Clinical characteristics.

Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. It is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually become symptomatic between age five and 25 years. Fewer than 5% of individuals become wheelchair dependent. Life span is not shortened.

Diagnosis/testing.

CMT1A (70%-80% of all CMT1) involves duplication of PMP22. CMT1B (6%-10% of all CMT1) is associated with single-nucleotide variants in MPZ. CMT1C (1%-2% of all CMT1) is associated with pathogenic variants in LITAF, and CMT1D (<2% of all CMT1) is associated with pathogenic variants in EGR2. CMT1E (<5% of all CMT1) is associated with single-nucleotide variants in PMP22. CMT2E/1F (<5% of all CMT1) is associated with pathogenic variants in NEFL.

Management.

Treatment of manifestations: Treatment by a multidisciplinary team including a neurologist, physiatrist, orthopedic surgeon, physical and occupational therapists; special shoes and/or ankle/foot orthoses 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.

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

Surveillance: Regular foot examination for pressure sores.

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

Pregnancy management: Affected pregnant women may experience worsening symptoms during or after gestation; a higher occurrence of presentation anomalies, use of forceps, and operative delivery; and/or an increased incidence of post-partum bleeding.

Genetic counseling.

CMT1 is inherited in an autosomal dominant manner. About two thirds of probands with CMT1A have inherited the PMP22 duplication; about one third have CMT1A as the result of a de novo pathogenic variant. Similar data are not available for the other subtypes of CMT1. The offspring of an individual with any of the subtypes of CMT1 have a 50% chance of inheriting the altered gene. Prenatal testing is possible if the pathogenic variant has been identified in the family. Requests for prenatal testing for typically adult-onset diseases that do not affect intellect or life span are uncommon.

Clinical Diagnosis

Charcot-Marie-Tooth neuropathy type (CMT1) is diagnosed in individuals with the following:

• A progressive peripheral motor and sensory neuropathy
• Slow nerve conduction velocity (NCV). NCVs are typically 10-30 meters per second, with a range of 5-38 m/s (normal: >40-45 m/s).
• Palpably enlarged nerves, especially the ulnar nerve at the olecranon groove and the greater auricular nerve running along the lateral aspect of the neck
• A family history consistent with autosomal dominant inheritance

Molecular Genetic Testing

Genes. The CMT1 subtypes and the genes associated with them are summarized in Table 1. The complicated genetic diversity of hereditary neuropathies with emphasis on CMT syndrome has been addressed by Baets et al [2014], Pareyson et al [2014] and Bird [Charcot-Marie-Tooth Hereditary Neuropathy Overview.] Many genetic testing strategies have been proposed including that of Saporta et al [2011a].

Clinical testing

Testing Strategy

To confirm/establish the diagnosis in a proband with slow nerve conduction velocities, one genetic testing strategy is serial single gene molecular genetic testing based on the order in which pathogenic variants most commonly occur.

1.

Because CMT1A (caused by the 1.5-Mb duplication at 17p11.2 including PMP22) is by far the most common type of CMT1, it is appropriate to test a proband with very slow nerve conduction velocities for this duplication first [Klein & Dyck 2005].

2.

If no PMP22 duplication is identified, the next step is molecular genetic testing of MPZ and GJB1 (a cause of X-linked CMT). Note: If the family history shows male to male transmission, testing of GJB1, mutation of which causes Charcot-Marie-Tooth Neuropathy X Type 1, is not appropriate.

3.

If no PMP22 duplication, MPZ pathogenic variant, or GJB1 pathogenic variant is identified, consider sequence analysis of LITAF, EGR2, PMP22 (single nucleotide variants) and NEFL [Saporta et al 2011a].

Note: This testing strategy is different from that for axonal neuropathies and autosomal recessive neuropathies.

An alternative genetic testing strategy is use of a multigene panel that includes PMP22, MPZ, GJB1, and other genes of interest (see Table 1 and Differential Diagnosis). Note: The genes included and the methods used in multigene panels vary by laboratory and over time. Success of this approach is demonstrated by Klein et al [2014], who were able to identify the genetic cause of CMT in five of 15 kindreds (using exome sequencing) who had escaped earlier detection by single-gene analysis. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Genotype-Phenotype Correlations

CMT1A. A relative gene dosage effect exists regarding genotype-phenotype correlation:

• One normal allele (as in HNPP with the 17p11.2 deletion) results in a mild phenotype.
• Two normal alleles represent the normal wild-type condition.
• Three normal alleles (as in the common CMT1A 17p11.2 heterozygous duplication) cause a more severe phenotype.
• Four normal alleles (as in homozygosity for the 17p11.2 duplication) result in the most severe phenotype.
• Taioli et al [2011] described a variety of microdeletions in PMP22 associated with CMT1 or HNPP.
• Saporta et al [2011b] reported a child having a homozygous deletion of the entire PMP22 gene associated with sensory neuropathy and facial weakness.
• Deletions or duplications of this same chromosomal region (17p11.2) can result in multiple congenital anomaly syndromes of Smith-Magenis or Potocki-Lupski (OMIM 610883) [Potocki et al 2007], respectively.

Severe neuropathy has been reported in persons with CMT1A and a second neuropathy-causing disease such as CMT1C [Meggouh et al 2005], CMTX1, myotonic dystrophy type 1 (DM1) or adrenomyeloneuropathy (see X-Linked Adrenoleukodystrophy) [Hodapp et al 2006].

CMT1B

• MPZ pathogenic variants with normal or near-normal NCVs include: p.Ser44Phe, p.Ser59Thr, p.Asp75Val, p.His81Arg, p.Tyr82His, p.Thr124Met, p.Lys130Arg, and p.Gly167Arg [Marrosu et al 1998, De Jonghe et al 1999, Young et al 2001, Hattori et al 2003, Bienfait et al 2006a, Finsterer et al 2006].
• The p.Thr124Met pathogenic variant in MPZ has been associated with late-onset sensorineural hearing loss, pupillary abnormalities, and motor NCVs ranging from slow (24-35 m/s) to normal (48-59 m/s) [Chapon et al 1999].
• Pupillary abnormalities have been reported in individuals with two MPZ pathogenic variants in cis configuration (p.[His81Tyr;Val113Phe]) [Bienfait et al 2002].
• Young et al [2013] reported sibs with CMT and pupillary abnormalities who were heterozygous for both CMT1A and CMT1B.
• Mild late onset (>40 years) neuropathy was associated with four pathogenic variants (p.Ser55Ile, p.Asn116Ser, p.Pro217Ser, c.645+1G>T) by Kleffner et al [2010].
• The p.Gly163Arg pathogenic variant in MPZ has been associated with a mild neuropathy and carpal tunnel syndrome [Street et al 2002].
• Severe Dejerine-Sottas syndrome phenotype is associated with the p.Ile30Thr and p.Met197TyrTer38 pathogenic variants [Floroskufi et al 2007, Zschüntzsch et al 2009].
• p.Asp104ThrfsTer14 is associated with a mild neuropathy in the heterozygous state and a severe neuropathy in the homozygous state [Steck et al 2006]. A similar phenomenon has been reported with p.Asp224Tyr [Fabrizi et al 2006].
• Høyer et al [2011] reported a Norwegian family with an autosomal dominant, early-onset (first decade), severe, demyelinating CMT syndrome associated with duplication of the entire MPZ gene.
• Maeda et al [2012] reported a family with CMT1 and increased gene dosage of MPZ estimated at five copies by chromosomal microarray; a similar family was also reported by Speevak & Farrell [2013].
• Yonekawa et al [2013] reported a boy age two years with severe congenital hypomyelinating neuropathy and a p.Asp61Asn pathogenic variant in MPZ.
• Brozková et al [2010] discuss the care which must be taken in sorting out the pathogenicity of ten different DNA variants in MPZ.

CMT1C

• The p.Gly112Ser pathogenic variant in LITAF has occurred in several different families [Bueno et al 2011].
• The p.Pro135Arg and p.Ala129Thr pathogenic variants have occurred in two unrelated Italian families [Ciotti et al 2014, Luigetti et al 2014].

CMT1D

• The p.Arg381His pathogenic variant in EGR2 is associated with CMT1 with sensorineural hearing loss, third cranial nerve palsy, and vocal cord palsy [Pareyson et al 2000].
• The p.Asp383Tyr pathogenic variant is associated with a severe phenotype previously referred to as Dejerine-Sottas syndrome [Numakura et al 2003].
• More severe neuropathy was seen in a girl with a p.Arg359Trp pathogenic variant in EGR2 and a p.Val136Ala pathogenic variant in GJB1 (NM_000166.5), the gene associated with CMTX1 [Chung et al 2005].
• Szigeti et al [2007] have contrasted the findings of persons with autosomal dominant and recessive pathogenic variants in EGR2, noting cranial nerve involvement and respiratory compromise and a wide range of disability in one person with a dominant pathogenic variant (p.Arg359Trp). Scoliosis has also been noted in individuals with the p.Arg359Gln pathogenic variant [Mikesová et al 2005].
• A novel dominant EGR2 pathogenic variant (p.Thr387Asn) has been associated with a mild demyelinating CMT1D phenotype [Shiga et al 2012].

CMT1E

• Individuals with PMP22 single-nucleotide variants tend to have more severe clinical disability than persons with a single 17p11.2 duplication, presumably because of a dominant-negative or loss of protein-function effect [Fabrizi et al 2001b].
• Deafness [Postelmans & Stokroos 2006], pressure palsies [Kleopa et al 2004] or vestibular loss [Jen et al 2005] may also occur.
• de Vries et al [2011] have reviewed 13 patients from seven families with the p.Arg95GlnfsTer128 pathogenic variant. Findings included cranial nerve involvement and often pressure palsies similar to HNPP.
• The pathogenicity of p.Thr118Met has been debated, but Shy et al [2006] present evidence that it causes a mild neuropathy.
• Abe et al [2010] reported a child with severe CMT and compound heterozygosity for complete deletion of PMP22 on one allele and deletion of PMP22 exon 5 on the other allele.
• Taioli et al [2012] have reported two sibs with early onset demyelinating CMT both heterozygous for a p.Trp39Cys pathogenic variant in PMP22 and their mother was mosaic (20% in blood) for the same variant and had mild signs of neuropathy.

CMT1F. Two different pathogenic variants in codon 22 of NEFL (p.Pro22Thr and p.Pro22Arg) have been reported with demyelinating autosomal dominant CMT1F [Shin et al 2008]. The p.Pro22Ser pathogenic variant in NEFL is associated with autosomal recessive CMT2E.

Penetrance

Penetrance of CMT1 is usually nearly 100%, but the wide range in age of onset and severity may result in under-recognition of individuals with mild or late-onset disease.

Nomenclature

CMT1A/CMT1E. CMT1A refers to CMT1 caused by duplication of PMP22; CMT1E refers to CMT1 caused by single-nucleotide variants in PMP22.

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.

Dejerine-Sottas syndrome (DSS). The severe phenotype associated with onset in early childhood has in the past been called Dejerine-Sottas syndrome (DSS). However, DSS is a confusing term because it no longer refers to a specific phenotype caused by pathogenic variants in a specific gene. Pathogenic variants in at least three genes (PMP22, MPZ, and EGR2) have been associated with a severe early-onset phenotype:

• Heterozygosity for de novo autosomal dominant single-nucleotide variants in both PMP22 and MPZ and homozygosity for PMP22 pathogenic variants have been found in individuals with severe childhood-onset disease.
• Thirteen heterozygous missense variants in PMP22 are associated with this phenotype.
• Three missense variants at codon 72 of PMP22 are associated with this phenotype, suggesting that codon 72 pathogenic variants lead to a severe phenotype [Nelis et al 1999a].
• Pathogenic variants in EGR2 may also cause the severe early-onset phenotype [Boerkoel et al 2002].
• Autosomal recessive forms of CMT may cause the DSS phenotype.
• Persons with pathogenic variants in two different neuropathy-causing genes may have a DSS phenotype [Hodapp et al 2006].

Prevalence

The overall prevalence of hereditary neuropathies is estimated at approximately 30:100,000 population. The prevalence of CMT1 is 15:100,000-20:100,000. The prevalence of CMT1A is approximately 10:100,000. These numbers hold true in a great variety of regions including China [Song et al 2006, Szigeti et al 2006].

CMT1A represents about 70% of CMT1 [Reilly & Shy 2009] and CMT1B represents about 6%-10% of CMT1 [Mandich et al 2009].

In a large study of German individuals with a CMT1 phenotype (776), Gess et al [2013] found the following percentages: CMT1A (51%), CMTX1 (9%), and CMT1B (5%). Among those with a CMT1 phenotype, 66% had a genetic diagnosis.

Figure 1 shows the frequency of various genetic causes of CMT [Rossor et al 2013], indicating that the PMP22 duplication on chromosome 17p is responsible for approximately 31% of all CMT cases and approximately 70% of those with the CMT1 phenotype.

Figure 1.

Genetic diagnoses in CMT and related disorders From Rossor et al [2013]; reprinted with permission

In a Chinese population Liu et al [2013] found pathogenic variants in MPZ in 3% of individuals with CMT1 and in 6% of those with CMT2.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 1 (CMT1), the following evaluations are recommended:

• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
• NCV to help distinguish demyelinating, axonal, and mixed forms of neuropathy
• Detailed family history
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Individuals with CMT1 are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Carter 1997, Grandis & Shy 2005].

Treatment is symptomatic and may include the following:

• Special shoes, including those with good ankle support; affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking [Ramdharry et al 2012a].
• Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000, Ward et al 2008, Boffeli & Tabatt 2015]
• Forearm crutches or canes for gait stability for some individuals; fewer than 5% of individuals need wheelchairs.
• Exercise within the individual's capability; many remain physically active. Exercise is not detrimental to persons with CMT [Piscosquito et al 2014].
• Serial night casting to help increase ankle flexibility [Rose et al 2010]
• Accurate identification, as far as possible, of the cause of pain:
  • Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [Carter et al 1998].
  • Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
• Career and employment counseling to address persistent weakness of hands and/or feet
• Interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility, thereby improving quality of life; see Burns et al [2010] study of children with CMT1A.

Prevention of Primary Manifestations

No treatment reverses or slows the natural progression of CMT.

Prevention of Secondary Complications

Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.

Surveillance

Individuals should be evaluated regularly by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability.

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

Rudnik-Schöneborn et al [1993] evaluated 45 pregnancies in 21 women with CMT1. Worsening of the CMT1 symptoms during or after gestation was reported in about half of pregnancies. A follow-up study of 63 pregnancies in 33 women with CMT showed no serious complications but 20% of women reported a worsening of symptoms during pregnancy [Awater et al 2012]. In a study of affected pregnant women in Norway, deliveries involved a higher occurrence of presentation anomalies, use of forceps, and operative delivery; the women also experienced increased post-partum bleeding [Hoff et al 2005].

Therapies Under Investigation

Reilly & Shy [2009], Roberts [2012], and Patel & Pleasure [2013] have reviewed research on potential new treatments of CMT.

Dyck et al [1982], Ginsberg et al [2004], and Carvalho et al [2005] have described a few individuals with CMT1 and sudden deterioration in whom treatment with steroids (prednisone) or IVIg has produced variable levels of improvement. Nerve biopsy has shown lymphocytic infiltration. One such family had a specific MPZ pathogenic variant (p.Ile99Thr) [Donaghy et al 2000].

Sahenk et al [2005] studied the effects of neurotrophin-3 (NT3) on individuals with CMT1A. This same group has shown benefit of NT3 delivered by adeno-associated virus (AAV) gene therapy in a mouse model of CMT1A [Sahenk et al 2014].

Passage et al [2004] reported benefit from ascorbic acid (vitamin C) in a mouse model of CMT1. Similar benefit was reported with a progesterone receptor antagonist in a rat model of CMT [Meyer zu Horste et al 2007]. Two high-dose (1,000-1,500 mg/day) treatment trials of ascorbic acid in CMT1A have found no beneficial effect over a period of one to two years [Verhamme et al 2009b, Pareyson et al 2011]. Lewis et al [2013] also could not find a positive treatment response to ascorbic acid vs. placebo in 110 subjects with CMT1A.

Patzkó et al [2012] provided evidence for the potential use of curcumin in the treatment of individuals with CMT1B who have pathogenic variants in MPZ.

Fledrich et al [2014] suggested neuregulin-1 as a potential treatment for CMT1A based on experiments in a rat model of the disease.

Search Clinical Trials.gov 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.

Mode of Inheritance

Charcot-Marie-Tooth neuropathy type 1 (CMT1) is inherited an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• About 67%-80% of individuals with CMT1A have inherited the PMP22 duplication from an affected parent and about 20% [Marques et al 2005] to 33% [Boerkoel et al 2002] have a de novo pathogenic variant.
• Similar data are not available for the other subtypes of CMT1.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include neurologic examination and molecular genetic testing.

Note: Although most individuals diagnosed with CMT1 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. If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs depends on the genetic status of the proband's parents.
• If a parent has the PMP22, MPZ, LITAF, or EGR2 pathogenic variant, the risk to 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 cannot be detected in leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism [Fabrizi et al 2001a].

Offspring of a proband. Every child of an individual with CMT1 has a 50% chance of inheriting the PMP22, MPZ, LITAF, or EGR2 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 has the pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adult relatives of individuals with CMT1 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. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

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.

In a family with an established diagnosis of CMT1, testing is appropriate to consider in symptomatic individuals regardless of age.

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.

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 variant occurred de novo in the proband. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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 PMP22, MPZ, LITAF, or EGR2 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of the gene or custom prenatal testing.

Requests for prenatal testing for typically adult-onset conditions which (like CMT1) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic testing (PGT) may be an option for some families in which the PMP22, MPZ, LITAF, or EGR2 pathogenic variant has been identified. Successful use of PGT for CMT1A has been reported [Lee et al 2013].

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.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2017. Accessed 4-30-18.

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Suggested Reading

• Lupski JR, Garcia CA. Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 227. New York, NY: McGraw-Hill.

Revision History

• 5 July 2018 (ma) Chapter retired: covered in Charcot-Marie-Tooth Hereditary Neuropathy Overview
• 26 March 2015 (ks) Revision: MPZ pathogenic variants renamed to correspond with RefSeq NM_000530.6
• 18 December 2014 (me) Comprehensive update posted live
• 20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
• 7 November 2013 (tb) Revision: additions to Prevalence; figure added [Rossor et al 2013]
• 11 July 2013 (tb) Revision: additions to Prevalence and Natural History
• 18 October 2012 (me) Comprehensive update posted live
• 18 August 2011 (tb) Revision: Høyer et al 2011; see Testing, Genotype-Phenotype Correlations, Molecular Genetics
• 16 June 2011 (tb) Revision: additions to Differential Diagnosis – FBLN5
• 1 March 2011 (cd) Revision: edits to Testing Strategy
• 14 September 2010 (me) Comprehensive update posted live
• 18 December 2007 (cd) Revision: prenatal diagnosis available for CMT1D
• 30 March 2007 (me) Comprehensive update posted to live Web site
• 20 October 2006 (cd) Revision: targeted mutation analysis, mutation scanning, and prenatal diagnosis for CMT1D no longer available
• 30 December 2005 (cd) Revision: prenatal diagnosis and mutation scanning clinically available for CMT1C
• 26 April 2005 (me) Comprehensive update posted live
• 9 September 2004 (tb,cd) Revision: addition of LITAF; sequence analysis clinically available
• 10 May 2004 (tb) Author revisions
• 29 December 2003 (tb) Author revisions
• 22 April 2003 (tb) Author revisions
• 27 March 2003 (me) Comprehensive update posted live
• 10 May 2002 (tb) Author revisions
• 20 December 2001 (tb) Author revisions
• 12 September 2001 (tb) Author revisions
• 24 July 2001 (tb) Author revisions
• 27 June 2001 (tb) Author revisions
• 1 June 2001 (tb) Author revisions
• 16 January 2001 (tb) Author revisions
• 25 August 2000 (ca) Comprehensive update posted live
• 15 June 2000 (tb) Author revisions
• 15 May 2000 (tb) Author revisions
• 14 January 2000 (tb) Author revisions
• 31 August 1999 (tb) Author revisions
• 18 June 1999 (tb) Author revisions
• 8 April 1999 (tb) Author revisions
• 5 March 1999 (tb) Author revisions
• 12 October 1998 (tb) Author revisions
• 31 August 1998 (pb) Review posted live
• April 1996 (tb) Original submission