#614895
Table of Contents
A number sign (#) is used with this entry because autosomal recessive Charcot-Marie-Tooth disease type 4F (CMT4F) is caused by homozygous or compound heterozygous mutation in the periaxin gene (PRX; 605725) on chromosome 19q13.
Charcot-Marie-Tooth disease type 4F is an autosomal recessive demyelinating neuropathy characterized by distal sensory impairment and distal muscle weakness and atrophy affecting the lower more than the upper limbs. Nerve conduction velocities are decreased and sural nerve biopsy shows loss of myelinated fibers. The age at onset is variable and can range from childhood to adult years. When the onset is in infancy, the phenotype is characterized as Dejerine-Sottas syndrome (DSS; 145900).
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Delague et al. (2000) reported a large inbred Lebanese family affected with autosomal recessive demyelinating Charcot-Marie-Tooth disease in which they excluded linkage to the previously known CMT4 loci. Clinical features and results of histopathologic studies confirmed that the disease in this family represented a demyelinating autosomal recessive CMT subtype, which the authors referred to as CMT4F. Histopathologic and immunohistochemical analysis of a sural nerve biopsy of 1 patient revealed common features with the periaxin-null mouse and the absence of L-periaxin from the myelin sheath. These data confirmed the importance of the periaxin proteins to normal Schwann cell function.
Takashima et al. (2002) reported 2 sibs with CMT4F. Both had much worse sensory than motor impairment. Despite early onset of disease, these sibs had a relatively slow disease progression and adult motor impairment typical for classic demyelinating Charcot-Marie-Tooth neuropathy. Neuropathology showed demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon.
Kijima et al. (2004) reported 3 unrelated Japanese patients with CMT4F. They presented with early-onset and slowly progressive distal motor and sensory neuropathy. All 3 patients were born of healthy, consanguineous parents. Two of the patients also had an affected sib. On sural nerve biopsy, 1 patient had atypical onion bulb formation, the second had more typical onion bulb formation, and the third had onion bulb and tomacula formation.
Kabzinska et al. (2006) reported an 8-year-old boy with severe CMT4F. He began to walk with a clumsy gait at age 2 years and showed foot drop at age 5. He had weak distal muscle weakness of the upper and lower extremities which was more pronounced in the lower limbs, absent reflexes, sensory ataxia, distal sensory impairment, and pes cavus. Electrophysiologic studies showed severely prolonged or absent motor conduction velocities. EMG was consistent with mild stable chronic reinnervation. Sural nerve biopsy showed severe loss of myelinated axons of all diameters, onion bulb formation, and some areas of focally folded myelin.
Marchesi et al. (2010) reported 4 adult patients, including 2 sibs, with CMT4F due to homozygous or compound heterozygous truncating mutations in the PRX gene. The patients were between 34 and 45 years of age at the time of the report. All had onset in early childhood with delayed motor development, and achieved walking with an unsteady gait by 2 or 3 years of age. All developed pes cavus and scoliosis of varying severity. There was variable distal muscle weakness and atrophy affecting both the upper and lower limbs and associated with distal sensory impairment; deep tendon reflexes were absent. The patients tended to walk with a steppage gait and some showed sensory ataxia. Nerve conduction velocities were severely decreased, between 3 and 13.3 m/s in the median nerve. Sensory nerve action potentials were undetectable. Sural nerve biopsy of 2 patients showed severe demyelination and complex onion bulb formation and occasional myelin foldings. In a review of previously reported patients with PRX mutations, Marchesi et al. (2010) concluded that the disorder was phenotypically homogeneous with mild variability in severity, and was slowly progressive, despite the early age at onset.
Tokunaga et al. (2012) reported 2 unrelated Japanese patients with adult-onset CMT4F due to a homozygous R1070X mutation (605725.0008). One patient developed mild distal muscle wasting and sensory disturbance in all limbs at age 50 years. The disorder was slowly progressive, and she could still walk independently at age 63 despite having pes cavus. Sural nerve biopsy showed moderate demyelination and complex onion bulb formation. The other patient developed lower limb weakness at age 37 years. At age 47, he could walk with a walking vehicle. Other features included scoliosis and areflexia. Sural nerve biopsy showed myelin thinning and onion bulbs. Motor nerve conduction velocities in the median nerve were 20 m/s in both patients. Tokunaga et al. (2012) reported another Japanese woman with adult-onset CMT4F. Although she had delayed independent ambulation due to nonspecific infantile paralysis at age 18 months, she developed mild distal muscle weakness and sensory impairment in the lower limbs at age 30 years. Upper limb wasting was observed at age 44 years, and she had vocal cord paralysis. Other features included pes cavus, scoliosis, and areflexia. The disorder was slowly progressive. At age 65, she had to use leg braces and a wheelchair. Nerve conduction velocities were not recordable and sural nerve biopsy showed significant demyelination. Tokunaga et al. (2012) emphasized the late onset and relatively mild phenotype in these 3 patients.
The transmission pattern of demyelinating CMT in the family reported by Delague et al. (2000) was consistent with autosomal recessive inheritance.
In a Lebanese family, Delague et al. (2000) found linkage of a severe autosomal recessive demyelinating neuropathy, which they called Charcot-Marie-Tooth disease type 4F, to chromosome 19q13.1-q13.3 with a maximum pairwise lod score of 5.37 for D19S420.
In affected members of a Lebanese family with CMT4F studied by Delague et al. (2000), Guilbot et al. (2001) identified a homozygous truncating mutation in the PRX gene (R196X; 605725.0005).
In 2 sibs with CMT4F, Takashima et al. (2002) identified a homozygous mutation in the PRX gene (C715X; 605725.0006).
In 3 unrelated Japanese patients with Charcot-Marie-Tooth disease type 4F, Kijima et al. (2004) identified a homozygous mutation in the PRX gene (R1070X; 605725.0008).
In a Japanese woman with adult-onset CMT4F, Tokunaga et al. (2012) identified a homozygous missense mutation in the PRX gene (D651N; 605725.0011). The mutation was not found in 292 control chromosomes, but was found in 1 of 2,188 exomes. Her 3 unaffected brothers were all heterozygous for the mutation. Functional analysis was not performed. This was the first reported missense mutation in this gene.
Delague, V., Bareil, C., Tuffery, S., Bouvagnet, P., Chouery, E., Koussa, S., Maisonobe, T., Loiselet, J., Megarbane, A., Claustres, M. Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene. Am. J. Hum. Genet. 67: 236-243, 2000. [PubMed: 10848494, images, related citations] [Full Text]
Guilbot, A., Williams, A., Ravise, N., Verny, C., Brice, A., Sherman, D. L., Brophy, P. J., LeGuern, E., Delague, V., Bareil, C., Megarbane, A., Claustres, M. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum. Molec. Genet. 10: 415-421, 2001. [PubMed: 11157804, related citations] [Full Text]
Kabzinska, D., Drac, H., Sherman, D. L., Kostera-Pruszczyk, A., Brophy, P. J., Kochanski, A., Hausmanowa-Petrusewicz, I. Charcot-Marie-Tooth type 4F disease caused by S399fsx410 mutation in the PRX gene. Neurology 66: 745-747, 2006. [PubMed: 16534116, related citations] [Full Text]
Kijima, K., Numakura, C., Shirahata, E., Sawaishi, Y., Shimohata, M., Igarashi, S., Tanaka, T., Hayasaka, K. Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth disease. J. Hum. Genet. 49: 376-379, 2004. [PubMed: 15197604, related citations] [Full Text]
Marchesi, C., Milani, M., Morbin, M., Cesani, M., Lauria, G., Scaioli, V., Piccolo, G., Fabrizi, G. M., Cavallaro, T., Taroni, F., Pareyson, D. Four novel cases of periaxin-related neuropathy and review of the literature. Neurology 75: 1830-1838, 2010. [PubMed: 21079185, related citations] [Full Text]
Takashima, H., Boerkoel, C. F., De Jonghe, P., Ceuterick, C., Martin, J.-J., Voit, T., Schroder, J.-M., Williams, A., Brophy, P. J., Timmerman, V., Lupski, J. R. Periaxin mutations cause a broad spectrum of demyelinating neuropathies. Ann. Neurol. 51: 709-715, 2002. [PubMed: 12112076, related citations] [Full Text]
Tokunaga, S., Hashiguchi, A., Yoshimura, A., Maeda, K., Suzuki, T., Haruki, H., Nakamura, T., Okamoto, Y., Takashima, H. Late-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation. Neurogenetics 13: 359-365, 2012. [PubMed: 22847150, related citations] [Full Text]
ORPHA: 99952; DO: 0110193;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.2 | Charcot-Marie-Tooth disease, type 4F | 614895 | Autosomal recessive | 3 | PRX | 605725 |
A number sign (#) is used with this entry because autosomal recessive Charcot-Marie-Tooth disease type 4F (CMT4F) is caused by homozygous or compound heterozygous mutation in the periaxin gene (PRX; 605725) on chromosome 19q13.
Charcot-Marie-Tooth disease type 4F is an autosomal recessive demyelinating neuropathy characterized by distal sensory impairment and distal muscle weakness and atrophy affecting the lower more than the upper limbs. Nerve conduction velocities are decreased and sural nerve biopsy shows loss of myelinated fibers. The age at onset is variable and can range from childhood to adult years. When the onset is in infancy, the phenotype is characterized as Dejerine-Sottas syndrome (DSS; 145900).
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Delague et al. (2000) reported a large inbred Lebanese family affected with autosomal recessive demyelinating Charcot-Marie-Tooth disease in which they excluded linkage to the previously known CMT4 loci. Clinical features and results of histopathologic studies confirmed that the disease in this family represented a demyelinating autosomal recessive CMT subtype, which the authors referred to as CMT4F. Histopathologic and immunohistochemical analysis of a sural nerve biopsy of 1 patient revealed common features with the periaxin-null mouse and the absence of L-periaxin from the myelin sheath. These data confirmed the importance of the periaxin proteins to normal Schwann cell function.
Takashima et al. (2002) reported 2 sibs with CMT4F. Both had much worse sensory than motor impairment. Despite early onset of disease, these sibs had a relatively slow disease progression and adult motor impairment typical for classic demyelinating Charcot-Marie-Tooth neuropathy. Neuropathology showed demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon.
Kijima et al. (2004) reported 3 unrelated Japanese patients with CMT4F. They presented with early-onset and slowly progressive distal motor and sensory neuropathy. All 3 patients were born of healthy, consanguineous parents. Two of the patients also had an affected sib. On sural nerve biopsy, 1 patient had atypical onion bulb formation, the second had more typical onion bulb formation, and the third had onion bulb and tomacula formation.
Kabzinska et al. (2006) reported an 8-year-old boy with severe CMT4F. He began to walk with a clumsy gait at age 2 years and showed foot drop at age 5. He had weak distal muscle weakness of the upper and lower extremities which was more pronounced in the lower limbs, absent reflexes, sensory ataxia, distal sensory impairment, and pes cavus. Electrophysiologic studies showed severely prolonged or absent motor conduction velocities. EMG was consistent with mild stable chronic reinnervation. Sural nerve biopsy showed severe loss of myelinated axons of all diameters, onion bulb formation, and some areas of focally folded myelin.
Marchesi et al. (2010) reported 4 adult patients, including 2 sibs, with CMT4F due to homozygous or compound heterozygous truncating mutations in the PRX gene. The patients were between 34 and 45 years of age at the time of the report. All had onset in early childhood with delayed motor development, and achieved walking with an unsteady gait by 2 or 3 years of age. All developed pes cavus and scoliosis of varying severity. There was variable distal muscle weakness and atrophy affecting both the upper and lower limbs and associated with distal sensory impairment; deep tendon reflexes were absent. The patients tended to walk with a steppage gait and some showed sensory ataxia. Nerve conduction velocities were severely decreased, between 3 and 13.3 m/s in the median nerve. Sensory nerve action potentials were undetectable. Sural nerve biopsy of 2 patients showed severe demyelination and complex onion bulb formation and occasional myelin foldings. In a review of previously reported patients with PRX mutations, Marchesi et al. (2010) concluded that the disorder was phenotypically homogeneous with mild variability in severity, and was slowly progressive, despite the early age at onset.
Tokunaga et al. (2012) reported 2 unrelated Japanese patients with adult-onset CMT4F due to a homozygous R1070X mutation (605725.0008). One patient developed mild distal muscle wasting and sensory disturbance in all limbs at age 50 years. The disorder was slowly progressive, and she could still walk independently at age 63 despite having pes cavus. Sural nerve biopsy showed moderate demyelination and complex onion bulb formation. The other patient developed lower limb weakness at age 37 years. At age 47, he could walk with a walking vehicle. Other features included scoliosis and areflexia. Sural nerve biopsy showed myelin thinning and onion bulbs. Motor nerve conduction velocities in the median nerve were 20 m/s in both patients. Tokunaga et al. (2012) reported another Japanese woman with adult-onset CMT4F. Although she had delayed independent ambulation due to nonspecific infantile paralysis at age 18 months, she developed mild distal muscle weakness and sensory impairment in the lower limbs at age 30 years. Upper limb wasting was observed at age 44 years, and she had vocal cord paralysis. Other features included pes cavus, scoliosis, and areflexia. The disorder was slowly progressive. At age 65, she had to use leg braces and a wheelchair. Nerve conduction velocities were not recordable and sural nerve biopsy showed significant demyelination. Tokunaga et al. (2012) emphasized the late onset and relatively mild phenotype in these 3 patients.
The transmission pattern of demyelinating CMT in the family reported by Delague et al. (2000) was consistent with autosomal recessive inheritance.
In a Lebanese family, Delague et al. (2000) found linkage of a severe autosomal recessive demyelinating neuropathy, which they called Charcot-Marie-Tooth disease type 4F, to chromosome 19q13.1-q13.3 with a maximum pairwise lod score of 5.37 for D19S420.
In affected members of a Lebanese family with CMT4F studied by Delague et al. (2000), Guilbot et al. (2001) identified a homozygous truncating mutation in the PRX gene (R196X; 605725.0005).
In 2 sibs with CMT4F, Takashima et al. (2002) identified a homozygous mutation in the PRX gene (C715X; 605725.0006).
In 3 unrelated Japanese patients with Charcot-Marie-Tooth disease type 4F, Kijima et al. (2004) identified a homozygous mutation in the PRX gene (R1070X; 605725.0008).
In a Japanese woman with adult-onset CMT4F, Tokunaga et al. (2012) identified a homozygous missense mutation in the PRX gene (D651N; 605725.0011). The mutation was not found in 292 control chromosomes, but was found in 1 of 2,188 exomes. Her 3 unaffected brothers were all heterozygous for the mutation. Functional analysis was not performed. This was the first reported missense mutation in this gene.
Delague, V., Bareil, C., Tuffery, S., Bouvagnet, P., Chouery, E., Koussa, S., Maisonobe, T., Loiselet, J., Megarbane, A., Claustres, M. Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene. Am. J. Hum. Genet. 67: 236-243, 2000. [PubMed: 10848494] [Full Text: https://doi.org/10.1086/302980]
Guilbot, A., Williams, A., Ravise, N., Verny, C., Brice, A., Sherman, D. L., Brophy, P. J., LeGuern, E., Delague, V., Bareil, C., Megarbane, A., Claustres, M. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum. Molec. Genet. 10: 415-421, 2001. [PubMed: 11157804] [Full Text: https://doi.org/10.1093/hmg/10.4.415]
Kabzinska, D., Drac, H., Sherman, D. L., Kostera-Pruszczyk, A., Brophy, P. J., Kochanski, A., Hausmanowa-Petrusewicz, I. Charcot-Marie-Tooth type 4F disease caused by S399fsx410 mutation in the PRX gene. Neurology 66: 745-747, 2006. [PubMed: 16534116] [Full Text: https://doi.org/10.1212/01.wnl.0000201269.46071.35]
Kijima, K., Numakura, C., Shirahata, E., Sawaishi, Y., Shimohata, M., Igarashi, S., Tanaka, T., Hayasaka, K. Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth disease. J. Hum. Genet. 49: 376-379, 2004. [PubMed: 15197604] [Full Text: https://doi.org/10.1007/s10038-004-0162-3]
Marchesi, C., Milani, M., Morbin, M., Cesani, M., Lauria, G., Scaioli, V., Piccolo, G., Fabrizi, G. M., Cavallaro, T., Taroni, F., Pareyson, D. Four novel cases of periaxin-related neuropathy and review of the literature. Neurology 75: 1830-1838, 2010. [PubMed: 21079185] [Full Text: https://doi.org/10.1212/WNL.0b013e3181fd6314]
Takashima, H., Boerkoel, C. F., De Jonghe, P., Ceuterick, C., Martin, J.-J., Voit, T., Schroder, J.-M., Williams, A., Brophy, P. J., Timmerman, V., Lupski, J. R. Periaxin mutations cause a broad spectrum of demyelinating neuropathies. Ann. Neurol. 51: 709-715, 2002. [PubMed: 12112076] [Full Text: https://doi.org/10.1002/ana.10213]
Tokunaga, S., Hashiguchi, A., Yoshimura, A., Maeda, K., Suzuki, T., Haruki, H., Nakamura, T., Okamoto, Y., Takashima, H. Late-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation. Neurogenetics 13: 359-365, 2012. [PubMed: 22847150] [Full Text: https://doi.org/10.1007/s10048-012-0338-5]
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