Clinical Diagnosis

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

• A progressive peripheral motor and sensory neuropathy
• Nerve conduction velocities (NCVs) that are usually within the normal range (>40-45 m/s), although occasionally in a mildly abnormal range (30-40 m/s)
• EMG testing that shows evidence of an axonal neuropathy with such findings as positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses
• Greatly reduced compound motor action potentials (CMAP)
• A family history consistent with autosomal dominant inheritance

Testing

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

Testing Strategy

To establish the diagnosis of a CMT2 subtype the proband should first be tested for mutations in MFN2, MPZ, and GJB1 (encoding connexin 32), as mutations 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].

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

If no mutation 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. Affected individuals who wish to exhaust all possibilities may want to proceed with the other tests relevant to CMT2 (e.g., NEFL, GDAP1, RAB7A, MED25, TRPV4, AARS). If the phenotype includes vocal cord paresis, molecular genetic testing of GDAP1 and TRPV4 is appropriate.

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

Genetically Related (Allelic) Disorders

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

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

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

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

• Hutchinson-Gilford progeria syndrome (HGPS or progeria)
• Autosomal dominant Emery-Dreifuss muscular dystrophy type 2 (EMD2). See Emery-Dreifuss Muscular Dystrophy (EDMD).
• Autosomal recessive Emery-Dreifuss muscular dystrophy type 2 (EMD2). See EDMD.
• Autosomal dominant familial dilated cardiomyopathy and conduction system defects (CMD1A). See Dilated Cardiomyopathy Overview.
• Autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD)
• Autosomal dominant limb-girdle muscular dystrophy 1B (LGMD1B). See Limb-Girdle Muscular Dystrophy Overview.
• A normal allelic variant in LMNA (NM_170707.2:c.1908C>T) associated with obesity-related traits in Canadian Oji-Cree
• Autosomal recessive mandibuloacral dysplasia (MAD). A compound heterozygous mutation p.[Arg471Cys]+ [Arg527Cys] in a 28-year-old woman with mandibuloacral dysplasia, previously diagnosed as "atypical progeria," was reported [Cao & Hegele 2003].
• Atypical Werner syndrome [Chen et al 2003]
• A single case report of a male heterozygous for the mutation p.Arg133Leu with lipoatrophy, disseminated white skin papules, hypertrophic cardiomyopathy, hepatic steatosis, and insulin resistance [Caux et al 2003]
• Co-occurrence of myopathy and neuropathy [Benedetti et al 2005, Walter et al 2005]

See OMIM 150330 for additional references regarding other laminopathies.

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

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

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

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

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

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

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

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

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

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

Natural History

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

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

• CMT2A (comprising CMT2A1 and CMT2A2) has a typical CMT phenotype with onset in the second or third decade of distal muscle weakness and atrophy, less severe sensory loss, and depressed tendon reflexes. NCVs fall within the normal or near-normal range, compatible with an axonal neuropathy. Clinical features of families with MFN2 mutations are described by Züchner et al [2004a] and Kijima et al [2005]. Optic atrophy may occur in CMT2A [Züchner et al 2006]. CMT2A can mimic multiple sclerosis including white matter lesions on brain MRI [Genari et al 2011, Klein et al 2011a]. Early-onset, severe pure motor neuropathy is common in CMT2A with mutation in MFN2 [Feely et al 2011].
• CMT2B has prominent sensory loss with distal ulceration; controversy exists regarding its exact classification. Additional phenotype information is presented in Auer-Grumbach et al [2000], Verhoeven et al [2003], and Houlden et al [2004]. Late onset (age >50 years) has been noted [Shimizu et al 2010].
• CMT2B1 is found primarily in Algeria. Mean age of onset is 14 years (range 6-27 years); functional disability ranges from mild to severe [Tazir et al 2004].
• CMT2B2 occurred in a Costa Rican family with adult onset [Leal et al 2001, Berghoff et al 2004].
• CMT2C is associated with frequent vocal cord and phrenic nerve paralysis sometimes requiring tracheotomy [Santoro et al 2002, McEntagart et al 2005, Chen et al 2010, Deng et al 2010, Landoure et al 2010]. Mild sensory loss was noted in the individuals reported by Dyck et al [1994].
• CMT2D is characterized by predominantly distal motor weakness with wasting of the hand muscles [Antonellis et al 2003].
• CMT2E/1F has been reported in several families with a progressive sensory and motor neuropathy. The full range of phenotype may overlap with the CMT1 syndrome characterized by slow NCV [Georgiou et al 2002, Jordanova et al 2003, Züchner et al 2004a]. A Belgian family had NCVs ranging from 25 to 42 m/s, overlapping both axonal and demyelinating phenotypes [De Jonghe et al 2001]. A Russian family had relatively normal NCV and hyperkeratosis [Mersiyanova et al 2000]. It is unknown if the presence of hyperkeratosis is coincidental or represents variable expressivity of the CMT2E/1F phenotype.
• CMT2F has been reported in a single Russian family with distal weakness, atrophy, and sensory loss beginning between ages 15 and 25 years. This disorder is similar to distal hereditary motor neuropathy (HMN), except that there is no sensory loss in HMN [Ismailov et al 2001, Evgrafov et al 2004, Irobi et al 2004a]. Mutations in HSPB1 occurred in 4% of a series of CMT2 cases in Italy [Capponi et al 2011]. Primary motor neuropathy has been described [Solla et al 2010] but sensory loss can occur [Rossor et al 2012].
• CMT2G has been reported in a single Spanish family [Nelis et al 2004].
• CMT2H has associated pyramidal features [Barhoumi et al 2001] and CMT2K is associated with the p.Arg120Trp and p.Thr157Pro mutations in GDAP1 [Claramunt et al 2005].
• CMT2I has only mild slowing of NCV [Li et al 2006].
• CMT2J. The MPZ mutation p.Thr134Met is associated with an axonal neuropathy with deafness and Argyll Robertson pupils [Chapon et al 1999]. In addition, the pathologic allelic variants p.Thr134Met and p.Asp85Val have been associated with axonal neuropathy and marked sensory impairment, Adie's pupil, and deafness [Misu et al 2000].
• CMT2L has been reported in a single Chinese family, with onset between ages 15 and 33 years and normal NCV [Tang et al 2004, Tang et al 2005].
• CMT2N has been reported in two French families and in one Australian family. The recurrent loss-of-function AARS mutation p.Arg329His segregates with and results in the CMT phenotype in each of these families [Latour et al 2010, McLaughlin et al 2012].
• CMT2O has been reported in a large family with childhood onset of delayed motor milestones associated with progressive distal lower limb weakness, pes cavus, variable sensory loss, and normal nerve conductions. Occasional proximal weakness and waddling gait were noted [Weedon et al 2011].
• CMT2P has been reported in a large rural Canadian family with onset of progressive distal muscle weakness and atrophy usually starting in young adulthood [Guernsey et al 2010]. Nerve electrophysiology was consistent with an axonal neuropathy. The inheritance was autosomal recessive and associated with a homozygous single nucleotide change in an intronic consensus acceptor splicing site of LRSAM1. Weterman et al [2012] reported a three-generation Dutch family with onset in the second or third decade of slowly progressive distal weakness and atrophy with mild sensory loss and an axonal neuropathy. The disease was autosomal dominant and caused by a frameshift mutation (p.Leu708Arg fx28) in LRSAM1. Nicolaou et al [2012] have described a multi-generational Sardinian family with a splice site mutation in LRSAM1 resulting in a frameshift and stop codon (p.Ala683Profs*3).
• CMT2/DHTKD1. Xu et al [2012] have reported a large Chinese family with autosomal dominant CMT2 and a nonsense mutation (c.1455T>G; p.Tyr485*) in exon 8 of DHTKD1, the gene encoding dehydrogenase E1 and transketolase domain-containing protein 1.

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

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

Genotype-Phenotype Correlations

Few specific genotype-phenotype correlations are known. Considerable variability of phenotype has been observed within families with CMT2A [Züchner et al 2004a, Klein et al 2011a].

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

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

Penetrance

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

Nomenclature

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 mutations [Zhu et al 2005] and with mutations in BSCL2 [Bienfait et al 2007] (see BSCL2-Related Neurologic Disorders).

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

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

Prevalence

The overall prevalence of hereditary neuropathies is estimated at approximately 3:10,000 population. About 30% of these individuals (1:10,000) may have CMT2. The prevalence of the various subtypes of CMT2 is unknown. CMT2A represented 3.4%-16% of all CMT families in Norway and Spain respectively [Braathen et al 2010, Casasnovas et al 2010].

Evaluations Following Initial Diagnosis

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

• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
• Nerve conduction velocity (NCV)
• Complete family history
• 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.

Surveillance

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

Agents/Circumstances to Avoid

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

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

• Definite high risk. Vinca alkaloids (Vincristine)
  • This category should be avoided by all persons with CMT, including those who are asymptomatic.
• Other potential risk levels. See Table 4. For more information, click here (pdf).

Evaluation of Relatives at Risk

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

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

Other

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

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 new gene mutation. The proportion of cases caused by de novo mutations is unknown but likely very small.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include neurologic examination and molecular genetic testing if the mutation in the proband has been identified.

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

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

• If a parent has a disease-causing mutation, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. No instances of germline mosaicism have been reported, although it remains a possibility.

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

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

Risk to Family Members — Autosomal Recessive CMT2

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

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

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

Carrier Detection

Carrier testing for at-risk family members for autosomal recessive forms of CMT2 is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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

Testing of at-risk asymptomatic individuals during childhood. Testing of at-risk asymptomatic individuals who are younger than age 18 years is not appropriate. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(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 has been reported [Sharapova et al 2004]. Preimplantation genetic diagnosis of other CMT2 subtypes may be an option for some families in which the disease-causing mutation(s) have been identified.

Molecular Genetic Pathogenesis

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

Published Guidelines/Consensus Statements

1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 12-28-12. [PMC free article: PMC1801355] [PubMed: 7485175]
2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 12-28-12.

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Revision History

• 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