#609311
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 4H (CMT4H) is caused by homozygous mutation in the gene encoding frabin (FGD4; 611104) on chromosome 12p11.
For a discussion of genetic heterogeneity of autosomal recessive Charcot-Marie-Tooth disease, see CMT4A (214400).
De Sandre-Giovannoli et al. (2005) reported a total of 10 individuals from 2 families, 1 Lebanese and 1 Algerian, with a severe form of CMT. Onset occurred within the first 2 years of life and was manifested by delayed walking, unsteady gait, areflexia, scoliosis, and foot abnormalities, including pes cavus and pes equinus. Two members of the Lebanese family had upper limb involvement with thenar and hypothenar hypoplasia. Electrophysiologic studies showed severely reduced motor and sensory nerve conduction velocities, consistent with a demyelinating process. Sural nerve biopsy of 1 member of the Lebanese family showed severe loss of myelinated fibers, as well as some features of congenital hypomyelination and occasional onion bulb formations. The Algerian family was consanguineous, suggesting autosomal recessive inheritance.
Houlden et al. (2009) reported 2 sibs with CMT4H confirmed by genetic analysis (R275X; 611104.0006). Although both patients had onset of walking difficulties in childhood, there was slow progression of the disorder, and both remained ambulatory into middle age. At age 58, the proband had pes cavus, distal muscle weakness and atrophy, areflexia, stocking and glove sensory loss, and pupil size asymmetry. Her brother had a similar phenotype. Nerve conduction velocities were significantly decreased. Houlden et al. (2009) noted that the phenotype was relatively mild compared to patients with other FGD4 mutations.
Fabrizi et al. (2009) reported a 20-year-old woman, born of consanguineous Italian parents, with CMT4H confirmed by genetic analysis (611104.0007). The patient was from a small mountain village in northeast Italy. She had a clumsy gait since childhood, steppage gait, pes equinovarus, lower limb areflexia, and mild distal sensory loss. She also had scoliosis and hypotrophy of thenar and hypothenar muscles. Pathologic and electrophysiologic studies showed a demyelinating neuropathy. There was slow disease progression.
The transmission pattern of CMT4H in the Algerian family reported by De Sandre-Giovannoli et al. (2005) was consistent with autosomal recessive inheritance.
In 2 unrelated families with severe early-onset demyelinating CMT, De Sandre-Giovannoli et al. (2005) found linkage of the disorder, designated CMT4H, to an 11.5-cM region on chromosome 12p11.21-q13.11 between markers D12S1648 and D12S1661 (maximum pairwise lod score of 6.97 at D12S345). Mutation analysis excluded peripherin (PRPH; 170710) and contactin-1 (CNTN1; 600016) as candidate genes.
In affected members of the Lebanese and Algerian families with CMT4H reported by De Sandre-Giovannoli et al. (2005), Delague et al. (2007) identified 2 different homozygous mutations in the FGD4 gene (611104.0002 and 611104.0005, respectively). Stendel et al. (2007) also identified homozygous mutations in the FGD4 gene in patients with CMT4H (611104.0001-611104.0005).
De Sandre-Giovannoli, A., Delague, V., Hamadouche, T., Chaouch, M., Krahn, M., Boccaccio, I., Maisonobe, T., Chouery, E., Jabbour, R., Atweh, S., Grid, D., Megarbane, A., Levy, N. Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11. (Letter) J. Med. Genet. 42: 260-265, 2005. [PubMed: 15744041, related citations] [Full Text]
Delague, V., Jacquier, A., Hamadouche, T., Poitelon, Y., Baudot, C., Boccaccio, I., Chouery, E., Chaouch, M., Kassouri, N., Jabbour, R., Grid, D., Megarbane, A., Haase, G., Levy, N. Mutations in FGD4 encoding the Rho GDP/GTP exchange factor frabin cause autosomal recessive Charcot-Marie-Tooth type 4H. Am. J. Hum. Genet. 81: 1-16, 2007. [PubMed: 17564959, images, related citations] [Full Text]
Fabrizi, G. M., Taioli, F., Cavallaro, T., Ferrari, S., Bertolasi, L., Casarotto, M., Rizzuto, N., Deconinck, T., Timmerman, V., De Jonghe, P. Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease type 4H. Neurology 72: 1160-1164, 2009. [PubMed: 19332693, related citations] [Full Text]
Houlden, H., Hammans, S., Katifi, H., Reilly, M. M. A novel frabin (FGD4) nonsense mutation p.R275X associated with phenotypic variability in CMT4H. Neurology 72: 617-620, 2009. [PubMed: 19221294, images, related citations] [Full Text]
Stendel, C., Roos, A., Deconinck, T., Pereira, J., Castagner, F., Niemann, A., Kirschner, J., Korinthenberg, R., Ketelsen, U.-P., Battaloglu, E., Parman, Y., Nicholson, G., and 12 others. Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, Frabin/FGD4. Am. J. Hum. Genet. 81: 158-164, 2007. [PubMed: 17564972, images, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 715802008; ORPHA: 99954; DO: 0110192;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p11.21 | Charcot-Marie-Tooth disease, type 4H | 609311 | Autosomal recessive | 3 | FGD4 | 611104 |
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 4H (CMT4H) is caused by homozygous mutation in the gene encoding frabin (FGD4; 611104) on chromosome 12p11.
For a discussion of genetic heterogeneity of autosomal recessive Charcot-Marie-Tooth disease, see CMT4A (214400).
De Sandre-Giovannoli et al. (2005) reported a total of 10 individuals from 2 families, 1 Lebanese and 1 Algerian, with a severe form of CMT. Onset occurred within the first 2 years of life and was manifested by delayed walking, unsteady gait, areflexia, scoliosis, and foot abnormalities, including pes cavus and pes equinus. Two members of the Lebanese family had upper limb involvement with thenar and hypothenar hypoplasia. Electrophysiologic studies showed severely reduced motor and sensory nerve conduction velocities, consistent with a demyelinating process. Sural nerve biopsy of 1 member of the Lebanese family showed severe loss of myelinated fibers, as well as some features of congenital hypomyelination and occasional onion bulb formations. The Algerian family was consanguineous, suggesting autosomal recessive inheritance.
Houlden et al. (2009) reported 2 sibs with CMT4H confirmed by genetic analysis (R275X; 611104.0006). Although both patients had onset of walking difficulties in childhood, there was slow progression of the disorder, and both remained ambulatory into middle age. At age 58, the proband had pes cavus, distal muscle weakness and atrophy, areflexia, stocking and glove sensory loss, and pupil size asymmetry. Her brother had a similar phenotype. Nerve conduction velocities were significantly decreased. Houlden et al. (2009) noted that the phenotype was relatively mild compared to patients with other FGD4 mutations.
Fabrizi et al. (2009) reported a 20-year-old woman, born of consanguineous Italian parents, with CMT4H confirmed by genetic analysis (611104.0007). The patient was from a small mountain village in northeast Italy. She had a clumsy gait since childhood, steppage gait, pes equinovarus, lower limb areflexia, and mild distal sensory loss. She also had scoliosis and hypotrophy of thenar and hypothenar muscles. Pathologic and electrophysiologic studies showed a demyelinating neuropathy. There was slow disease progression.
The transmission pattern of CMT4H in the Algerian family reported by De Sandre-Giovannoli et al. (2005) was consistent with autosomal recessive inheritance.
In 2 unrelated families with severe early-onset demyelinating CMT, De Sandre-Giovannoli et al. (2005) found linkage of the disorder, designated CMT4H, to an 11.5-cM region on chromosome 12p11.21-q13.11 between markers D12S1648 and D12S1661 (maximum pairwise lod score of 6.97 at D12S345). Mutation analysis excluded peripherin (PRPH; 170710) and contactin-1 (CNTN1; 600016) as candidate genes.
In affected members of the Lebanese and Algerian families with CMT4H reported by De Sandre-Giovannoli et al. (2005), Delague et al. (2007) identified 2 different homozygous mutations in the FGD4 gene (611104.0002 and 611104.0005, respectively). Stendel et al. (2007) also identified homozygous mutations in the FGD4 gene in patients with CMT4H (611104.0001-611104.0005).
De Sandre-Giovannoli, A., Delague, V., Hamadouche, T., Chaouch, M., Krahn, M., Boccaccio, I., Maisonobe, T., Chouery, E., Jabbour, R., Atweh, S., Grid, D., Megarbane, A., Levy, N. Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11. (Letter) J. Med. Genet. 42: 260-265, 2005. [PubMed: 15744041] [Full Text: https://doi.org/10.1136/jmg.2004.024364]
Delague, V., Jacquier, A., Hamadouche, T., Poitelon, Y., Baudot, C., Boccaccio, I., Chouery, E., Chaouch, M., Kassouri, N., Jabbour, R., Grid, D., Megarbane, A., Haase, G., Levy, N. Mutations in FGD4 encoding the Rho GDP/GTP exchange factor frabin cause autosomal recessive Charcot-Marie-Tooth type 4H. Am. J. Hum. Genet. 81: 1-16, 2007. [PubMed: 17564959] [Full Text: https://doi.org/10.1086/518428]
Fabrizi, G. M., Taioli, F., Cavallaro, T., Ferrari, S., Bertolasi, L., Casarotto, M., Rizzuto, N., Deconinck, T., Timmerman, V., De Jonghe, P. Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease type 4H. Neurology 72: 1160-1164, 2009. [PubMed: 19332693] [Full Text: https://doi.org/10.1212/01.wnl.0000345373.58618.b6]
Houlden, H., Hammans, S., Katifi, H., Reilly, M. M. A novel frabin (FGD4) nonsense mutation p.R275X associated with phenotypic variability in CMT4H. Neurology 72: 617-620, 2009. [PubMed: 19221294] [Full Text: https://doi.org/10.1212/01.wnl.0000342463.35089.cc]
Stendel, C., Roos, A., Deconinck, T., Pereira, J., Castagner, F., Niemann, A., Kirschner, J., Korinthenberg, R., Ketelsen, U.-P., Battaloglu, E., Parman, Y., Nicholson, G., and 12 others. Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, Frabin/FGD4. Am. J. Hum. Genet. 81: 158-164, 2007. [PubMed: 17564972] [Full Text: https://doi.org/10.1086/518770]
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