Funded by the NIH  •  Developed at the University of Washington, Seattle

Charcot-Marie-Tooth Neuropathy Type 1

[CMT1, HMSN1, Hereditary Motor and Sensory Neuropathy 1]

Summary

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 represents 70%-80% of all CMT1 and involves abnormalities of the PMP22 gene. All individuals with CMT1A have a duplication of PMP22. CMT1B (5%-10% of all CMT1) is associated with point mutations in the MPZ gene. CMT1C (1%-2% of all CMT1) is associated with mutations in LITAF (SIMPLE), 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. Molecular genetic testing is clinically available for all of these genes.

Management.  Treatment of manifestations: treatment by a 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 (such as 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 affected individual have a 50% risk of inheriting the altered gene. Prenatal testing is possible for all subtypes of CMT1 when 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.

Diagnosis

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

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

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 (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 uses

• Diagnostic testing
• Prenatal diagnosis

Clinical testing

CMT1A, CMT1B, CMT1C, CMT1D, CMT1E, CMT2E/1F

• Targeted mutation analysis

  • Pulsed field gel electrophoresis detects a duplication of the PMP22 gene resulting in the presence of three copies of the PMP22 gene in all individuals with CMT1A.

  • FISH and Southern blot analysis can also be used to detect the PMP22 duplication [Shaffer et al 1997].

• Sequence analysis/mutation scanning detects mutations in 100% of individuals with CMT1B (MPZ), CMT1C (LITAF), CMT1D (ERG), CMT1E (PMP22), and CMT2E/1F (NEFL).

Table 1 summarizes molecular genetic testing for this disorder.

Table 1: Molecular Genetic Testing Used in CMT1 CMT1 Subtype Test Method Mutation Detected Proportion of CMT1 Attributed to Mutations in this Gene Mutation Detection Frequency  1 Test Availability CMT1A Deletion/duplication analysis Duplication of PMP22 70%-80% 100% Clinical CMT1B Sequence analysis/mutation scanning MPZ sequence variant 5%-10% 100%  2 Clinical CMT1C LITAF (SIMPLE) sequence variant 1%-2% 100%  2 Clinical CMT1D EGR2 sequence variant <2% 100%  2 Clinical CMT1E PMP22 sequence variant <5% 100%  2 Clinical CMT2E/1F Sequence analysis NEFL sequence variant <5% 100%  2 Clinical

1.  Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method 2. Each of these subtypes is identified based on detection of a mutation in the causative gene; hence, the mutation detection rate is 100%.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Because CMT1A caused by the PMP22 duplication is by far the most common subtype of CMT1, it is appropriate to test a proband for this duplication first [Klein & Dyck 2005].

Genetically Related (Allelic) Disorders

PMP22.   Other phenotypes associated with mutations of PMP22:

• Hereditary neuropathy with liability to pressure palsies (HNPP), caused by deletions of PMP22
• The very rare autosomal recessive neuropathy CMT4 , caused by homozygosity for point mutations in PMP22 [Parman et al 1999 , Numakura et al 2000]. Autosomal recessive CMT is sometimes referred to as Dejerine-Sotas syndrome (DSS) (see Nomenclature). In one family, sibs homozygous for a PMP22 point mutation (R157W) are reported to have DSS, while their heterozygous parents are clinically normal [Parman et al 1999].

MPZ

• Mutations in the MPZ gene are also associated with congenital hypomyelinating neuropathy and the CMT2 phenotype. One individual with the CMT2 phenotype and three separate mutations in MPZ has been described [Boerkoel et al 2002].
• The Roussy-Levy syndrome of CMT associated with ataxia or tremor has been shown to be caused by an MPZ mutation (p.Asn131Lys) in the original family [Plante-Bordeneuve et al 1999].

LITAF (SIMPLE).  CMT1C is the only phenotype associated with LITAF.

EGR2.  Mutations in EGR2 are also associated with autosomal  recessive CMT4 [Warner et al 1998 , Timmerman et al 1999 , Warner et al 1999 , Boerkoel et al 2002].

NEFL.  Some individuals with mutations in NEFL, which typically cause CMT2E, may have slow NCV [Jordanova, De Jonghe et al 2003], causing them to have been diagnosed with CMT1F [Fabrizi et al 2007]. To accommodate these two phenotypes associated with mutations in NEFL, the designation CMT2E/1F has been used.

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. The initial physical findings are depressed or absent tendon reflexes with weakness of foot dorsiflexion at the ankle. The typical adult individual has bilateral foot drop, symmetrical atrophy of muscles below the knee (stork leg appearance), atrophy of intrinsic hand muscles, and absent tendon reflexes in both upper and lower extremities.

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.

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].

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. 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.  Rudnik-Schoneborn 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-fpartum bleeding [Hoff et al 2005].

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 the MPZ gene (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].

• CMT1D.  A few families with CMT1D have been identified [Warner et al 1998 ; Nelis, Timmerman et al 1999 ; Numakura et al 2003].

• CMT1E

  • A point mutation in the PMP22 gene in exon three (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 point mutation p.Trp28Arg was associated with profound deafness in one family [Boerkoel et al 2002].
  • A 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:

• Pyramidal tract features
• Optic atrophy [Chalmers et al 1996 , Dillman et al 1997]
• Asymptomatic phrenic nerve involvement [Sagliocco et al 2003]
• Other distinctive signs such as keratitis, skeletal dysplasia, or tonic pupils

Neuropathology

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 , Schroder et al 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 p.Val102fs 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.
• 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 mutations with normal or near-normal NCVs include: p.Ser44Phe, p.Cys59Thr, 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, Faber et al 2006 ; Finsterer et al 2006].
• The p.Thr124Met mutation 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 mutations in cis configuration (p.His81Tyr/p.Val113Phe) [Bienfait et al 2002].
• The p.Gly163Arg mutation in the MPZ gene 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 mutation [Floroskufi et al 2006].
• p.Val102fs 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.Asp195Tyr [Fabrizi et al 2006].

CMT1D

• The p.Arg381His mutation 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 mutation is associated with a severe phenotype previously referred to as Dejerine-Sottas syndrome [Numakura et al 2003].
• Scoliosis has been noted with the p.Arg359Gln mutation [Mikesova et al 2005].
• More severe neuropathy was seen in a girl with a p.Arg359Trp mutation in EGR2 and a p.Val136Ala mutation in GJB1, the gene associated with CMTX1 [Chung et al 2005].

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, Simonati et al 2001].

• Deafness [Postelmans & Stokroos 2006] or pressure palsies [Kleopa et al 2004] may also occur.
• The pathogenicity of the p.Thr118Met mutation has been debated, but Shy et al (2006) present evidence that it causes a mild neuropathy.

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.

Anticipation

Anticipation has not been observed.

Nomenclature

CMT1A/CMT1E.  CMT1A refers to cases with duplication of PMP22; CMT1E refers to cases with point mutations in 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, Haites et al 1999].
• 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].

Prevalence

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

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

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, Verhamme et al 2006].

GJB3.  Lopez-Bigas et al (2001) have described an autosomal dominant neuropathy associated with hearing impairment caused by a mutation in the GJB3 gene. 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 the gene ARHGEF10, which encodes the protein rho guanine-nucleotide exchange factor 10.

In the autosomal dominant intermediate form 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. At least three chromosomal loci (1p, 10q, and 19p) for this intermediate form have been identified by linkage analysis [Kennerson et al 2001 ; Verhoeven et al 2001 ; Jordanova, Thomas et al 2003].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 1 (CMT1):

• 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

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 to correct foot drop and aid walking.
• Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000]
• For some individuals, forearm crutches or canes for gait stability; fewer than 5% of individuals need wheelchairs.
• Exercise within the individual's capability; many remain physically active.
• As far as possible, accurate identification 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

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

Drugs and medications that are known to cause nerve damage should be avoided [Graf et al 1996 , Chaudhry et al 2003]. These include:

• Vincristine
• Taxol
• Cisplatin
• Isoniazid
• Nitrofurantoin

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

Testing of Relatives at Risk

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

Therapies Under Investigation

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

Sahenk et al (2003) are studying 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].

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

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —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

• About 67%-80% of individuals with CMT1A have inherited the mutation from an affected parent and about 20% [Marques et al 2005] to 33% [Boerkoel et al 2002] have de novo mutations.
• 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 mutation include physical 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 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 upon the genetic status of the proband's parents.
• If a parent has a disease-causing mutation, the risk is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the disease-causing mutation cannot be detected in the 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, Ferrarini et al 2001].

Offspring of a proband.   Every child of an individual with CMT1 has a 50% chance of inheriting the disease-causing mutation.

Other family members of a proband.   The risk to other family members depends upon the status of the proband's parents. If a parent is found to have a disease-causing mutation, 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 gene may wish to pursue further evaluation, either through molecular genetic testing if a disease-causing mutation 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 resolution on genetic testing of children 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 (Genetic Testing; pdf).

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 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 about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. Pfieffer et al (2001) found that many individuals with CMT consider themselves to have significant disability and 36% would not choose to have children.

DNA banking.   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 disease will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal testing for pregnancies at increased risk for all subtypes of CMT1 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 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 such as CMT1 that 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, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD).  Sharapova et al (2004) reported successful preimplantation diagnosis for several couples at risk of having children with CMT1A. PGD may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Molecular Genetic Pathogenesis

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].

PMP22 (CMT1A, CMT1E)

Normal allelic variants: PMP22 has approximately 1,660 nucleotides and contains four exons [Patel et al 1992]. It is similar to a growth arrest-specific gene in mouse and rat.

Pathologic allelic variants: The molecular defect in CMT1A is a 1.5-Mb duplication at 17p11.2 that includes the PMP22 gene [Lupski et al 1991 , Raeymaekers et al 1991]. This duplication results from unequal crossing over of homologous chromosomes at regions of repetitive elements that flank the duplicated region.

More than 30 point mutations in the PMP22 gene can cause the CMT1E phenotype and the p.Leu16Pro mutation is found in the Trembler J mouse [Devaux & Scherer 2005]. (For more information, see Genomic Databases table above.)

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: A mouse containing eight copies of the human PMP22 gene 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, Haites et al 1999]. 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.

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].

MPZ (CMT1B)

Normal allelic variants: The MPZ gene spans approximately seven kilobases and contains six exons.

Pathologic allelic variants: Nearly 100 mutations in the MPZ gene have been reported [De Jonghe et al 1997 ; Nelis, Haites et al 1999 ; Kochanski et al 2004 ; Lee et al 2004 , Shy 2006]. More than 70% of the mutations are localized in exons two and three of the MPZ gene coding 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 Genomic Databases table above.)

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].

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.

LITAF (SIMPLE) (CMT1C)

Normal allelic variants: The LITAF gene has three coding exons. A polymorphism was reported by Bennett et al (2004).

Pathologic allelic variants: Missense mutations have been reported in LITAF (p.Ala111Gly, p.Gly112Ser, p.Thr115Asn, p.Trp116Gly, p.Pro135Ser, p.Pro135Thr) by Street et al (2003), Bennett et al (2004), Saifi et al (2005), and Latour et al (2006). (For more information, see Genomic Databases table above.) The pathogenicity of some DNA changes is difficult to determine [Kochanski 2006].

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.

EGR2 (CMT1D)

Normal allelic variants: EGR2 spans 4.3 kb and contains two coding exons.

Pathologic allelic variants: Autosomal dominant mutations include p.Ser382Arg-p.Asp383Tyr, p.Arg409W, p.Ala359Trp [Timmerman et al 1999], and p.Arg381His [Pareyson et al 2000]. (For more information, see Genomic Databases table above.) The pathogenicity of some DNA changes is difficult to determine [Kochanski 2006].

Normal gene product: Early growth response-2 protein is a zinc finger transcription factor. It is the orthologue of the murine Krox-2. 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.

NEFL (CMT2E/1F)

Normal allelic variants: The mouse and human NEFL gene contains four coding exons and the 5' UTRs are highly conserved.

Pathologic allelic variants: Human mutations in NEFL include: p.Gln33Pro, p.Pro8Arg, p.Pro22Thr, p.Asn97Ser, and p.Ala148Val. (For more information, see Genomic Databases table above.)

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 the p.Leu394Pro mutation in NEFL has massive degeneration of spinal motor neurons and abnormal neurofilament accumulation with severe neurogenic skeletal muscle atrophy.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents (pdf; Genetic Testing).
  
  
• National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders.

Literature Cited

• Bai Y, Ianokova E, Pu Q, Ghandour K, Levinson R, Martin JJ, Ceuterick-de Groote C, Mazanec R, Seeman P, Shy ME, Li J (2006) Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes. Arch Neurol 63:1787-94 [Medline]
  
  
• Bennett CL, Shirk AJ, Huynh HM, Street VA, Nelis E, Van Maldergem L, De Jonghe P, Jordanova A, Guergueltcheva V, Tournev I, Van Den Bergh P, Seeman P, Mazanec R, Prochazka T, Kremensky I, Haberlova J, Weiss MD, Timmerman V, Bird TD, Chance PF (2004) SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve. Ann Neurol 55:713-20 [Medline]
  
  
• Bernard R, Boyer A, Negre P, Malzac P, Latour P, Vandenberghe A, Philip N, Levy N (2002) Prenatal detection of the 17p11.2 duplication in Charcot-Marie-Tooth disease type 1A: necessity of a multidisciplinary approach for heterogeneous disorders. Eur J Hum Genet 10:297-302 [Medline]
  
  
• Bienfait HM, Baas F, Gabreels-Festen AA, Koelman JH, Langerhorst CT, de Visser M (2002) Two amino-acid substitutions in the myelin protein zero gene of a case of Charcot-Marie-Tooth disease associated with light-near dissociation. Neuromuscul Disord 12:281-5 [Medline]
  
  
• Bienfait HM, Faber CG, Baas F, Gabreels-Festen AA, Koelman JH, Hoogendijk JE, Verschuuren JJ, Wokke JH, de Visser M (2006) Late onset axonal Charcot-Marie-Tooth phenotype caused by a novel myelin protein zero mutation. J Neurol Neurosurg Psychiatry 77:534-7 [Medline]
  
  
• Bienfait HM, Verhamme C, van Schaik IN, Koelman JH, de Visser BW, de Haan RJ, Baas F, van Engelen BG, de Visser M (2006) Comparison of CMT1A and CMT2: similarities and differences. J Neurol 253:1572-80 [Medline]
  
  
• Bird TD, Lipe HP, Crabtree LD (1994) Impotence associated with the Charcot-Marie-Tooth syndrome. Eur Neurol 34:155-7 [Medline]
  
  
• Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K, Russo P, Kennedy S, Teebi AS, Scavina M, Williams LL, Mancias P, Butler IJ, Krajewski K, Shy M, Lupski JR (2002) Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol 51:190-201 [Medline]
  
  
• Carter GT (1997) Rehabilitation management in neuromuscular disease. J Neurol Rehab 11:69-80
  
  
• Carter GT, Jensen MP, Galer BS, Kraft GH, Crabtree LD, Beardsley RM, Abresch RT, Bird TD (1998) Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil 79:1560-4 [Medline]
  
  
• Carvalho AA, Vital A, Ferrer X, Latour P, Lagueny A, Brechenmacher C, Vital C (2005) Charcot-Marie-Tooth disease type 1A: clinicopathological correlations in 24 patients. J Peripher Nerv Syst 10:85-92 [Medline]
  
  
• Chalmers RM, Bird AC, Harding AE (1996) Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy. J Neurol Neurosurg Psychiatry 60:195-6 [Medline]
  
  
• Chapon F, Latour P, Diraison P, Schaeffer S, Vandenberghe A (1999) Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene. J Neurol Neurosurg Psychiatry 66:779-82 [Medline]
  
  
• Chaudhry V, Chaudhry M, Crawford TO, Simmons-O'Brien E, Griffin JW (2003) Toxic neuropathy in patients with pre-existing neuropathy. Neurology 60:337-40 [Medline]
  
  
• Chung KW, Sunwoo IN, Kim SM, Park KD, Kim WK, Kim TS, Koo H, Cho M, Lee J, Choi BO (2005) Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family. Neurogenetics 6:159-63 [Medline]
  
  
• De Angelis MV, Di Muzio A, Capasso M, Angiari C, Cavallaro T, Fabrizi GM, Rizzuto N, Uncini A (2004) Segmental conduction abnormalities and myelin thickenings in Val102/fs null mutation of MPZ gene. Neurology 63:2180-3 [Medline]
  
  
• De Jonghe P, Timmerman V, Ceuterick C, Nelis E, De Vriendt E, Lofgren A, Vercruyssen A, Verellen C, Van Maldergem L, Martin JJ, Van Broeckhoven C (1999) The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot-Marie-Tooth phenotype. Brain 122 (Pt 2):281-90 [Medline]
  
  
• De Jonghe P, Timmerman V, Nelis E, Martin JJ, Van Broeckhoven C (1997) Charcot-Marie-Tooth disease and related peripheral neuropathies. J Peripher Nerv Syst 2:370-87 [Medline]
  
  
• Dematteis M, Pepin JL, Jeanmart M, Deschaux C, Labarre-Vila A, Levy P (2001) Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study. Lancet 357:267-72 [Medline]
  
  
• Devaux JJ and Scherer SS (2005) Altered ion channels in an animal model of Charcot-Marie-Tooth disease type IA. J Neurosci 25:1470-80 [Medline]
  
  
• Dillmann U, Heide G, Dietz B, Teshmar E, Schimrigk K (1997) Hereditary motor and sensory neuropathy with spastic paraplegia and optic atrophy: report on a family. J Neurol 244:562-5 [Medline]
  
  
• Donaghy M, Sisodiya SM, Kennett R, McDonald B, Haites N, Bell C (2000) Steroid responsive polyneuropathy in a family with a novel myelin protein zero mutation. J Neurol Neurosurg Psychiatry 69:799-805 [Medline]
  
  
• Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH (1982) Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc 57:239-46 [Medline]
  
  
• Fabrizi GM, Cavallaro T, Angiari C, Cabrini I, Taioli F, Malerba G, Bertolasi L, Rizzuto N (2007) Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton. Brain 130:394-403 [Medline]
  
  
• Fabrizi GM, Pellegrini M, Angiari C, Cavallaro T, Morini A, Taioli F, Cabrini I, Orrico D, Rizzuto N (2006) Gene dosage sensitivity of a novel mutation in the intracellular domain of P0 associated with Charcot-Marie-Tooth disease type 1B. Neuromuscul Disord 16:183-7 [Medline]
  
  
• Fabrizi GM, Simonati A, Taioli F, Cavallaro T, Ferrarini M, Rigatelli F, Pini A, Mostacciuolo ML, Rizzuto N (2001) PMP22 related congenital hypomyelination neuropathy. J Neurol Neurosurg Psychiatry 70:123-6 [Medline]
  
  
• Fabrizi GM, Ferrarini M, Cavallaro T, Jarre L, Polo A, Rizzuto N (2001) A somatic and germline mosaic mutation in MPZ/P(0) mimics recessive inheritance of CMT1B. Neurology 57:101-5 [Medline]
  
  
• Finsterer J, Miltenberger G, Rauschka H, Janecke A (2006) Novel C59T leader peptide mutation in the MPZ gene associated with late-onset, axonal, sensorimotor polyneuropathy. Eur J Neurol 13:1149-52 [Medline]
  
  
• Floroskufi P, Panas M, Karadima G, Vassilopoulos D (2006) New mutation of the MPZ gene in a family with the Dejerine-Sottas disease phenotype. Muscle Nerve [Epub ahead of print] [Medline]
  
  
• Gabriel JM, Erne B, Pareyson D, Sghirlanzoni A, Taroni F, Steck AJ (1997) Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies. Neurology 49:1635-40 [Medline]
  
  
• Gallardo E, Garcia A, Combarros O, Berciano J (2006) Charcot-Marie-Tooth disease type 1A duplication: spectrum of clinical and magnetic resonance imaging features in leg and foot muscles. Brain 129:426-37 [Medline]
  
  
• Garcia A, Combarros O, Calleja J, Berciano J (1998) Charcot-Marie-Tooth disease type 1A with 17p duplication in infancy and early childhood: a longitudinal clinical and electrophysiologic study. Neurology 50:1061-7 [Medline]
  
  
• Gemignani F, Melli G, Alfieri S, Inglese C, Marbini A (2004) Sensory manifestations in Charcot-Marie-Tooth disease. J Peripher Nerv Syst 9:7-14 [Medline]
  
  
• Giambonini-Brugnoli G, Buchstaller J, Sommer L, Suter U, Mantei N (2005) Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation. Neurobiol Dis 18:656-68 [Medline]
  
  
• Ginsberg L, Malik O, Kenton AR, Sharp D, Muddle JR, Davis MB, Winer JB, Orrell RW, King RH (2004) Coexistent hereditary and inflammatory neuropathy. Brain 127:193-202 [Medline]
  
  
• Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD (1996) Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer 77:1356-62 [Medline]
  
  
• Grandis M and Shy ME (2005) Current Therapy for Charcot-Marie-Tooth Disease. Curr Treat Options Neurol 7:23-31 [Medline]
  
  
• Guyton GP and Mann RA (2000) The pathogenesis and surgical management of foot deformity in Charcot- Marie-Tooth disease. Foot Ankle Clin 5:317-26 [Medline]
  
  
• Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, Ohnishi A, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakashima K, Kira J, Kaji R, Oka N, Sobue G (2003) Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain 126:134-51 [Medline]
  
  
• Hodapp JA, Carter GT, Lipe HP, Michelson SJ, Kraft GH, Bird TD (2006) Double trouble in hereditary neuropathy: concomitant mutations in the PMP-22 gene and another gene produce novel phenotypes. Arch Neurol 63:112-7 [Medline]
  
  
• Hoff JM, Gilhus NE, Daltveit AK (2005) Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease. Neurology 64:459-62 [Medline]
  
  
• Houlden H and Reilly MM (2006) Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease. Neuromolecular Med 8:43-62 [Medline]
  
  
• Jordanova A, De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick C, Martin JJ, Butler IJ, Mancias P, Papasozomenos SCh, Terespolsky D, Potocki L, Brown CW, Shy M, Rita DA, Tournev I, Kremensky I, Lupski JR, Timmerman V (2003) Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 126:590-7 [Medline]
  
  
• Jordanova A, Thomas FP, Guergueltcheva V, Tournev I, Gondim FA, Ishpekova B, De Vriendt E, Jacobs A, Litvinenko I, Ivanova N, Buzhov B, De Jonghe P, Kremensky I, Timmerman V (2003) Dominant Intermediate Charcot-Marie-Tooth Type C Maps to Chromosome 1p34-p35. Am J Hum Genet 73:1423-30 [Medline]
  
  
• Kennerson ML, Zhu D, Gardner RJ, Storey E, Merory J, Robertson SP, Nicholson GA (2001) Dominant intermediate charcot-marie-tooth neuropathy maps to chromosome 19p12-p13.2. Am J Hum Genet 69:883-8 [Medline]
  
  
• Klein CJ and Dyck PJ (2005) Genetic testing in inherited peripheral neuropathies. J Peripher Nerv Syst 10:77-84 [Medline]
  
  
• Kleopa KA, Georgiou DM, Nicolaou P, Koutsou P, Papathanasiou E, Kyriakides T, Christodoulou K (2004) A novel PMP22 mutation Ser22Phe in a family with hereditary neuropathy with liability to pressure palsies and CMT1A phenotypes. Neurogenetics 5:171-5 [Medline]
  
  
• Kochanski A (2006) How to assess the pathogenicity of mutations in Charcot-Marie-Tooth disease and other diseases? J Appl Genet 47:255-60 [Medline]
  
  
• Kochanski A, Kabzinska D, Drac H, Ryniewicz B, Rowinska-Marcinska K, Hausmanowa-Petrusewicz I (2004) Early onset Charcot-Marie-Tooth type 1B disease caused by a novel Leu190fs mutation in the myelin protein zero gene. Eur J Paediatr Neurol 8:221-4 [Medline]
  
  
• Kousseff BG, Hadro TA, Treiber DL, Wollner T, Morris C (1982) Charcot-Marie-Tooth disease with sensorineural hearing loss--an autosomal dominant trait. Birth Defects Orig Artic Ser 18:223-8 [Medline]
  
  
• Kovach MJ, Campbell KC, Herman K, Waggoner B, Gelber D, Hughes LF, Kimonis VE (2002) Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness: delineation of the clinical features and review of the literature. Am J Med Genet 108:295-303 [Medline]
  
  
• Kovach MJ, Lin JP, Boyadjiev S, Campbell K, Mazzeo L, Herman K, Rimer LA, Frank W, Llewellyn B, Wang Jabs E, Gelber D, Kimonis VE (1999) A unique point mutation in the PMP22 gene is associated with Charcot- Marie-Tooth disease and deafness. Am J Hum Genet 64:1580-93 [Medline]
  
  
• Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, Kamholz J, Shy ME (2000) Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain 123 (Pt 7):1516-27 [Medline]
  
  
• Latour P, Gonnaud PM, Ollagnon E, Chan V, Perelman S, Stojkovic T, Stoll C, Vial C, Ziegler F, Vandenberghe A, Maire I (2006) SIMPLE mutation analysis in dominant demyelinating Charcot-Marie-Tooth disease: three novel mutations. J Peripher Nerv Syst 11:148-55 [Medline]
  
  
• Lee YC, Soong BW, Lin KP, Lee HY, Wu ZA, Kao KP (2004) Myelin protein zero gene mutations in Taiwanese patients with Charcot-Marie-Tooth disease type 1. J Neurol Sci 219:95-100 [Medline]
  
  
• Lopez-Bigas N, Olive M, Rabionet R, Ben-David O, Martinez-Matos JA, Bravo O, Banchs I, Volpini V, Gasparini P, Avraham KB, Ferrer I, Arbones ML, Estivill X (2001) Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Hum Mol Genet 10:947-52 [Medline]
  
  
• Lupski JR, de Oca-Luna RM, Slaugenhaupt S, Pentao L, Guzzetta V, Trask BJ, Saucedo-Cardenas O, Barker DF, Killian JM, Garcia CA, et al (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219-32 [Medline]
  
  
• Marques W Jr, Freitas MR, Nascimento OJ, Oliveira AB, Calia L, Melo A, Lucena R, Rocha V, Barreira AA (2005) 17p duplicated Charcot-Marie-Tooth 1A Characteristics of a new population. J Neurol. Mar 18; [Epub ahead of print] [Medline]
  
  
• Marrosu MG, Vaccargiu S, Marrosu G, Vannelli A, Cianchetti C, Muntoni F (1998) Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Neurology 50:1397-401 [Medline]
  
  
• McGann R and Gurd A (2002) The association between Charcot-Marie-Tooth disease and developmental dysplasia of the hip. Orthopedics 25:337-9 [Medline]
  
  
• Meggouh F, de Visser M, Arts WF, De Coo RI, van Schaik IN, Baas F (2005) Early onset neuropathy in a compound form of Charcot-Marie-Tooth disease. Ann Neurol 57:589-91 [Medline]
  
  
• Meyer zu Horste G, Prukop T, Liebetanz D, Mobius W, Nave KA, Sereda MW (2007) Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathy. Ann Neurol 61:61-72 [Medline]
  
  
• Mikesova E, Huhne K, Rautenstrauss B, Mazanec R, Barankova L, Vyhnalek M, Horacek O, Seeman P (2005) Novel EGR2 mutation R359Q is associated with CMT type 1 and progressive scoliosis. Neuromuscul Disord 15:764-7 [Medline]
  
  
• Nelis E, Haites N, Van Broeckhoven C (1999) Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies. Hum Mutat 13:11-28 [Medline]
  
  
• Nelis E, Timmerman V, De Jonghe P, Van Broeckhoven C, Rautenstrauss B (1999) Molecular genetics and biology of inherited peripheral neuropathies: a fast-moving field. Neurogenetics 2:137-48 [Medline]
  
  
• Numakura C, Lin C, Oka N, Akiguchi I, Hayasaka K (2000) Hemizygous mutation of the peripheral myelin protein 22 gene associated with Charcot-Marie-Tooth disease type 1. Ann Neurol 47:101-3 [Medline]
  
  
• Numakura C, Shirahata E, Yamashita S, Kanai M, Kijima K, Matsuki T, Hayasaka K (2003) Screening of the early growth response 2 gene in Japanese patients with Charcot-Marie-Tooth disease type 1. J Neurol Sci 210:61-4 [Medline]
  
  
• Pareyson D, Scaioli V, Laura M (2006) Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med 8:3-22 [Medline]
  
  
• Pareyson D, Taroni F, Botti S, Morbin M, Baratta S, Lauria G, Ciano C, Sghirlanzoni A (2000) Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation. Neurology 54:1696-8 [Medline]
  
  
• Parman Y, Plante-Bordeneuve V, Guiochon-Mantel A, Eraksoy M, Said G (1999) Recessive inheritance of a new point mutation of the PMP22 gene in Dejerine-Sottas disease. Ann Neurol 45:518-22 [Medline]
  
  
• Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J, Thirion X, Robaglia-Schlupp A, Pellissier JF, Fontes M (2004) Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med 10:396-401 [Medline]
  
  
• Patel PI, Roa BB, Welcher AA, Schoener-Scott R, Trask BJ, Pentao L, Snipes GJ, Garcia CA, Francke U, Shooter EM, et al (1992) The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nat Genet 1:159-65 [Medline]
  
  
• Perea J, Robertson A, Tolmachova T, Muddle J, King RH, Ponsford S, Thomas PK, Huxley C (2001) Induced myelination and demyelination in a conditional mouse model of Charcot-Marie-Tooth disease type 1A. Hum Mol Genet 10:1007-18 [Medline]
  
  
• Pfeiffer G, Wicklein EM, Ratusinski T, Schmitt L, Kunze K (2001) Disability and quality of life in Charcot-Marie-Tooth disease type 1. J Neurol Neurosurg Psychiatry 70:548-50 [Medline]
  
  
• Plaisier E, Mougenot B, Verpont MC, Jouanneau C, Archelos JJ, Martini R, Kerjaschki D, Ronco P (2005) Glomerular permeability is altered by loss of P0, a myelin protein expressed in glomerular epithelial cells. J Am Soc Nephrol 16:3350-6 [Medline]
  
  
• Plante-Bordeneuve V, Guiochon-Mantel A, Lacroix C, Lapresle J, Said G (1999) The Roussy-Levy family: from the original description to the gene. Ann Neurol 46:770-3 [Medline]
  
  
• Postelmans JT and Stokroos RJ (2006) Cochlear implantation in a patient with deafness induced by Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathies). J Laryngol Otol 120:508-10 [Medline]
  
  
• Raeymaekers P, Timmerman V, Nelis E, De Jonghe P, Hoogendijk JE, Baas F, Barker DF, Martin JJ, De Visser M, Bolhuis PA, et al (1991) Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscul Disord 1:93-97 [Medline]
  
  
• Rudnik-Schoneborn S, Rohrig D, Nicholson G, Zerres K (1993) Pregnancy and delivery in Charcot-Marie-Tooth disease type 1. Neurology 43:2011-6 [Medline]
  
  
• Sabet A, Li J, Ghandour K, Pu Q, Wu X, Kamholz J, Shy ME, Cambi F (2006) Skin biopsies demonstrate MPZ splicing abnormalities in Charcot-Marie-Tooth neuropathy 1B. Neurology 67:1141-6 [Medline]
  
  
• Sagliocco L, Orlandi G, Calabrese R, Pellegrinetti A, Baglini O, Castelli F, Baldinotti F, Sartucci F (2003) Electrodiagnostic evidence of phrenic nerve demyelination in Charcot-Marie-Tooth disease 1A. Am J Phys Med Rehabil 82:754-9 [Medline]
  
  
• Sahenk Z, Nagaraja HN, McCracken BS, King WM, Freimer ML, Cedarbaum JM, Mendell HR (2003) Neurotrophin-3 treatment promotes nerve regeneration and improvements in sensory function in patients with CMT1A. Ann Neurol 54(Suppl 7):S19
  
  
• Saifi GM, Szigeti K, Wiszniewski W, Shy ME, Krajewski K, Hausmanowa-Petrusewicz I, Kochanski A, Reeser S, Mancias P, Butler I, Lupski JR (2005) SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. Hum Mutat 25:372-383 [Medline]
  
  
• Sambuughin N, de Bantel A, McWilliams S, Sivakumar K (2003) Deafness and CMT disease associated with a novel four amino acid deletion in the PMP22 gene. Neurology 60:506-8 [Medline]
  
  
• Schroder JM (2006) Neuropathology of Charcot-Marie-Tooth and related disorders. Neuromolecular Med 8:23-42 [Medline]
  
  
• Seeman P, Mazanec R, Huehne K, SuEslikova P, Keller O, Rautenstrauss B (2004) Hearing loss as the first feature of late-onset axonal CMT disease due to a novel P0 mutation. Neurology 63:733-5 [Medline]
  
  
• Sereda MW and Nave KA (2006) Animal models of Charcot-Marie-Tooth disease type 1A. Neuromolecular Med 8:205-16 [Medline]
  
  
• Shaffer LG, Kennedy GM, Spikes AS, Lupski JR (1997) Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. Am J Med Genet 69:325-31 [Medline]
  
  
• Sharapova T, Rechitsky S, Verlinsky Y (2004) Preimplantation genetic diagnosis (PGD) for three types of Charcot-Marie-Tooth (CMT) disease. Am J Hum Genet S75:A2806
  
  
• Shirk AJ, Anderson SK, Hashemi SH, Chance PF, Bennett CL (2005) SIMPLE interacts with NEDD4 and TSG101: evidence for a role in lysosomal sorting and implications for Charcot-Marie-Tooth disease. J Neurosci Res 82:43-50 [Medline]
  
  
• Shy ME (2006) Peripheral neuropathies caused by mutations in the myelin protein zero. J Neurol Sci 242:55-66 [Medline]
  
  
• Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, Shy RR, Balsamo J, Lilien J, Garbern JY, Kamholz J (2004) Phenotypic clustering in MPZ mutations. Brain 127:371-84 [Medline]
  
  
• Shy ME, Scavina MT, Clark A, Krajewski KM, Li J, Kamholz J, Kolodny E, Szigeti K, Fischer RA, Saifi GM, Scherer SS, Lupski JR (2006) T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy. Ann Neurol 59:358-64 [Medline]
  
  
• Song S, Zhang Y, Chen B, Zhang Y, Wang M, Wang Y, Yan M, Zou J, Huang Y, Zhong N (2006) Mutation frequency for Charcot-Marie-Tooth disease type 1 in the Chinese population is similar to that in the global ethnic patients. Genet Med 8:532-5 [Medline]
  
  
• Starr A, Michalewski HJ, Zeng FG, Fujikawa-Brooks S, Linthicum F, Kim CS, Winnier D, Keats B (2003) Pathology and physiology of auditory neuropathy with a novel mutation in the MPZ gene (Tyr145->Ser). Brain 126:1604-19 [Medline]
  
  
• Steck AJ, Erne B, Pareyson D, Sghirlanzoni A, Taroni F, Schaeren-Wiemers N (2006) Normal expression of myelin protein zero with frame-shift mutation correlates with mild phenotype. J Peripher Nerv Syst 11:61-6 [Medline]
  
  
• Street VA, Bennett CL, Goldy JD, Shirk AJ, Kleopa KA, Tempel BL, Lipe HP, Scherer SS, Bird TD, Chance PF (2003) Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot- Marie-Tooth disease 1C. Neurology 60:22-6 [Medline]
  
  
• Street VA, Meekins G, Lipe HP, Seltzer WK, Carter GT, Kraft GH, Bird TD (2002) Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes. Neuromuscul Disord 12:643-50 [Medline]
  
  
• Szigeti K, Garcia CA, Lupski JR (2006) Charcot-Marie-Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genet Med 8:86-92 [Medline]
  
  
• Teunissen LL, Notermans NC, Franssen H, Van Engelen BG, Baas F, Wokke JH (2003) Disease course of Charcot-Marie-Tooth disease type 2: a 5-year follow-up study. Arch Neurol 60:823-8 [Medline]
  
  
• Timmerman V, De Jonghe P, Ceuterick C, De Vriendt E, Lofgren A, Nelis E, Warner LE, Lupski JR, Martin JJ, Van Broeckhoven C (1999) Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype. Neurology 52:1827-32 [Medline]
  
  
• Verhoeven K, De Jonghe P, Van de Putte T, Nelis E, Zwijsen A, Verpoorten N, De Vriendt E, Jacobs A, Van Gerwen V, Francis A, Ceuterick C, Huylebroeck D, Timmerman V (2003) Slowed conduction and thin myelination of peripheral nerves associated with mutant rho Guanine-nucleotide exchange factor 10. Am J Hum Genet 73:926-32 [Medline]
  
  
• Verhoeven K, Villanova M, Rossi A, Malandrini A, De Jonghe P, Timmerman V (2001) Localization of the gene for the intermediate form of charcot-marie- tooth to chromosome 10q24.1-q25.1. Am J Hum Genet 69:889-94 [Medline]
  
  
• Villanova M, Timmerman V, De Jonghe P, Malandrini A, Rizzuto N, Van Broeckhoven C, Guazzi G, Rossi A (1998) Charcot-Marie-Tooth disease: an intermediate form. Neuromuscul Disord 8:392-3 [Medline]
  
  
• Walker JL, Nelson KR, Heavilon JA, Stevens DB, Lubicky JP, Ogden JA, VandenBrink KA (1994) Hip abnormalities in children with Charcot-Marie-Tooth disease. J Pediatr Orthop 14:54-9 [Medline]
  
  
• Warner LE, Mancias P, Butler IJ, McDonald CM, Keppen L, Koob KG, Lupski JR (1998) Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 18:382-4 [Medline]
  
  
• Warner LE, Svaren J, Milbrandt J, Lupski JR (1999) Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies. Hum Mol Genet 8:1245-51 [Medline]
  
  
• Wells CA, Saavedra RA, Inouye H, Kirschner DA (1993) Myelin P0-glycoprotein: predicted structure and interactions of extracellular domain. J Neurochem 61:1987-95 [Medline]
  
  
• Wrabetz L, D'Antonio M, Pennuto M, Dati G, Tinelli E, Fratta P, Previtali S, Imperiale D, Zielasek J, Toyka K, Avila RL, Kirschner DA, Messing A, Feltri ML, Quattrini A (2006) Different intracellular pathomechanisms produce diverse Myelin Protein Zero neuropathies in transgenic mice. J Neurosci 26:2358-68 [Medline]
  
  
• Young P, Grote K, Kuhlenbaumer G, Debus O, Kurlemann H, Halfter H, Funke H, Ringelstein EB, Stogbauer F (2001) Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity. J Neurol 248:410-5 [Medline]
  
  

Suggested Readings

• Lupski JR and Garcia CA (revised 2002) Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 227. www.ommbid.com
  
  

Author Information