Alternative titles; symbols
SNOMEDCT: 715797002; ORPHA: 99949; DO: 0110183;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q32 | Charcot-Marie-Tooth disease, type 4C | 601596 | Autosomal recessive | 3 | SH3TC2 | 608206 |
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 4C (CMT4C) is caused by homozygous or compound heterozygous mutation in the SH3TC2 gene (608206) on chromosome 5q32.
Mild mononeuropathy of the median nerve (MNMN; 613353) is a less severe allelic disorder caused by heterozygous mutation in the SH3TC2 gene.
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Kessali et al. (1997) reported 2 large consanguineous Algerian families with autosomal recessive demyelinating CMT. Mean age at onset was 5.2 years (range 2 to 10 years). All patients had foot deformities and scoliosis, often requiring surgery. Motor nerve conduction velocities were severely decreased, and sural nerve biopsy of 1 patient showed concentric Schwann cell proliferation with multiple small onion bulbs. Linkage analysis excluded known CMT loci.
Gabreels-Festen et al. (1999) reported the phenotypic findings in 5 Dutch families, a Turkish family, and a sporadic patient with a unique type of autosomal recessive demyelinating CMT. In addition to classic CMT features, such as distal muscle atrophy and weakness, areflexia, foot deformities, and distal sensory impairment, many patients had early onset of a severe scoliosis, often requiring surgery. Nerve biopsy findings were characterized by an increase of basal membranes around myelinated, demyelinated, and unmyelinated axons, relatively few onion bulbs, and, most typically, large cytoplasmic extensions of Schwann cells.
Senderek et al. (2003) reported phenotypic and molecular characterization of 17 patients from 11 families, as well as 1 sporadic case, with autosomal recessive demyelinating CMT linked to chromosome 5. Age at onset ranged from infancy to 12 years, and many patients had a delay in learning to walk. Prominent scoliosis was observed in 11 patients. Mean median motor nerve conduction velocity (NCV) was 22.6 m/s, and nerve biopsy, when obtained, showed demyelination, onion bulb formation, and extended Schwann cell processes. Other classic CMT features included foot deformities, distal muscle weakness and atrophy, mild distal sensory loss, and decreased reflexes.
Colomer et al. (2006) reported detailed clinical features of 15 individuals from European Gypsy families with CMT4C and homozygous for the R1109X mutation (608206.0006). Nine patients were members of a large consanguineous Spanish Gypsy kindred (Gooding et al., 2005), with 3 patients each from 3 branches of the family. Within each branch, affected individuals were sibs or first cousins, whereas the relation between branches was as first cousins once removed or second cousins. In the first branch, patients had a relatively late onset at ages 16, 26, and 37 years, respectively, with mild foot deformities, lower limb weakness and walking difficulties. One patient could walk with crutches, 1 could stand with support, and the youngest remained ambulatory. All 3 eventually developed mild upper limb involvement. All also had cranial nerve involvement with deafness, slow pupillary light reflexes, and lingual fasciculations. None had scoliosis. Three patients in the second branch of the family had a more severe disease with onset at ages 6, 6, and 7 years, foot deformities, and distal lower limb weakness and areflexia; 1 had severe scoliosis. There was no evidence of cranial nerve involvement. Affected members of the third branch of the family were the most severely affected. Two boys were hypotonic from birth, never achieved ambulation, had severe scoliosis, and remained wheelchair-bound and totally disabled with generalized muscle weakness and wasting. One died at age 22 years. An affected sister had delayed motor development and severe sensory ataxia, but no scoliosis. Two patients showed prolonged brainstem auditory evoked potentials (BAEP), but no other cranial nerve findings. Six additional patients with the R1109X mutation from 5 different families showed variable features, including 4 with delayed motor development, 3 with scoliosis, and 4 with abnormal BAEP recordings. Common features included foot deformities, distal muscle weakness and atrophy, and difficulty walking. Colomer et al. (2006) noted the highly variable phenotype associated with the same homozygous mutation, especially in the large Spanish Gypsy kindred, and suggested that genetic modifiers may play a role in the manifestation of CMT4C.
Azzedine et al. (2006) reported 10 families with CMT4C from Europe and North Africa. Onset occurred between ages 2 and 10 years, and almost all patients presented with scoliosis, kyphoscoliosis, and foot deformities. The functional disability was low, and most patients could walk without help. Median motor nerve conduction velocities were decreased but not associated with disease duration. Azzedine et al. (2006) emphasized that spine deformities are a hallmark of this disorder.
LeGuern et al. (1996) reported results of linkage analysis and homozygosity mapping in 2 large consanguineous Algerian pedigrees with Charcot-Marie-Tooth disease. Affected individuals had peripheral motor and sensory neuropathy in at least the lower limbs and reduced median nerve conduction (mean, 24 +/- 5.1 m/s), consistent with a demyelinating process. LeGuern et al. (1996) excluded linkage of CMT in these families to 17p (CMT1A; 118220), 1q (CMT1B; 118200), and 8q (CMT4A). In 1 family, the 8 affected sibs were homozygous for the markers D5S643 and D5S436. When these 2 loci were considered as 1 marker, a lod score of 4.81 at theta = 0.00 was calculated. In the second family, the 3 affected individuals were homozygous for 5 markers overlapping the region of homozygosity in the first family. The authors determined that the minimal overlapping region of homozygosity in the 2 families restricted the locus to a 4-cM interval between D5S658 and D5S402 (or D5S638, which maps to the same position).
Guilbot et al. (1999) constructed a physical map of the candidate region by screening YACs for microsatellites that had been used for the genetic analysis. Combined genetic, cytogenetic, and physical mapping restricted the locus to a region of less than 2 Mb on 5q32. They found probable linkage to 5q31-q33 in 3 of 17 consanguineous affected families, suggesting that the 5q locus may account for almost 20% of demyelinating autosomal recessive CMT. Guilbot et al. (1999) excluded several candidate genes in the region on the basis of their position on the contig and/or by sequence analysis, including EGR1 (128990), which is expressed specifically in Schwann cells.
Gabreels-Festen et al. (1999) refined the locus for autosomal recessive demyelinating CMT to a 7-cM region between D5S643 and D5S670 on chromosome 5q23-q33. A maximum lod score of 3.10 was obtained for marker D5S413.
By homozygosity mapping and allele-sharing analysis in 5 families with autosomal recessive demyelinating CMT that mapped to chromosome 5, Senderek et al. (2003) refined the CMT4C locus to a 1.7-Mb region on 5q32.
The transmission pattern of CMT4C in the families reported by Senderek et al. (2003) was consistent with autosomal recessive inheritance.
In affected members of 11 families and a sporadic patient with CMT4C, Senderek et al. (2003) identified 11 different mutations in the SH3TC2 gene (see 608206.0001-608206.0005), of which 8 were protein-truncating and 3 missense. Segregation analyses were consistent with autosomal recessive inheritance.
In 8 affected members of a large Spanish Gypsy kindred with CMT4C, Gooding et al. (2005) identified a homozygous mutation in the SH3TC2 gene (R1109X; 608206.0006). Four additional European Gypsy patients also had the mutation. Haplotype analysis indicated a founder effect.
In affected members of 10 families with CMT4C, Azzedine et al. (2006) identified compound heterozygous or homozygous mutations in the SH3TC2 gene. The authors identified a total of 10 different mutations, including 8 novel ones. R954X (608206.0005) was a recurrent mutation, occurring in 4 Dutch families and 1 Algerian family. Some of the families had been reported by Kessali et al. (1997) and Gabreels-Festen et al. (1999).
Lupski et al. (2010) reported 4 sibs with CMT4C caused by compound heterozygous mutations in the SH3TC2 gene: R954X (608206.0005) and Y169H (608206.0008). Three additional family members who were heterozygous for the R954X mutation, resulting in loss of function, had a mild mononeuropathy of the median nerve, and 2 additional family members heterozygous for the Y169H mutation had an apparently autosomal dominant axonal neuropathy with definite median nerve involvement, as shown by electrophysiologic studies. These findings suggested a toxic gain of function for the Y169H-mutant protein. Lupski et al. (2010) commented on the subtle autosomal dominant phenotypes segregating independently with the respective mutations.
Gooding et al. (2005) found that CMT4C occurs across European Gypsy populations, with prevalence among Spanish Gypsies. Other inherited conditions associated with peripheral neuropathy common in the European Gypsy population include HMSNL (601455), HMSNR (605285), and CCFDN (604168).
Claramunt et al. (2007) found that 10 of 20 Spanish Gypsy families with autosomal recessive demyelinating neuropathy had CMT4C. The most common mutation was R1109X, which was identified in 20 of 21 mutation-carrying chromosomes. Haplotype analysis indicated a founder effect that likely arose about 225 years ago, probably as a result of a bottleneck. Among the cohort of 20 families, 4 had HMSNL, and 3 had HMSNR.
In a French Canadian cluster of 17 CMT4C patients from Quebec, Canada, Gosselin et al. (2008) identified the R954X mutation in homozygosity in 12 patients from 7 families and in compound heterozygosity with an unidentified mutation in 2 patients from 1 family. In total, the R954X mutation was identified in 26 (76%) of 34 alleles from 10 families. Thirteen patients, including 10 homozygous for R954X, originated from a series of coastal villages in the Gaspesie, a sparsely populated peninsular region of Quebec, near the Maine/U.S. border. The villages are distributed along a 150-km stretch of the western shore of Chaleur Bay. Haplotype analysis demonstrated that at least 2 distinct CMT4C mutations are present in the French Canadian population and indicated a founder effect for the R954X mutation.
Houlden et al. (2009) identified a homozygous R954X mutation in affected members of 4 English families with CMT4C. A fifth English family was compound heterozygous for R954X and E657K (608206.0007). There was significant phenotypic variability between these families: some presented with severe childhood onset, respiratory and cranial nerve involvement, and became wheelchair-bound, whereas others had only mild scoliosis and foot deformity. One patient homozygous for the R954X mutation had a superimposed inflammatory neuropathy associated with steroid treatment for ulcerative colitis.
By screening of the SH3TC2 gene in 60 unrelated Czech patients with CMT, Lassuthova et al. (2011) found that 13 (21.7%) carried at least 1 pathogenic mutation and 7 (11.6%) had 2 pathogenic mutations. Nine novel mutations were identified. Screening for only the R954X mutation showed that 8 (1.94%) of 412 additional patients carried this variant; overall, R954X accounted for 63% of the mutant alleles. Lassuthova et al. (2011) concluded that CMT4C is relatively common in the Czech population.
Arnaud et al. (2009) found that Sh3tc2-null mice developed a progressive peripheral neuropathy manifest by decreased motor and sensory nerve conduction velocity and hypomyelination. Murine Sh3tc2 was specifically expressed in Schwann cells and localized to the plasma membrane and to the perinuclear endocytic recycling compartment, suggesting a possible function in myelination and/or in regions of axoglial interactions. Analysis of myelin in the peripheral nerve of mutant mice showed abnormal organization of the node of Ranvier, a phenotype that was confirmed in CMT4C patient nerve biopsies. The findings suggested a role for the SH3TC2 gene product in myelination and in the integrity of the node of Ranvier.
Arnaud, E., Zenker, J., de Preux Charles, A.-S., Stendel, C., Roos, A., Medard, J.-J., Tricaud, N., Kleine, H., Luscher, B., Weis, J., Suter, U., Senderek, J., Chrast, R. SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system. Proc. Nat. Acad. Sci. 106: 17528-17533, 2009. Note: Erratum: Proc. Nat. Acad. Sci. 107: 15305 only, 2010. [PubMed: 19805030] [Full Text: https://doi.org/10.1073/pnas.0905523106]
Azzedine, H., Ravise, N., Verny, C., Gabreels-Festen, A., Lammens, M., Grid, D., Vallat, J. M., Durosier, G., Senderek, J., Nouioua, S., Hamadouche, T., Bouhouche, A., Guilbot, A., Stendel, C., Ruberg, M., Brice, A., Birouk, N., Dubourg, O., Tazir, M., LeGuern, E. Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations. Neurology 67: 602-606, 2006. [PubMed: 16924012] [Full Text: https://doi.org/10.1212/01.wnl.0000230225.19797.93]
Claramunt, R., Sevilla, T., Lupo, V., Cuesta, A., Millan, J.M., Vilchez, J. J., Palau, F., Espinos, C. The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4. Clin. Genet. 71: 343-349, 2007. [PubMed: 17470135] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00774.x]
Colomer, J., Gooding, R., Angelicheva, D., King, R. H. M., Guillen-Navarro, E., Parman, Y., Nascimento, A., Conill, J., Kalaydjieva, L. Clinical spectrum of CMT4C disease in patients homozygous for the p.Arg1109X mutation in SH3TC2. Neuromusc. Disord. 16: 449-453, 2006. [PubMed: 16806930] [Full Text: https://doi.org/10.1016/j.nmd.2006.05.005]
Gabreels-Festen, A., van Beersum, S., Eshuis, L., LeGuern, E., Gabreels, F., van Engelen, B., Mariman, E. Study on the gene and phenotypic characterisation of autosomal recessive demyelinating motor and sensory neuropathy (Charcot-Marie-Tooth disease) with a gene locus on chromosome 5q23-q33. J. Neurol. Neurosurg. Psychiat. 66: 569-574, 1999. [PubMed: 10209165] [Full Text: https://doi.org/10.1136/jnnp.66.5.569]
Gooding, R., Colomer, J., King, R., Angelicheva, D., Marns, L., Parman, Y., Chandler, D., Bertranpetit, J., Kalaydjieva, L. A novel Gypsy founder mutation, pArg1109X in the CMT4C gene, causes variable peripheral neuropathy phenotypes. J. Med. Genet. 42: e69, 2005. Note: Electronic Article. [PubMed: 16326826] [Full Text: https://doi.org/10.1136/jmg.2005.034132]
Gosselin, I., Thiffault, I., Tetreault, M., Chau, V., Dicaire, M.-J., Loisel, L., Emond, M., Senderek, J., Mathieu, J., Dupre, N., Vanasse, M., Puymirat, J., Brais, B. Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster. Neuromusc. Disord. 18: 483-492, 2008. [PubMed: 18511281] [Full Text: https://doi.org/10.1016/j.nmd.2008.04.001]
Guilbot, A., Ravise, N., Bouhouche, A., Coullin, P., Birouk, N., Maisonobe, T., Kuntzer, T., Vial, C., Grid, D., Brice, A., LeGuern, E. Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31-q33: exclusion of candidate genes including EGR1. Europ. J. Hum. Genet. 7: 849-859, 1999. [PubMed: 10602360] [Full Text: https://doi.org/10.1038/sj.ejhg.5200382]
Houlden, H., Laura, M., Ginsberg, L., Jungbluth, H., Robb, S. A., Blake, J., Robinson, S., King, R. H. M., Reilly, M. M. The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy. Neuromusc. Disord. 19: 264-269, 2009. [PubMed: 19272779] [Full Text: https://doi.org/10.1016/j.nmd.2009.01.006]
Kessali, M., Zemmouri, R., Guilbot, A., Maisonobe, T., Brice, A., LeGuern, E., Grid, D. A clinical, electrophysiologic, neuropathologic, and genetic study of two large Algerian families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease. Neurology 48: 867-873, 1997. [PubMed: 9109869] [Full Text: https://doi.org/10.1212/wnl.48.4.867]
Lassuthova, P., Mazanec, R., Vondracek, P., Siskova, D., Haberlova, J., Sabova, J., Seeman, P. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin. Genet. 80: 334-345, 2011. [PubMed: 21291453] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01640.x]
LeGuern, E., Guilbot, A., Kessali, M., Ravise, N., Tassin, J., Maisonobe, T., Grid, D., Brice, A. Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33. Hum. Molec. Genet. 5: 1685-1688, 1996. [PubMed: 8894708] [Full Text: https://doi.org/10.1093/hmg/5.10.1685]
Lupski, J. R., Reid, J. G., Gonzaga-Jauregui, C., Rio Deiros, D., Chen, D. C. Y., Nazareth, L., Bainbridge, M., Dinh, H., Jing, C., Wheeler, D. A., McGuire, A. L., Zhang, F., and 10 others. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. New Eng. J. Med. 362: 1181-1191, 2010. [PubMed: 20220177] [Full Text: https://doi.org/10.1056/NEJMoa0908094]
Senderek, J., Bergmann, C., Stendel, C., Kirfel, J., Verpoorten, N., De Jonghe, P., Timmerman, V., Chrast, R., Verheijen, M. H. G., Lemke, G., Battaloglu, E., Parman, Y., and 19 others. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am. J. Hum. Genet. 73: 1106-1119, 2003. [PubMed: 14574644] [Full Text: https://doi.org/10.1086/379525]