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Charcot-Marie-Tooth Neuropathy Type 1

Synonyms: CMT1, HMSN1, Hereditary Motor and Sensory Neuropathy 1
, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: February 20, 2014.


Disease 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 point mutations in MPZ. CMT1C (1%-2% of all CMT1) is associated with mutations in LITAF, and CMT1D (<2% of all CMT1) is associated with mutations in EGR2. CMT1E (<5% of all CMT1) is associated with point mutations in PMP22. CMT2E/1F (<5% of all CMT1) is associated with mutations in NEFL.

Management. Treatment of manifestations: Treatment by a multidisciplinary team including a neurologist, physiatrists, orthopedic surgeons, physical and occupational therapist; 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.

Genetic counseling. CMT1 is inherited in an autosomal dominant manner. About two thirds of probands with CMT1A have inherited the disease-causing mutation; about one third have CMT1A as the result of a de novo mutation. 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 disease-causing mutation 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:

  • CMT1A. PMP22 duplication; 70%-80% of CMT1
  • CMT1B. MPZ; 5%-10% of CMT1
  • CMT1C. LITAF (previously known as SIMPLE); 1%-2% of CMT1
  • CMT1D. EGR2; less than 2% of CMT1
  • CMT1E. PMP22 point mutations; less than 5% of CMT1
  • CMT2E/1F. NEFL; less than 5% of CMT1

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 1 (CMT1)

CMT1 SubtypeGene 1Proportion of CMT1 Attributed to Mutations in This GeneTest MethodMutations Detected 2Mutation Detection Frequency by Gene and Test Method 3
CMT1APMP2270%-80%Targeted mutation analysisPMP22 duplication>95% 4
CMT1BMPZ5%-10%Sequence analysis 5 / mutation scanning 6Sequence variants100% 7
Unknown 8Deletion/duplication analysis 8Partial- or whole-gene deletion or duplicationSee footnote 9
CMT1CLITAF1%-2%Sequence analysis 5Sequence variants~100% 7
CMT1DEGR2<2%Sequence analysis 5Sequence variants~100% 7
CMT1EPMP22<5%Sequence analysis 5 / mutation scanning 6Sequence variants~100% 7
CMT2E/1FNEFL<5%Sequence analysis 5Sequence variants~100% 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

4. Detects a1.5-Mb duplication at 17p11.2 that includes PMP22 resulting in the presence of three copies of PMP22 in all individuals with CMT1A. The test method is a deletion/duplication analysis targeted specifically at the PMP22 duplication; a variety of test methods can be used (see footnote 8) in addition to FISH.

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

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

7. Each of these subtypes is identified based on detection of a mutation in the associated gene; hence, the mutation detection rate is 100%.

8. 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.

9. Høyer et al [2011]

Testing Strategy

To confirm/establish the diagnosis in a proband with slow nerve conduction velocities


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].


If no PMP22 duplication is identified, the next step is molecular genetic testing of MPZ and GJB1, a cause of a different type of X-linked CMT.

Note: If the family history shows male to male transmission, testing of GJB1, mutations in which cause Charcot-Marie-Tooth Neuropathy X Type 1 is not appropriate.


If no PMP22 duplication, MPZ sequence variant, or GJB1 sequence variant is identified, the next step is to consider sequence analysis of LITAF, EGR2, PMP22 (point mutations) and NEFL [Saporta et al 2011a].

Note: This testing strategy is different from that for axonal neuropathies (CMT2) and autosomal recessive neuropathies (CMT4).

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

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

Clinical Description

Natural History

Classic CMT1 Phenotype

Individuals with CMT1 usually become symptomatic between age five and 25 years [Marques et al 2005, Houlden & Reilly 2006]; age of onset ranges from infancy (resulting in delayed walking) to the fourth and subsequent decades. Clinical severity is variable, ranging from extremely mild disease that goes unrecognized by the affected individual and physician to considerable weakness and disability.

The typical presenting symptom of CMT1 is weakness of the feet and ankles [Ferrarini et al 2012]. The initial physical findings are depressed or absent tendon reflexes with weakness of foot dorsiflexion at the ankle. The typical affected adult has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance), atrophy of intrinsic hand muscles, and absent tendon reflexes in both upper and lower extremities.

Onset in the first year of life often suggests an autosomal recessive cause of CMT but autosomal dominant types of CMT caused by duplication of PMP22 (CMT1A) and missense mutations in PMP22 (CMT1E), MPZ (CMT1B), and NEFL have been reported in this age group [Baets et al 2011].

Proximal muscles usually remain strong.

Mild to moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet, but many affected individuals are unaware of this finding. Pain, especially in the feet, is reported by 20%-30% of individuals [Carter et al 1998, Gemignani et al 2004, Carvalho et al 2005]. The pain is often musculoskeletal in origin but may be neuropathic in some cases [Pazzaglia et al 2010].

Poretti et al [2013] have shown that the vestibular impairment may contribute to the poor balance often present in CMT1.

In a study of 61 subjects with CMT1, Boentert et al [2013] found that 37% had obstructive sleep apnea and 40% had restless leg syndrome. If these findings are confirmed they would represent an important newly recognized aspect of the CMT1 phenotype.

Episodic pressure palsies have been reported [Kleopa et al 2004].

In CMT1A, prolonged distal motor latencies may already be present in the first months of life, and slow motor nerve conduction velocities (NCVs) have been found in some individuals by age two years [Krajewski et al 2000]. However, the full clinical picture may not occur until the second decade of life or later [Garcia et al 1998]. In a study of 57 individuals with CMT1A, three had floppy infant syndrome, two had marked proximal and distal weakness (one requiring a wheelchair), one had severe scoliosis, five had calf muscle hypertrophy, and three had hand deformity [Marques et al 2005].

Some individuals with CMT1B have onset in the first decade of life; others have a much later onset. The age of onset trend tends to run true in families [Hattori et al 2003].

CMT1 is slowly progressive over many years. Affected individuals experience long plateau periods without obvious deterioration [Teunissen et al 2003]. NCVs slow progressively over the first two to six years of life and are relatively stable throughout adulthood. Early onset of symptoms and severity of disease show some correlation with slower NCVs, but this is only a general trend. Muscle weakness correlates with progressive decrease in the compound muscle action potential (CMAP) and suggests that developing axonal pathology is of considerable clinical relevance [Hattori et al 2003, Pareyson et al 2006].

In a study of persons with CMT1A over a five-year period, Verhamme et al [2009a] found increasing disability at least partially related to “a process of normal aging.” In a study of a large family with CMT1A over two decades, Berciano et al [2010] found that deterioration varied from mild to marked. It remains unclear why such a wide range of severity is observed in persons with CMT1A with the same mutation (PMP22 dup).

In CMT1A Kim et al [2012] found that severity of weakness and sensory loss correlated with CMAPs and SNAPs (sensory nerve action potential), but not with conduction velocities.

The disease does not decrease life span.

Other findings in individuals with CMT1. A few men with CMT1 have reported impotence [Bird et al 1994].

Pes cavus foot deformity is common (>50%) and hip dysplasia may be under-recognized [Walker et al 1994, McGann & Gurd 2002].

Pulmonary insufficiency and sleep apnea are sometimes seen [Dematteis et al 2001].

Deafness has been occasionally reported in the CMT1 phenotype and early mild hearing loss may be common [Rance et al 2012]. Hearing loss has been associated with point mutations in PMP22 (CMT1E) [Kovach et al 1999, Sambuughin et al 2003, Postelmans & Stokroos 2006] and MPZ (CMT1B) [Starr et al 2003, Seeman et al 2004].

Lower-limb muscle atrophy and fatty infiltration can be demonstrated by MRI and followed longitudinally [Gallardo et al 2006].

Pregnancy. See Pregnancy Management.

CMT1 Subtypes

The CMT1 subtypes, identified solely by molecular findings, are often clinically indistinguishable.

CMT1A. NCVs vary. Mean median motor NCVs were 21±5.7 m/s in one study [Hattori et al 2003] and 16.5 m/s (range: 5-26.5 m/s) in another [Carvalho et al 2005]. In a third study, the range was 12.6-35 m/s [Marques et al 2005]. CMAP is decreased [Hattori et al 2003].

CMT1B. The NCV shows a bimodal curve, with some families having slow median motor NCV (mean: 16.5 m/s) and others having normal or near-normal NCV (mean: 44.3 m/s). The individuals in this latter "normal" NCV group tend to have lower CMAP, later age of onset, and more frequent hearing loss and pupillary abnormalities. These findings suggest the existence of two types of CMT1B: primarily demyelinating and primarily axonal. The two types probably reflect functional differences in the MPZ protein caused by different mutations in MPZ (see Genotype-Phenotype Correlations) [Hattori et al 2003, Shy et al 2004].

CMT1C. This subtype appears to be clinically identical to CMT1A [Bennett et al 2004, Saifi et al 2005, Latour et al 2006]. NCVs range from 7.5 to 27 m/s with occasional temporal dispersion [Bennett et al 2004] and conduction block with variable age of onset including early childhood [Gerding et al 2009].

CMT1D. A few families with CMT1D have been identified [Warner et al 1998, Nelis et al 1999b, Numakura et al 2003, Shiga et al 2012].

CMT1E. An amino acid substitution in PMP22 in exon 3 (p.Ala67Pro) is associated with deafness in a family with CMT1 previously reported by Kousseff et al [1982], Kovach et al [1999], Kovach et al [2002].

The amino acid substitution, p.Trp28Arg, was associated with profound deafness in one family [Boerkoel et al 2002].

The amino acid substitution p.Ser22Phe mutation in PMP22 is associated with pressure palsies as well as the CMT1 phenotype in a Cypriot family [Kleopa et al 2004].

In addition to the above, the following findings in affected families demonstrate further heterogeneity in the CMT1 phenotype:


CMT1A. Microscopically, the enlarged nerves show hypertrophy and onion bulb formation thought to result from repeated demyelination and remyelination of Schwann cell wrappings around individual axons [Carvalho et al 2005, Schröder 2006].

CMT1B. Individuals with slow NCVs tend to have demyelinating features on nerve biopsy, whereas those with normal NCVs have more axonal pathology with axonal sprouting [Hattori et al 2003]. Onion bulb formation has been seen [Bai et al 2006]. Excessive myelin folding and thickness were reported in a family with a c.336delA null mutation in MPZ [De Angelis et al 2004].

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.

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].




CMT1E. Individuals with PMP22 point mutations 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] or pressure palsies [Kleopa et al 2004] may also occur.

De Vries et al [2011] have reviewed 13 patients from seven families with the p.Arg95GlnfsTer128 mutation. Findings included cranial nerve involvement and often pressure palsies similar to HNPP.

The pathogenicity of the p.Thr118Met mutation 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.

CMT1F. Two different mutations 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 mutation in NEFL is associated with autosomal recessive CMT2E.


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.


CMT1A/CMT1E. CMT1A refers to CMT1 caused by duplication of PMP22; CMT1E refers to CMT1 caused by point mutation of PMP22.

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.

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 mutations in a specific gene. Mutations in at least three genes (PMP22, MPZ, and EGR2) have been associated with a severe early-onset phenotype:

  • Heterozygosity for de novo autosomal dominant point mutations in both PMP22 and MPZ and homozygosity for PMP22 mutations have been found in individuals with severe childhood-onset disease.
  • Thirteen heterozygous missense mutations in PMP22 are associated with this phenotype.
  • Three missense mutations at codon 72 of PMP22 are associated with this phenotype, suggesting that codon 72 mutations lead to a severe phenotype [Nelis et al 1999a].
  • Mutations in EGR2 may also cause the severe early-onset phenotype [Boerkoel et al 2002].
  • Autosomal recessive forms of CMT (see CMT4) may cause the DSS phenotype.
  • Persons with mutations in two different neuropathy-causing genes may have a DSS phenotype [Hodapp et al 2006].


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


Figure 1. Genetic diagnoses in CMT and related disorders

From Rossor et al [2013]; reprinted with permission

Differential Diagnosis

Acquired causes of neuropathy and other inherited neuropathies need to be considered (see CMT Overview). The differential diagnosis includes other genetic neuropathies, especially CMTX, CMT2, CMT4, and HNPP, all of which show considerable phenotypic overlap [Bienfait et al 2006b].

FBLN5. Auer-Grumbach et al [2011] found mutations in FBLN5 in families with features of CMT1; FBLN5 mutations were additionally associated with age-related macular degeneration and hyperelastic skin (similar to cutis laxa). Safka Brozkova et al [2013] have found the same missense mutation in FBLN5 (c.1117 C>T (p.Arg373Cys)) in a Czech family with CMT1 and a different background haplotype compared with the Austrian family of Auer-Grumbach.

GJB3. López-Bigas et al [2001] have described an autosomal dominant neuropathy associated with hearing impairment caused by a mutation in GJB3. Although the sural nerve pathology showed demylination compatible with CMT1, the nerve conduction velocities (NCVs) were not markedly slow and may suggest an axonal neuropathy (CMT2).

Familial slow NCV. Verhoeven et al [2003] have described a family with no symptoms or signs, but with slow NCVs associated with a mutation in ARHGEF10, encoding the protein rho guanine nucleotide exchange factor 10.

In the autosomal dominant intermediate forms of CMT, individuals have a relatively typical CMT phenotype with NCVs that overlap those observed in CMT1 (demyelinating neuropathy) and CMT2 (axonal neuropathy) [Villanova et al 1998]. Motor NCVs in these families usually range between 25 and 50 m/s. Three types are recognized to date:

It is usually not possible to differentiate between intermediate forms of CMT and most CMT2 subtypes based on clinical findings [Nicholson & Myers 2006] unless cataract and/or neutropenia, occasional findings in DI-CMTB, are present.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


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
  • Medical genetics consultation

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 2012].
  • Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000, Ward et al 2008]
  • 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.
  • 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.


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 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 2 or for more information click here.

Table 2. Medications Potentially Toxic to Persons with CMT

Moderate to Significant Risk 1
- Amiodarone (Cordarone)
- Bortezomib (Velcade)
- Cisplatin & oxaliplatin
- Colchicine (extended use)
- Dapsone
- Didanosine (ddI, Videx)
- Dichloroacetate
- Disulfiram (Antabuse)
- Gold salts
- Leflunomide (Arava)
- Metronidazole/misonidazole (extended use)
- Nitrofurantoin (Macrodantin, Furadantin, Macrobid)
- Nitrous oxide (inhalation abuse or vitamin B12 deficiency)
- Perhexiline (not used in US)
- Pyridoxine (mega dose of vitamin B6)
- Stavudine (d4T, Zerit)
- Suramin
- Taxols (paclitaxel, docetaxel)
- Thalidomide
- Zalcitabine (ddC, Hivid)

Additional medications in lesser-risk categories are listed here.

The medications listed here present differing degrees of potential risk for worsening CMT neuropathy. Always consult your treating physician before taking or changing any medication.

1. Based on: Weimer & Podwall [2006]. See also Graf et al [1996], Nishikawa et al [2008], and Porter et al [2009].

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 the pregnancies. 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] have reviewed research on potential new treatments of CMT.

Patel & Pleasure [2013] have summarized the potential treatment approaches to CMT1.

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 mutation (p.Ile99Thr) [Donaghy et al 2000].

Sahenk et al [2005] studied the effects of neurotrophin-3 on individuals with CMT1A.

Passage et al [2004] have 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.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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

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

Risk to Family Members

Parents of a proband

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 mutation first occurred, s/he may have somatic mosaicism for the mutation 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 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 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 adults. Asymptomatic adults at risk of inheriting a CMT1-causing mutation may wish to pursue further evaluation, either through molecular genetic testing if a pathogenic variant has been identified in the family or through clinical evaluation and NCV testing. Since no treatment is available to individuals early in the course of the disease, such testing is for personal decision making only.

Testing of at-risk individuals during childhood. Consensus holds that asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders should not have testing. 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.

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

Prenatal Testing

Prenatal testing for pregnancies at increased risk for all CMT1 subtypes is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele in the family must be identified before prenatal testing can be performed.

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

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 diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified. Successful use of PGD for CMT1A has been reported [Lee et al 2013].


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
    13 allée de Grèce
    35140 Saint Aubin du Cormier
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    2700 Chestnut Street
    Chester PA 19013-4867
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@charcot-marie-tooth.org
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Fax: 03 2651002
    Email: gisele.smeyers@ua.ac.be
  • Hereditary Neuropathy Foundation, Inc.
    1751 2nd Avenue
    Suite 103
    New York NY 10128
    Phone: 877-463-1287 (toll-free); 212-722-8396
    Email: info@hnf-cure.org
  • 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 8605
    Fax: 44 0 191 241 8770
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    Evry 91002
    Phone: +33 01 69 47 28 28
    Fax: 01 69 47 77 12 16
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    JN Baarn 3743
    Phone: 035 54 80 481
    Fax: 035 54 80 499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • 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 B. OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 1 (View All in OMIM)



Gene structure. PMP22 transcript variant 1 (NM_000304.2) has1828 bp nucleotides and five exons, four of which encode amino acids [Patel et al 1992]. It is similar to a growth arrest-specific gene in mouse and rat. For a detailed summary of gene and protein information for the following genes, see Table A, Gene Symbol.

Pathogenic allelic variants

Table 3. Selected PMP22 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
(1.5-Mb duplication at 17p11.2)--

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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Peripheral myelin protein 22 is a 160-amino acid protein that is present in compact myelin and has four transmembrane domains.

Abnormal gene product. Duplication of PMP22 is associated with increased mRNA message for PMP22 in peripheral nerve and by an unknown mechanism that results in abnormal myelination [Gabriel et al 1997].

Most missense mutations are localized in the transmembrane domains of peripheral myelin protein 22, indicating the functional importance of these domains. Individuals with PMP22 point mutations tend to have more severe clinical disability than those with a single 17p11.2 duplication, presumably because of a dominant-negative or loss-of-protein function effect [Sereda & Nave 2006].

A mouse containing eight copies of human PMP22 shows a phenotype similar to but more severe than that seen in individuals with CMT1A, while mice containing 16 and 30 additional copies of mouse PMP22 show severe hypomyelination [Nelis et al 1999a]. This supports the hypothesis that more copies of PMP22 result in a more severe phenotype [Giambonini-Brugnoli et al 2005].

Perea et al [2001] have generated a transgenic mouse model in which mouse PMP22 over-expression can be regulated, possibly providing a system for evaluation of potential therapeutic approaches.


Gene structure. MPZ spans approximately seven kilobases and contains six exons. Two reference sequences are given in Table 4. NM_000530.5 uses an upstream alternative start site. NM_000530.6 was updated to shorten the N-terminus to one that is more supported by current research community use. The updated start codon has a stronger Kozak signal and is better conserved across vertebrate species than the previously represented upstream start codon. There is no experimental evidence indicating which start codon is preferentially used in vivo [Excerpted from Consensus CDS not in NM_000530.6]. For a detailed summary of gene and protein information for the following genes, see Table A, Gene Symbol.

Pathogenic allelic variants. Nearly 100 mutations in MPZ have been reported [De Jonghe et al 1997, Nelis et al 1999a, Kochański et al 2004, Lee et al 2004, Shy 2006]. More than 70% of the mutations are localized in exons 2 and 3 of MPZ, which code for the extracellular domain, indicating the functional importance of this domain. Intronic mutations affecting MPZ splicing have been reported [Sabet et al 2006]. (For more information, see Table A.) A duplication of the entire MPZ gene was detected in a Norwegian family with an autosomal dominant, early onset (first decade), severe, demyelinating CMT syndrome [Høyer et al 2011].

Table 4. Selected MPZ Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
(Ile30Thr) 2
(Ser44Phe) 2
c.205T>A p.Ser69Thr
(Asp75Val) 2
(His81Tyr) 2
(Tyr82His) 2
(Val102fs) 2
(Val113Phe) 2
(Thr124Met) 2
(Lys130Arg) 2
(Gly163Arg) 2
c.517G>C or c.517G>Ap.Gly177Arg
(Gly167Arg) 2
c.347A>Gp.Asn116Ser NM_000530​.6
645+1 G>TNA

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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable

1. Variant designation that does not conform to current naming conventions

2. Designation of amino acid change if the NP_000521​.2 reference sequence was used

Normal gene product. P0 myelin 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 [Wells et al 1993]. 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. It is also expressed in glomerular epithelial cells of the kidney [Plaisier et al 2005]. Both the longer NP_000521.2 and shorter NP_000521.1 N-termini have predicted signal peptides, but the signal peptide is ten amino acids longer when the upstream start codon is used as in NM_000530.5. The mature proteins of NP_000521.1 and NP_000521.2 are the same.

Abnormal gene product. Different mutations affect all portions of the protein and may alter myelin adhesion or produce an unfolded protein response [Wrabetz et al 2006]. Either demyelinating or axonal phenotypes can result. Grandis et al [2008] found that mutations associated with late-onset disease cause a partial loss of function in transfected cells, whereas mutations associated with early-onset disease cause abnormal gain of function.


Gene structure. LITAF has three coding exons. For a detailed summary of gene and protein information for the following genes, see Table A, Gene Symbol.

Benign allelic variants. A benign variant was reported by Bennett et al [2004].

Pathogenic allelic variants. Missense mutations have been reported in LITAF [Street et al 2003, Bennett et al 2004, Saifi et al 2005, Latour et al 2006] (Table 5). (For more information, see Table A.) The pathogenicity of some DNA changes is difficult to determine [Kochański 2006].

Table 5. Selected LITAF 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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein product of LITAF has two names: lipopolysaccaride-induced tumor necrosis factor-α factor (LITAF) and small integral membrane protein of the lysosome/late endosome (SIMPLE) [Saifi et al 2005]. The gene may play a role in the lysosomal sorting of plasma membrane proteins [Shirk et al 2005].

Abnormal gene product. Mutations may alter the ability of the Schwann cell to degrade proteins.


Gene structure. EGR2 spans 4.3 kb and contains two coding exons. For a detailed summary of gene and protein information for the following genes, see Table A, Gene Symbol.

Pathogenic allelic variants. Selected autosomal dominant mutations are listed in Table 6 [Timmerman et al 1999, Pareyson et al 2000]. (For more information, see Table A.) The pathogenicity of some DNA changes is difficult to determine [Kochański 2006].

Table 6. Selected EGR2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1144A>C or c.1146T>Ap.Ser382Arg

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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Early growth response-2 protein is a zinc finger transcription factor. It is the ortholog of the murine Krox-2 protein. EGR2 induces expression of several proteins involved in myelin sheath formation and maintenance.

Abnormal gene product. Krox-2 null mice show a block in Schwann cell differentiation.


Gene structure. Both the mouse and human NEFL have four coding exons; the 5' UTRs are highly conserved. For a detailed summary of gene and protein information for the following genes, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 7. (For more information, see Table A.)

Table 7. Selected NEFL 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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. 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 neurofilments have diminished axon caliber and delayed regeneration of myelinated axons following crush injury. A mouse with a point mutation in NEFL has massive degeneration of spinal motor neurons and abnormal neurofilament accumulation with severe neurogenic skeletal muscle atrophy.


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 6-24-14. [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 6-24-14.

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Suggested Reading

  1. 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). New York: McGraw-Hill. Chap 227. 2014. Available online. Accessed 6-24-14.

Chapter Notes

Revision History

  • 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 to live Web site
  • 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 to live Web site
  • 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 to live Web site
  • 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 to live Web site
  • April 1996 (tb) Original submission
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