Alternative titles; symbols
SNOMEDCT: 715796006; ORPHA: 99948; DO: 0110185;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q21.11 | Charcot-Marie-Tooth disease, type 4A | 214400 | Autosomal recessive | 3 | GDAP1 | 606598 |
A number sign (#) is used with this entry because autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A) is caused by homozygous mutation in the GDAP1 gene (606598), which encodes ganglioside-induced differentiation-associated protein-1, on chromosome 8q21.
Mutations in the GDAP1 gene also cause select forms of autosomal recessive axonal neuropathy (e.g., 607706 and CMT2K, 607831) as well as an intermediate form of CMT (CMTRIA; 608340). Mutations in the GDAP1 gene may also cause the axonal form CMT2H (607731) because the locus for that disorder has been mapped to 8q21.
By convention, the designation CMT4 is applied to autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease, which is a peripheral neuropathy characterized by distal motor and sensory impairment resulting in gait difficulties and associated with foot deformities. Motor nerve conduction velocities are decreased, and sural nerve biopsies show loss of myelinated fibers. The age at onset and severity is variable (summary by Patzko and Shy, 2012).
Genetic Heterogeneity of Charcot-Marie-Tooth Disease Type 4
Several different subtypes of autosomal recessive demyelinating CMT (CMT4) have been identified, each with particular ethnic, pathologic, or clinical characteristics: CMT4A; CMT4B, which includes CMT4B1 (601382), caused by mutation in the MTMR2 gene (603557), CMT4B2 (604563), caused by mutation in the SBF2 gene (607697), and CMT4B3 (615284), caused by mutation in the SBF1 gene (603560); CMT4C (601596), caused by mutation in the SH3TC2 gene (608206); CMT4D (601455), caused by mutation in the NDRG1 gene (605262); CMT4E (605253), caused by mutation in the EGR2 (129010) or MPZ (159440) genes; CMT4F (614895), caused by mutation in the PRX gene (605725); CMT4G, or Russe-type hereditary motor and sensory neuropathy, (605285), which maps to chromosome 10q23; CMT4H (609311), caused by mutation in the FGD4 gene (611104); CMT4J (611228), caused by mutation in the FIG4 gene (609390); and CMT4K (616684), caused by mutation in the SURF1 gene (185620).
Allan (1939) found 8 young girls with a recessive form of peroneal atrophy in a North Carolina orthopedic hospital which catered to patients under the age of 16 years. The 8 came from 6 families in which both parents were normal. In 4 of the 6 families the parents were cousins. Beighton (1971) described 9 (possibly 10) cases of recessive CMT disease in an inbred Amish group. Identical twins were concordantly affected.
Ben Othmane et al. (1993, 1993) reported 4 Tunisian families with a homogeneous form of autosomal recessive demyelinating CMT. The disorder, which they designated type 4A, was a severe neuropathy of childhood characterized by early age of onset (before 2 years of age), rapidly progressive distal weakness and atrophy of the limbs leading to an inability to walk in late childhood or adolescence, mild sensory loss with abolished deep tendon reflexes, normal cerebrospinal fluid, severely decreased motor nerve conduction velocity (NCV), and hypomyelination.
By genetic linkage studies, Ben Othmane et al. (1993, 1993) mapped the CMT4 gene to 8q-q21.1. A two-point peak lod score of 9.19 at theta = 0.00 was obtained for D8S164. The gene encoding peripheral myelin protein-2 (PMP2; 170715) maps to the same area and was, therefore, a candidate for the site of the mutation in this disorder. Ben Othmane et al. (1995) demonstrated, however, that the PMP2 gene lies distal to the CMT4A gene region. Using a PAC contig and haplotype analysis, Ben Othmane et al. (1998) further narrowed the assignment of the CMT4A locus.
The transmission pattern of CMT4A in the families reported by Ben Othmane et al. (1993, 1993) and studied by Baxter et al. (2002) was consistent with autosomal recessive inheritance.
By positional cloning, Baxter et al. (2002) identified the GDAP1 gene as the site of 3 different homozygous mutations (606598.0001-606598.0003) in the 4 Tunisian families with CMT4A reported by Ben Othmane et al. (1993, 1993).
See comments of Nicholson and Ouvrier (2002) concerning the mixed axonal and demyelinating type of CMT resulting from GDAP1 mutations.
The autosomal recessive form of demyelinating CMT is less frequent than the dominant (118200, 118210) or X-linked recessive (302801) forms. Peroneal atrophy is one of the conditions used by Allan (1939) to illustrate the 'law' that recessive disorders are more severe than dominant ones and that X-linked disorders tend to be intermediate in severity. This disorder may have been unusually frequent in the hill folk of the western part of North Carolina where Allan worked.
In western Norway, Skre (1974) estimated the frequency of the 3 types of CMT as follows: autosomal dominant, 36 per 100,000; autosomal recessive, 1.4 per 100,000; X-linked recessive, 3.6 per 100,000. His discussion of the autosomal recessive form was particularly useful. He concluded that it is a more generalized disorder than the other two forms.
Mahloudji (1969) described 2 sisters and a brother, born of consanguineous Iranian parents, with early childhood onset of a sensorimotor polyneuropathy. The 2 older sibs, sister and brother, were ages 17 and 18.5 years, respectively, at the time of the report. Both had delayed motor development, achieving walking at age 3 to 4 years. Gait was also awkward, with frequent falls, and Romberg sign was positive. Physical examination showed absence of all deep tendon reflexes and superficial abdominal reflexes. There was distal impairment of all sensory modalities affecting both the upper and lower limbs, which was more severe in the sister, extending up to her knees and thighs. Neither had muscle wasting, but both had mild weakness in the distal muscles, more prominent in the lower limbs. Cranial nerves were intact, intelligence was normal, and there were no foot deformities or dysarthria. The brother had scoliosis of the thoracic side and a supernumerary nipple on the right. The youngest 7-year-old sister had delayed development, abnormal gait, areflexia, and was unable to run.
Allan, W. Relation of hereditary pattern to clinical severity as illustrated by peroneal atrophy. Arch. Intern. Med. 63: 1123-1131, 1939.
Baxter, R. V., Ben Othmane, K., Rochelle, J. M., Stajich, J. E., Hulette, C., Dew-Knight, S., Hentati, F., Ben Hamida, M., Bel, S., Stenger, J. E., Gilbert, J. R., Pericak-Vance, M. A., Vance, J. M. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nature Genet. 30: 21-22, 2002. [PubMed: 11743579] [Full Text: https://doi.org/10.1038/ng796]
Beighton, P. H. Recessively inherited Charcot-Marie-Tooth syndrome in identical twins. Birth Defects Orig. Art. Ser. VII(2): 105, 1971. [PubMed: 5173114]
Ben Othmane, K. B., Rochelle, J. M., Hamida, M. B., Slotterbeck, B., Rao, N., Hentati, F., Pericak-Vance, M. A., Vance, J.M. Fine localization of the CMT4A locus using a PAC contig and haplotype analysis. Neurogenetics 2: 18-23, 1998. [PubMed: 9933296] [Full Text: https://doi.org/10.1007/s100480050047]
Ben Othmane, K., Ben Hamida, M., Lennon, F., Loeb, D., Hentati, F., Ben Hamida, C., Blel, S., Pericak-Vance, M. A., Vance, J. M. Autosomal recessive Charcot-Marie-Tooth disease (CMT4) type A: evidence of genetic linkage to chromosome 8q21. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A149, 1993.
Ben Othmane, K., Hentati, F., Lennon, F., Ben Hamida, C., Blel, S., Roses, A. D., Pericak-Vance, M. A., Ben Hamida, M., Vance, J. M. Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum. Molec. Genet. 2: 1625-1628, 1993. [PubMed: 8268915] [Full Text: https://doi.org/10.1093/hmg/2.10.1625]
Ben Othmane, K., Loeb, D., Hayworth-Hodgte, R., Hentati, F., Rao, N., Roses, A. D., Ben Hamida, M., Pericak-Vance, M. A., Vance, J. M. Physical and genetic mapping of the CMT4A locus and exclusion of PMP-2 as the defect in CMT4A. Genomics 28: 286-290, 1995. [PubMed: 8530038] [Full Text: https://doi.org/10.1006/geno.1995.1143]
Mahloudji, M. A recessively inherited mixed polyneuropathy of early onset. J. Med. Genet. 6: 411-412, 1969. [PubMed: 5365950] [Full Text: https://doi.org/10.1136/jmg.6.4.411]
Nicholson, G., Ouvrier, R. GDAP1 mutations in CMT4: axonal and demyelinating phenotypes? (Editorial) Neurology 59: 1835-1836, 2002. [PubMed: 12499472] [Full Text: https://doi.org/10.1212/wnl.59.12.1835]
Patzko, A., Shy, M. E. Charcot-Marie-Tooth disease and related genetic neuropathies. Continuum (Minneap. Minn.) 18: 39-59, 2012. [PubMed: 22810069] [Full Text: https://doi.org/10.1212/01.CON.0000411567.34085.da]
Skre, H. Genetic and clinical aspects of Charcot-Marie-Tooth's disease. Clin. Genet. 6: 98-118, 1974. [PubMed: 4430158] [Full Text: https://doi.org/10.1111/j.1399-0004.1974.tb00638.x]