#607734
Table of Contents
A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 1F is caused by mutation in the NEFL gene (162280).
For a phenotypic description and discussion of genetic heterogeneity of CMT type 1, see CMT1B (118200).
Jordanova et al. (2003) reported 3 families with a form of autosomal dominant CMT1. Disease onset was in infancy or childhood (range 1 to 13 years), with distal limb muscle weakness and atrophy, worse in the lower limbs, distal sensory loss, diminished reflexes, pes cavus, and reduced motor nerve conduction velocity (NCV). Three sporadic patients with similar features were also described. Nerve biopsy of 1 of the sporadic patients showed loss of myelinated fibers, onion bulb formation, irregular myelin foldings, and clusters of axonal regeneration. Jordanova et al. (2003) noted that some of the patients were diagnosed with Dejerine-Sottas syndrome (DSS; 145900) because of early onset and increased severity.
Abe et al. (2009) reported 5 unrelated Japanese patients with autosomal dominant demyelinating CMT caused by heterozygous mutations in the NEFL gene. Four had onset before age 2 years, and 1 had onset before age 10 years. Initial symptoms included delayed walking or gait disturbance. Other features included upper and lower muscle weakness and atrophy, distal sensory loss, and hypo- or areflexia. Nerve conduction velocities were severely decreased. Four patients had hearing disturbances, 1 had mental retardation, and 1 had pyramidal signs and cerebellar atrophy.
Abe et al. (2009) also reported a patient with demyelinating CMT caused by a homozygous truncating mutation (162280.0007) in the NEFL gene. This patient was born of consanguineous parents and had onset before age 10 years. He had a similarly affected brother, but neither parent was affected. Abe et al. (2009) postulated that the nonsense mutation would result in loss of function, in contrast to missense mutations which result in toxic gain of function, and concluded that homozygous nonsense mutations in the NEFL gene cause a recessive disorder.
Yum et al. (2009) reported a consanguineous Palestinian family in which 4 sibs had a severe, progressive peripheral neuropathy beginning in early childhood. All had hypotonia in infancy and early childhood, mildly delayed motor development, pes cavus, and slowly progressive atrophy and weakness in the distal muscles of the legs and arms. All also had moderate distal sensory impairment. Visual evoked responses were prolonged in 3 of 4 children, suggesting the involvement of central nervous system axons. Sural nerve biopsy of 1 patient showed lack of immunostaining for NEFL, decreased numbers of myelinated axons, and some regenerating axons. Intermediate filaments were not present in remaining myelinated axons. Although Yum et al. (2009) referred to this phenotype as an 'axonal' neuropathy, the median nerve conduction velocities in all affected patients ranged from 14 to 25 m/s, which is more consistent with a 'demyelinating' neuropathy, as in CMT1F.
In 3 families and 3 sporadic patients with CMT1, Jordanova et al. (2003) identified mutations in the NEFL gene (see, e.g., 162280.0003 and 162280.0004).
In 4 Palestinian sibs with severe early-onset neuropathy and decreased NCV, Yum et al. (2009) identified a homozygous mutation in the (E210X; 162280.0008) in the NEFL gene. The unaffected consanguineous parents were heterozygous for the mutation. In vitro functional expression studies showed that mutant NEFL did not accumulate properly, suggesting an inability to form filaments or enhanced degradation, consistent with a loss of function.
In keeping with the most common designations used in the medical community, 'CMT1' referring to autosomal dominant demyelinating CMT and 'CMT2' referring to axonal CMT, we have chosen to designate this form of autosomal dominant demyelinating CMT caused by mutation in the NEFL gene as 'CMT1F.'
Abe, A., Numakura, C., Saito, K., Koide, H., Oka, N., Honma, A., Kishikawa, Y., Hayasaka, K. Neurofilament light chain polypeptide gene mutations in Charcot-Marie-Tooth disease: nonsense mutation probably causes a recessive phenotype. J. Hum. Genet. 54: 94-97, 2009. [PubMed: 19158810, related citations] [Full Text]
Jordanova, A., De Jonghe, P., Boerkoel, C. F., Takashima, H., De Vriendt, E., Ceuterick, C., Martin, J.-J., Butler, I. J., Mancias, P., Papasozomenos, S. C., Terespolsky, D., Potocki, L., Brown, C. W., Shy, M., Rita, D. A., Tournev, I., Kremensky, I., Lupski, J. R., Timmerman, V. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 126: 590-597, 2003. [PubMed: 12566280, related citations] [Full Text]
Yum, S. W., Zhang, J., Mo, K., Li, J., Scherer, S. S. A novel recessive NEFL mutation causes a severe, early-onset axonal neuropathy. Ann. Neurol. 66: 759-770, 2009. [PubMed: 20039262, images, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 719980006; ORPHA: 101085, 228374; DO: 0110149;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p21.2 | Charcot-Marie-Tooth disease, type 1F | 607734 | Autosomal dominant; Autosomal recessive | 3 | NEFL | 162280 |
A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 1F is caused by mutation in the NEFL gene (162280).
For a phenotypic description and discussion of genetic heterogeneity of CMT type 1, see CMT1B (118200).
Jordanova et al. (2003) reported 3 families with a form of autosomal dominant CMT1. Disease onset was in infancy or childhood (range 1 to 13 years), with distal limb muscle weakness and atrophy, worse in the lower limbs, distal sensory loss, diminished reflexes, pes cavus, and reduced motor nerve conduction velocity (NCV). Three sporadic patients with similar features were also described. Nerve biopsy of 1 of the sporadic patients showed loss of myelinated fibers, onion bulb formation, irregular myelin foldings, and clusters of axonal regeneration. Jordanova et al. (2003) noted that some of the patients were diagnosed with Dejerine-Sottas syndrome (DSS; 145900) because of early onset and increased severity.
Abe et al. (2009) reported 5 unrelated Japanese patients with autosomal dominant demyelinating CMT caused by heterozygous mutations in the NEFL gene. Four had onset before age 2 years, and 1 had onset before age 10 years. Initial symptoms included delayed walking or gait disturbance. Other features included upper and lower muscle weakness and atrophy, distal sensory loss, and hypo- or areflexia. Nerve conduction velocities were severely decreased. Four patients had hearing disturbances, 1 had mental retardation, and 1 had pyramidal signs and cerebellar atrophy.
Abe et al. (2009) also reported a patient with demyelinating CMT caused by a homozygous truncating mutation (162280.0007) in the NEFL gene. This patient was born of consanguineous parents and had onset before age 10 years. He had a similarly affected brother, but neither parent was affected. Abe et al. (2009) postulated that the nonsense mutation would result in loss of function, in contrast to missense mutations which result in toxic gain of function, and concluded that homozygous nonsense mutations in the NEFL gene cause a recessive disorder.
Yum et al. (2009) reported a consanguineous Palestinian family in which 4 sibs had a severe, progressive peripheral neuropathy beginning in early childhood. All had hypotonia in infancy and early childhood, mildly delayed motor development, pes cavus, and slowly progressive atrophy and weakness in the distal muscles of the legs and arms. All also had moderate distal sensory impairment. Visual evoked responses were prolonged in 3 of 4 children, suggesting the involvement of central nervous system axons. Sural nerve biopsy of 1 patient showed lack of immunostaining for NEFL, decreased numbers of myelinated axons, and some regenerating axons. Intermediate filaments were not present in remaining myelinated axons. Although Yum et al. (2009) referred to this phenotype as an 'axonal' neuropathy, the median nerve conduction velocities in all affected patients ranged from 14 to 25 m/s, which is more consistent with a 'demyelinating' neuropathy, as in CMT1F.
In 3 families and 3 sporadic patients with CMT1, Jordanova et al. (2003) identified mutations in the NEFL gene (see, e.g., 162280.0003 and 162280.0004).
In 4 Palestinian sibs with severe early-onset neuropathy and decreased NCV, Yum et al. (2009) identified a homozygous mutation in the (E210X; 162280.0008) in the NEFL gene. The unaffected consanguineous parents were heterozygous for the mutation. In vitro functional expression studies showed that mutant NEFL did not accumulate properly, suggesting an inability to form filaments or enhanced degradation, consistent with a loss of function.
In keeping with the most common designations used in the medical community, 'CMT1' referring to autosomal dominant demyelinating CMT and 'CMT2' referring to axonal CMT, we have chosen to designate this form of autosomal dominant demyelinating CMT caused by mutation in the NEFL gene as 'CMT1F.'
Abe, A., Numakura, C., Saito, K., Koide, H., Oka, N., Honma, A., Kishikawa, Y., Hayasaka, K. Neurofilament light chain polypeptide gene mutations in Charcot-Marie-Tooth disease: nonsense mutation probably causes a recessive phenotype. J. Hum. Genet. 54: 94-97, 2009. [PubMed: 19158810] [Full Text: https://doi.org/10.1038/jhg.2008.13]
Jordanova, A., De Jonghe, P., Boerkoel, C. F., Takashima, H., De Vriendt, E., Ceuterick, C., Martin, J.-J., Butler, I. J., Mancias, P., Papasozomenos, S. C., Terespolsky, D., Potocki, L., Brown, C. W., Shy, M., Rita, D. A., Tournev, I., Kremensky, I., Lupski, J. R., Timmerman, V. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 126: 590-597, 2003. [PubMed: 12566280] [Full Text: https://doi.org/10.1093/brain/awg059]
Yum, S. W., Zhang, J., Mo, K., Li, J., Scherer, S. S. A novel recessive NEFL mutation causes a severe, early-onset axonal neuropathy. Ann. Neurol. 66: 759-770, 2009. [PubMed: 20039262] [Full Text: https://doi.org/10.1002/ana.21728]
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