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Charcot-Marie-Tooth Neuropathy Type 4A

Synonyms: Charcot-Marie-Tooth Disease Type 4A, CMT4A

, MD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: February 28, 2013.


Clinical characteristics.

Charcot-Marie-Tooth neuropathy type 4A (CMT4A), an aggressive form of hereditary motor and sensory neuropathy (HMSN), is confined to the peripheral nervous system, and typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Even proximal muscles can become weak. Age at onset is from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.


Diagnosis of CMT4A is based on clinical findings and confirmed by molecular genetic testing of GDAP1, the only gene in which pathogenic variants are known to cause CMT4A.


Treatment of manifestations: Treatment is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. Treatment may include: ankle/foot orthoses, orthopedic surgery, forearm crutches or canes, wheelchairs, treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents, and career and employment counseling.

Prevention of primary manifestations: Daily heel cord stretching exercises to prevent Achilles tendon shortening.

Surveillance: Regular evaluation by the multidisciplinary team to determine neurologic status and functional disability.

Agents/circumstances to avoid: Drugs and medications known to cause nerve damage; obesity.

Genetic counseling.

CMT4A is usually inherited in an autosomal recessive manner. The asymptomatic parents of an affected individual are obligate heterozygotes (carriers) and therefore carry one mutated allele. 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which the pathogenic variants have been identified.


A diagnostic algorithm has been published for inherited neuropathies as a practice parameter [England et al 2009]. However, the relative frequencies of inherited neuropathies, especially CMT4A, can change regionally, so clinicians should adjust accordingly (see Prevalence).

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 in which pathogenic variants are known to cause CMT4A [Baxter et al 2002, Cuesta et al 2002].

Clinical testing

Table 1.

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

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
GDAP1Sequence analysis 4Sequence variants~100% 5

See Molecular Genetics for information on allelic variants.


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


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice-site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


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

Testing Strategy

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

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants 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 pathogenic variants in the family.

Clinical Characteristics

Clinical Description

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 pathogenic variant 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 normal, but on occasion may be reduced because of secondary complications.

Genotype-Phenotype Correlations

Genotype-phenotype correlations have been reported but are not common enough to be confirmed.


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 appear to be free of symptoms. However, some families have been reported to have affected individuals who are heterozygous for one disease-causing allele in GDAP1. This is sometimes referred to as CMT2K and is inherited in an autosomal dominant manner (see Nomenclature).


Anticipation has not been observed.


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


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:


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
  • Clinical genetics consultation and/or pediatric neurology consultation

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.


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

Agents/Circumstances to Avoid

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

Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. Click here (pdf) for an up-to-date list.

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 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Charcot-Marie-Tooth neuropathy type 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 mutated 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 pathogenic variant 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 pathogenic variants 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GDAP1 pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for CMT4A are possible options.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association CMT France
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Fax: 03 2651002
  • Hereditary Neuropathy Foundation, Inc.
    432 Park Avenue South
    4th Floor
    New York NY 10016
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
    Institute of Genetic Medicine
    University of Newcastle upon Tyne
    International Centre for Life
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Phone: 44 (0)191 241 8617
    Fax: 44 (0)191 241 8770
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    Evry cedex 91002
    Phone: +33 01 69 47 28 28
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Phone: 31 35 5480481
    Fax: 31 35 5480499
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
  • Muscular Dystrophy Campaign
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Charcot-Marie-Tooth Neuropathy Type 4A: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 4A (View All in OMIM)


Gene structure. GDAP1 comprises six exons spanning about 14 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. To date, more than 40 pathogenic variants have been identified. Known pathogenic variants include deletions, insertions, and nonsense, missense, and splice-site variants throughout the gene. (See Table A.)

Note: A number of pathogenic variants in GDAP1 associated with autosomal dominant CMT2K have been described. See CMT2 [Claramunt et al 2005, Chung et al 2008, Sahin-Calapoglu et al 2009].

Table 2.

Selected GDAP1 Pathogenic Allelic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein ganglioside-induced differentiation-associated protein-1 comprises 358 amino acids. It contains a glutathione-S-transferase (GST) domain and belongs to a new class of GST-like proteins, which have a transmembrane domain in the C-terminal extension [Marco et al 2004]. Pedrola et al [2005] investigated a human neuroblastoma cell line that transiently over-expressed GDAP1 and found co-localization with mitochondrial marker proteins. Western blots of subcellular fractions confirmed this finding. They also showed that C-terminal transmembrane domains are necessary for the correct localization in mitochondria; however, missense variants did not change the mitochondrial pattern of the wild-type protein [Pedrola et al 2005].

Niemann et al [2005] showed that GDAP1 is located in the mitochondrial outer membrane and regulates the mitochondrial network. GDAP1 induces fragmentation (fission) of mitochondria, the opposite function of mitofusin-2, encoded by MFN2, pathogenic variants in which cause CMT2A.

Abnormal gene product. Truncating GDAP1 pathogenic variants have lost mitochondrial fragmentation activity. Such activity is also strongly reduced for disease-associated GDAP1 single-nucleotide variants [Niemann et al 2005]. Different pathogenic variants affect all portions of the protein. Either demyelinating or axonal phenotypes can result.


Literature Cited

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  2. Azzedine H, Ruberg M, Ente D, Gilardeau C, Perie S, Wechsler B, Brice A, LeGuern E, Dubourg O. Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. Neuromuscul Disord. 2003;13:341–6. [PubMed: 12868504]
  3. Baránková L, Vyhnálková E, Züchner S, Mazanec R, Sakmaryová I, Vondrácek P, Merlini L, Bojar M, Nelis E, De Jonghe P, Seeman P. GDAP1 mutations in Czech families with early-onset CMT. Neuromuscul Disord. 2007;17:482–9. [PubMed: 17433678]
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Chapter Notes

Revision History

  • 28 February 2013 (me) Comprehensive update posted live
  • 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
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