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Synonyms: Charcot-Marie-Tooth Disease, Axonal Type; CMT2; Hereditary Motor and Sensory Neuropathy 2; HMSN2

, MD.

Author Information

Initial Posting: ; Last Revision: April 14, 2016.

Estimated reading time: 38 minutes



Clinical characteristics.

Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy, mild sensory loss, and normal or near-normal nerve conduction velocities. CMT2 is clinically similar to CMT1, although typically less severe. Peripheral nerves are not enlarged or hypertrophic. The subtypes of CMT2 are similar clinically and distinguished only by molecular genetic findings.


The diagnosis is based on clinical and EMG/NCV findings, and in many instances by identification of diagnostic changes in one of the genes that determine the CMT2 subtypes.


Treatment of manifestations: Treatment by a team including a neurologist, physiatrists, orthopedic surgeons, physical, and occupational therapist; special shoes and/or ankle/foot orthoses (AFO) to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; exercise as tolerated; symptomatic treatment of pain, depression, sleep apnea, restless legs syndrome.

Prevention of secondary complications: Daily heel cord stretching to prevent Achilles' tendon shortening.

Surveillance: Monitoring gait and condition of feet to determine need for bracing, special shoes, surgery.

Agents/circumstances to avoid: Obesity, which makes ambulation more difficult; medications known to cause nerve damage (e.g., vincristine, isoniazid, nitrofurantoin).

Other: Career and employment counseling.

Genetic counseling.

Most subtypes of CMT2 are inherited in an autosomal dominant manner; however, some are inherited in an autosomal recessive manner. Most probands with an autosomal dominant CMT2 subtype have inherited the pathogenic variant from an affected parent. The offspring of an individual with autosomal dominant CMT2 are at a 50% risk of inheriting the pathogenic variant.


Establishing the Diagnosis

The diagnosis of Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is made clinically in individuals with the following findings:

  • 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 that is typically (but not always) consistent with autosomal dominant inheritance. Note: Some subtypes are inherited in an autosomal recessive manner.

Note: Nerve biopsy is not required for diagnosis.

Establishing the genetic cause of CMT2 requires molecular genetic testing to identify diagnostic changes in one of the genes listed in Table 1a and Table 1b. Note that it has been estimated that a molecular diagnosis of CMT2 cannot be established in 75% of individuals with a clinical diagnosis of CMT2 [Rossor et al 2013].

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing can be considered based on the following:

  • The order in which pathogenic variants most commonly occur (Table 1a)
  • Ethnicity, if founder variants are present (Table 1a and Table 1b)
  • Phenotypic findings that suggest specific CMT2 subtypes; for example:
    • Optic atrophy: CMT2A2 (MFN2)
    • Vocal cord paresis: CMT2C (TRPV4) and CMT2H/K (GDAP1)

A multigene panel that includes some or all of the genes included in Table 1a and Table 1b and other genes of interest (see Differential Diagnosis) may also be considered [Rossor et al 2013]. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes some or all of the genes associated with CMT2) fails to confirm a diagnosis in an individual with features of CMT2. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

See Table 1a for the most common genetic causes (i.e., pathogenic variants of any one of the genes included in this table account for >2% of CMT2) and Table 1b for less common genetic causes (i.e., pathogenic variants of any one of the genes included in this table are reported in only a few families).

Table 1a.

CMT2 Subtypes: Most Common Genetic Causes

CMT2 SubtypeGene 1MOIComment
CMT2A2 MFN2 AD, AR10%-30% of CMT2 [Rossor et al 2013, Rudnik-Schöneborn et al 2016]
16% of CMT in Spain [Casasnovas et al 2010]
3.4% of CMT in Norway [Braathen et al 2010]
8% of Germans w/CMT2 [Gess et al 2013]
18% of CMT2 in mainland China [Xie et al 2016]
Deletion of exons 7 and 8 is a founder variant in the UK [Carr et al 2015].
CMT2I/J MPZ AD8% [Rudnik-Schöneborn et al 2016]
2% of Germans with CMT2 [DiVincenzo et al 2014]
1% of CMT2 [Rossor et al 2013]
CMT2FHSPB1 (HSP27)AD4% of CMT2 in Italy [Capponi et al 2011]

CMT2 subtypes/genes/loci accounting for >2% of the disorder; listed in order of frequency


See Molecular Genetics for information on the genes included in Table 1a.

Table 1b.

CMT2 Subtypes: Less Common Genetic Causes

CMT2 SubtypeGene 1MOIComment
CMT2A1 KIF1B ADCan mimic MS incl white-matter lesions on brain MRI [Genari et al 2011, Klein et al 2011b]
CMT2B RAB7A ADProminent sensory loss, reduced tendon reflexes, distal weakness w/distal ulceration. Also reported: onset > age 50 yrs [Shimizu et al 2010] & autonomic dysfunction [Manganelli et al 2012]. See also Auer-Grumbach et al [2000], Verhoeven et al [2003], Houlden et al [2004], Meggouh et al [2006].
CMT2B1 LMNA ARPrimarily in Algeria; mean age of onset 14 yrs (range 6-27 yrs); functional disability ranging from mild to severe [Tazir et al 2004]
CMT2B2 MED25 ARIn a Costa Rican family w/adult onset [Leal et al 2001, Berghoff et al 2004, Leal et al 2009]
CMT2C TRPV4 ADFrequent vocal cord & phrenic nerve paralysis that may require tracheotomy [Santoro et al 2002, McEntagart et al 2005, Chen et al 2010, Deng et al 2010, Landouré et al 2010]. Also reported: mild sensory loss [Chen et al 2010], scapular winging, elevated serum CK, respiratory insufficiency, hearing loss, skeletal dysplasia [Echaniz-Laguna et al 2014, Evangelista et al 2015]
CMT2D GARS ADMainly distal motor weakness w/wasting of hand muscles [Antonellis et al 2003]
CMT2E/1F NEFL ADIn multiple families w/a progressive SMN; phenotypic overlap w/CMT1 w/slow NCVs & overlap w/dominant intermediate CMT [Berciano et al 2016]
CMT2G12q12-q13.3 (gene unknown)ADIn 1 Spanish family [Nelis et al 2004]
CMT2H/K GDAP1 ARIncl pyramidal findings [Barhoumi et al 2001]
AD Zimoń et al [2011]
CMT2LHSPB8 (HSP22)ADIn 1 Chinese family; onset 15-33 yrs; normal NCV [Tang et al 2004, Tang et al 2005]; myofibrillar myopathy in some families [Ghaoui et al 2016]
CMT2N AARS ADIn 3 families: 2 French & 1 Australian [Latour et al 2010, McLaughlin et al 2012]; hyperreflexia & myelopathy reported in a 4th family [Motley et al 2015]
CMT2O DYNC1H1 ADIn a 4-generation family w/childhood-onset delayed motor milestones w/progressive distal lower-limb weakness, pes cavus, variable sensory loss, nml CNVs; occasional proximal weakness, & waddling gait [Weedon et al 2011]. Also reported: arthrogryposis, SMA, cognitive impairment, spasticity [Scoto et al 2015, Strickland et al 2015]. HMSN in 1 family & SMA in an individual w/a de novo pathogenic variant [Peeters et al 2015].
CMT2P LRSAM1 AR1 family w/onset in 2nd-3rd decade; progressive distal muscle weakness & atrophy [Guernsey et al 2010]
AD2 families w/mild sensory loss [Weterman et al 2012, Nicolaou et al 2013].
CMT2Q DHTKD1 ADIn a large Chinese family [Xu et al 2012]
CMT2R TRIM2 AREarly onset ± vocal cord paralysis [Ylikallio et al 2013, Pehlivan et al 2015]
CMT2S IGHMBP2 ARAxonal neuropathy [Cottenie et al 2014, Schottmann et al 2015]
CMT2T DNAJB2 ARDistal motor neuropathy [Gess et al 2014]
CMT2U MARS ADIn 2 families; onset age >50 yrs [Gonzalez et al 2013, Hyun et al 2014]
CMT2V NAGLU ADPainful axonal neuropathy [Tétreault et al 2015]
CMT2W HARS AD5 families, incl both axonal & demyelinating motor & sensory neuropathies [Safka Brozkova et al 2015]
Not assigned MME ARWeakness, muscle atrophy, sensory loss, no dementia
Late onset (4th-6th decades) [Higuchi et al 2016]

CMT2 subtypes accounting for ≤2% of the disorder; listed alphabetically by subtype.


Click here (pdf) for information on the genes included in Table 1b.

Clinical Characteristics

Clinical Description

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. Baets et al [2011] review the clinical presentations in the first year of life.

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].

Vocal cord or phrenic nerve involvement resulting in difficulty with phonation or breathing has been observed [Dematteis et al 2001, Sulica et al 2001].

Restless legs and sleep apnea have been observed [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.

Nerve biopsy shows:

  • Loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments (not the hypertrophy or onion bulb formation seen in Charcot-Marie-Tooth hereditary neuropathy type 1 [CMT1]);
  • Large nodal gaps and shorter internodal lengths than controls, suggesting a developmental abnormality of internode formation [Manganelli et al 2015].

Phenotype Correlations with Genes Included in Table 1a



See also Differential Diagnosis, Intermediate CMT neuropathy.

HSPB1. CMT2F was initially reported in a Russian family with distal weakness, atrophy, and sensory loss beginning between ages 15 and 25 years. Primary motor neuropathy has been described [Solla et al 2010]; sensory loss can also occur [Rossor et al 2012]. CMT2F is similar to distal hereditary motor neuropathy (HMN), except that sensory loss does not occur in HMN [Irobi et al 2004].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known for any of the genes known to cause CMT2.


Editor's note: In GeneReviews, CMT1 refers to a demyelinating neuropathy and CMT2 refers to an axonal neuropathy. CMT1 and CMT2 are usually inherited in an autosomal dominant manner, although exceptions occasionally occur. CMT4 refers to autosomal recessive varieties of CMT. CMTX refers to X-linked forms.

Other experts in the field emphasize the physiology of the phenotypes such that all axonal varieties are classified as CMT2 regardless of mode of inheritance. Examples include:

The nomenclature for all types of CMT is undergoing revision. A new nomenclature for CMT is likely to name the subtypes by gene.


The overall prevalence of hereditary neuropathies is estimated at 3:10,000 population, varying by country from 10:100,000 to 80:100,000 [Barreto et al 2016]. About 30% of these individuals (1:10,000) may have CMT2. The prevalence of the various subtypes of CMT2 is unknown.

In a study of 776 Germans with a CMT2 phenotype, Gess et al [2013] found the following: 11% had CMTX1 (GJB1), 8% had CMT2A2 (MFN2) and 6% had giant axonal neuropathy (GAN1). Among those with CMT2, 35% had a genetic diagnosis.

Rossor et al [2013] show the prevalence of various subtypes of CMT2 and note that 75% of individuals with CMT2 have no known genetic cause.

Differential Diagnosis

See CMT Overview, particularly to exclude potentially treatable causes of acquired neuropathy.

Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) can sometimes be difficult to distinguish from chronic idiopathic axonal neuropathy.

Bienfait et al [2006] found extensive clinical overlap between individuals with CMT1A (caused by mutation of PMP22) and CMT2, while noting that people with CMT1A are more likely to have earlier-onset disease, foot deformity, and total areflexia.

A median motor NCV of 38 m/s is often used as a threshold for differentiating CMT1 from CMT2; however, the CMT2 phenotype can result from mutation of genes primarily associated with CMT1 (caused by mutation of PMP22) and CMTX1 (caused by mutation of GJB1) [Gutierrez et al 2000, Young et al 2001, Shy et al 2004].

CMT2B1 (LMNA) can resemble several other types of autosomal dominant hereditary axonal neuropathy with predominantly sensory symptoms, including:

CMT2C resembles phenotypes caused by mutation of the following genes:

  • SLC5A7 resulting in a similar, but pure motor syndrome without sensory loss, termed distal hereditary motor neuropathy VIIA (HMN7A;OMIM 158580)
  • DCTN1 resulting in autosomal dominant motor neuropathy with vocal paralysis (HMN7B; OMIM 607641) [Puls et al 2003]

Bellone et al [2002] reported a family with autosomal dominant mutilating neuropathy that was not linked to the CMT2B locus or the HSN1A locus.

Table 3.

Additional Disorders to Consider in the Differential Diagnosis of Charcot-Marie-Tooth Neuropathy Type 2

Distinguishing Clinical FeaturesGeneReview / OMIM
  • Giant axons infrequently seen on nerve biopsy
  • Mild cardiomyopathy
  • Likely associated w/neurofilament degradation
  • Mixed axonal & mild demyelinating disease
  • Early onset
  • Sensory ataxia
  • Tremor
  • Slow disease progression
  • Usually causes centronuclear myopathy
  • May be an overlap w/a predominantly CMT2 presentation
  • Sensory neuropathy associated w/hearing loss & later dementia
DNMT1-Related Dementia, Deafness, and Sensory Neuropathy
  • Spinal muscular atrophy w/calf predominance (but also including triceps & hand weakness)
  • Onset ranges from age 13 to 48 yrs
  • Severity ranges from mild to severe
  • Nerve conductions show reduced motor evoked amplitudes
  • May be referred to as distal hereditary motor neuronopathy 2D (HMN2D)
GJB1 XLCMT2 phenotype reported in some females
  • Moderate to severe motor & sensory neuropathy in males
  • Usually mild to no symptoms in females
  • Sensorineural deafness & central nervous system symptoms in some families
Charcot-Marie-Tooth Neuropathy X Type 1
GJB3 5ADNerve condition velocities not markedly slow, possibly suggesting a clinical diagnosis of CMT2
  • Sural nerve pathology shows demyelination compatible w/CMT1
  • Hearing impairment
  • Childhood-onset CMT syndrome later complicated by renal glomerulosclerosis
  • Nerve conductions vary from moderately slow to normal
  • Intellectual disability & hearing loss reported 7
MORC2 AD 616661
  • One family reported w/a CMT2 syndrome
  • One family reported presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome [Whittaker et al 2015]
TFG 9AD 602498
VCP 10, 11AD
  • One family reported w/mixed NCV CMT
YARS AD 608323

The CMT2 phenotype may sometimes be associated with signs of spasticity (e.g., hyperactive tendon reflexes and/or Babinski signs), a phenotype sometimes referred to as HMSN V. Mutation of two genes has been identified:

Intermediate CMT neuropathy inherited in an autosomal dominant manner has been described; affected individuals have a relatively typical CMT phenotype with nerve conduction velocities that overlap those observed in CMT1 (demyelinating form) and CMT2 (axonal form). Motor NCVs in these families usually range between 25 and 50 m/sec. Four genes (DNM2, GNB4, MPZ, and YARS) and one locus (10q24.1-q25.1) are included in this dominant intermediate category. See CMT Overview.

Mitochondrial causes. Mitochondrial abnormalities are known to sometimes be associated with peripheral neuropathy.

  • Mutation of the nuclear gene MFN2 produces abnormal mitochondrial fusion/fission and resultant neuropathy (CMT2A).
  • Mutation in the mitochondrial genome may also be associated with neuropathy (e.g., in NARP).


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Consultation with a clinical geneticist and/or genetic counselor

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, McCorquodale et al 2016].

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 within the individual's capability. In a systematic review of all reports of exercise for CMT, Sman et al [2015] identified the following significant improvements following exercise: strength, functional activities, and physiologic adaptations. The optimal exercise modality and intensity for people with CMT as well as the long-term safety of exercise remain unclear.

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

Prevention of Secondary Complications

Daily heel cord-stretching exercises help prevent Achilles' tendon shortening.


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 that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list.

Evaluation of Relatives at Risk

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

Pregnancy Management

A German study reviewed 63 pregnancies in 33 women with CMT and found no increase in the frequency of cesarean sections, forceps deliveries, premature births, or neonatal problems [Awater et al 2012].

Argov & de Visser [2009] reviewed pregnancy issues in hereditary neuromuscular disorders including CMT.

Greenwood & Scott [2007] have described the obstetric approach to women with mild and severe forms of CMT.

A Norway study found a higher than average rate of operative deliveries among women with CMT [Hoff et al 2005].

Therapies Under Investigation

Mathis et al [2015] have reviewed the future of therapeutic options in CMT.

Search Clinical in the US and EU Clinical Trials Register in Europe 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Most CMT2 subtypes are inherited in an autosomal dominant manner. (Of note, CMT2 associated with pathogenic variants in DNAJB2, IGHMBP2, LMNA, MED25, MME, or TRIM2 is inherited in an autosomal recessive manner.)

CMT2 associated with pathogenic variants in MFN2, GDAP1, or LRSAM1 has been reported to be inherited both in an autosomal recessive manner and in an autosomal dominant manner.

Risk to Family Members — Autosomal Dominant CMT2

Parents of a proband

  • Most individuals diagnosed with autosomal dominant CMT2 have an affected parent.
  • A proband with autosomal dominant CMT2 may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown but likely very small.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include neurologic examination and molecular genetic testing if the pathogenic variant in the proband has been identified.
  • 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 of the proband is affected, 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.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. (Although no instances of germline mosaicism have been reported, it remains a possibility.)

Offspring of a proband. Each child of an individual with autosomal dominant CMT2 has a 50% chance of inheriting the pathogenic variant.

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 pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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 adult relatives of individuals with CMT2 is possible after molecular genetic testing has identified the specific pathogenic variant in the family. Such testing should be performed in the context of formal genetic counseling.

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of CMT2.

For more information, see the National Society of Genetic Counselors Position Statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics Policy Statement: ethical and policy issues in genetic testing and screening of children.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CMT2 are possible.

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association CMT France
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Fax: 03 2651002
  • Hereditary Neuropathy Foundation, Inc.
    432 Park Avenue South
    4th Floor
    New York NY 10016
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
    Institute of Genetic Medicine
    University of Newcastle upon Tyne
    International Centre for Life
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Phone: 44 (0)191 241 8617
    Fax: 44 (0)191 241 8770
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    Evry cedex 91002
    Phone: +33 01 69 47 28 28
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Phone: 31 35 5480481
    Fax: 31 35 5480499
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Charcot-Marie-Tooth Neuropathy Type 2: Genes and Databases

Locus NameGeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CMT2A1 KIF1B 1p36​.22 Kinesin-like protein KIF1B KIF1B homepage - Leiden Muscular Dystrophy pages
IPN Mutations, KIF1B
CMT2A2 MFN2 1p36​.22 Mitofusin-2 MFN2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MFN2
CMT2B RAB7A 3q21​.3 Ras-related protein Rab-7a RAB7A homepage - Leiden Muscular Dystrophy pages
IPN Mutations, RAB7A
CMT2B1 LMNA 1q22 Prelamin-A​/C Human Intermediate Filament Database LMNA (lamin C1)
Human Intermediate Filament Database LMNA (lamin A)
Human Intermediate Filament Database LMNA (lamin C2)
LMNA homepage - Leiden Muscular Dystrophy pages
IPN Mutations, LMNA
The UMD-LMNA mutations database
CMT2B2 MED25 19q13​.33 Mediator of RNA polymerase II transcription subunit 25 MED25 database MED25 MED25
CMT2C TRPV4 12q24​.11 Transient receptor potential cation channel subfamily V member 4 TRPV4 database TRPV4 TRPV4
CMT2D GARS 7p14​.3 Glycine--tRNA ligase alsod/GARS genetic mutations
GARS homepage - Leiden Muscular Dystrophy pages
IPN Mutations, GARS
CMT2E NEFL 8p21​.2 Neurofilament light polypeptide Human Intermediate Filament Database NEFL
NEFL homepage - Leiden Muscular Dystrophy pages
IPN Mutations, NEFL
CMT2F HSPB1 7q11​.23 Heat shock protein beta-1 HSPB1 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, HSPB1
CMT2GUnknown 12q12-q13​.3 Unknown
CMT2H/2K GDAP1 8q21​.11 Ganglioside-induced differentiation-associated protein 1 GDAP1 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, GAPD1
CMT2I MPZ 1q23​.3 Myelin protein P0 MPZ homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MPZ
CMT2J MPZ 1q23​.3 Myelin protein P0 MPZ homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MPZ
CMT2L HSPB8 12q24​.23 Heat shock protein beta-8 HSPB8 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, HSPB8
CMT2N AARS 16q22​.1 Alanine--tRNA ligase, cytoplasmic AARS @ LOVD AARS AARS
CMT2O DYNC1H1 14q32​.31 Cytoplasmic dynein 1 heavy chain 1 alsod/DYNC1H1 genetic mutations DYNC1H1 DYNC1H1
CMT2P LRSAM1 9q33​.3-q34.1 E3 ubiquitin-protein ligase LRSAM1 LRSAM1 LRSAM1
CMT2Q DHTKD1 10p14 Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial DHTKD1 DHTKD1
CMT2R TRIM2 4q31​.3 Tripartite motif-containing protein 2 TRIM2 TRIM2
CMT2S IGHMBP2 11q13​.3 DNA-binding protein SMUBP-2 IGHMBP2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, IGHMBP2
CMT2T DNAJB2 2q35 DnaJ homolog subfamily B member 2 DNAJB2 DNAJB2
CMT2U MARS 12q13​.3 Methionine--tRNA ligase, cytoplasmic MARS MARS
CMT2V NAGLU 17q21​.2 Alpha-N-acetylglucosaminidase NAGLU database NAGLU NAGLU
CMT2W HARS 5q31​.3 Histidine--tRNA ligase, cytoplasmic HARS @ LOVD HARS HARS
MME 3q25​.2 Neprilysin MME MME

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 2 (View All in OMIM)

150330 LAMIN A/C; LMNA
608507 MITOFUSIN 2; MFN2
608591 none found
616233 none found

Molecular Pathogenesis

The relationship of myelin and axon pathology to the pathogenesis of CMT is discussed in detail in several reviews [Züchner & Vance 2006a, Züchner & Vance 2006b, Manganelli et al 2015]. Rossor et al [2013] show the molecular and anatomic relationships of the various genes and proteins associated with CMT.

Information on the three genes that account for more than 2% of CMT2 (Table 1a) follows.

Click here (pdf) for molecular genetic information on genes less commonly associated with CMT2 (Table 1b).


Gene structure.MFN2 has 19 exons with a 2274-bp open reading frame. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants.Züchner et al [2004b] and Verhoeven et al [2006] have reported more than 25 pathogenic missense variants in MFN2. See also Table A.

Deletion of exons 7 and 8 in MFN2 represent a founder variant in the UK [Carr et al 2015].

Normal gene product. Mitofusin-2, encoded by MFN2, is involved in mitochondrial network architecture and mediates mitochondrial fusion.

Abnormal gene product. Mutation of MFN2 may disrupt the mitochondrial fusion-fission balance in peripheral nerve. Diminished axonal mitochondrial transport has been described [Baloh et al 2007].


Gene structure.HSPB1 contains three exons with a central HSP20-α-crystallin domain. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table A.

Normal gene product. The heat shock protein beta-1 (also referred to as heat-shock protein 27) has many possible functions including antiapoptotic and cytoprotective properties, inhibition of caspase activation, prevention of aggresome formation, and involvement in the neurofilament network.

Abnormal gene product. Pathogenic variants in HSPB1 result in altered neurofilament assembly [Evgrafov et al 2004].


Gene structure.MPZ spans approximately 7 kb and contains six exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table A.

Table 4.

Selected MPZ Pathogenic Variants

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. Myelin protein P0 is a major structural component of peripheral myelin representing about 50% of peripheral myelin protein by weight and about 7% of Schwann cell message. It is a homophilic adhesion molecule of the immunoglobulin family that plays an important role in myelin compaction. It has a single transmembrane domain, a large extracellular domain, and a smaller intracellular domain.

Abnormal gene product. Different pathogenic variants affect all portions of the protein and may alter myelin adhesion. Either demyelinating or axonal phenotypes can result.


Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 4-30-18. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 4-30-18.

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Chapter Notes

Revision History

  • 5 July 2018 (ma) Chapter retired: covered in Charcot-Marie-Tooth Hereditary Neuropathy Overview
  • 14 April 2016 (tb) Revision: MME and related reference added
  • 24 March 2016 (bp) Comprehensive update posted live
  • 30 April 2015 (tb) Revision: heterozygous mutation of IGHMBP2 as causative of CMT2S, of DNAJB2 as causative of CMT2T, and of MARS as causative of CMT2U
  • 12 March 2015 (tb) Revision: discussion of CMT nomenclature; additions to Differential Diagnosis; references added [Cottenie et al 2014, Gess et al 2014, Gonzalez et al 2014, Mathis et al 2015, Schottmann et al 2015, Scoto et al 2015]
  • 2 October 2014 (tb) Revision: edits to Differential Diagnosis
  • 31 July 2014 (tb) Revision: addition of KIF5A to Differential Diagnosis [Crimella et al 2012, Liu et al 2014]
  • 3 April 2014 (tb) Revision: addition of DCAF8 to Differential Diagnosis [Klein et al 2014]
  • 20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
  • 30 January 2014 (tb) Revision: Sumner et al [2013]; edits to Testing Strategy
  • 14 November 2013 (tb) Revision: figure added to Prevalence and Molecular Genetics [Rossor et al 2013]
  • 11 July 2013 (tb) Revision: additions to Prevalence and Differential Diagnosis
  • 3 January 2013 (cd) Revision: sequence analysis of select exons of LRSAM1 available clinically
  • 13 December 2012 (tb) Revision: mutations in DHTKD1 identified as causative of a form of CMT2 [Xu et al 2012]
  • 13 September 2012 (tb) Revision: addition of Ishiura et al [2012], Pitceathly et al [2012], Nicolaou et al [2013]
  • 30 August 2012 (cd) Revision: sequence analysis for MED25 and DYNC1H1 available clinically
  • 5 July 2012 (me) Comprehensive update posted live
  • 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 live
  • 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 live
  • 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 live
  • 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 live
  • 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 live
  • April 1996 (tb) Original submission
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