#605589
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2B2 (CMT2B2) is caused by homozygous or compound heterozygous mutation in the PNKP gene (605610) on chromosome 19q13.
Biallelic mutation in the PNKP gene can also cause oculomotor apraxia-4 (AOA4; 616267), which shows some overlapping features.
Charcot-Marie-Tooth disease type 2B2 (CMT2B2) is an autosomal recessive sensorineural axonal peripheral neuropathy manifest as distal muscle weakness and atrophy and distal sensory impairment. The disorder predominantly affects the lower limbs, resulting in gait impairment, although upper limb and hand involvement also occurs. The age at onset and severity is variable: most have onset in the third decade, although earlier onset has been reported. The disorder is slowly progressive, and some patients may lose independent ambulation later in life. More variable features may include ataxia, dysarthria, cerebellar atrophy, and eye movement abnormalities (summary by Leal et al., 2018).
For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A1 (118210).
Leal et al. (2001) reported a large consanguineous Costa Rican family with autosomal recessive axonal CMT. Mean age at onset was 33.8 years (range, 28 to 42 years). Symptoms included symmetrical weakness and atrophy in the ankles, hyporeflexia, distal weakness and atrophy in the upper extremities, and sensory deficits in a symmetrical 'stocking-glove' pattern. Motor nerve conduction velocities were normal or slightly reduced, indicative of an axonal degenerative process.
Berghoff et al. (2004), who referred to the disease locus as ARCMT2B, provided follow-up of 8 affected members of the family reported by Leal et al. (2001). Five patients showed muscle weakness and atrophy in the distal upper limbs, particularly in finger extension and abduction and wrist flexion. Six patients had sensory deficits in the distal upper limbs. Two patients had developed claw toes later in the disease, and 3 of the 8 patients required a cane to walk. The authors emphasized the adult onset in this family.
Pedroso et al. (2015) reported a 17-year-old Brazilian boy, born of unrelated parents, who presented in the first year of life with gait abnormalities and foot deformities, including pes cavus and hammertoes. After the age of 9 years, the disorder showed slow progression with gait deterioration. Physical examination showed steppage gait, mild ataxia, slurred speech, and absent deep tendon reflexes. Electrophysiologic studies were consistent with a sensorimotor axonal neuropathy. He never had oculomotor apraxia. Brain MRI showed mild cerebellar atrophy.
Leal et al. (2018) provided follow-up of the large Costa Rican family reported by Leal et al. (2001), and reported 5 additional adult probands of Costa Rican origin with a similar disorder. Two of these probands had a family history of the disorder (families CMT1003 and CMT1038), although clinical details and genetic studies were not available for all the affected family members. Clinical information for 4 patients, including 2 members of the original family and 2 unrelated probands from families CMT1003 and CMT1190, showed onset of symptoms in the third decade. Affected individuals had distal muscle weakness and atrophy with impaired sensation of all modalities predominantly affecting the lower limbs; there was more variable involvement of the distal upper limbs. Two patients had intermittent mobility, 1 had gait ataxia, and the fourth became wheelchair-bound at age 50. Additional features included slurred speech, atrophy of the intrinsic hand and foot muscles, claw hands, and hyporeflexia. Two patients from the newly reported families had evidence of oculomotor apraxia (AOA). An affected member of the original family had slow saccades without frank AOA, although another affected family member reportedly had AOA; however, this feature was not found in most of the patients from the original family. Brain imaging in all 4 patients reported by Leal et al. (2018) showed cerebellar atrophy without white matter abnormalities. Electrophysiologic testing was consistent with an axonal peripheral polyneuropathy, showing reduction of the CMAP in affected nerves. None had pyramidal signs, cognitive impairment, microcephaly, or seizures.
The transmission pattern of CMT2B2 in the families reported by Leal et al. (2018) was consistent with autosomal recessive inheritance.
By linkage studies in the large Costa Rican family with CMT2, Leal et al. (2001) identified a second locus for an axonal form of autosomal recessive CMT, designated CMT2B2. Linkage to 19q13.3 was found in 3 branches of the family, and subsequent homozygosity mapping defined shared haplotypes in a 5.5-cM interval between markers D19S902 and D19S907 (maximum 2-point lod score of 9.08 at D19S867). The epithelial membrane protein-3 gene (EMP3; 602335) was excluded as a candidate for mutation in this disorder. The phenotype was clearly different from that of demyelinating CMT4F (145900), which had been mapped to 19q13.1-q13.3.
In a 17-year-old Brazilian boy with CMT2B2, Pedroso et al. (2015) identified a homozygous in-frame deletion in the PNKP gene (Thr408del; 605610.0007). The mutation, which was found by whole-exome sequencing, was heterozygous in the unaffected parents. In vitro functional expression studies showed that patient fibroblasts were more sensitive to genotoxic chemical injury compared to control fibroblasts. Patient cells showed increased apoptosis, increased caspase-3 (CASP3; 600636) activity, a disruption of cell cycle dynamics, and evidence of DNA damage. The findings indicated that the mutation rendered the cells unable to efficiently repair DNA for both base-excision repair (BER) and nonhomologous end-joining (NHE) pathways.
In affected members of a large multigenerational consanguineous Costa Rican family with CMT2B2, originally reported by Leal et al. (2001), Leal et al. (2018) identified a homozygous nonsense mutation in the PNKP gene (Q517X; 605610.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of the PNKP coding sequence in 5 additional Costa Rican probands with a similar phenotype showed that all were compound heterozygous for the Q517X mutation and the previously identified Thr408del mutation (605610.0007) Molecular modeling predicted a damaging effect for the Q517X mutation, although functional studies and studies of patient cells were not performed. Leal et al. (2018) concluded that the mutant protein would lack an important functional C-terminal domain, causing increased DNA damage with subsequent cell death.
In the family with CMT2B2 originally reported by Leal et al. (2001), Leal et al. (2009) identified a homozygous mutation in the MED25 gene (R140W; 610197.0001), which was erroneously thought to be causative.
Berghoff, C., Berghoff, M., Leal, A., Morera, B., Barrantes, R., Reis, A., Neundorfer, B., Rautenstrauss, B., Del Valle, G., Heuss, D. Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3. Neuromusc. Disord. 14: 301-306, 2004. [PubMed: 15099588, related citations] [Full Text]
Leal, A., Bogantes-Ledezma, S., Ekici, A. B., Uebe, S., Thiel, C. T., Sticht, H., Berghoff, M., Berghoff, C., Morera, B., Meisterernst, M., Reis, A. The polynucleotide kinase 3-prime-phosphatase (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. Neurogenetics 19: 215-225, 2018. [PubMed: 30039206, related citations] [Full Text]
Leal, A., Huehne, K., Bauer, F., Sticht, H., Berger, P., Suter, U., Morera, B., Del Valle, G., Lupski, J. R., Ekici, A., Pasutto, F., Endele, S., and 15 others. Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models. Neurogenetics 10: 275-287, 2009. Note: Erratum: Neurogenetics 10: 375-376, 2009. [PubMed: 19290556, images, related citations] [Full Text]
Leal, A., Morera, B., Del Valle, G., Heuss, D., Kayser, C., Berghoff, M., Villegas, R., Hernandez, E., Mendez, M., Hennies, H. C., Neundorfer, B., Barrantes, R., Reis, A., Rautenstrauss, B. A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3. Am. J. Hum. Genet. 68: 269-274, 2001. [PubMed: 11112660, images, related citations] [Full Text]
Pedroso, J. L., Rocha, C. R. R., Macedo-Souza, L. I., De Mario, V., Marques, W., Jr., Barsottini, O. G. P., Oliveira, A. S. B., Menck, C. F. M., Kok, F. Mutation in PNKP presenting initially as axonal Charcot-Marie-Tooth disease. Neurol. Genet. 1: e30, 2015. Note: Electronic Article. [PubMed: 27066567, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 719981005; ORPHA: 101101; DO: 0110179;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
19q13.33 | ?Charcot-Marie-Tooth disease, type 2B2 | 605589 | Autosomal recessive | 3 | PNKP | 605610 |
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2B2 (CMT2B2) is caused by homozygous or compound heterozygous mutation in the PNKP gene (605610) on chromosome 19q13.
Biallelic mutation in the PNKP gene can also cause oculomotor apraxia-4 (AOA4; 616267), which shows some overlapping features.
Charcot-Marie-Tooth disease type 2B2 (CMT2B2) is an autosomal recessive sensorineural axonal peripheral neuropathy manifest as distal muscle weakness and atrophy and distal sensory impairment. The disorder predominantly affects the lower limbs, resulting in gait impairment, although upper limb and hand involvement also occurs. The age at onset and severity is variable: most have onset in the third decade, although earlier onset has been reported. The disorder is slowly progressive, and some patients may lose independent ambulation later in life. More variable features may include ataxia, dysarthria, cerebellar atrophy, and eye movement abnormalities (summary by Leal et al., 2018).
For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A1 (118210).
Leal et al. (2001) reported a large consanguineous Costa Rican family with autosomal recessive axonal CMT. Mean age at onset was 33.8 years (range, 28 to 42 years). Symptoms included symmetrical weakness and atrophy in the ankles, hyporeflexia, distal weakness and atrophy in the upper extremities, and sensory deficits in a symmetrical 'stocking-glove' pattern. Motor nerve conduction velocities were normal or slightly reduced, indicative of an axonal degenerative process.
Berghoff et al. (2004), who referred to the disease locus as ARCMT2B, provided follow-up of 8 affected members of the family reported by Leal et al. (2001). Five patients showed muscle weakness and atrophy in the distal upper limbs, particularly in finger extension and abduction and wrist flexion. Six patients had sensory deficits in the distal upper limbs. Two patients had developed claw toes later in the disease, and 3 of the 8 patients required a cane to walk. The authors emphasized the adult onset in this family.
Pedroso et al. (2015) reported a 17-year-old Brazilian boy, born of unrelated parents, who presented in the first year of life with gait abnormalities and foot deformities, including pes cavus and hammertoes. After the age of 9 years, the disorder showed slow progression with gait deterioration. Physical examination showed steppage gait, mild ataxia, slurred speech, and absent deep tendon reflexes. Electrophysiologic studies were consistent with a sensorimotor axonal neuropathy. He never had oculomotor apraxia. Brain MRI showed mild cerebellar atrophy.
Leal et al. (2018) provided follow-up of the large Costa Rican family reported by Leal et al. (2001), and reported 5 additional adult probands of Costa Rican origin with a similar disorder. Two of these probands had a family history of the disorder (families CMT1003 and CMT1038), although clinical details and genetic studies were not available for all the affected family members. Clinical information for 4 patients, including 2 members of the original family and 2 unrelated probands from families CMT1003 and CMT1190, showed onset of symptoms in the third decade. Affected individuals had distal muscle weakness and atrophy with impaired sensation of all modalities predominantly affecting the lower limbs; there was more variable involvement of the distal upper limbs. Two patients had intermittent mobility, 1 had gait ataxia, and the fourth became wheelchair-bound at age 50. Additional features included slurred speech, atrophy of the intrinsic hand and foot muscles, claw hands, and hyporeflexia. Two patients from the newly reported families had evidence of oculomotor apraxia (AOA). An affected member of the original family had slow saccades without frank AOA, although another affected family member reportedly had AOA; however, this feature was not found in most of the patients from the original family. Brain imaging in all 4 patients reported by Leal et al. (2018) showed cerebellar atrophy without white matter abnormalities. Electrophysiologic testing was consistent with an axonal peripheral polyneuropathy, showing reduction of the CMAP in affected nerves. None had pyramidal signs, cognitive impairment, microcephaly, or seizures.
The transmission pattern of CMT2B2 in the families reported by Leal et al. (2018) was consistent with autosomal recessive inheritance.
By linkage studies in the large Costa Rican family with CMT2, Leal et al. (2001) identified a second locus for an axonal form of autosomal recessive CMT, designated CMT2B2. Linkage to 19q13.3 was found in 3 branches of the family, and subsequent homozygosity mapping defined shared haplotypes in a 5.5-cM interval between markers D19S902 and D19S907 (maximum 2-point lod score of 9.08 at D19S867). The epithelial membrane protein-3 gene (EMP3; 602335) was excluded as a candidate for mutation in this disorder. The phenotype was clearly different from that of demyelinating CMT4F (145900), which had been mapped to 19q13.1-q13.3.
In a 17-year-old Brazilian boy with CMT2B2, Pedroso et al. (2015) identified a homozygous in-frame deletion in the PNKP gene (Thr408del; 605610.0007). The mutation, which was found by whole-exome sequencing, was heterozygous in the unaffected parents. In vitro functional expression studies showed that patient fibroblasts were more sensitive to genotoxic chemical injury compared to control fibroblasts. Patient cells showed increased apoptosis, increased caspase-3 (CASP3; 600636) activity, a disruption of cell cycle dynamics, and evidence of DNA damage. The findings indicated that the mutation rendered the cells unable to efficiently repair DNA for both base-excision repair (BER) and nonhomologous end-joining (NHE) pathways.
In affected members of a large multigenerational consanguineous Costa Rican family with CMT2B2, originally reported by Leal et al. (2001), Leal et al. (2018) identified a homozygous nonsense mutation in the PNKP gene (Q517X; 605610.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of the PNKP coding sequence in 5 additional Costa Rican probands with a similar phenotype showed that all were compound heterozygous for the Q517X mutation and the previously identified Thr408del mutation (605610.0007) Molecular modeling predicted a damaging effect for the Q517X mutation, although functional studies and studies of patient cells were not performed. Leal et al. (2018) concluded that the mutant protein would lack an important functional C-terminal domain, causing increased DNA damage with subsequent cell death.
In the family with CMT2B2 originally reported by Leal et al. (2001), Leal et al. (2009) identified a homozygous mutation in the MED25 gene (R140W; 610197.0001), which was erroneously thought to be causative.
Berghoff, C., Berghoff, M., Leal, A., Morera, B., Barrantes, R., Reis, A., Neundorfer, B., Rautenstrauss, B., Del Valle, G., Heuss, D. Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3. Neuromusc. Disord. 14: 301-306, 2004. [PubMed: 15099588] [Full Text: https://doi.org/10.1016/j.nmd.2004.02.004]
Leal, A., Bogantes-Ledezma, S., Ekici, A. B., Uebe, S., Thiel, C. T., Sticht, H., Berghoff, M., Berghoff, C., Morera, B., Meisterernst, M., Reis, A. The polynucleotide kinase 3-prime-phosphatase (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. Neurogenetics 19: 215-225, 2018. [PubMed: 30039206] [Full Text: https://doi.org/10.1007/s10048-018-0555-7]
Leal, A., Huehne, K., Bauer, F., Sticht, H., Berger, P., Suter, U., Morera, B., Del Valle, G., Lupski, J. R., Ekici, A., Pasutto, F., Endele, S., and 15 others. Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models. Neurogenetics 10: 275-287, 2009. Note: Erratum: Neurogenetics 10: 375-376, 2009. [PubMed: 19290556] [Full Text: https://doi.org/10.1007/s10048-009-0183-3]
Leal, A., Morera, B., Del Valle, G., Heuss, D., Kayser, C., Berghoff, M., Villegas, R., Hernandez, E., Mendez, M., Hennies, H. C., Neundorfer, B., Barrantes, R., Reis, A., Rautenstrauss, B. A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3. Am. J. Hum. Genet. 68: 269-274, 2001. [PubMed: 11112660] [Full Text: https://doi.org/10.1086/316934]
Pedroso, J. L., Rocha, C. R. R., Macedo-Souza, L. I., De Mario, V., Marques, W., Jr., Barsottini, O. G. P., Oliveira, A. S. B., Menck, C. F. M., Kok, F. Mutation in PNKP presenting initially as axonal Charcot-Marie-Tooth disease. Neurol. Genet. 1: e30, 2015. Note: Electronic Article. [PubMed: 27066567] [Full Text: https://doi.org/10.1212/NXG.0000000000000030]
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