#607684
Table of Contents
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2E (CMT2E) is caused by heterozygous mutation in the light polypeptide neurofilament protein gene (NEFL; 162280) on chromosome 8p21.
For a phenotypic description and a discussion of genetic heterogeneity of axonal Charcot-Marie-Tooth disease type 2, see CMT2A1 (118210).
Mersiyanova et al. (2000) reported a large 6-generation family from Russia with autosomal dominant CMT2. Onset was in the second and third decade, characterized by difficulty in walking and weakness and atrophy of the distal lower limb muscles and a variable degree of deformity of the feet (pes cavus). Affected individuals did not exhibit enlarged nerves, ulcerated feet, hearing impairment, or paralysis of the vocal cords. Several patients had hyperkeratosis, although the association, if any, between the 2 disorders was not clear. The authors suggested the designation CMT2E for this disorder.
Georgiou et al. (2002) described a large 5-generation Slovenian family with autosomal dominant CMT type 2E. Disease onset in most patients was in the first decade of life. The presenting symptoms were difficulty in walking or running, due to a slowly progressive distal weakness and wasting of the lower limbs. A steppage gait, pes cavus, and hammertoes were typically present. Over a period of 20 years after disease onset, two-thirds of patients developed upper limb involvement resulting in claw hands. All patients were ambulatory 20 to 30 years after onset.
Fabrizi et al. (2004) reported a large kindred from southern Italy with autosomal dominant CMT2E spanning 5 generations and caused by mutation in the NEFL gene (162280.0002). An affected woman and her 2 affected sons had steppage gait, ataxic gait, peroneal muscular atrophy, decreased vibration sense with stocking and glove distribution, and hypotrophy of the hand muscles. One of the sons had claw hand deformities. Motor nerve conduction velocities (NCV) were decreased, consistent with a demyelinating neuropathy, but sural nerve biopsy of the mother showed a primary axonopathy characterized by giant axons containing disorganized neurofilaments.
Miltenberger-Miltenyi et al. (2007) reported a large Austrian family in which at least 4 members had CMT2E confirmed by genetic analysis (162880.0006). Disease onset was in the second decade of life with pes cavus, progressive plantar extensor weakness, and distal lower limb atrophy and weakness. Two patients became wheelchair-bound. Affected members of a second Austrian family, with a different NEFL mutation (162280.0003), had disease onset before age 15 years in all but 1 patient. The disorder was slowly progressive but resulted in a severe and disabling phenotype. Electrophysiologic studies of both families showed intermediate motor nerve conduction velocities consistent with axonal pathology.
Clinical Variability
Agrawal et al. (2014) reported a family in which a mother and her 3 adult sons presented with congenital myopathy. All 4 had manifested hypotonia since early infancy but did not have feeding or respiratory problems or congenital contractures. Foot drop was noted in all 4 during childhood. One patient never learned to walk, and all became wheelchair-dependent at ages ranging from early childhood to mid-fifties. Features included muscle weakness of the face, shoulder, and distal lower extremities, respiratory difficulties, scoliosis, hypo- or areflexia, and joint contractures; the mother had hammertoes. Serum creatine kinase was normal in all patients. Muscle biopsy showed fiber size variation, predominance of type 1 or type 2 fibers, internal nuclei, and connective tissue. Two patients had nemaline rods and myofibrillar disruption and 2 had myofiber degeneration. However, there was also evidence of neurogenic atrophy with angulated fibers. Nerve conduction and EMG studies were performed only in the mother: NCV was normal, and EMG was consistent with a primary chronic neurogenic disorder. Sural nerve biopsy was not performed in any of the patients. Whole-genome sequencing identified a heterozygous truncating mutation in the NEFL gene (R421X; 162280.0009) that segregated with the disorder in the family. The mutant transcript was stable, suggesting that the truncated protein was expressed and could potentially interfere with normal functioning of NEFL. Agrawal et al. (2014) noted that NEFL is not known to be expressed in skeletal muscle, and concluded that the muscle pathology and weakness in this family was secondary to neuronal dysfunction likely resulting from a disrupted neuronal cytoskeleton. The report expanded the phenotypic spectrum of diseases associated with NEFL mutations to include myopathic as well as neurogenic features.
In a large Russian family with CMT2, Mersiyanova et al. (2000) excluded linkage to known CMT2 loci. Genomewide screening localized the disease locus in this family to 8p21. A maximum 2-point lod score of 5.93 was yielded by a microsatellite from the 5-prime region of the NEFL gene.
The transmission pattern of CMT2E in the family reported by Mersiyanova et al. (2000) was consistent with autosomal dominant inheritance.
Lin et al. (2011) identified NEFL mutations in 6 (16.7%) of 36 Taiwanese families of Han Chinese descent with CMT2.
In affected members of the large Russian family with CMT2, Mersiyanova et al. (2000) identified a mutation in the NEFL gene (Q333P; 162280.0001).
Georgiou et al. (2002) determined that all 10 members with CMT2E from the Slovenian family had a mutation in the NEFL gene (162280.0002).
In a 71-year-old man with CMT2E, Leung et al. (2006) identified a heterozygous 13-bp duplication/insertion in the NEFL gene (162280.0005).
In cultured mouse motor neurons, Zhai et al. (2007) found that expression of Q333P- and P8R (162280.0003)-mutant NEFL led to progressive degeneration and loss of neuronal viability. Degenerating motor neurons showed fragmentation and loss of neuritic processes associated with disruption of the neurofilament network and aggregation of the NEFL protein. Coexpression of mutant NEFL with wildtype HSPB1 (602195) diminished aggregation of mutant NEFL, induced reversal of mutant NEFL aggregates and reduced mutant NEFL-induced loss of motor neuron viability. Similarly, expression of mutant HSPB1 (S135F; 602195.0001), which causes CMT2F (606595), also led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL protein. The 2 proteins were found to associate together, and the S135F-mutant HSPB1 had a dominant effect. Zhai et al. (2007) suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E and CMT2F.
Agrawal, P. B., Joshi, M., Marinakis, N. S., Schmitz-Abe, K., Ciarlini, P. D. S. C., Sargent, J. C., Markianos, K., De Girolami, U., Chad, D. A., Beggs, A. H. Expanding the phenotype associated with the NEFL mutation: neuromuscular disease in a family with overlapping myopathic and neurogenic findings. JAMA Neurol. 71: 1413-1420, 2014. [PubMed: 25264603, images, related citations] [Full Text]
Fabrizi, G. M., Cavallaro, T., Angiari, C., Bertolasi, L., Cabrini, I., Ferrarini, M., Rizzuto, N. Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Neurology 62: 1429-1431, 2004. [PubMed: 15111691, related citations] [Full Text]
Georgiou, D.-M., Zidar, J., Korosec, M., Middleton, L. T., Kyriakides, T., Christodoulou, K. A novel NF-L mutation pro22-to-ser is associated with CMT2 in a large Slovenian family. Neurogenetics 4: 93-96, 2002. [PubMed: 12481988, related citations] [Full Text]
Leung, C. L., Nagan, N., Graham, T. H., Liem, R. K. H. A novel duplication/insertion mutation of NEFL in a patient with Charcot-Marie-Tooth disease. Am. J. Med. Genet. 140A: 1021-1025, 2006. [PubMed: 16619203, related citations] [Full Text]
Lin, K.-P., Soong, B.-W., Yang, C.-C., Huang, L.-W., Chang, M.-H., Lee, I.-H., Antonellis, A., Lee, Y.-C. The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in Taiwan. PLoS One 6: e29393, 2011. Note: Electronic Article. Erratum published online. [PubMed: 22206013, images, related citations] [Full Text]
Mersiyanova, I. V., Perepelov, A. V., Polyakov, A. V., Sitnikov, V. F., Dadali, E. L., Oparin, R. B., Petrin, A. N., Evgrafov, O. V. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am. J. Hum. Genet. 67: 37-46, 2000. [PubMed: 10841809, images, related citations] [Full Text]
Miltenberger-Miltenyi, G., Janecke, A. R., Wanschitz, J. V., Timmerman, V., Windpassinger, C., Auer-Grumbach, M., Loscher, W. N. Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene. Arch. Neurol. 64: 966-970, 2007. [PubMed: 17620486, related citations] [Full Text]
Zhai, J., Lin, H., Julien, J.-P., Schlaepfer, W. W. Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1. Hum. Molec. Genet. 16: 3103-3116, 2007. [PubMed: 17881652, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 717012004; ORPHA: 99939; DO: 0110165;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p21.2 | Charcot-Marie-Tooth disease, type 2E | 607684 | Autosomal dominant | 3 | NEFL | 162280 |
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2E (CMT2E) is caused by heterozygous mutation in the light polypeptide neurofilament protein gene (NEFL; 162280) on chromosome 8p21.
For a phenotypic description and a discussion of genetic heterogeneity of axonal Charcot-Marie-Tooth disease type 2, see CMT2A1 (118210).
Mersiyanova et al. (2000) reported a large 6-generation family from Russia with autosomal dominant CMT2. Onset was in the second and third decade, characterized by difficulty in walking and weakness and atrophy of the distal lower limb muscles and a variable degree of deformity of the feet (pes cavus). Affected individuals did not exhibit enlarged nerves, ulcerated feet, hearing impairment, or paralysis of the vocal cords. Several patients had hyperkeratosis, although the association, if any, between the 2 disorders was not clear. The authors suggested the designation CMT2E for this disorder.
Georgiou et al. (2002) described a large 5-generation Slovenian family with autosomal dominant CMT type 2E. Disease onset in most patients was in the first decade of life. The presenting symptoms were difficulty in walking or running, due to a slowly progressive distal weakness and wasting of the lower limbs. A steppage gait, pes cavus, and hammertoes were typically present. Over a period of 20 years after disease onset, two-thirds of patients developed upper limb involvement resulting in claw hands. All patients were ambulatory 20 to 30 years after onset.
Fabrizi et al. (2004) reported a large kindred from southern Italy with autosomal dominant CMT2E spanning 5 generations and caused by mutation in the NEFL gene (162280.0002). An affected woman and her 2 affected sons had steppage gait, ataxic gait, peroneal muscular atrophy, decreased vibration sense with stocking and glove distribution, and hypotrophy of the hand muscles. One of the sons had claw hand deformities. Motor nerve conduction velocities (NCV) were decreased, consistent with a demyelinating neuropathy, but sural nerve biopsy of the mother showed a primary axonopathy characterized by giant axons containing disorganized neurofilaments.
Miltenberger-Miltenyi et al. (2007) reported a large Austrian family in which at least 4 members had CMT2E confirmed by genetic analysis (162880.0006). Disease onset was in the second decade of life with pes cavus, progressive plantar extensor weakness, and distal lower limb atrophy and weakness. Two patients became wheelchair-bound. Affected members of a second Austrian family, with a different NEFL mutation (162280.0003), had disease onset before age 15 years in all but 1 patient. The disorder was slowly progressive but resulted in a severe and disabling phenotype. Electrophysiologic studies of both families showed intermediate motor nerve conduction velocities consistent with axonal pathology.
Clinical Variability
Agrawal et al. (2014) reported a family in which a mother and her 3 adult sons presented with congenital myopathy. All 4 had manifested hypotonia since early infancy but did not have feeding or respiratory problems or congenital contractures. Foot drop was noted in all 4 during childhood. One patient never learned to walk, and all became wheelchair-dependent at ages ranging from early childhood to mid-fifties. Features included muscle weakness of the face, shoulder, and distal lower extremities, respiratory difficulties, scoliosis, hypo- or areflexia, and joint contractures; the mother had hammertoes. Serum creatine kinase was normal in all patients. Muscle biopsy showed fiber size variation, predominance of type 1 or type 2 fibers, internal nuclei, and connective tissue. Two patients had nemaline rods and myofibrillar disruption and 2 had myofiber degeneration. However, there was also evidence of neurogenic atrophy with angulated fibers. Nerve conduction and EMG studies were performed only in the mother: NCV was normal, and EMG was consistent with a primary chronic neurogenic disorder. Sural nerve biopsy was not performed in any of the patients. Whole-genome sequencing identified a heterozygous truncating mutation in the NEFL gene (R421X; 162280.0009) that segregated with the disorder in the family. The mutant transcript was stable, suggesting that the truncated protein was expressed and could potentially interfere with normal functioning of NEFL. Agrawal et al. (2014) noted that NEFL is not known to be expressed in skeletal muscle, and concluded that the muscle pathology and weakness in this family was secondary to neuronal dysfunction likely resulting from a disrupted neuronal cytoskeleton. The report expanded the phenotypic spectrum of diseases associated with NEFL mutations to include myopathic as well as neurogenic features.
In a large Russian family with CMT2, Mersiyanova et al. (2000) excluded linkage to known CMT2 loci. Genomewide screening localized the disease locus in this family to 8p21. A maximum 2-point lod score of 5.93 was yielded by a microsatellite from the 5-prime region of the NEFL gene.
The transmission pattern of CMT2E in the family reported by Mersiyanova et al. (2000) was consistent with autosomal dominant inheritance.
Lin et al. (2011) identified NEFL mutations in 6 (16.7%) of 36 Taiwanese families of Han Chinese descent with CMT2.
In affected members of the large Russian family with CMT2, Mersiyanova et al. (2000) identified a mutation in the NEFL gene (Q333P; 162280.0001).
Georgiou et al. (2002) determined that all 10 members with CMT2E from the Slovenian family had a mutation in the NEFL gene (162280.0002).
In a 71-year-old man with CMT2E, Leung et al. (2006) identified a heterozygous 13-bp duplication/insertion in the NEFL gene (162280.0005).
In cultured mouse motor neurons, Zhai et al. (2007) found that expression of Q333P- and P8R (162280.0003)-mutant NEFL led to progressive degeneration and loss of neuronal viability. Degenerating motor neurons showed fragmentation and loss of neuritic processes associated with disruption of the neurofilament network and aggregation of the NEFL protein. Coexpression of mutant NEFL with wildtype HSPB1 (602195) diminished aggregation of mutant NEFL, induced reversal of mutant NEFL aggregates and reduced mutant NEFL-induced loss of motor neuron viability. Similarly, expression of mutant HSPB1 (S135F; 602195.0001), which causes CMT2F (606595), also led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL protein. The 2 proteins were found to associate together, and the S135F-mutant HSPB1 had a dominant effect. Zhai et al. (2007) suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E and CMT2F.
Agrawal, P. B., Joshi, M., Marinakis, N. S., Schmitz-Abe, K., Ciarlini, P. D. S. C., Sargent, J. C., Markianos, K., De Girolami, U., Chad, D. A., Beggs, A. H. Expanding the phenotype associated with the NEFL mutation: neuromuscular disease in a family with overlapping myopathic and neurogenic findings. JAMA Neurol. 71: 1413-1420, 2014. [PubMed: 25264603] [Full Text: https://doi.org/10.1001/jamaneurol.2014.1432]
Fabrizi, G. M., Cavallaro, T., Angiari, C., Bertolasi, L., Cabrini, I., Ferrarini, M., Rizzuto, N. Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Neurology 62: 1429-1431, 2004. [PubMed: 15111691] [Full Text: https://doi.org/10.1212/01.wnl.0000120664.07186.3c]
Georgiou, D.-M., Zidar, J., Korosec, M., Middleton, L. T., Kyriakides, T., Christodoulou, K. A novel NF-L mutation pro22-to-ser is associated with CMT2 in a large Slovenian family. Neurogenetics 4: 93-96, 2002. [PubMed: 12481988] [Full Text: https://doi.org/10.1007/s10048-002-0138-4]
Leung, C. L., Nagan, N., Graham, T. H., Liem, R. K. H. A novel duplication/insertion mutation of NEFL in a patient with Charcot-Marie-Tooth disease. Am. J. Med. Genet. 140A: 1021-1025, 2006. [PubMed: 16619203] [Full Text: https://doi.org/10.1002/ajmg.a.31242]
Lin, K.-P., Soong, B.-W., Yang, C.-C., Huang, L.-W., Chang, M.-H., Lee, I.-H., Antonellis, A., Lee, Y.-C. The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in Taiwan. PLoS One 6: e29393, 2011. Note: Electronic Article. Erratum published online. [PubMed: 22206013] [Full Text: https://doi.org/10.1371/journal.pone.0029393]
Mersiyanova, I. V., Perepelov, A. V., Polyakov, A. V., Sitnikov, V. F., Dadali, E. L., Oparin, R. B., Petrin, A. N., Evgrafov, O. V. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am. J. Hum. Genet. 67: 37-46, 2000. [PubMed: 10841809] [Full Text: https://doi.org/10.1086/302962]
Miltenberger-Miltenyi, G., Janecke, A. R., Wanschitz, J. V., Timmerman, V., Windpassinger, C., Auer-Grumbach, M., Loscher, W. N. Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene. Arch. Neurol. 64: 966-970, 2007. [PubMed: 17620486] [Full Text: https://doi.org/10.1001/archneur.64.7.966]
Zhai, J., Lin, H., Julien, J.-P., Schlaepfer, W. W. Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1. Hum. Molec. Genet. 16: 3103-3116, 2007. [PubMed: 17881652] [Full Text: https://doi.org/10.1093/hmg/ddm272]
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