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Other entities represented in this entry:
SNOMEDCT: 725047007; ORPHA: 101097, 99944; DO: 0110167;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q21.11 | {?Charcot-Marie-Tooth disease, axonal, autosomal dominant, type 2K, modifier of} | 607831 | Autosomal dominant; Autosomal recessive | 3 | JPH1 | 605266 |
| 8q21.11 | Charcot-Marie-Tooth disease, axonal, type 2K | 607831 | Autosomal dominant; Autosomal recessive | 3 | GDAP1 | 606598 |
A number sign (#) is used with this entry because autosomal recessive axonal Charcot-Marie-Tooth disease type 2K (CMT2K) is caused by homozygous or compound heterozygous mutation in the GDAP1 gene (606598) on chromosome 8q21. Some patients with a milder phenotype carry heterozygous mutations in the GDAP1 gene, consistent with autosomal dominant inheritance.
For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Autosomal Recessive CMT2K
Birouk et al. (2003) reported a consanguineous Moroccan family in which 4 members were affected with a severe form of autosomal recessive axonal CMT. Onset was in early childhood (younger than 3 years) in all patients. The proband had hypotonia at birth and delayed development of early motor milestones. All patients had difficulty walking, foot deformities, kyphoscoliosis, distal limb muscle weakness and atrophy, areflexia, and diminished sensation in the lower limbs. Weakness in the upper limbs occurred in the first decade, with clawing of the fingers in all patients. There was no cranial nerve involvement, vocal cord paresis, or cerebellar or pyramidal signs. Motor nerve conduction velocity in 1 patient was slightly reduced at 40 m/s, and pathologic examination of 1 patient showed loss of myelinated fibers without signs of obvious demyelination and regenerating axon clusters consistent with an axonal neuropathy.
Xin et al. (2008) reported 3 sibs from a consanguineous Amish family with autosomal recessive axonal CMT2K. The patients had onset in childhood of distal lower muscle weakness and borderline nerve conduction velocity measurements, consistent with an axonal neuropathy. The disorder was gradually progressive with worsening of the lower limb symptoms, but the patients were still able to do some daily activities in their twenties. There was no vocal cord or hand muscle involvement.
Kabzinska et al. (2010) reported affected individuals from 4 families and 2 individual patients with early-onset autosomal recessive CMT2K. Five of the families were Polish and 1 was Bulgarian. The age at onset ranged from 2 to 10 years, and all had gait abnormalities due to lower limb weakness and atrophy. Electrophysiologic studies showed that most patients had normal motor and sensory nerve conduction velocities, whereas a few had reduced responses. Two patients became wheelchair-bound as young adults.
Autosomal Dominant CMT2K
Chung et al. (2008) reported a Korean father and daughter with late-onset autosomal dominant axonal CMT associated with a heterozygous mutation in the GDAP1 gene (Q218E; 606598.0012). The patients had onset of gait difficulties at ages 25 and 16 years, respectively. Other features included hand muscle atrophy, decreased distal sensation in the upper and lower limbs, and normal or mildly reduced nerve conduction velocities. Sural nerve biopsy findings in the father were consistent with a primarily axonal process, but there were also signs of demyelination. The phenotype in this family was much milder than that observed in patients with recessive GDAP1 mutations.
Crimella et al. (2010) reported 3 Italian probands with autosomal dominant CMT2K. In all cases, the proband presented in the first decade (range, 3 to 8 years), whereas their affected parents had much later onset of the disorder in their twenties through forties. The probands also showed a more severe phenotype than their parents, with loss of independent ambulation in 2. None had vocal cord paresis or pyramidal signs. The study indicated significant intrafamilial variability of the autosomal dominant form of this disorder.
Zimon et al. (2011) reported 8 unrelated families with autosomal dominant CMT due to 4 different heterozygous mutations in the GDAP1 gene (606598.0009; 606598.0017-606598.0019). The phenotype varied considerably, even within a family, and some mutation carriers were asymptomatic, consistent with incomplete penetrance. The age at onset ranged from childhood to adulthood, and the most common initial symptom was walking difficulties due to distal muscle weakness and atrophy. The disorder was slowly progressive, but most patients remained ambulatory. A few patients also developed proximal weakness. The majority of patients had an axonal pattern on electrophysiologic studies, but 2 unrelated patients with a more severe phenotype had an intermediate pattern between axonal and demyelinating neuropathy. Zimon et al. (2011) noted that the phenotype in heterozygous GDAP1 mutation carriers was generally milder than that in patients with 2 GDAP1 mutations.
Homozygous or Compound Heterozygous GDAP1 Mutations
In all 4 affected members of a consanguineous Moroccan family with severe axonal CMT, Birouk et al. (2003) identified a homozygous mutation in the GDAP1 gene (606598.0002). The authors noted that the same mutation had been identified in patients with a demyelinating CMT phenotype (CMT4A; 214400) and with an axonal phenotype with vocal cord paresis (607706).
In 3 sibs from a consanguineous Amish family with autosomal recessive axonal CMT2K, Xin et al. (2008) identified a homozygous mutation in the GDAP1 gene (P231L; 606598.0013). The variant was not seen in 100 control chromosomes from a Lancaster County Amish settlement, but was observed in heterozygosity in 7 (14%) of 50 control individuals from a Geauga County Amish settlement.
Kabzinska et al. (2010) identified an L239F mutation (606598.0011) in the GDAP1 gene, in either homozygous or compound heterozygous state with another pathogenic GDAP1 mutation (see, e.g., R282C, 606598.0006), in affected individuals from 4 families and in 2 individual patients with CMT2K.
Heterozygous GDAP1 Mutations
In affected members of 2 unrelated Spanish families with autosomal dominant inheritance of axonal CMT, Claramunt et al. (2005) identified a heterozygous mutation in the GDAP1 gene (606598.0009). The patients had onset at the end of their second decade and very slow progression of the disorder, which was a milder phenotype than that seen in patients carrying 2 GDAP1 mutations. Claramunt et al. (2005) noted that autosomal dominant inheritance had not previously been reported in CMT patients with GDAP1 mutations.
Crimella et al. (2010) identified 3 different heterozygous mutations in the GDAP1 gene (see, e.g., R226S; 606598.0015) in 3 (27%) of 11 Italian probands with dominant inheritance of axonal CMT2K. Two of the mutations occurred in the GST domain, and 1 was a truncating mutation resulting in the elimination of the GST domain, suggesting that the GST domain is a frequent target of mutations for the dominant form of CMT2K.
Zimon et al. (2011) reported 8 unrelated families with autosomal dominant CMT2K due to 4 different heterozygous mutations in the GDAP1 gene (606598.0009; 606598.0017-606598.0019). In vitro functional expression studies of 1 variant (A156G; 606598.0017) showed that the mutation resulted in impaired mitochondrial fusion, caused mitochondrial fragmentation, and increased cell sensitivity to apoptosis.
Modifier Genes
In a 29-year-old woman with autosomal dominant CMT2K (family fCMT-408) resulting from a heterozygous missense mutation in the GDAP1 gene (R120W; 606598.0009), Pla-Martin et al. (2015) identified a heterozygous missense variant in the JPH1 gene (R213P; 605266.0001). The patient had a moderately severe phenotype, with onset of walking difficulties in her early teens, amyotrophy of the legs, and pes cavus with claw toes. Sural nerve biopsy showed a loss of large myelinated fibers and the presence of onion bulb formations. The R120W GDAP1 mutation was inherited from her father, who had a very mild CMT phenotype, and the R213P JPH1 variant was inherited from her unaffected mother; the father did not carry the JPH1 variant. In vitro functional expression studies showed that the JPH1 R213P variant was unable to rescue store-operated calcium entry (SOCE) defects in GDAP1-null cells, suggesting that the 2 genes operate in the same pathway. Additional studies showed that the GDAP1 and JHP1 variants together resulted in significantly impaired SOCE, causing an increase in cytosolic calcium levels, which may be toxic to the cell. The findings suggested that the JPH1 R213P variant is a modifier of the severity of CMT2K caused by the GDAP1 R120W mutation.
Kabzinska et al. (2010) identified a mutation in the GDAP1 gene (L239F; 606598.0011), either in the homozygous state or in the compound heterozygous state with another pathogenic GDAP1 mutation (see, e.g., R282C, 606598.0006), in affected individuals from 4 families and in 2 individuals patients with autosomal recessive CMT2K. Haplotype analysis indicated a founder effect for the L239F mutation, indicating that it is prevalent in the Central and Eastern European populations. Kabzinska et al. (2010) observed that the phenotype resulting from this missense mutation was slightly milder than that associated with GDAP1 nonsense mutations (e.g., S194X, 606598.0002).
Zimon et al. (2011) identified a heterozygous R120W mutation in the GDAP1 gene (606598.0009) in affected members of 3 unrelated families of Italian, Austrian, and Ashkenazi Jewish descent, respectively, with dominant CMT2K. Haplotype analysis indicated a founder effect.
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 recessive axonal CMT as 'CMT2K.'
Birouk, N., Azzedine, H., Dubourg, O., Muriel, M.-P., Benomar, A., Hamadouche, T., Maisonobe, T., Ouazzani, R., Brice, A., Yahyaoui, M., Chkili, T., LeGuern, E. Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene. Arch. Neurol. 60: 598-604, 2003. [PubMed: 12707075] [Full Text: https://doi.org/10.1001/archneur.60.4.598]
Chung, K. W., Kim, S. M., Sunwoo, I. N., Cho, S. Y., Hwang, S. J., Kim, J., Kang, S. H., Park, K.-D., Choi, K.-G., Choi, I. S., Choi, B.-O. A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease. J. Hum. Genet. 53: 360-364, 2008. [PubMed: 18231710] [Full Text: https://doi.org/10.1007/s10038-008-0249-3]
Claramunt, R., Pedrola, L., Sevilla, T., Lopez de Munain, A., Berciano, J., Cuesta, A., Sanchez-Navarro, B., Millan, J. M., Saifi, G. M., Lupski, J. R., Vilchez, J. J., Espinos, C., Palau, F. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. (Letter) J. Med. Genet. 42: 358-365, 2005. [PubMed: 15805163] [Full Text: https://doi.org/10.1136/jmg.2004.022178]
Crimella, C., Tonelli, A., Airoldi, G., Baschirotto, C., D'Angelo, M. G., Bonato, S., Losito, L., Trabacca, A., Bresolin, N., Bassi, M. T. The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K. J. Med. Genet. 47: 712-716, 2010. [PubMed: 20685671] [Full Text: https://doi.org/10.1136/jmg.2010.077909]
Kabzinska, D., Strugalska-Cynowska, H., Kostera-Pruszczyk, A., Ryniewicz, B., Posmyk, R., Midro, A., Seeman, P., Barankova, L., Zimon, M., Baets, J., Timmerman, V., Guergueltcheva, V., Tournev, I., Sarafov, S., De Jonghe, P., Jordanova, A., Hausmanowa-Petrusewicz, I., Kochanski, A. L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype. Neurogenetics 11: 357-366, 2010. [PubMed: 20232219] [Full Text: https://doi.org/10.1007/s10048-010-0237-6]
Pla-Martin, D., Calpena, E., Lupo, V., Marquez, C., Rivas, E., Sivera, R., Sevilla, T., Palau, F., Espinos, C. Junctophilin-1 is a modifier gene of GDAP1-related Charcot-Marie-Tooth disease. Hum. Molec. Genet. 24: 213-229, 2015. [PubMed: 25168384] [Full Text: https://doi.org/10.1093/hmg/ddu440]
Xin, B., Puffenberger, E., Nye, L., Wiznitzer, M., Wang, H. A novel mutation in the GDAP1 gene is associated with autosomal recessive Charcot-Marie-Tooth disease in an Amish family. Clin. Genet. 74: 274-278, 2008. [PubMed: 18492089] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01018.x]
Zimon, M., Baets, J., Fabrizi, G. M., Jaakkola, E., Kabzinska, D., Pilch, J., Schindler, A. B., Cornblath, D. R., Fischbeck, K. H., Auer-Grumbach, M., Guelly, C., Huber, N., De Vriendt, E., Timmerman, V., Suter, U., Hausmanowa-Petrusewicz, I., Niemann, A., Kochanski, A., De Jonghe, P., Jordanova, A. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology 77: 540-548, 2011. [PubMed: 21753178] [Full Text: https://doi.org/10.1212/WNL.0b013e318228fc70]