#302802
Table of Contents
Cytogenetic location: Xq26 Genomic coordinates (GRCh38): X:129,500,001-138,900,000
A number sign (#) is used with this entry because of evidence that X-linked recessive Charcot-Marie-Tooth disease-3 (CMTX3) is caused by a genomic rearrangement between chromosomes 8q24.3 and Xq27.1.
For a phenotypic description and discussion of genetic heterogeneity of X-linked CMT, see CMTX1 (302800).
Ionasescu et al. (1991, 1992) studied 3 families with X-linked recessive Charcot-Marie-Tooth neuropathy of the type reported by Erwin (1944). In 2 of the families, affected males had distal muscle atrophy and weakness and distal sensory loss with onset at age 10 to 14 years; in 1 of these families affected members also showed pes cavus and areflexia, and in the other family they also showed spastic paraparesis. Electrophysiologic studies were consistent with both demyelination and axonal involvement. Carrier females were unaffected. One of the families (US-PED2) reported by Ionasescu et al. (1991) was found by Chaudhry et al. (2013) to carry a heterozygous mutation in the BSCL2 gene (N88S; 606158.0013), consistent with a diagnosis of SPG17 (270685). Affected members of this family showed spastic paraparesis.
Huttner et al. (2006) reported a large Australian family (CMT623) with X-linked CMT. Male patients presented in the first decade with lower limb weakness and atrophy followed by upper limb involvement in most about 10 years later. Most patients (80%) reported pain and paresthesia as the initial sensory symptom before the onset of sensory loss. EMG studies showed variable nerve conduction velocities that were both above and below 38 m/s. There was no central nervous system involvement. The phenotype appeared to be milder than that described for CMTX1. Obligate female carriers were clinically unaffected.
Brewer et al. (2008) reported a second large Australian family (CMT193-ext) with X-linked CMT with similar clinical features to those reported by Huttner et al. (2006). Kanhangad et al. (2018) reviewed the clinical and neurophysiologic findings in family CMT193-ext, which included 10 affected boys and 1 symptomatic girl. Compared to other forms of CMT, CMTX3 was characterized by earlier onset, severe hand weakness, and more rapidly progressive disability. Age at most recent examination ranged from 2 to 19 years. Age of onset ranged from birth to 5 years in the boys, and nearly all had findings before age 2 years; age of onset in the girl was 12 years. Six boys presented with a foot deformity, and 4 presented with a gait abnormality. Equinovarus foot deformity was evident before 1 year of age in 5 children, while the other child had a mild hindfoot valgus deformity at 2 years of age. Abnormalities in hand function, identified between age 4 months and 12 years, were seen in 7 children. Scoliosis was seen in 2 children. Two children had hip dysplasia, leading the authors to recommend that children with CMTX3 have at least biennial x-ray surveillance for hip dysplasia. Nerve conduction studies showed a demyelinating sensorimotor neuropathy, with decreased nerve conduction velocity. Because of the early onset and rapid progression, many children with CMTX3 are expected to have severe disability within the first 2 decades of life. Kanhangad et al. (2018) recommended early institution of rehabilitative or surgical interventions for children with this condition.
In 2 of the families reported by Ionasescu et al. (1991, 1992), linkage analysis showed tight linkage to Xq26 markers. The third family showed linkage to Xp22.2 (302801).
By linkage analysis of a large Australian family with X-linked CMT, Huttner et al. (2006) mapped the disorder to Xq26.3-Xq27.1 (maximum lod score of 6.58 at DXS1192) within the CMTX3 locus. Haplotype analysis delineated a 5.7-Mb region between DXS1041 and DXS8106.
Brewer et al. (2008) reported a second large Australian family with X-linked CMT mapping to the CMTX3 locus. Significant linkage was found with marker DXS984 (lod score of 4.75), and the disease haplotype was identical to that of the family reported by Huttner et al. (2006), suggesting a common founder. This shared haplotype was identified in 3 of 152 control chromosomes. The results refined the disease locus to a 2.5-Mb region between DXS984 and DXS8106. Molecular analysis excluded mutations in 10 genes within the interval. (One of the American families (US-PED2) reported by Ionasescu et al. (1991) was found to share the distal portion of the haplotype, but the disorder in that family was later found by Chaudhry et al. (2013) to be caused by a mutation in the BSCL2 gene.)
Using whole-genome sequencing in the 2 distantly related Australian families with CMT (CMT623 and CMT193-ext) reported by Huttner et al. (2006) and Brewer et al. (2008), Brewer et al. (2016) identified a large interchromosomal insertion from chromosome 8q24.3 into the CMTX3 locus [der(X)dir ins(X;8)(q27.1;q24.3)]. Both families had previously tested negative for all known protein-coding sequence variants. The inserted region from 8q24.3 was 77,856 bp and contained a partial transcript of exons 1-7 of the ARHGAP39 gene (615880) encoded on the negative strand. The duplicated 8q24.3 sequence was inserted into an intergenic region of Xq27.1 with the nearest flanking genes being LOC389895 (located 329 kb downstream proximal to the 78 kb insertion) and SOX3 (313430) (located 84 kb distal to the insertion). The insertion segregated with the phenotype in the family, was absent in 627 control X chromosomes from 252 neurologically normal females and 123 neurologically normal males, and was confirmed by Sanger sequencing. Studies of mRNA expression levels of candidate genes showed no difference in ARHGAP39 expression, suggesting that transcriptional dysregulation of one or more genes mapping within the CMT3 locus is likely to be the mechanism of disease. This was the first report of an interchromosomal insertion causing CMT.
Brewer, M., Changi, F., Antonellis, A., Fischbeck, K., Polly, P., Nicholson, G., Kennerson, M. Evidence of a founder haplotype refines the X-linked Charcot-Marie-Tooth (CMTX3) locus to a 2.5 Mb region. Neurogenetics 9: 191-195, 2008. [PubMed: 18458969, related citations] [Full Text]
Brewer, M. H., Chaudhry, R., Qi, J., Kidambi, A., Drew, A. P., Menezes, M. P., Ryan, M. M., Farrar, M. A., Mowat, D., Subramanian, G. M., Young, H. K., Zuchner, S., Reddel, S. W., Nicholson, G. A., Kennerson, M. L. Whole genome sequencing identifies a 78 kb insertion from chromosome 8 as the cause of Charcot-Marie-Tooth neuropathy CMTX3. PLoS Genet. 12: e1006177, 2016. Note: Electronic Article. [PubMed: 27438001, related citations] [Full Text]
Chaudhry, R., Kidambi, A., Brewer, M. H., Antonellis, A., Mathews, K., Nicholson, G., Kennerson, M. Re-analysis of an original CMTX3 family using exome sequencing identifies a known BSCL2 mutation. Muscle Nerve 47: 922-924, 2013. [PubMed: 23553728, related citations] [Full Text]
Erwin, W. G. A pedigree of sex-linked recessive peroneal atrophy. J. Hered. 35: 24-26, 1944.
Huttner, I. G., Kennerson, M. L., Reddel, S. W., Radovanovic, D., Nicholson, G. A. Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease. Neurology 67: 2016-2021, 2006. [PubMed: 17159110, related citations] [Full Text]
Ionasescu, V. V., Trofatter, J., Haines, J. L., Summers, A. M., Ionasescu, R., Searby, C. Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy. Am. J. Hum. Genet. 48: 1075-1083, 1991. [PubMed: 1674639, related citations]
Ionasescu, V. V., Trofatter, J., Haines, J. L., Summers, A. M., Ionasescu, R., Searby, C. X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve 15: 368-373, 1992. [PubMed: 1557086, related citations] [Full Text]
Kanhangad, M., Cornett, K., Brewer, M. H., Nicholson, G. A., Ryan, M. M., Smith, R. L., Subramanian, G. M., Young, H. K., Zuchner, S., Kennerson, M. L., Burns, J., Menezes, M. P. Unique clinical and neurophysiologic profile of a cohort of children with CMTX3. Neurology 90: e1706-e1710, 2018. Note: Electronic Article. [PubMed: 29626178, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 763458005; ORPHA: 101077; DO: 0110211;
Cytogenetic location: Xq26 Genomic coordinates (GRCh38): X:129,500,001-138,900,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq26 | Charcot-Marie-Tooth neuropathy, X-linked recessive, 3 | 302802 | X-linked recessive | 4 |
A number sign (#) is used with this entry because of evidence that X-linked recessive Charcot-Marie-Tooth disease-3 (CMTX3) is caused by a genomic rearrangement between chromosomes 8q24.3 and Xq27.1.
For a phenotypic description and discussion of genetic heterogeneity of X-linked CMT, see CMTX1 (302800).
Ionasescu et al. (1991, 1992) studied 3 families with X-linked recessive Charcot-Marie-Tooth neuropathy of the type reported by Erwin (1944). In 2 of the families, affected males had distal muscle atrophy and weakness and distal sensory loss with onset at age 10 to 14 years; in 1 of these families affected members also showed pes cavus and areflexia, and in the other family they also showed spastic paraparesis. Electrophysiologic studies were consistent with both demyelination and axonal involvement. Carrier females were unaffected. One of the families (US-PED2) reported by Ionasescu et al. (1991) was found by Chaudhry et al. (2013) to carry a heterozygous mutation in the BSCL2 gene (N88S; 606158.0013), consistent with a diagnosis of SPG17 (270685). Affected members of this family showed spastic paraparesis.
Huttner et al. (2006) reported a large Australian family (CMT623) with X-linked CMT. Male patients presented in the first decade with lower limb weakness and atrophy followed by upper limb involvement in most about 10 years later. Most patients (80%) reported pain and paresthesia as the initial sensory symptom before the onset of sensory loss. EMG studies showed variable nerve conduction velocities that were both above and below 38 m/s. There was no central nervous system involvement. The phenotype appeared to be milder than that described for CMTX1. Obligate female carriers were clinically unaffected.
Brewer et al. (2008) reported a second large Australian family (CMT193-ext) with X-linked CMT with similar clinical features to those reported by Huttner et al. (2006). Kanhangad et al. (2018) reviewed the clinical and neurophysiologic findings in family CMT193-ext, which included 10 affected boys and 1 symptomatic girl. Compared to other forms of CMT, CMTX3 was characterized by earlier onset, severe hand weakness, and more rapidly progressive disability. Age at most recent examination ranged from 2 to 19 years. Age of onset ranged from birth to 5 years in the boys, and nearly all had findings before age 2 years; age of onset in the girl was 12 years. Six boys presented with a foot deformity, and 4 presented with a gait abnormality. Equinovarus foot deformity was evident before 1 year of age in 5 children, while the other child had a mild hindfoot valgus deformity at 2 years of age. Abnormalities in hand function, identified between age 4 months and 12 years, were seen in 7 children. Scoliosis was seen in 2 children. Two children had hip dysplasia, leading the authors to recommend that children with CMTX3 have at least biennial x-ray surveillance for hip dysplasia. Nerve conduction studies showed a demyelinating sensorimotor neuropathy, with decreased nerve conduction velocity. Because of the early onset and rapid progression, many children with CMTX3 are expected to have severe disability within the first 2 decades of life. Kanhangad et al. (2018) recommended early institution of rehabilitative or surgical interventions for children with this condition.
In 2 of the families reported by Ionasescu et al. (1991, 1992), linkage analysis showed tight linkage to Xq26 markers. The third family showed linkage to Xp22.2 (302801).
By linkage analysis of a large Australian family with X-linked CMT, Huttner et al. (2006) mapped the disorder to Xq26.3-Xq27.1 (maximum lod score of 6.58 at DXS1192) within the CMTX3 locus. Haplotype analysis delineated a 5.7-Mb region between DXS1041 and DXS8106.
Brewer et al. (2008) reported a second large Australian family with X-linked CMT mapping to the CMTX3 locus. Significant linkage was found with marker DXS984 (lod score of 4.75), and the disease haplotype was identical to that of the family reported by Huttner et al. (2006), suggesting a common founder. This shared haplotype was identified in 3 of 152 control chromosomes. The results refined the disease locus to a 2.5-Mb region between DXS984 and DXS8106. Molecular analysis excluded mutations in 10 genes within the interval. (One of the American families (US-PED2) reported by Ionasescu et al. (1991) was found to share the distal portion of the haplotype, but the disorder in that family was later found by Chaudhry et al. (2013) to be caused by a mutation in the BSCL2 gene.)
Using whole-genome sequencing in the 2 distantly related Australian families with CMT (CMT623 and CMT193-ext) reported by Huttner et al. (2006) and Brewer et al. (2008), Brewer et al. (2016) identified a large interchromosomal insertion from chromosome 8q24.3 into the CMTX3 locus [der(X)dir ins(X;8)(q27.1;q24.3)]. Both families had previously tested negative for all known protein-coding sequence variants. The inserted region from 8q24.3 was 77,856 bp and contained a partial transcript of exons 1-7 of the ARHGAP39 gene (615880) encoded on the negative strand. The duplicated 8q24.3 sequence was inserted into an intergenic region of Xq27.1 with the nearest flanking genes being LOC389895 (located 329 kb downstream proximal to the 78 kb insertion) and SOX3 (313430) (located 84 kb distal to the insertion). The insertion segregated with the phenotype in the family, was absent in 627 control X chromosomes from 252 neurologically normal females and 123 neurologically normal males, and was confirmed by Sanger sequencing. Studies of mRNA expression levels of candidate genes showed no difference in ARHGAP39 expression, suggesting that transcriptional dysregulation of one or more genes mapping within the CMT3 locus is likely to be the mechanism of disease. This was the first report of an interchromosomal insertion causing CMT.
Brewer, M., Changi, F., Antonellis, A., Fischbeck, K., Polly, P., Nicholson, G., Kennerson, M. Evidence of a founder haplotype refines the X-linked Charcot-Marie-Tooth (CMTX3) locus to a 2.5 Mb region. Neurogenetics 9: 191-195, 2008. [PubMed: 18458969] [Full Text: https://doi.org/10.1007/s10048-008-0126-4]
Brewer, M. H., Chaudhry, R., Qi, J., Kidambi, A., Drew, A. P., Menezes, M. P., Ryan, M. M., Farrar, M. A., Mowat, D., Subramanian, G. M., Young, H. K., Zuchner, S., Reddel, S. W., Nicholson, G. A., Kennerson, M. L. Whole genome sequencing identifies a 78 kb insertion from chromosome 8 as the cause of Charcot-Marie-Tooth neuropathy CMTX3. PLoS Genet. 12: e1006177, 2016. Note: Electronic Article. [PubMed: 27438001] [Full Text: https://doi.org/10.1371/journal.pgen.1006177]
Chaudhry, R., Kidambi, A., Brewer, M. H., Antonellis, A., Mathews, K., Nicholson, G., Kennerson, M. Re-analysis of an original CMTX3 family using exome sequencing identifies a known BSCL2 mutation. Muscle Nerve 47: 922-924, 2013. [PubMed: 23553728] [Full Text: https://doi.org/10.1002/mus.23743]
Erwin, W. G. A pedigree of sex-linked recessive peroneal atrophy. J. Hered. 35: 24-26, 1944.
Huttner, I. G., Kennerson, M. L., Reddel, S. W., Radovanovic, D., Nicholson, G. A. Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease. Neurology 67: 2016-2021, 2006. [PubMed: 17159110] [Full Text: https://doi.org/10.1212/01.wnl.0000247271.40782.b7]
Ionasescu, V. V., Trofatter, J., Haines, J. L., Summers, A. M., Ionasescu, R., Searby, C. Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy. Am. J. Hum. Genet. 48: 1075-1083, 1991. [PubMed: 1674639]
Ionasescu, V. V., Trofatter, J., Haines, J. L., Summers, A. M., Ionasescu, R., Searby, C. X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve 15: 368-373, 1992. [PubMed: 1557086] [Full Text: https://doi.org/10.1002/mus.880150317]
Kanhangad, M., Cornett, K., Brewer, M. H., Nicholson, G. A., Ryan, M. M., Smith, R. L., Subramanian, G. M., Young, H. K., Zuchner, S., Kennerson, M. L., Burns, J., Menezes, M. P. Unique clinical and neurophysiologic profile of a cohort of children with CMTX3. Neurology 90: e1706-e1710, 2018. Note: Electronic Article. [PubMed: 29626178] [Full Text: https://doi.org/10.1212/WNL.0000000000005479]
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