#118210
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2A1 (CMT2A1) is caused by heterozygous mutation in the KIF1B gene (605995) on chromosome 1p36.
Other forms of CMT2A mapping to chromosome 1p36.2 are CMT2A2A (609260), caused by heterozygous mutation in the MFN2 gene (608507), and CMT2A2B (617087), caused by homozygous or compound heterozygous mutation in the MFN2 gene.
Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median nerve conduction velocity (NCV) (less than 38 m/s), and type 2, the axonal form, with a normal or slightly reduced NCV. Distal hereditary motor neuropathy (dHMN), also known as spinal CMT, is a third type of CMT characterized by normal motor and sensory NCV and degeneration of spinal cord anterior horn cells. See CMT1B (118200) and CMT1A (118220) for descriptions of autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth disease. See CMT4A (214400) and CMTX1 (302800) for autosomal recessive and X-linked forms of Charcot-Marie-Tooth disease, respectively.
Genetic Heterogeneity of Charcot-Marie-Tooth Disease Type 2
Several forms of axonal CMT neuropathies caused by mutations in different genes or at different loci have been described, including CMT2B (600882), CMT2B1 (605588), CMT2B2 (605589), CMT2C (606071), CMT2D (601472), CMT2E (607684), CMT2F (606595), CMT2H (607731), CMT2I (607677), CMT2J (607736), CMT2K (607831), CMT2L (608673), CMT2M (see 606482), CMT2N (613287), CMT2O (614228), CMT2P (614436), CMT2Q (615025), CMT2R (615490), CMT2S (616155), CMT2T (617017), CMT2U (616280), CMT2V (616491), CMT2W (616625), CMT2X (616668), CMT2Y (616687), CMT2Z (616688), CMT2CC (616924), CMT2DD (618036), CMT2EE (618400), CMT2FF (619519), CMT2GG (606483), CMT2HH (619574), and CMT2II (620068).
A form of axonal CMT that was previously designated CMT2G was found to be the same as CMT2P (614436).
Saito et al. (1997) reported a Japanese family (family 694) in which 4 members spanning 3 generations were affected with CMT2A1 inherited in an autosomal dominant pattern. The proband was an 11-year-old boy who developed difficulty running at age 7 years. At age 11 years, physical examination showed bilateral pes cavus, hammertoes, and mild lordosis. He had moderate muscle weakness and atrophy of the anterior tibial, peroneal, and posterior tibial muscles. Upper limb reflexes were normal, but patellar reflexes were decreased and ankle reflexes were absent. Sensation was normal, but sensory action potential could not be evoked in the sural nerve, and biopsy showed decreased numbers of large myelinated fibers without demyelination. Median nerve motor conduction velocity was normal.
Xu et al. (2018) reported 2 unrelated families with CMT2A1. The proband in the first family was a 55-year-old man with progressive, symmetric, length-dependent sensorimotor axonal polyneuropathy and intermittent cranial nerve involvement manifest as Bell palsy. He also had hearing loss. The proband in the second family was a 40-year-old man with impaired intellectual development and bipolar disorder whose nerve conduction studies were consistent with an axonal sensorimotor polyneuropathy. He had a similarly affected brother; their mother had CMT and mild cognitive dysfunction.
The transmission pattern of CMT2A1 in the family reported by Saito et al. (1997) was consistent with autosomal dominant inheritance.
In studies of 2 CMT2 pedigrees, Hentati et al. (1992) excluded the CMT2 locus from the region of chromosome 17 and the region of chromosome 1 where CMT1A and CMT1B are located, respectively. This was evidence of a fundamental distinction between the hypertrophic demyelinating and neuronal forms of Charcot-Marie-Tooth disease.
In linkage studies of 6 large autosomal dominant CMT2 families, Ben Othmane et al. (1993) demonstrated linkage to a series of microsatellite markers in the distal region of the short arm of chromosome 1. Using admixture analysis and 2-point lod scores, they were able, however, to demonstrate heterogeneity. Multipoint analysis examining the 'linked' families showed that the most favored location of the CMT2 gene is within the interval flanked by D1S244 and D1S228 in the region 1p36-p35.
In all affected members of the CMT2A1 pedigree (family 694) reported by Saito et al. (1997), Zhao et al. (2001) identified a heterozygous loss-of-function missense mutation in the KIF1B gene (Q98L; 605995.0001).
In affected members of 2 unrelated families with CMT2A1, Xu et al. (2018) identified a heterozygous missense mutation in the KIF1B gene (Y1087C; 605995.0006). The mutation, which was found by exome sequencing, segregated with the disorder in one of the families. In vitro functional expression studies in mouse cells showed that the mutation decreased the binding capacity with Igf1r (147370) and impaired the ability of Kif1b to transport Igf1r to the axon. The variant was unable to complement the defects of axonal outgrowth in Kif1b-null mouse primary hippocampal neurons, consistent with a pathogenic effect.
Associations Pending Confirmation
For discussion of a possible association between autosomal dominant axonal Charcot-Marie-Tooth disease and variation in the DGAT2 gene, see 606983.0001.
For discussion of a possible association between autosomal recessive early-onset peripheral neuropathy resembling axonal Charcot-Marie-Tooth disease and variation in the HADHB gene, see 143450.0010.
Ben Othmane, K., Middleton, L. T., Loprest, L. J., Wilkinson, K. M., Lennon, F., Rozear, M. P., Stajich, J. M., Gaskell, P. C., Roses, A. D., Pericak-Vance, M. A., Vance, J. M. Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics 17: 370-375, 1993. [PubMed: 8406488, related citations] [Full Text]
Hentati, A., Lamy, C., Melki, J., Zuber, M., Munnich, A., de Recondo, J. Clinical and genetic heterogeneity of Charcot-Marie-Tooth disease. Genomics 12: 155-157, 1992. [PubMed: 1733853, related citations] [Full Text]
Saito, M., Hayashi, Y., Suzuki, T., Tanaka, H., Hozumi, I., Tsuji, S. Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A. Neurology 49: 1630-1635, 1997. [PubMed: 9409358, related citations] [Full Text]
Xu, F., Takahashi, H., Tanaka, Y., Ichinose, S., Niwa, S., Wicklund, M. P., Hirokawa, N. KIF1B-beta mutations detected in hereditary neuropathy impair IGF1R transport and axon growth. J. Cell Biol. 217: 3480-3496, 2018. [PubMed: 30126838, images, related citations] [Full Text]
Zhao, C., Takita, J., Tanaka, Y., Setou, M., Nakagawa, T., Takeda, S., Yang, H. W., Terada, S., Nakata, T., Takei, Y., Saito, M., Tsuji, S., Hayashi, Y., Hirokawa, N. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1B-beta. Cell 105: 587-597, 2001. Note: Erratum: Cell 106: 127 only, 2001. [PubMed: 11389829, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 717016001; ORPHA: 99946; DO: 0110154;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.22 | Charcot-Marie-Tooth disease, type 2A1 | 118210 | Autosomal dominant | 3 | KIF1B | 605995 |
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2A1 (CMT2A1) is caused by heterozygous mutation in the KIF1B gene (605995) on chromosome 1p36.
Other forms of CMT2A mapping to chromosome 1p36.2 are CMT2A2A (609260), caused by heterozygous mutation in the MFN2 gene (608507), and CMT2A2B (617087), caused by homozygous or compound heterozygous mutation in the MFN2 gene.
Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median nerve conduction velocity (NCV) (less than 38 m/s), and type 2, the axonal form, with a normal or slightly reduced NCV. Distal hereditary motor neuropathy (dHMN), also known as spinal CMT, is a third type of CMT characterized by normal motor and sensory NCV and degeneration of spinal cord anterior horn cells. See CMT1B (118200) and CMT1A (118220) for descriptions of autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth disease. See CMT4A (214400) and CMTX1 (302800) for autosomal recessive and X-linked forms of Charcot-Marie-Tooth disease, respectively.
Genetic Heterogeneity of Charcot-Marie-Tooth Disease Type 2
Several forms of axonal CMT neuropathies caused by mutations in different genes or at different loci have been described, including CMT2B (600882), CMT2B1 (605588), CMT2B2 (605589), CMT2C (606071), CMT2D (601472), CMT2E (607684), CMT2F (606595), CMT2H (607731), CMT2I (607677), CMT2J (607736), CMT2K (607831), CMT2L (608673), CMT2M (see 606482), CMT2N (613287), CMT2O (614228), CMT2P (614436), CMT2Q (615025), CMT2R (615490), CMT2S (616155), CMT2T (617017), CMT2U (616280), CMT2V (616491), CMT2W (616625), CMT2X (616668), CMT2Y (616687), CMT2Z (616688), CMT2CC (616924), CMT2DD (618036), CMT2EE (618400), CMT2FF (619519), CMT2GG (606483), CMT2HH (619574), and CMT2II (620068).
A form of axonal CMT that was previously designated CMT2G was found to be the same as CMT2P (614436).
Saito et al. (1997) reported a Japanese family (family 694) in which 4 members spanning 3 generations were affected with CMT2A1 inherited in an autosomal dominant pattern. The proband was an 11-year-old boy who developed difficulty running at age 7 years. At age 11 years, physical examination showed bilateral pes cavus, hammertoes, and mild lordosis. He had moderate muscle weakness and atrophy of the anterior tibial, peroneal, and posterior tibial muscles. Upper limb reflexes were normal, but patellar reflexes were decreased and ankle reflexes were absent. Sensation was normal, but sensory action potential could not be evoked in the sural nerve, and biopsy showed decreased numbers of large myelinated fibers without demyelination. Median nerve motor conduction velocity was normal.
Xu et al. (2018) reported 2 unrelated families with CMT2A1. The proband in the first family was a 55-year-old man with progressive, symmetric, length-dependent sensorimotor axonal polyneuropathy and intermittent cranial nerve involvement manifest as Bell palsy. He also had hearing loss. The proband in the second family was a 40-year-old man with impaired intellectual development and bipolar disorder whose nerve conduction studies were consistent with an axonal sensorimotor polyneuropathy. He had a similarly affected brother; their mother had CMT and mild cognitive dysfunction.
The transmission pattern of CMT2A1 in the family reported by Saito et al. (1997) was consistent with autosomal dominant inheritance.
In studies of 2 CMT2 pedigrees, Hentati et al. (1992) excluded the CMT2 locus from the region of chromosome 17 and the region of chromosome 1 where CMT1A and CMT1B are located, respectively. This was evidence of a fundamental distinction between the hypertrophic demyelinating and neuronal forms of Charcot-Marie-Tooth disease.
In linkage studies of 6 large autosomal dominant CMT2 families, Ben Othmane et al. (1993) demonstrated linkage to a series of microsatellite markers in the distal region of the short arm of chromosome 1. Using admixture analysis and 2-point lod scores, they were able, however, to demonstrate heterogeneity. Multipoint analysis examining the 'linked' families showed that the most favored location of the CMT2 gene is within the interval flanked by D1S244 and D1S228 in the region 1p36-p35.
In all affected members of the CMT2A1 pedigree (family 694) reported by Saito et al. (1997), Zhao et al. (2001) identified a heterozygous loss-of-function missense mutation in the KIF1B gene (Q98L; 605995.0001).
In affected members of 2 unrelated families with CMT2A1, Xu et al. (2018) identified a heterozygous missense mutation in the KIF1B gene (Y1087C; 605995.0006). The mutation, which was found by exome sequencing, segregated with the disorder in one of the families. In vitro functional expression studies in mouse cells showed that the mutation decreased the binding capacity with Igf1r (147370) and impaired the ability of Kif1b to transport Igf1r to the axon. The variant was unable to complement the defects of axonal outgrowth in Kif1b-null mouse primary hippocampal neurons, consistent with a pathogenic effect.
Associations Pending Confirmation
For discussion of a possible association between autosomal dominant axonal Charcot-Marie-Tooth disease and variation in the DGAT2 gene, see 606983.0001.
For discussion of a possible association between autosomal recessive early-onset peripheral neuropathy resembling axonal Charcot-Marie-Tooth disease and variation in the HADHB gene, see 143450.0010.
Ben Othmane, K., Middleton, L. T., Loprest, L. J., Wilkinson, K. M., Lennon, F., Rozear, M. P., Stajich, J. M., Gaskell, P. C., Roses, A. D., Pericak-Vance, M. A., Vance, J. M. Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics 17: 370-375, 1993. [PubMed: 8406488] [Full Text: https://doi.org/10.1006/geno.1993.1334]
Hentati, A., Lamy, C., Melki, J., Zuber, M., Munnich, A., de Recondo, J. Clinical and genetic heterogeneity of Charcot-Marie-Tooth disease. Genomics 12: 155-157, 1992. [PubMed: 1733853] [Full Text: https://doi.org/10.1016/0888-7543(92)90419-s]
Saito, M., Hayashi, Y., Suzuki, T., Tanaka, H., Hozumi, I., Tsuji, S. Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A. Neurology 49: 1630-1635, 1997. [PubMed: 9409358] [Full Text: https://doi.org/10.1212/wnl.49.6.1630]
Xu, F., Takahashi, H., Tanaka, Y., Ichinose, S., Niwa, S., Wicklund, M. P., Hirokawa, N. KIF1B-beta mutations detected in hereditary neuropathy impair IGF1R transport and axon growth. J. Cell Biol. 217: 3480-3496, 2018. [PubMed: 30126838] [Full Text: https://doi.org/10.1083/jcb.201801085]
Zhao, C., Takita, J., Tanaka, Y., Setou, M., Nakagawa, T., Takeda, S., Yang, H. W., Terada, S., Nakata, T., Takei, Y., Saito, M., Tsuji, S., Hayashi, Y., Hirokawa, N. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1B-beta. Cell 105: 587-597, 2001. Note: Erratum: Cell 106: 127 only, 2001. [PubMed: 11389829] [Full Text: https://doi.org/10.1016/s0092-8674(01)00363-4]
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