, Nightingale M, Perry S, Rideout AL, Orr A, Ludman M, Skidmore DL, Benstead T, Samuels ME (2010) Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease. PLoS Genet. 2010 Aug 26;6(8). pii: e1001081.
34. Gutierrez A, England JD, Sumner AJ, Ferer S, Warner LE, Lupski JR, Garcia CA. Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth disease. Muscle Nerve. 2000;23:182–8. [PubMed: 10639608]
35. 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]
36. Houlden H, King RH, Muddle JR, Warner TT, Reilly MM, Orrell RW, Ginsberg L. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann Neurol. 2004;56:586–90. [PubMed: 15455439]
37. Irobi J, De Jonghe P, Timmerman V. Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet. 2004a;13(Spec No 2):R195–202. [PubMed: 15358725]
38. Irobi J, Van Impe K, Seeman P, Jordanova A, Dierick I, Verpoorten N, Michalik A, De Vriendt E, Jacobs A, Van Gerwen V, Vennekens K, Mazanec R, Tournev I, Hilton-Jones D, Talbot K, Kremensky I, Van Den Bosch L, Robberecht W, Van Vandekerckhove J, Van Broeckhoven C, Gettemans J, De Jonghe P, Timmerman V. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet. 2004b;36:597–601. [PubMed: 15122253]
39. Ismailov SM, Fedotov VP, Dadali EL, Polyakov AV, Van Broeckhoven C, Ivanov VI, De Jonghe P, Timmerman V, Evgrafov OV. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21. Eur J Hum Genet. 2001;9:646–50. [PubMed: 11528513]
40. Jordanova A, De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick C, Martin JJ, Butler IJ, Mancias P, Papasozomenos SCh, Terespolsky D, Potocki L, Brown CW, Shy M, Rita DA, Tournev I, Kremensky I, Lupski JR, Timmerman V. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain. 2003;126:590–7. [PubMed: 12566280]
41. 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]
42. Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M, Ishizaki Y, Kitamura T, Shozawa Y, Hayasaka K. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet. 2005;116:23–7. [PubMed: 15549395]
43. Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, Kamholz J, Shy ME. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain. 2000;123(Pt 7):1516–27. [PubMed: 10869062]
44. Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, Okenfuss EB, Janssens A, Voets T, Rimoin DL, Lachman RS, Nilius B, Cohn DH. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet. 2009;84:307–15. [PMC free article: PMC2667978] [PubMed: 19232556]
45. Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet. 2010;42:170–4. [PMC free article: PMC2812627] [PubMed: 20037586]
46. Latour P, Thauvin-Robinet C, Baudelet-Méry C, Soichot P, Cusin V, Faivre L, Locatelli MC, Mayençon M, Sarcey A, Broussolle E, Camu W, David A, Rousson R. A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet. 2010;86:77–82. [PMC free article: PMC2801750] [PubMed: 20045102]
47. Leal A, Morera B, Del Valle G, Heuss D, Kayser C, Berghoff M, Villegas R, Hernandez E, Mendez M, Hennies HC, Neundorfer B, Barrantes R, Reis A, Rautenstrauss B. A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3. Am J Hum Genet. 2001;68:269–74. [PMC free article: PMC1234926] [PubMed: 11112660]
48. Leal A, Huehne K, Bauer F, Sticht H, Berger P, Suter U, Morera B, Del Valle G, Lupski JR, Ekici A, Pasutto F, Endele S, Barrantes R, Berghoff C, Berghoff M, Neundörfer B, Heuss D, Dorn T, Young P, Santolin L, Uhlmann T, Meisterernst M, Sereda MW, Stassart RM, Zu Horste GM, Nave KA, Reis A, Rautenstrauss B. Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models. Neurogenetics. 2009;10:275–87. [PMC free article: PMC2847151] [PubMed: 19290556]
49. Li J, Bai Y, Ianakova E, Grandis M, Uchwat F, Trostinskaia A, Krajewski KM, Garbern J, Kupsky WJ, Shy ME. Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration. J Comp Neurol. 2006;498:252–65. [PubMed: 16856127]
50. Lopez-Bigas N, Olive M, Rabionet R, Ben-David O, Martinez-Matos JA, Bravo O, Banchs I, Volpini V, Gasparini P, Avraham KB, Ferrer I, Arbones ML, Estivill X. Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Hum Mol Genet. 2001;10:947–52. [PubMed: 11309368]
51. Maier M, Berger P, Suter U. Understanding Schwann cell-neurone interactions: the key to Charcot- Marie-Tooth disease? J Anat. 2002;200:357–66. [PMC free article: PMC1570699] [PubMed: 12090402]
52. McEntagart M, Norton N, Williams H, Teare MD, Dunstan M, Baker P, Houlden H, Reilly M, Wood N, Harper PS, Futreal PA, Williams N, Rahman N. Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14. Am J Hum Genet. 2001;68:1270–6. [PMC free article: PMC1226107] [PubMed: 11294660]
53. McEntagart ME, Reid SL, Irtthum A, Douglas JB, Eyre KE, Donaghy MJ, Anderson NE, Rahman N. Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24. Ann Neurol. 2005;57:293–7. [PubMed: 15668982]
54. McLaughlin HM, Sakaguchi R, Giblin W. A Recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with charcot-marie-tooth disease type 2N (CMT2N). Hum Mutat. 2012;33:244–53. [PMC free article: PMC3240693] [PubMed: 22009580]
55. Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, Oparin RB, Petrin AN, Evgrafov OV. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet. 2000;67:37–46. [PMC free article: PMC1287099] [PubMed: 10841809]
56. Misu K, Yoshihara T, Shikama Y, Awaki E, Yamamoto M, Hattori N, Hirayama M, Takegami T, Nakashima K, Sobue G. An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val). J Neurol Neurosurg Psychiatry. 2000;69:806–11. [PMC free article: PMC1737183] [PubMed: 11080237]
57. Nelis E, Berciano J, Verpoorten N, Coen K, Dierick I, Van Gerwen V, Combarros O, De Jonghe P, Timmerman V. Autosomal dominant axonal Charcot-Marie-Tooth disease type 2 (CMT2G) maps to chromosome 12q12-q13.3. J Med Genet. 2004;41:193–7. [PMC free article: PMC1735709] [PubMed: 14985381]
58. Nelis E, Haites N, Van Broeckhoven C. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies. Hum Mutat. 1999;13:11–28. [PubMed: 9888385]
59. 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]
60. 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]
61. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8:654–67. [PubMed: 19539237]
62. Pareyson D, Scaioli V, Laura M. Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:3–22. [PubMed: 16775364]
63. Perez-Olle R, Jones ST, Liem RK. Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models. Hum Mol Genet. 2004;13:2207–20. [PubMed: 15282209]
64. 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]
65. Rock MJ, Prenen J, Funari TL, Merriman B, Nelson SF, Lachman RS, Wilcox WR, Reyno S, Quadrelli R, Vaglio A, Owsianik G, Janssens A, Voets T, Ikegawa S, Nagai T, Rimoin DL, Nilius B, Cohn DH. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet. 2008;40:999–1003. [PubMed: 18587396]
66. Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, Brown RH, Ludlow CL, Fischbeck KH. Mutant dynactin in motor neuron disease. Nat Genet. 2003;33:455–6. [PubMed: 12627231]
67. Santoro L, Manganelli F, Di Maio L, Barbieri F, Carella M, D'Adamo P, Casari G. Charcot-Marie-Tooth disease type 2C: a distinct genetic entity. Clinical and molecular characterization of the first European family. Neuromuscul Disord. 2002;12:399–404. [PubMed: 12062259]
68. 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]
69. Schroder JM. Neuropathology of Charcot-Marie-Tooth and related disorders. Neuromolecular Med. 2006;8:23–42. [PubMed: 16775365]
70. Senderek J, Hermanns B, Lehmann U, Bergmann C, Marx G, Kabus C, Timmerman V, Stoltenburg-Didinger G, Schroder JM. Charcot-Marie-Tooth neuropathy type 2 and P0 point mutations: two novel amino acid substitutions (Asp61Gly; Tyr119Cys) and a possible "hotspot" on Thr124Met. Brain Pathol. 2000;10:235–48. [PubMed: 10764043]
71. 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.
72. Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, Shy RR, Balsamo J, Lilien J, Garbern JY, Kamholz J. Phenotypic clustering in MPZ mutations. Brain. 2004;127:371–84. [PubMed: 14711881]
73. 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]
74. Sowden JE, Logigian EL, Malik K, Herrmann DN. Genotype-phenotype correlation in a family with late onset CMT and an MPZ lys236del mutation. J Neurol Neurosurg Psychiatry. 2005;76:442–4. [PMC free article: PMC1739547] [PubMed: 15716547]
75. Sulica L, Blitzer A, Lovelace RE, Kaufmann P. Vocal fold paresis of Charcot-Marie-Tooth disease. Ann Otol Rhinol Laryngol. 2001;110:1072–6. [PubMed: 11713921]
76. Takashima H, Nakagawa M, Suehara M, Saito M, Saito A, Kanzato N, Matsuzaki T, Hirata K, Terwilliger JD, Osame M. Gene for hereditary motor and sensory neuropathy (proximal dominant form) mapped to 3q13.1. Neuromuscul Disord. 1999;9:368–71. [PubMed: 10545038]
77. Tang BS, Luo W, Xia K, Xiao JF, Jiang H, Shen L, Tang JG, Zhao GH, Cai F, Pan Q, Dai HP, Yang QD, Xia JH, Evgrafov OV. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Hum Genet. 2004;114:527–33. [PubMed: 15021985]
78. Tang BS, Zhao GH, Luo W, Xia K, Cai F, Pan Q, Zhang RX, Zhang FF, Liu XM, Chen B, Zhang C, Shen L, Jiang H, Long ZG, Dai HP. Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Hum Genet. 2005;116:222–4. [PubMed: 15565283]
79. Tazir M, Azzedine H, Assami S, Sindou P, Nouioua S, Zemmouri R, Hamadouche T, Chaouch M, Feingold J, Vallat JM, Leguern E, Grid D. Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C. Brain. 2004;127:154–63. [PubMed: 14607793]
80. Verhoeven K, Claeys KG, Züchner S, Schroder JM, Weis J, Ceuterick C, Jordanova A, Nelis E, De Vriendt E, Van Hul M, Seeman P, Mazanec R, Saifi GM, Szigeti K, Mancias P, Butler IJ, Kochanski A, Ryniewicz B, De Bleecker J, Van den Bergh P, Verellen C, Van Coster R, Goemans N, Auer-Grumbach M, Robberecht W, Milic Rasic V, Nevo Y, Tournev I, Guergueltcheva V, Roelens F, Vieregge P, Vinci P, Moreno MT, Christen HJ, Shy ME, Lupski JR, Vance JM, De Jonghe P, Timmerman V. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain. 2006;129:2093–102. [PubMed: 16714318]
81. Verhoeven K, De Jonghe P, Coen K, Verpoorten N, Auer-Grumbach M, Kwon JM, FitzPatrick D, Schmedding E, De Vriendt E, Jacobs A, Van Gerwen V, Wagner K, Hartung HP, Timmerman V. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet. 2003;72:722–7. [PMC free article: PMC1180247] [PubMed: 12545426]
82. 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]
83. Vucic S, Kennerson M, Zhu D, Miedema E, Kok C, Nicholson GA. CMT with pyramidal features. Neurology. 2003;60:696–9. [PubMed: 12601114]
84. Walter MC, Witt TN, Weigel BS, Reilich P, Richard P, Pongratz D, Bonne G, Wehnert MS, Lochmuller H. Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant Emery-Dreifuss muscular dystrophy. Neuromuscul Disord. 2005;15:40–4. [PubMed: 15639119]
85. 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]
86. Weimer LM, Podwall D. Medication-induced exacerbation of neuropathy in Charcot-Marie-Tooth Disease. J Neurol Sci. 2006;242:47–54. [PubMed: 16386273]
87. 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(2):358–70. [PMC free article: PMC3276280] [PubMed: 22012984]
88. Young P, Grote K, Kuhlenbaumer G, Debus O, Kurlemann H, Halfter H, Funke H, Ringelstein EB, Stogbauer F. Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity. J Neurol. 2001;248:410–5. [PubMed: 11437164]
89. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, Saito M, Tsuji S, Hayashi Y, Hirokawa N. Charcot-Marie-Tooth disease type 2a caused by mutation in a microtubule motor KIF1Bbeta. Cell. 2001;105:587–97. [PubMed: 11389829]
90. Zhu D, Kennerson ML, Walizada G, Züchner S, Vance JM, Nicholson GA. Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology. 2005;65:496–7. [PubMed: 16087932]
91. Züchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, Hamilton SR, Van Stavern G, Krajewski KM, Stajich J, Tournev I, Verhoeven K, Langerhorst CT, de Visser M, Baas F, Bird T, Timmerman V, Shy M, Vance JM. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol. 2006;59:276–81. [PubMed: 16437557]
92. Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battologlu E, Polyakov AV, Timmerman V, Schroder JM, Vance JM. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 2004a;36:449–51. [PubMed: 15064763]
93. Züchner S, Vance JM. Mechanisms of disease: a molecular genetic update on hereditary axonal neuropathies. Nat Clin Pract Neurol. 2006a;2:45–53. [PubMed: 16932520]
94. Züchner S, Vance JM. Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease. Neuromolecular Med. 2006b;8:63–74. [PubMed: 16775367]
95. Züchner S, Vorgerd M, Sindern E, Schroder JM. The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy. Neuromuscul Disord. 2004b;14:147–57. [PubMed: 14733962]

Revision History

• 9 February 2012 (tb) Revision: mutations in DYNC1H1 reported to be associated with CMT2O; mutation in LRSAM1 associated with CMT2P

• 22 December 2011 (tb) Revision: mutations in AARS cause CMT2N.

• 15 September 2011 (tb) Revision: Differential Diagnosis — intermediate form of CMT

• 18 August 2011 (cd) Revision: targeted mutation analysis for p.Ala335Val in MED25 associated with CMT2B2

• 1 March 2011 (cd) Revision: edits to Testing Strategy

• 27 January 2011 (cd) Revision: testing available clinically for CMT2C

• 27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid

• 11 March 2010 (me) Comprehensive update posted live

• 7 January 2008 (cd) Revision: prenatal diagnosis for CMT2D available

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

• 30 January 2007 (tb) Revision: sequence analysis clinically available on a limited basis for CMT2D

• 30 December 2005 (cd) Revision: testing and prenatal diagnosis for CMT2B clinically available; prenatal diagnosis for CMT2A clinically available

• 21 December 2005 (tb) Revision: Differential Diagnosis — HMSN-V

• 14 June 2005 (tb) Revision: CMT2K added

• 4 May 2005 (me) Comprehensive update posted to live Web site

• 6 December 2004 (tb) Revision: testing

• 9 September 2004 (tb,cd) Revision: MFN2 added; sequence analysis clinically available

• 9 August 2004 (tb,cd) Revision: CMT2B1

• 21 June 2004 (tb) Revision: CMT2F

• 10 May 2004 (tb) Author revisions

• 1 April 2004 (tb) Revision: prenatal diagnosis available for CMT2E

• 7 April 2003 (me) Comprehensive update posted to live Web site

• 12 September 2001 (tb) Author revisions

• 24 July 2001 (tb) Author revisions

• 27 June 2001 (tb) Author revisions

• 19 June 2001 (tb) Revision: CMT2A gene found

• 23 March 2001 (tb) Author revisions

• 16 January 2001 (tb) Author revisions

• 25 August 2000 (me) Comprehensive update posted to live Web site

• 15 June 2000 (tb) Author revisions

• 15 May 2000 (tb) Author revisions

• 3 February 2000 (tb) Author revisions

• 12 October 1998 (tb) Author revisions

• 24 September 1998 (pb) Review posted to live Web site

• April 1996 (tb) Original submission