#600882
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 2B (CMT2B) is caused by heterozygous mutation in the RAB7 gene (602298) on chromosome 3q21.
For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
In a single large kindred with an autosomal dominant peripheral sensory neuropathy, Kwon et al. (1995) demonstrated linkage of the disorder to the interval between microsatellite markers D3S1769 and D3S1744. Kwon et al. (1995) considered this to be a form of Charcot-Marie-Tooth disease, which they designated CMT2B. They noted that genetic studies of CMT2 are more complicated than those in CMT1 because of difficulties in establishing the diagnosis. Whereas in CMT1 both the clinical and the electrophysiologic findings of nerve conduction are present early in life, CMT2 often has its onset later in life and the neuropathic findings are those seen in common disorders such as diabetes mellitus or toxic exposures. Diagnosis of CMT2 relies not on a single test but on the combination of clinical history and medical examination by appropriate physical and electrodiagnostic studies.
Houlden et al. (2004) reported a family with an autosomal dominant ulcero-mutilating neuropathy affecting 3 individuals over 3 generations. The proband was a 56-year-old man who developed a painful ulcer on the left sole at age 16 years. The lesion never healed, and he had numerous operations on his foot, including amputation of the second digit. He later developed progressive right foot pain with swelling and deformity. Other features included mild scoliosis, absent ankle reflexes, decreased distal sensation, lateral-gaze nystagmus, and cerebellar degeneration on MRI. The patient also reported spontaneous lancinating pain in the left foot. Muscle tone, power, and coordination were normal. Nerve conduction studies and sural nerve biopsy showed a chronic sensory axonal neuropathy with axonal degeneration and prominent regeneration. Genetic studies identified a heterozygous mutation in the RAB7 gene (602298.0003). Houlden et al. (2004) commented that the findings expanded the phenotypic spectrum of CMT2B; in particular, the lack of motor symptoms and lancinating pain were suggestive of HSAN1. In addition, there was evidence of central nervous system involvement with nystagmus and cerebellar atrophy.
Auer-Grumbach et al. (2000) studied a large Austrian family with typical features of CMT2B, including prominent large and small fiber sensory loss and distal muscle weakness and atrophy. Linkage analysis from 19 family members refined the localization of the CMT2B locus to a 10-cM interval on chromosome 3q13-q22 between markers D3S1589 and D3S1549.
Genetic Heterogeneity
Auer-Grumbach et al. (2000) reported a second large Austrian family with an autosomal dominant ulcero-mutilating neuropathy that did not show linkage to the CMT2B locus on 3q13-q22 or the HSAN1 locus on 9q22. There were 12 definitely affected members and 16 probably affected members spanning 5 generations. Age at onset ranged from 15 to 30 years, and clinical severity was variable. The most common feature was distal sensory loss affecting all modalities, resulting in foot calluses and poorly healing ulcers leading to osteomyelitis and autoamputation. Some patients had early foot deformities such as pes cavus, pes planus, and hammertoes. Spontaneous shooting or lancinating pain was never observed. Only a few older patients had distal weakness and atrophy in the lower limbs. Motor and sensory nerve conduction velocities (NCVs) were normal or moderately decreased, suggesting axonal degeneration. In a follow-up report of this family (referred to as CMT126), Verhoeven et al. (2003) determined that a small branch of CMT126 was related to the Austrian family with CMT2B reported by Auer-Grumbach et al. (2000) (referred to as CMT140).
Verhoeven et al. (2003) performed molecular genetic study of 2 families with an ulcero-mutilating phenotype, which were previously linked to the CMT2B locus: an American family of Kwon et al. (1995) and a Scottish family of De Jonghe et al. (1997). They refined the CMT2B locus to a 2.5-cM region and reported a missense mutation in the RAB7 gene (602298.0002). In affected members of the Austrian family CMT140 reported by Auer-Grumbach et al. (2000) and affected members of a small branch of another Austrian family CMT126 reported by Auer-Grumbach et al. (2000), Verhoeven et al. (2003) identified the same mutation in the RAB7 gene (602298.0001). However, the remaining affected members of family CMT126 did not share the RAB7 mutation and were excluded by linkage analysis from the CMT2B locus, indicating genetic heterogeneity.
Meggouh et al. (2006) identified a de novo heterozygous missense mutation in the RAB7 gene (602298.0004) in a 32-year-old man with CMT2B. He had onset of decreased sensation in the feet leading to small injuries at age 12 years. At age 32, he had steppage gait, atrophy of the lower legs and hand muscles, high-arched feet, claw toes, and decreased sensation in the lower limbs.
Vance et al. (1996) found that this phenotype was not compatible with that in the CMT2 families they had observed and concluded that it should not be included in the same disease CMT2 classification, which typically has more motor involvement. Vance et al. (1996) suggested that it would better into the classification of hereditary autonomic and sensory neuropathy type 1 (HSAN1; 162400). Pericak-Vance et al. (1997) commented that the family reported by Kwon et al. (1995) and labeled CMT2B had a predominantly sensory neuropathy, with a motor component. Affected members commonly had ulcerations and amputations. Likewise, Kok et al. (2003) suggested that because of the severe sensory impairment and foot ulcers, the disorder should be considered to be a hereditary sensory neuropathy (HSN) and used the designation hereditary motor sensory neuropathy type IIB (HMSN2B).
Auer-Grumbach, M., De Jonghe, P., Wagner, K., Verhoeven, K., Hartung, H.-P., Timmerman, V. Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus. Neurology 55: 1552-1557, 2000. [PubMed: 11094113, related citations] [Full Text]
Auer-Grumbach, M., Wagner, K., Timmerman, V., De Jonghe, P., Hartung, H.-P. Ulcero-mutilating neuropathy in an Austrian kinship without linkage to hereditary motor and sensory neuropathy IIB and hereditary sensory neuropathy I loci. Neurology 54: 45-52, 2000. [PubMed: 10636124, related citations] [Full Text]
De Jonghe, P., Timmerman, V., FitzPatrick, D., Spoelders, P., Martin, J.-J., Van Broeckhoven, C. Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family. J. Neurol. Neurosurg. Psychiat. 62: 570-573, 1997. [PubMed: 9219740, related citations] [Full Text]
Houlden, H., King, R. H. M., Muddle, J. R., Warner, T. T., Reilly, M. M., Orrell, R. W., Ginsberg, L. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann. Neurol. 56: 586-590, 2004. [PubMed: 15455439, related citations] [Full Text]
Kok, C., Kennerson, M. L., Spring, P. J., Ing, A. J., Pollard, J. D., Nicholson, G. A. A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am. J. Hum. Genet. 73: 632-637, 2003. [PubMed: 12870133, images, related citations] [Full Text]
Kwon, J. M., Elliott, J. L., Yee, W.-C., Ivanovich, J., Scavarda, N. Charcot-Marie-Tooth type II locus to chromosome 3q. Am. J. Hum. Genet. 57: 853-858, 1995. [PubMed: 7573046, related citations]
Meggouh, F., Bienfait, H. M. E., Weterman, M. A. J., de Visser, M., Baas, F. Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene. Neurology 67: 1476-1478, 2006. [PubMed: 17060578, related citations] [Full Text]
Pericak-Vance, M. A., Speer, M. C., Lennon, F., West, S. G., Menold, M. M., Stajich, J. M., Wolpert, C. M., Slotterbeck, B. D., Saito, M., Tim, R. W., Rozear, M. P., Middleton, L. T., Tsuji, S., Vance, J. M. Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity. Neurogenetics 1: 89-93, 1997. [PubMed: 10732809, related citations] [Full Text]
Vance, J. M., Speer, M. C., Stajich, J. M., West, S., Wolpert, C., Gaskell, P., Lennon, F., Tim, R. M., Rozear, M., Ben Othmane, K., Pericak-Vance, M. A. Misclassification and linkage of hereditary sensory and autonomic neuropathy type 1 as Charcot-Marie-Tooth disease, type 2B. (Letter) Am. J. Hum. Genet. 59: 258-260, 1996. [PubMed: 8659534, related citations]
Verhoeven, K., De Jonghe, P., Coen, K., Verpoorten, N., Auer-Grumbach, M., Kwon, J. M., FitzPatrick, D., Schmedding, E., De Vriendt, E., Jacobs, A., Van Gerwen, V., Wagner, K., Hartung, H.-P., Timmerman, V. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72: 722-727, 2003. [PubMed: 12545426, images, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 717008005; ORPHA: 99936; DO: 0110159;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q21.3 | Charcot-Marie-Tooth disease, type 2B | 600882 | Autosomal dominant | 3 | RAB7 | 602298 |
A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 2B (CMT2B) is caused by heterozygous mutation in the RAB7 gene (602298) on chromosome 3q21.
For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
In a single large kindred with an autosomal dominant peripheral sensory neuropathy, Kwon et al. (1995) demonstrated linkage of the disorder to the interval between microsatellite markers D3S1769 and D3S1744. Kwon et al. (1995) considered this to be a form of Charcot-Marie-Tooth disease, which they designated CMT2B. They noted that genetic studies of CMT2 are more complicated than those in CMT1 because of difficulties in establishing the diagnosis. Whereas in CMT1 both the clinical and the electrophysiologic findings of nerve conduction are present early in life, CMT2 often has its onset later in life and the neuropathic findings are those seen in common disorders such as diabetes mellitus or toxic exposures. Diagnosis of CMT2 relies not on a single test but on the combination of clinical history and medical examination by appropriate physical and electrodiagnostic studies.
Houlden et al. (2004) reported a family with an autosomal dominant ulcero-mutilating neuropathy affecting 3 individuals over 3 generations. The proband was a 56-year-old man who developed a painful ulcer on the left sole at age 16 years. The lesion never healed, and he had numerous operations on his foot, including amputation of the second digit. He later developed progressive right foot pain with swelling and deformity. Other features included mild scoliosis, absent ankle reflexes, decreased distal sensation, lateral-gaze nystagmus, and cerebellar degeneration on MRI. The patient also reported spontaneous lancinating pain in the left foot. Muscle tone, power, and coordination were normal. Nerve conduction studies and sural nerve biopsy showed a chronic sensory axonal neuropathy with axonal degeneration and prominent regeneration. Genetic studies identified a heterozygous mutation in the RAB7 gene (602298.0003). Houlden et al. (2004) commented that the findings expanded the phenotypic spectrum of CMT2B; in particular, the lack of motor symptoms and lancinating pain were suggestive of HSAN1. In addition, there was evidence of central nervous system involvement with nystagmus and cerebellar atrophy.
Auer-Grumbach et al. (2000) studied a large Austrian family with typical features of CMT2B, including prominent large and small fiber sensory loss and distal muscle weakness and atrophy. Linkage analysis from 19 family members refined the localization of the CMT2B locus to a 10-cM interval on chromosome 3q13-q22 between markers D3S1589 and D3S1549.
Genetic Heterogeneity
Auer-Grumbach et al. (2000) reported a second large Austrian family with an autosomal dominant ulcero-mutilating neuropathy that did not show linkage to the CMT2B locus on 3q13-q22 or the HSAN1 locus on 9q22. There were 12 definitely affected members and 16 probably affected members spanning 5 generations. Age at onset ranged from 15 to 30 years, and clinical severity was variable. The most common feature was distal sensory loss affecting all modalities, resulting in foot calluses and poorly healing ulcers leading to osteomyelitis and autoamputation. Some patients had early foot deformities such as pes cavus, pes planus, and hammertoes. Spontaneous shooting or lancinating pain was never observed. Only a few older patients had distal weakness and atrophy in the lower limbs. Motor and sensory nerve conduction velocities (NCVs) were normal or moderately decreased, suggesting axonal degeneration. In a follow-up report of this family (referred to as CMT126), Verhoeven et al. (2003) determined that a small branch of CMT126 was related to the Austrian family with CMT2B reported by Auer-Grumbach et al. (2000) (referred to as CMT140).
Verhoeven et al. (2003) performed molecular genetic study of 2 families with an ulcero-mutilating phenotype, which were previously linked to the CMT2B locus: an American family of Kwon et al. (1995) and a Scottish family of De Jonghe et al. (1997). They refined the CMT2B locus to a 2.5-cM region and reported a missense mutation in the RAB7 gene (602298.0002). In affected members of the Austrian family CMT140 reported by Auer-Grumbach et al. (2000) and affected members of a small branch of another Austrian family CMT126 reported by Auer-Grumbach et al. (2000), Verhoeven et al. (2003) identified the same mutation in the RAB7 gene (602298.0001). However, the remaining affected members of family CMT126 did not share the RAB7 mutation and were excluded by linkage analysis from the CMT2B locus, indicating genetic heterogeneity.
Meggouh et al. (2006) identified a de novo heterozygous missense mutation in the RAB7 gene (602298.0004) in a 32-year-old man with CMT2B. He had onset of decreased sensation in the feet leading to small injuries at age 12 years. At age 32, he had steppage gait, atrophy of the lower legs and hand muscles, high-arched feet, claw toes, and decreased sensation in the lower limbs.
Vance et al. (1996) found that this phenotype was not compatible with that in the CMT2 families they had observed and concluded that it should not be included in the same disease CMT2 classification, which typically has more motor involvement. Vance et al. (1996) suggested that it would better into the classification of hereditary autonomic and sensory neuropathy type 1 (HSAN1; 162400). Pericak-Vance et al. (1997) commented that the family reported by Kwon et al. (1995) and labeled CMT2B had a predominantly sensory neuropathy, with a motor component. Affected members commonly had ulcerations and amputations. Likewise, Kok et al. (2003) suggested that because of the severe sensory impairment and foot ulcers, the disorder should be considered to be a hereditary sensory neuropathy (HSN) and used the designation hereditary motor sensory neuropathy type IIB (HMSN2B).
Auer-Grumbach, M., De Jonghe, P., Wagner, K., Verhoeven, K., Hartung, H.-P., Timmerman, V. Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus. Neurology 55: 1552-1557, 2000. [PubMed: 11094113] [Full Text: https://doi.org/10.1212/wnl.55.10.1552]
Auer-Grumbach, M., Wagner, K., Timmerman, V., De Jonghe, P., Hartung, H.-P. Ulcero-mutilating neuropathy in an Austrian kinship without linkage to hereditary motor and sensory neuropathy IIB and hereditary sensory neuropathy I loci. Neurology 54: 45-52, 2000. [PubMed: 10636124] [Full Text: https://doi.org/10.1212/wnl.54.1.45]
De Jonghe, P., Timmerman, V., FitzPatrick, D., Spoelders, P., Martin, J.-J., Van Broeckhoven, C. Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family. J. Neurol. Neurosurg. Psychiat. 62: 570-573, 1997. [PubMed: 9219740] [Full Text: https://doi.org/10.1136/jnnp.62.6.570]
Houlden, H., King, R. H. M., Muddle, J. R., Warner, T. T., Reilly, M. M., Orrell, R. W., Ginsberg, L. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann. Neurol. 56: 586-590, 2004. [PubMed: 15455439] [Full Text: https://doi.org/10.1002/ana.20281]
Kok, C., Kennerson, M. L., Spring, P. J., Ing, A. J., Pollard, J. D., Nicholson, G. A. A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am. J. Hum. Genet. 73: 632-637, 2003. [PubMed: 12870133] [Full Text: https://doi.org/10.1086/377591]
Kwon, J. M., Elliott, J. L., Yee, W.-C., Ivanovich, J., Scavarda, N. Charcot-Marie-Tooth type II locus to chromosome 3q. Am. J. Hum. Genet. 57: 853-858, 1995. [PubMed: 7573046]
Meggouh, F., Bienfait, H. M. E., Weterman, M. A. J., de Visser, M., Baas, F. Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene. Neurology 67: 1476-1478, 2006. [PubMed: 17060578] [Full Text: https://doi.org/10.1212/01.wnl.0000240068.21499.f5]
Pericak-Vance, M. A., Speer, M. C., Lennon, F., West, S. G., Menold, M. M., Stajich, J. M., Wolpert, C. M., Slotterbeck, B. D., Saito, M., Tim, R. W., Rozear, M. P., Middleton, L. T., Tsuji, S., Vance, J. M. Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity. Neurogenetics 1: 89-93, 1997. [PubMed: 10732809] [Full Text: https://doi.org/10.1007/s100480050013]
Vance, J. M., Speer, M. C., Stajich, J. M., West, S., Wolpert, C., Gaskell, P., Lennon, F., Tim, R. M., Rozear, M., Ben Othmane, K., Pericak-Vance, M. A. Misclassification and linkage of hereditary sensory and autonomic neuropathy type 1 as Charcot-Marie-Tooth disease, type 2B. (Letter) Am. J. Hum. Genet. 59: 258-260, 1996. [PubMed: 8659534]
Verhoeven, K., De Jonghe, P., Coen, K., Verpoorten, N., Auer-Grumbach, M., Kwon, J. M., FitzPatrick, D., Schmedding, E., De Vriendt, E., Jacobs, A., Van Gerwen, V., Wagner, K., Hartung, H.-P., Timmerman, V. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72: 722-727, 2003. [PubMed: 12545426] [Full Text: https://doi.org/10.1086/367847]
Dear OMIM User,
To ensure long-term funding for the OMIM project, we have diversified our revenue stream. We are determined to keep this website freely accessible. Unfortunately, it is not free to produce. Expert curators review the literature and organize it to facilitate your work. Over 90% of the OMIM's operating expenses go to salary support for MD and PhD science writers and biocurators. Please join your colleagues by making a donation now and again in the future. Donations are an important component of our efforts to ensure long-term funding to provide you the information that you need at your fingertips.
Thank you in advance for your generous support,
Ada Hamosh, MD, MPH
Scientific Director, OMIM