DiagnosisA 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 DiagnosisThe 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 TestingGene. GDAP1 is the only gene in which mutations 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 4AView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityGDAP1Sequence analysis Sequence variants 2~100% 3Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.3. Mutations in GDAP1 are identified in nearly 100% of individuals with autosomal recessive CMT whose disease has been mapped to 8q13-q21.1.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).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 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.Genetically Related (Allelic) DisordersIn addition to CMT4A, mutations in GDAP1 cause autosomal dominant CMT2K [Claramunt et al 2005]. (See CMT2).}

Natural HistoryCMT4A 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 CorrelationsGenotype-phenotype correlations have been reported but are not common enough to be confirmed.

Differential DiagnosisSee Charcot-Marie-Tooth Hereditary Neuropathy Overview and Charcot-Marie-Tooth Type 4.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 Medical genetics consultation and/or pediatric neurology consultationTreatment of ManifestationsIndividuals 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 ComplicationsDaily heel cord stretching exercises are recommended to prevent Achilles tendon shortening.SurveillanceIndividuals 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 AvoidObesity 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).Table 2. Medications Potentially Toxic to Persons with CMTView in own windowModerate to Significant Risk <sup>1- Amiodarone (Cordarone)
- Bortezomib (Velcade)
- Cisplatin & Oxaliplatin
- Colchicine (extended use)
- Dapsone
- Didanosine (ddI, Videx)
- Dichloroacetate
- Disulfiram (Antabuse)
- Gold salts
- Leflunomide (Arava) - Metronidazole/Misonidazole (extended use)
- Nitrofurantoin (Macrodantin, Furadantin, Macrobid)
- Nitrous oxide (inhalation abuse or Vitamin B₁₂ deficiency)
- Perhexiline (not used in US)
- Pyridoxine (mega dose of Vitamin B₆)
- Stavudine (d4T, Zerit)
- Suramin
- Taxols (paclitaxel, docetaxel)
- Thalidomide
- Zalcitabine (ddC, Hivid)Click here (pdf) for additional medications in lesser-risk categories.The medications listed here present differing degrees of potential risk for worsening CMT neuropathy. Always consult your treating physician before taking or changing any medication.1. Based on: Weimer & Podwall [2006]. See also Graf et al [1996], Nishikawa et al [2008], and Porter et al [2009].Therapies Under InvestigationDonaghy 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.</sup>

Molecular GeneticsInformation 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 DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCMT4AGDAP18q21​.11Ganglioside-induced differentiation-associated protein 1IPN Mutations, GAPD1
GDAP1 homepage - Leiden Muscular Dystrophy pagesGDAP1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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) View in own window 214400CHARCOT-MARIE-TOOTH DISEASE, TYPE 4A; CMT4A 606598GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1Normal allelic variants. GDAP1 comprises six exons spanning about 14 kb. Pathologic allelic variants. To date, over 40 pathologic mutations have been identified. Known mutations include nonsense exonic, missense, splice site, deletion, and insertion mutations throughout the gene. (See Table A.)Founder effects have been shown in the Hispanic population for the mutation p.Gln163* [Boerkoel et al 2003] and for p.Leu239Phe in the central and eastern European population [Kabzińska et al 2010]A case with a missense mutation and 3' splice site mutation has been reported from Poland [Kabzińska et al 2005]. In a Spanish population, Claramunt et al [2005] reported 12 mutations in 125 index cases in which more common CMT-related genes had been excluded. Three of these cases were heterozygous mutations compatible with autosomal dominant inheritance. Dominant cases are now subsumed under CMT2K. See Charcot-Marie-Tooth Neuropathy Type 2 (CMT2).In Italy, four of 76 persons with normal parents and no identifiable mutations in four other CMT-causing genes were homozygous for the same mutation (p.Met116Arg) in GDAP1 [Di Maria et al 2004]. A founder effect was suggested. Note: A number of mutations 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 3. Selected GDAP1 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.347T>Gp.Met116ArgNM_018972​.2
NP_061845​.2c.487C>Tp.Gln163*c.715C>Tp.Leu239PheSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).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 mutations 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, mutations in which cause CMT2A.Abnormal gene product. Truncating GDAP1 mutations have lost mitochondrial fragmentation activity. Such activity is also strongly reduced for disease-associated GDAP1 point mutations [Niemann et al 2005]. Different mutations affect all portions of the protein. Either demyelinating or axonal phenotypes can result.