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SNOMEDCT: 765745007; ORPHA: 100044, 228179; DO: 0110197;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.2 | Charcot-Marie-Tooth disease, axonal type 2M | 606482 | Autosomal dominant | 3 | DNM2 | 602378 |
| 19p13.2 | Charcot-Marie-Tooth disease, dominant intermediate B | 606482 | Autosomal dominant | 3 | DNM2 | 602378 |
A number sign (#) is used with this entry because of evidence that the forms of dominant intermediate Charcot-Marie-Tooth (CMT) disease and axonal CMT that map to chromosome 19p, here designated CMTDIB and CMT2M, respectively, are caused by heterozygous mutation in the gene encoding dynamin-2 (DNM2; 602378) on chromosome 19p13.
Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms.
Classification
CMT neuropathy is subdivided into CMT1 (see 118200) and CMT2 (see 118210) types on the basis of electrophysiologic and neuropathologic criteria. CMT1, or hereditary motor and sensory neuropathy type I (HMSN I), is a demyelinating neuropathy, whereas CMT2, or HMSN II, is an axonal neuropathy. Most patients with CMT are classified as having CMT1 or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve conduction velocity (NCV). However, in some families with CMT, patients have motor median NCVs ranging from 25 to 45 m/s. Families of this type were reported by Salisachs (1974) and Davis et al. (1978). Davis et al. (1978) proposed that this form be designated 'intermediate' CMT.
Claeys et al. (2009) stated that some CMT families may have an even broader range of NCV than 25 to 45 m/s, with the lowest levels around 25 and the highest levels within the normal range (50+ m/s). They also suggested that the term 'intermediate' should not be used to describe a single NCV value, but rather the CMT subtype at the level of the family (e.g., in families with a range or combinations of NCV values).
Berciano et al. (2017) provided a detailed review of the different forms of intermediate CMT, noting that diagnoses may be controversial because of variable classification issues. The authors presented an algorithm for the interpretation of electrophysiologic studies in CMT, and suggested that nerve conduction studies should be conducted on the upper arm (axilla to elbow). They noted that distal axonal degeneration can result in secondary myelination defects, which may cause significantly decreased motor NCV and CMAP values that may be misinterpreted.
Genetic Heterogeneity of Autosomal Dominant Intermediate CMT
In addition to CMTDIB, which is caused by mutation in the DNM2 gene, other forms of dominant intermediate CMT include CMTDIA (620378), mapped to chromosome 10q24-q25; CMTDIC (608323), caused by mutation in the YARS gene (603623) on chromosome 1p35; CMTDID (607791), caused by mutation in the MPZ gene (159440) on chromosome 1q22; CMTDIE with focal segmental glomerulosclerosis (CMTDIE; 614455), caused by mutation in the INF2 gene (610982) on chromosome 14q32; CMTDIF (615185), caused by mutation in the GNB4 gene (610863) on chromosome 3q26; and CMTDIG (617882), caused by mutation in the NEFL gene (162280) on chromosome 8p21.
Kennerson et al. (2001) described a form of CMT that they referred to as 'dominant intermediate CMT.' They used the term 'intermediate conduction velocity' to describe CMT families with nerve conduction velocities, in different affected individuals, that overlap the division between CMT1 and CMT2. Kennerson et al. (2001) reported a large Australian family in which affected members had nerve conduction velocities ranging from 24 to 54 m/s. The sural nerve biopsy in this family showed axonal degeneration, loss of large diameter fibers, rare segmental demyelination, and remyelination with onion bulb formation.
Claeys et al. (2009) reviewed the phenotypic spectrum of CMT in 37 patients from 6 families with dynamin-2 mutations. Several of the families had previously been reported (see, e.g., Kennerson et al., 2001). The mean age at onset was 16 years (range, 2-50). Patients presented with a classic CMT phenotype of distal lower limb weakness and atrophy resulting in gait abnormalities and frequent falls. Electrophysiologic studies showed intermediate or axonal motor median nerve conduction velocities ranging from 26 m/s to 54 m/s; variations occurred in the same family. Sural nerve biopsy in 1 family showed diffuse loss of myelinated fibers, regenerating axons, and focal myelin thickenings without segmental demyelination. Two families had associated neutropenia, and 1 family developed early-onset cataracts.
Axonal Charcot-Marie-Tooth Disease 2M
Fabrizi et al. (2007) reported 2 unrelated families with CMT due to heterozygous mutations in the DNM2 gene (602378.0008; 602378.0009, respectively). The proband of 1 family had pes cavus, mildly ataxic gait, weakness of foot dorsiflexion, peripheral sensory neuropathy, and mild wasting of the intrinsic hand muscles. Her son had painful paresthesias, pes cavus, clawed toes, wasting of the peroneal muscles, steppage gait with sensory ataxia, and preservation of intrinsic hand muscles. Median nerve conduction velocities were normal, consistent with an axonal form of CMT. Sural nerve biopsy showed loss of large diameter fibers and rare onion bulb formations. Overall, the histology was consistent with an axonal neuropathy without detectable demyelination. Fabrizi et al. (2007) noted that the phenotype in this family was milder than that reported in other families with DNM2 mutations, and emphasized that axonal changes without demyelinating changes can be present.
Gallardo et al. (2008) reported a mother and her 2 adult daughters with axonal Charcot-Marie-Tooth disease (CMT2M). The patients were ages 55, 32, and 23, and motor nerve conduction velocities were 33, 46, and 50 m/s, respectively. All had progressive gait unsteadiness and foot deformities, including pes cavus and toe clawing, in the first decade of life. All had distal muscle weakness and atrophy of the lower limbs, and the mother also had hand weakness and atrophy. Ankle reflexes were absent in all 3, and all had hypoesthesia of the lower limbs. MRI studies showed fatty infiltration of the calf muscles, particularly in the anterior compartment. The fatty infiltration increased distally and was massive in the foot musculature. Muscle edema was also present in affected muscles. In a follow-up of the family reported by Gallardo et al. (2008), Claeys et al. (2009) concluded that the phenotype was consistent with axonal CMT.
By genomewide analysis of a large Australian family with dominant intermediate CMT, Kennerson et al. (2001) found strong linkage to the short arm of chromosome 19 (maximum lod score of 4.3 with a recombination fraction of 0.0 at D19S221, and maximum lod score of 5.28 with a recombination fraction of 0.0 at D19S226). Haplotype analysis performed with 14 additional markers placed the CMTDIB locus within a 16.8-cM region flanked by the markers D19S586 and D19S546. Multipoint linkage analysis suggested that the most likely location is at D19S226 (maximum multipoint lod score of 6.77) with a 10-cM confidence interval. The cytogenetic location is 19p13.2-p12. Speer et al. (2002) reduced the minimum candidate interval for CMTDI1 to a 9-cM interval spanned by markers D19S586 and D19S432.
Zhu et al. (2003) performed extended haplotype analysis and clinical assessment of additional members of the family described by Kennerson et al. (2001), which together with the report of a second family linked to the CMTDI1 locus (Speer et al., 2002) enabled them to narrow the candidate region for the CMTDI1 gene to a 6-cM interval flanked by D19S558 and D19S432. Selection of positional candidate genes for screening was performed on the basis of neural expression and microarray analysis of Schwann cell differentiation in vivo. Six genes localized in the original linkage interval and 1 in the newly refined region were excluded as the cause of dominant intermediate CMT neuropathy.
Zuchner et al. (2005) presented evidence that the form of dominant intermediate CMT that maps to 19p13.2-p12 is caused by mutations in the gene encoding dynamin-2 (DNM2; 602378). They refined the locus associated with DI-CMTB to 4.2 Mb and found unique mutations in DNM2 in the American family described by Speer et al. (2002), the Australian family of Kennerson et al. (2001) and Zhu et al. (2003), and in an additional multigenerational Belgian family. In the Australian and Belgian pedigrees, which carried 2 different mutations affecting the same amino acid, lys558 (602378.0002, 602378.0003), CMT cosegregated with neutropenia, which had not previously been associated with CMT neuropathies.
In a mother and her 2 daughters with axonal CMT, Gallardo et al. (2008) identified a heterozygous mutation in the DNM2 gene (G358R; 602378.0012).
Associations Pending Confirmation
For discussion of a possible association between dominant intermediate Charcot-Marie-Tooth disease and variation in the C1ORF194 (CFAP296) gene, see 618682.0001.
Berciano, J., Garcia, A., Gallardo, E., Peeters, K., Pelayo-Negro, A. L., Alvarez-Paradelo, S., Gazulla, J., Martinez-Tames, M., Infante, J., Jordanova, A. Intermediate Charcot-Marie-Tooth disease: an electrophysiological reappraisal and systematic review. J. Neurol. 264: 1655-1677, 2017. [PubMed: 28364294] [Full Text: https://doi.org/10.1007/s00415-017-8474-3]
Claeys, K. G., Zuchner, S., Kennerson, M., Berciano, J., Garcia, A., Verhoeven, K., Storey, E., Merory, J. R., Bienfait, H. M. E., Lammens, M., Nelis, E., Baets, J., De Vriendt, E., Berneman, Z. N., De Veuster, I., Vance, J. M., Nicholson, G., Timmerman, V., De Jonghe, P. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain 132: 1741-1752, 2009. [PubMed: 19502294] [Full Text: https://doi.org/10.1093/brain/awp115]
Davis, C. J. F., Bradley, W., Madrid, R. The peroneal muscular atrophy syndrome: clinical, genetic, electrophysiological and nerve biopsy studies. J. Genet. Hum. 26: 311-349, 1978. [PubMed: 752065]
Fabrizi, G. M., Ferrarini, M., Cavallaro, T., Cabrini, I., Cerini, R., Bertolasi, L., Rizzuto, N. Two novel mutations in dynamin-2 cause axonal Charcot-Marie-Tooth disease. Neurology 69: 291-295, 2007. [PubMed: 17636067] [Full Text: https://doi.org/10.1212/01.wnl.0000265820.51075.61]
Gallardo, E., Claeys, K. G., Nelis, E., Garcia, A., Canga, A., Combarros, O., Timmerman, V., De Jonghe, P., Berciano, J. Magnetic resonance imaging findings of leg musculature in Charcot-Marie-Tooth disease type 2 due to dynamin 2 mutation. J. Neurol. 255: 986-992, 2008. [PubMed: 18560793] [Full Text: https://doi.org/10.1007/s00415-008-0808-8]
Kennerson, M. L., Zhu, D., Gardner, R. J. M., Storey, E., Merory, J., Robertson, S. P., Nicholson, G. A. Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2. Am. J. Hum. Genet. 69: 883-888, 2001. [PubMed: 11533912] [Full Text: https://doi.org/10.1086/323743]
Salisachs, P. Wide spectrum of motor conduction velocity in Charcot-Marie-Tooth disease: an anatomico-physiological interpretation. J. Neurol. Sci. 23: 25-31, 1974. [PubMed: 4855423] [Full Text: https://doi.org/10.1016/0022-510x(74)90138-5]
Speer, M. C., Graham, F. L., Bonner, E., Collier, K., Stajich, J. M., Gaskell, P. C., Pericak-Vance, M. A., Vance, J. M. Reduction in the minimum candidate interval in the dominant-intermediate form of Charcot-Marie-Tooth neuropathy to D19S586 to D19S432. Neurogenetics 4: 83-85, 2002. [PubMed: 12481986] [Full Text: https://doi.org/10.1007/s10048-002-0139-3]
Zhu, D., Kennerson, M., Merory, J., Chrast, R., Verheijen, M., Lemke, G., Nicholson, G. Refined localization of dominant intermediate Charcot-Marie-Tooth neuropathy and exclusion of seven known candidate genes in the region. Neurogenetics 4: 179-183, 2003. [PubMed: 12761657] [Full Text: https://doi.org/10.1007/s10048-003-0147-y]
Zuchner, S., Noureddine, M., Kennerson, M., Verhoeven, K., Claeys, K., De Jonghe, P., Merory, J., Oliveira, S. A., Speer, M. C., Stenger, J. E., Walizada, G., Zhu, D., Pericak-Vance, M. A., Nicholson, G., Timmerman, V., Vance, J. M. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nature Genet. 37: 289-294, 2005. [PubMed: 15731758] [Full Text: https://doi.org/10.1038/ng1514]