Clinical Diagnosis

The following findings suggest the clinical diagnosis of CMT4A – findings that overlap those in other CMT forms:

• Early onset of peripheral neuropathy, presenting especially with foot deformities, muscle wasting, and involvement of the sensory nerves

• Disability within the first and second decade of life

• Vocal cord paresis (hoarse voice)

• Diaphragm paralysis

• Facultative involvement of cranial and enteric nerves

• Proximal muscle involvement later in the disease course

Electrophysiology. Motor nerve conduction velocities (NCVs) are variable. Most affected individuals exhibit an axonal neuropathy with normal NCVs and reduced amplitudes [Sevilla et al 2003]. Some families have a demyelinating neuropathy with slowed NCVs [Baxter et al 2002, Nelis et al 2002, Ammar et al 2003, De Sandre-Giovannoli et al 2003] and others have NCVs that fall in the intermediate range [Senderek et al 2003].

The axonal phenotype is probably more often associated with vocal cord paresis than the demyelinating phenotype [Cuesta et al 2002], but the converse has also been observed [Boerkoel et al 2003].

Sensory NCVs are moderately reduced.

Neuropathology. Both demyelinating and axonal peripheral nerve lesions have been observed. Prominent loss of medium-sized and large myelinated fibers has been described [Nelis et al 2002, Ammar et al 2003, Boerkoel et al 2003, Sevilla et al 2003]. Onion bulb formations as well as thinly myelinated and unmyelinated axons have been observed [Nelis et al 2002, De Sandre-Giovannoli et al 2003]. In one study, findings were interpreted as an intermediate type of neuropathy [Senderek et al 2003]. Focally folded myelin is not a feature.

Molecular Genetic Testing

Gene. GDAP1 is the only gene known to be associated with CMT4A [Baxter et al 2002, Cuesta et al 2002].

Clinical testing

• Sequence analysis. Mutations in GDAP1 are identified in nearly 100% of individuals with autosomal recessive CMT whose disease has been mapped to 8q13-q21.1.

Table 1. Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 4A

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
GDAP1	Sequence analysis	Sequence variants 2	~100%	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. 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.

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

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

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of CMT4A is made by sequence analysis of the GDAP1 gene.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

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

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

In addition to CMT4A, mutations in GDAP1 cause autosomal dominant CMT2K [Claramunt et al 2005]. (See CMT2).

Natural History

CMT4A is an aggressive form of hereditary motor and sensory neuropathy (HMSN) with early onset, increased severity, and unusual symptoms. The disease is confined to the peripheral nervous system. Intelligence is normal. Variability in disease progression has been reported within one family [Azzedine et al 2003].

Onset is in infancy, often before two years of age. At birth, children may be hypotonic (the so-called "floppy infant").

As an exception, the p.Leu239Phe mutation appears to be associated with a comparably milder phenotype Kabzińska et al 2010.

Affected children can show delayed achievement of motor milestones, including walking. Typically, initial symptoms are in the distal lower extremities, including foot deformities such as high arch, hammertoe, and pes cavus or equinovarus; muscle wasting; areflexia; and sensory loss.

Most authors describe early involvement of the upper extremities with muscle wasting and finger contractions (claw hands), weakness of proximal muscles, and a hoarse voice caused by vocal cord paresis, which occurs during the disease progression [Sevilla et al 2003, Stojkovic et al 2004].

Progression leads to disability of the lower and upper extremities. At the end of the second decade, most individuals are wheelchair bound. Respiratory dysfunction has not been described in CMT4A.

Rare symptoms are spinal deformities [Birouk et al 2003, De Sandre-Giovannoli et al 2003, Sevilla et al 2003], facial weakness [Boerkoel et al 2003], and painless lower-leg ulcers [Nelis et al 2002].

Life expectancy is usually not affected, but on occasion may be reduced because of secondary complications.

Genotype-Phenotype Correlations

Genotype-phenotype correlations have not been reported.

Penetrance

All published pedigrees demonstrating CMT4A with the expected autosomal recessive inheritance show complete penetrance of the phenotype. In these families, heterozygotes for one disease-causing allele appeared to be free of symptoms.

Anticipation

Anticipation has not been observed.

Nomenclature

Autosomal-dominant forms of GDAP1-associated neuropathies are termed CMT2K.

Prevalence

Currently, CMT4A is considered the most frequent of all autosomal recessive forms of CMT.

Molecular genetic testing has shown that the following proportion of individuals with CMT have two disease-causing GDAP1 alleles:

• Five of 33 (15%) individuals from Europe with autosomal recessive (AR) CMT [Nelis et al 2002]

• One of 153 (0.7%) individuals from North America with CMT

• Three of 14 (14%) Hispanics, caused by a founder effect [Boerkoel et al 2003]

• Four of 119 (3.3%) individuals from Europe with AR CMT [Ammar et al 2003]

• Three of 69 (4.3%) unrelated Czech patients AR CMT [Baránková et al 2007].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4A (CMT4A), the following evaluations are recommended:

• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss

• NCV to help distinguish demyelinating, axonal, and mixed forms of neuropathy

• Detailed family history

Treatment of Manifestations

Individuals with CMT4A are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Carter et al 1995, Grandis & Shy 2005]. Treatment is symptomatic and may include the following:

• Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [Carter et al 1995]

• Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000]

• Forearm crutches or canes for gait stability

• Wheelchairs for mobility because of gait instability

• Exercise within the affected individual's capability

• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAID) [Carter et al 1998]

• Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin

• Career and employment counseling because of persistent weakness of hands and/or feet

Prevention of Secondary Complications

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

Surveillance

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

Agents/Circumstances to Avoid

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

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

• Definite high risk: Vinca alkaloids (Vincristine)

  • This category should be avoided by all persons with CMT, including those who are asymptomatic.

• Other potential risk levels: See Table 2. For more information, click here (pdf).

Therapies Under Investigation

Donaghy et al [2000] and Ginsberg et al [2004] have described a few individuals with CMT1 and sudden deterioration in whom treatment with steroids (prednisone) or IVIg has produced variable levels of improvement. There is no similar report for individuals with CMT4A.

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

Evaluation of Relatives at Risk

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

Other

Genetics clinics, staffed by genetics professionals, provide 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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Charcot-Marie-Tooth neuropathy type 4A is usually inherited in an autosomal recessive manner.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with CMT4A are obligate heterozygotes (carriers) for a disease-causing mutation in GDAP1.

Other family members of a proband. Sibs of the proband's parents are at a 50% risk of being carriers.

Carrier Detection

Carrier testing is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations 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.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Revision History

• 3 June 2010 (me) Comprehensive update posted live

• 6 March 2007 (jv) Revision: prenatal testing available

• 23 June 2006 (ca) Comprehensive update posted to live Web site

• 11 May 2004 (me) Review posted to live Web site

• 23 February 2004 (jv,sz) Original submission