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Charcot-Marie-Tooth Neuropathy Type 2

Synonyms: CMT2; Charcot-Marie-Tooth Disease, Axonal Type; HMSN2; Hereditary Motor and Sensory Neuropathy 2
, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: April 30, 2015.


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 findings and EMG/NCV characteristics. The 18 genes in which mutation is known to cause CMT2 subtypes are KIF1B (CMT2A1), MFN2 (CMT2A2), RAB7A (formerly RAB7) (CMT2B), LMNA (CMT2B1), MED25 (CMT2B2), TRPV4 (CMT2C), GARS (CMT2D), NEFL (CMT2E/1F), HSPB1 (CMT2F), MPZ (CMT2I/J), GDAP1 (CMT2H/K), HSPB8 (CMT2L), AARS (CMT2N), DYNC1H1 (CMT2O), LRSAM1 (CMT2P), IGHMBP2 (CMT2S), DNAJB2 (CMT2T), and MARS (CMT2U).


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.

CMT2B1, CMT2B2, and CMT2H/K are inherited in an autosomal recessive manner; all other subtypes of CMT2 are inherited in an autosomal dominant manner. Most probands with autosomal dominant subtypes of CMT2 have inherited the pathogenic variant from an affected parent. The offspring of an affected individual with autosomal dominant CMT2 are at a 50% risk of inheriting the altered gene.

GeneReview Scope

Charcot-Marie-Tooth Neuropathy Type 2: Included Disorders
  • CMT2A1
  • CMT2A2
  • CMT2B
  • CMT2B1
  • CMT2B2
  • CMT2C
  • CMT2D
  • CMT2E/1F
  • CMT2F
  • CMT2G
  • CMT2I/J
  • CMT2H/K
  • CMT2L
  • CMT2N
  • CMT2O
  • CMT2P
  • CMT2S
  • CMT2T
  • CMT2U

For synonyms and outdated names see Nomenclature.


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


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. Fifteen genes in which pathogenic variants are known to cause subtypes of CMT2 have been identified [Züchner & Vance 2006b] (Table 1).

Evidence for locus heterogeneity. Another locus for CMT2 has been mapped; no gene has yet been identified (see Table 2).

Table 2.

CMT2: Other Locus

CMT2 SubtypeChromosomal LocusReference
CMT2G12q12-q13.3Nelis et al [2004]

Table 3.

Summary of Molecular Genetic Testing Used in CMT2

Gene 1 / Locus NameTest MethodAllelic Variants Detected 2Proportion of CMT2 Attributed to Mutation of This GeneMutation Detection Frequency 3
KIF1B / CMT2A1Sequence analysis 4Sequence variantsRareUnknown
MFN2 / CMT2A2Sequence analysis 4
Mutation scanning 5, 6
Sequence variants20%Unknown
Deletion/duplication analysis 6Exon or whole-gene deletions
RAB7A / CMT2BSequence analysis 4Sequence variantsRareUnknown
LMNA / CMT2B1Sequence analysis 4Sequence variantsRareUnknown
Deletion/duplication analysis 7Exon or whole-gene deletionsUnknown, none reported
MED25 / CMT2B2Sequence analysis 4Sequence variantsRareUnknown
Mutation scanning of select exons 5Sequence variants in exon5
Targeted mutation analysisp.Ala335Val
TRPV4 / CMT2CSequence analysis 4Sequence variantsRareUnknown
Sequence analysis of select exons 4Sequence variants in exons 5,6 5RareUnknown
GARS / CMT2DSequence analysis 4Sequence variantsRareUnknown, none reported
Deletion/duplication analysis 7Exon or whole-gene deletions
NEFL / CMT2E/1FSequence analysis 4Sequence variantsRareUnknown
HSPB1 / CMT2FSequence analysis 4Sequence variantsRareUnknown, none reported
Deletion/duplication analysis 7Exon or whole-gene deletions
Unknown / CMT2GLinkage analysisNot applicableRareNot applicable
MPZ / CMT2I/JSequence analysis 4
Mutation scanning 6
Sequence variantsRareUnknown
Deletion/duplication analysis 7Deletions or duplicationsUnknown, none reported
GDAP1 / CMT2H/KSequence analysis 4Sequence variantsRareUnknown
HSPB8 / CMT2LSequence analysis 4Sequence variantsRareUnknown
Deletion/duplication analysis 7Exon or whole-gene deletionsUnknown, none reported
AARS / CMT2NSequence analysis 4Sequence variantsRareUnknown
DYNC1H1 / CMT2OSequence analysis 4Sequence variantsRareUnknown
LRSAM1 / CMT2PSequence analysis of select exons 4Sequence variants in exon 25RareUnknown
IGHMBP2/CMT2SSequence analysis 4Sequence variantsRareUnknown
DNAJB2/CMT2TSequence analysis 4Sequence variantsRareUnknown
MARS/CMT2USequence analysis 4Sequence variantsRareUnknown

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Selected exons for testing may vary among laboratories.


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.


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

One genetic testing strategy is serial single gene molecular genetic testing based on the individual’s family history and neurophysiologic data [England et al 2009, Saporta et al 2011]. The relative frequencies of various CMT2 subtypes are shown in Figure 1.

Figure 1.

Figure 1.

Genetic diagnoses in CMT and related disorders

From Rossor et al [2013]; reprinted with permission

Specifically, to establish the diagnosis of a CMT2 subtype the proband should first be tested for pathogenic variants in MFN2, MPZ, and GJB1 (encoding connexin 32), as variants in these genes are most commonly responsible for this syndrome, probably accounting for 20%-25% of cases [Züchner & Vance 2006b, Bienfait et al 2007, Saporta et al 2011]. If the phenotype includes vocal cord paresis, molecular genetic testing of GDAP1 and TRPV4 is appropriate.

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

If no pathogenic variant is identified in these three genes, many neurologists do no further genetic testing because the other known genes are quite rare and many genetic causes remain to be discovered.

An alternative genetic testing strategy is use of a multi-gene panel that includes genes associated with CMT2 and other genes of interest (see Differential Diagnosis) [Rossor et al 2013]. Panels exist for dominantly and recessively inherited CMTs as well as demyelination and axonal forms. Larger (all-inclusive) panels may also be available. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

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].

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

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 [Schröder 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 families with CMT2A [Züchner et al 2004a, Klein et al 2011b].

Optic atrophy is associated with mutation of MFN2 [Verhoeven et al 2006, Züchner et al 2006].

Some pathogenic variants in TRPV4 are associated with diseases of bone [Verma et al 2010].


Penetrance is usually nearly complete. However, because some subtypes of CMT2 are associated with adult onset of symptoms, penetrance is age dependent.


Editor’s note: The nomenclature for all types of CMT is undergoing revision. In GeneReviews, CMT1 and CMT2 (and their subtypes) are all autosomal dominant disorders with CMT1 being demyelinating and CMT2 being axonal. CMT4 refers to all autosomal recessive varieties of CMT. CMTX refers to X-linked forms. However, other experts in the field emphasize the physiology of the phenotypes such that all axonal varieties are classified as CMT2 whether they are dominant or recessive. An example is the type caused by mutation of IGHMBP2, which is autosomal recessive and axonal. Thus, in GeneReviews it is classified under CMT4 (because it is autosomal recessive), whereas the authors of the paper describing the disorder [Cottenie et al 2014] classify it as CMT2 (because it is axonal). A new nomenclature for CMT is likely to name the subtypes by gene.

CMT2A. 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 pathogenic variants [Zhu et al 2005] and with pathogenic variants 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 pathogenic variants in NEFL, which typically cause CMT2E, may have slow NCVs, resulting in a diagnosis of CMT1F. To accommodate these two phenotypes associated with mutation of NEFL, the designation CMT2E/1F has been used.


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. CMT2A represented 3.4%-16% of all CMT families in Norway and Spain respectively [Braathen et al 2010, Casasnovas et al 2010].

In a large study of German individuals with a CMT2 phenotype (776), Gess et al [2013] found the following percentages: 11% had CMTX1, 8% had CMT2Aand 6% had the rare giant axonal neuropathy. 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 cases have no known associated gene. See Figure 1.

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 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 and CMTX1 [Gutierrez et al 2000, Young et al 2001, Shy et al 2004].

CMT2C resembles two other disorders:

  • A similar, but pure motor syndrome without sensory loss, termed distal hereditary motor neuropathy VII (dHMV-VII) and linked to chromosome 2q14 [McEntagart et al 2001]
  • Autosomal dominant motor neuropathy with vocal paralysis associated with a missense variant in DCTN1, encoding the protein dynactin 1 [Puls et al 2003]

Several different types of autosomal dominant hereditary axonal neuropathy may cause predominantly sensory symptoms, including the "burning feet syndrome" [Stögbauer et al 1999, Auer-Grumbach et al 2003]. Families with hereditary sensory neuropathy (including hereditary sensory neuropathy type 1 caused by mutation of SPTLC1 [Bejaoui et al 2001]) usually do not have motor symptoms such as muscle weakness, but findings can sometimes overlap with CMT2B.

Bellone et al [2002] reported a family with autosomal dominant mutilating neuropathy that was not linked to the CMT2B locus or the HSN1 locus.

The CMT2 phenotype may sometimes be associated with signs of spasticity (e.g., hyperactive tendon reflexes and/or Babinski signs). This phenotype has sometimes been referred to as HMSN V. Two affected families have been reported by Vucic et al [2003]. One gene associated with this phenotype has been identified (see BSCL2-Related Neurologic Disorders). In addition, both Crimella et al [2012] and Liu et al [2014] have identified missense variants in KIF5A that are usually associated with a form of spastic paraplegia (HSP10) and may also cause an axonal neuropathy fitting the CMT2 phenotype – sometimes including pyramidal tract signs.

  • Females with CMTX1 (caused by mutation of GJB1, encoding connexin 32) may have a CMT2 phenotype.
  • Another form of autosomal dominant motor and sensory neuropathy from Okinawa has been mapped to 3q13 [Takashima et al 1999]. The relationship of this entity to CMT2B, which is linked to a similar region, is undetermined. Ishiura et al [2012] have found pathogenic variants in TFG causing hereditary motor and sensory neuropathy with proximal dominant involvement. Lee et al [2013a] have found the same pathogenic variant in TFG in a Korean family with proximal dominant HMSN. Tsai et al [2014] identified a pathogenic variant in TFG in a large Taiwanese family with CMT2.
  • Boyer et al [2011] have reported heterozygous mutation of INF2 associated with childhood-onset CMT syndrome later complicated by renal glomerulosclerosis. Nerve conductions have varied from moderately slow to normal. Intellectual disability and hearing loss are also reported [Mademan et al 2013].
  • López-Bigas et al [2001] have described an autosomal dominant neuropathy associated with hearing impairment caused by mutation of GJB3, encoding the protein connexin 31. Although the sural nerve pathology showed demyelination compatible with CMT1, the nerve condition velocities were not markedly slow and may suggest a clinical diagnosis of CMT2.
  • Weedon et al [2011] have described a large four-generation family with childhood-onset axonal CMT and a missense variant (p.His306Arg) in DYNC1H1, the gene encoding cytoplasmic dynein 1 heavy chain 1.
  • Mutation of DNM2 (dynamin 2) usually causes centronuclear myopathy, but there may be an overlap with a predominantly CMT2 presentation [Böhm et al 2012].
  • Klein et al [2011a] have reported several families with an autosomal dominant sensory neuropathy associated with hearing loss and later dementia caused by mutation of DNMT1. See DNMT1-Related Dementia, Deafness, and Sensory Neuropathy.
  • Sumner et al [2013] have reported an autosomal dominant spinal muscular atrophy with calf predominance (but also including triceps and hand weakness) associated with a missense variant (p.Cys206Arg) in FBX038. Onset ranged from age 13 to 48 years, severity ranged from mild and severe and nerve conductions showed reduced motor evoked amplitudes. This has also been called distal hereditary motor neuronopathy 2D (HMN2D).
  • A novel variant in VCP (Glu185Lys) has been reported in a family with autosomal dominant mixed NCV CMT [Gonzalez et al 2014]. Other pathogenic variants in VCP are associated with a specific type of inclusion body myopathy (see Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia).
  • Klein et al [2014] reported a missense variant (p.Arg317Cys) in DCAF8 responsible for a specific variety of autosomal dominant CMT2/HMSN2 in a German family with infrequent giant axons seen on nerve biopsy and mild cardiomyopathy. This variant results in decreased DDb1-DCAF8 association, leading to an E3 ubiquitin ligase defect that is likely associated with neurofilament degradation.
  • Herrmann et al [2014] reported two different missense variants in SYT2 (encoding synaptotagmin-2) in two families, one with a CMT2 syndrome and the other with a presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome.
  • Tétreault et al [2015] report that individuals who are heterozygous for the missense variant Ile403Thr in NAGLU have a painful axonal neuropathy. Biallelic pathogenic variants in NAGLU, which encodes α-N-acetyl-glucosaminidase, result in the childhood lysosomal storage disease mucopolysacharidosis IIIB.

An intermediate form of CMT 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. At least three chromosomal loci (1p, 10q, and 19p) for this intermediate form have been identified by linkage analysis [Kennerson et al 2001, Verhoeven et al 2001]. Mutation of YARS and DNM2 may cause this syndrome.

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


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)
  • Medical genetics consultation

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.


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. Click here (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

Argov & de Visser [2009] reviewed pregnancy issues in hereditary neuromuscular disorders including CMT. About 50% of women with CMT describe increased weakness during pregnancy that usually resolves post partum [Rudnik-Schöneborn et al 1993]. Operative deliveries were reported more commonly in women with CMT in Norway [Hoff et al 2005]. Greenwood & Scott [2007] have described the obstetric approach to women with mild and severe forms of CMT.

A recent German study reviewed 63 pregnancies in 33 individuals with CMT [Awater et al 2012] and found no increase in the frequency of Cesarean sections, forceps deliveries, premature births, or neonatal problems. About one third of mothers felt a worsening of CMT symptoms during pregnancy; in one fifth of mothers the changes were felt to be persistent.

Therapies Under Investigation

Search 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.

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


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

Genetic Counseling

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

Mode of Inheritance

CMT2B1, CMT2B2, and CMT2H/2K 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 de novo pathogenic variant. The proportion of cases caused by de novo variants is unknown but likely very small.
  • Recommendations for the evaluation of parents of a proband with apparent de novo pathogenic variant include neurologic examination and molecular genetic testing if the pathogenic variant 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 pathogenic variant, 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 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.

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 pathogenic variant.

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 autosomal recessive forms of CMT2 is possible if the pathogenic variants have been identified in the family.

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 or clinical evidence of the disorder, it is likely that the proband has a de novo variant. 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 pathogenic variant 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 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

If the pathogenic variant(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

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

Requests for prenatal 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 [Sharapova et al 2004] and CMT2F [Lee et al 2013b] has been reported. Preimplantation genetic diagnosis of other CMT2 subtypes may be an option for some families in which the pathogenic variant(s) have been identified.


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
  • 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 Campaign
    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 SpecificHGMD
CMT2NAARS16q22​.1Alanyl-tRNA synthetase, cytoplasmicAARS @ LOVDAARS
CMT2A1KIF1B1p36​.22Kinesin-like protein KIF1BKIF1B homepage - Leiden Muscular Dystrophy pages
IPN Mutations, KIF1B
CMT2A2MFN21p36​.22Mitofusin-2MFN2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MFN2
CMT2BRAB7A3q21​.3Ras-related protein Rab-7aRAB7A homepage - Leiden Muscular Dystrophy pages
IPN Mutations, RAB7A
CMT2B1LMNA1q22Prelamin-A​/CHuman 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
CMT2B2MED2519q13​.33Mediator of RNA polymerase II transcription subunit 25MED25 databaseMED25
CMT2CTRPV412q24​.11Transient receptor potential cation channel subfamily V member 4TRPV4 databaseTRPV4
CMT2DGARS7p14​.3Glycine--tRNA ligasealsod/GARS genetic mutations
GARS homepage - Leiden Muscular Dystrophy pages
IPN Mutations, GARS
CMT2ENEFL8p21​.2Neurofilament light polypeptideHuman Intermediate Filament Database NEFL
NEFL homepage - Leiden Muscular Dystrophy pages
IPN Mutations, NEFL
CMT2FHSPB17q11​.23Heat shock protein beta-1HSPB1 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, HSPB1
CMT2H/2KGDAP18q21​.11Ganglioside-induced differentiation-associated protein 1GDAP1 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, GAPD1
CMT2IMPZ1q23​.3Myelin P0 proteinMPZ homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MPZ
CMT2JMPZ1q23​.3Myelin P0 proteinMPZ homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MPZ
CMT2LHSPB812q24​.23Heat shock protein beta-8HSPB8 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, HSPB8
CMT2ODYNC1H114q32​.31Cytoplasmic dynein 1 heavy chain 1alsod/DYNC1H1 genetic mutationsDYNC1H1
CMT2PLRSAM19q33​.3-q34.1E3 ubiquitin-protein ligase LRSAM1 LRSAM1
CMT2SIGHMBP211q13​.3DNA-binding protein SMUBP-2IGHMBP2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, IGHMBP2
CMT2TDNAJB22q35DnaJ homolog subfamily B member 2 DNAJB2
CMT2UMARS12q13​.3Methionine--tRNA ligase, cytoplasmic MARS

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

Table B.

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


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]. Rossor et al [2013] show the molecular and anatomic relationships of the various genes and proteins associated with CMT; see Figure 1.

For a detailed summary of gene and protein information for the following genes, see Table A, Gene.


Gene structure. KIF1B comprises 47 exons and 167.13 kb of DNA.

Pathogenic allelic variants. A p.Gln98Leu variant was reported in a single family [Zhao et al 2001]. See Table 4 and Table A.

Table 4.

Selected KIF1B Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. Kinesin-like protein KIF1B is involved in axonal transport of synaptic vesicle precursors [Zhao et al 2001]. The kinesin superfamily of proteins is essential for intracellular transport along microtubules.

Abnormal gene product. There may be a defect in the transport of synaptic vesicles.


Gene structure. MFN2 has 19 exons with a 2274-bp open reading frame.

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

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

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


Gene structure. RAB7A has six exons and 87.9 kb of DNA.

Pathogenic allelic variants. See Table A.

Normal gene product. Ras-related protein Rab-7a belongs to the RAB family of Ras-related GTPases essential for the regulation of intracellular membrane trafficking. Rab-7a is involved in transport between late endosomes and lysosomes. RAB-interacting lysosomal protein (RILP) induces the recruitment of dynein-dynactin motors and regulates transport toward the minus-end of microtubules [Verhoeven et al 2003].

Abnormal gene product. Abnormal Rab-7a may cause malfunction of lysosomes.


Gene structure. LMNA has 12 exons spread over 24 kb of genomic DNA.

Pathogenic allelic variants. The most common pathogenic variant found in individuals with CMT2B1 is p.Arg298Cys. See Table 5 and Table A.

Table 5.

Selected LMNA Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benignc.1908C>Tp.= 1NM_170707​.2

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

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


p.= signifies that protein has been analyzed but no amino acid change is expected.

Normal gene product. Lamins are the principal component of the nuclear lamina, a major portion of the nuclear envelope. Two A-type lamins exist: A and C. Lamins play a role in DNA replication, chromatin organization, spatial arrangement of nuclear pore complexes, nuclear growth, mechanical stabilization of the nucleus, and anchorage of the nuclear envelope protein.

Abnormal gene product. Position 29 is located in the lamin-A/C rod domain. The manner in which disruption of this domain adversely affects peripheral nerve function is unknown. Other LMNA variants are associated with a wide variety of disorders (see Genetically Related Disorders).


Gene structure. MED25 has 18 exons.

Pathogenic allelic variants. One pathogenic variant has been described in an extended Costa Rican family with autosomal recessively inherited CMT neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. Affected individuals were homozygous for p.Ala335Val [Leal et al 2009].

Table 6.

Selected MED25 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. MED25 encodes a 747-amino acid protein designated the mediator complex subunit 25 protein (reference sequence NM_030973.2). This protein is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes. Its precise function in transcriptional regulation is unknown.

Abnormal gene product. The p.Ala335Val substitution is located in a proline-rich region with high affinity for SH3 domains of the Abelson type. The pathogenic variant causes a decrease in binding specificity leading to the recognition of a broader range of SH3 domain proteins.


Gene structure. TRPV4 has 16 exons; exon 1 of NM_021625.3 is non-coding.

Pathogenic allelic variants. The pathogenic variants in Table 7 have been associated with CMT2C.

Table 7.

Selected TRPV4 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. TRPV is a vanilloid receptor-related transient receptor potential channel which plays an important role in neural signal. The protein is composed of a cytosolic N-terminal region and six transmembrane domains, including the pore region and an intracellular C-terminal tail. The N-terminal region contains the ankyrin repeat domain (ARD).

Abnormal gene product. Landouré et al [2010] demonstrated cellular toxicity and increased constitutive and activated channel currents in TRPV4-transected cells. Deng et al [2010] showed increased calcium channel activity resulting from the two pathogenic variants found in two families with CMT2C. The effect of pathogenic variants on molecular functions like oligomerization, surface expression and ubiquitination are reviewed by Verma et al [2010].


Gene structure. GARS is a 40-kb gene with 17 exons.

Pathogenic allelic variants. See Table A.

Normal gene product. Glycyl-tRNA synthetase ligates amino acids to their cognate tRNA.

Abnormal gene product. Pathogenic missense variants in this gene may produce a loss of function that allows the incorporation of the wrong amino acid in the place of glycine [Motley et al 2010].


Gene structure. NEFL contains four coding exons; the 5' UTRs are highly conserved.

Pathogenic allelic variants. One family with CMT2E/1F has a variant in exon 1 of NEFL [Mersiyanova et al 2000] and another family has a deletion/insertion variant in exon 1 (c.22_23delCCinsAG) [De Jonghe et al 2001]. See Table 8 and Table A.

Table 8.

Selected NEFL Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. Neurofilament light polypeptide, the protein encoded by NEFL, contains 543 amino acids with a head, rod, and tail domain. Neurofilaments form the cytoskeletal component of myelinated axons.

Abnormal gene product. Knockout mice lacking neurofilaments have diminished axon caliber and delayed regeneration of myelinated axons following crush injury. A mouse mutation of Nefl has massive degeneration of spinal motor neurons and abnormal neurofilament accumulation with severe neurogenic skeletal muscle atrophy. Defects in transport and assembly of neurofilaments have been reported [Perez-Olle et al 2004].


Gene structure. HSPB1 contains three exons with a central HSP20-α-crystallin domain.

Pathogenic allelic 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.

Pathogenic allelic variants. More than 56 single nucleotide variants in MPZ have been reported [Nelis et al 1999]. More than 70% of the variants are localized in exons 2 and 3 of MPZ coding for the extracellular domain, indicating the functional importance of this domain. See Table 9 and Table A.

Table 9.

Selected MPZ Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences

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

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


Variant designation that does not conform to current naming conventions

Normal gene product. Myelin P0 protein 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.


Gene structure. GDAP1 has six exons, 13.9 kb of DNA, and a 1007-nucleotide open reading frame.

Pathogenic allelic variants. See Table 10 and Table A.

Table 10.

Selected GDAP1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. Ganglioside-induced differentiation-associated protein-1 [Baxter et al 2002]

Abnormal gene product. It is speculated that GDAP1 pathogenic variants may prevent the correct catalyzing S conjugation of reduced GCH, resulting in progressive attrition of both axons and Schwann cells.


Gene structure. HSPB8 has three exons and spans about 16 kb.

Pathogenic allelic variants. Three variants have been reported. See Table 11 [Irobi et al 2004b, Tang et al 2005].

Table 11.

Selected HSPB8 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. HSPB8 (also called HSP22) is a phosphor protein that interacts with HSPB1.

Abnormal gene product. Mutant HSPB8 proteins interact with HSPB1 and form aggregates that may lead to dysfunctional axonal transport and dysregulation of the cytoskeleton [Irobi et al 2004b].


Gene structure. AARS has 21 exons and is located on chromosome 16.

Pathogenic allelic variants. Two variants have been associated with CMT (p.Arg329His and p.Glu778Ala). See Table 12. The variant p.Asn71Tyr (c.211A>T) may also be pathogenic.

Table 12.

Selected AARS Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. Alanyl-tRNA synthetase attaches alanine to tRNA molecules in cytoplasm and mitochondria completing the first step in protein translation.

Abnormal gene product. Functional studies suggest these are loss-of-function variants [McLaughlin et al 2012].


Gene structure. DYNC1H1 has 78 exons.

Pathogenic allelic variants. One pathogenic variant has been described (p.His306Arg) by Weedon et al [2011]. See Table 13. Recently, ten novel pathogenic missense variants have been reported by Scoto et al [2015].

Table 13.

Selected DYNC1H1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. 4,646-amino acid protein. DYNC1H1 is a subunit of cytoplasmic dynein, the primary motor protein producing retrograde axonal transport in neurons.

Abnormal gene product. Presumably the abnormal protein produces defective retrograde axonal transport in peripheral nerves.


Gene structure. LRSAM1 has 25 exons.

Pathogenic allelic variants. A single autosomal dominant and a single autosomal recessive pathogenic variant have been described. See Table 14.

Table 14.

Selected LRSAM1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.2121_2122 dupGCp.Leu708ArgfsTer28NM_138361​.5

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

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

Normal gene product. A ubiquitin ligase (E3) involved with sorting ubiquitinylated cytoplasmic cargo (TSG101); 723-amino acid protein.

Abnormal gene product. Disturbs sorting of ubiquitinylated cargo in neuronal cytoplasm.


Gene structure. IGHMBP2 has 15 exons.

Pathogenic allelic variants. See Table 15.

Table 15.

Selected IGHMBP2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. The 993-amino acid protein has seven putative helicase motifs and a DEAD box-like motif typical for RNA helicases.

Abnormal gene product. Mutation may lead to dysfunction of helicase activity.


Gene structure. Transcript variant 1 (NM_001039550.1) has ten exons and is the predominant transcript.

Pathogenic allelic variants. See Table 16.

Table 16.

Selected DNAJB2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. Transcript variant 1 encodes a protein of 277 amino acids. It belongs to the HSP40 chaperone protein family involved with protein folding. It may clear toxic proteins involved in disease aggregations such as those associated with ALS (SOD1) and Huntington.

Abnormal gene product. Mutation results in an inability to clear toxic protein aggregates.


Gene structure. The gene has 21 exons.

Pathogenic allelic variants. Two missense pathogenic variants have been reported.

Table 17.

Selected MARS Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

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

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

Normal gene product. Methionine--tRNA ligase, cytoplasmic has 900 amino acids.

Abnormal gene product. The two reported pathogenic variants likely cause loss of function [Gonzalez et al 2013].


Published Guidelines/Consensus Statements

  1. 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 7-21-15. [PubMed: 23428972]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 7-21-15.

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Chapter Notes

Revision History

  • 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 Nicolaou et al [2012], Ishiura et al [2012], Pitceathly et al [2012]
  • 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 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
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