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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.