#608340
Table of Contents
A number sign (#) is used with this entry because autosomal recessive intermediate Charcot-Marie-Tooth disease A (CMTRIA) is caused by homozygous mutation in the GDAP1 gene (606598) on chromosome 8q21.
Mutations in the same gene cause several forms of autosomal recessive Charcot-Marie-Tooth disease (see CMT4A, 214400).
Autosomal recessive intermediate Charcot-Marie-Tooth disease A (CMTRIA) is a peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. Onset is usually in early childhood (summary by Senderek et al., 2003).
Genetic Heterogeneity of Recessive Intermediate Charcot-Marie-Tooth Disease
See also CMTRIB (613641), caused by mutation in the KARS gene (601421) on chromosome 16q; CMTRIC (615376), caused by mutation in the PLEKHG5 gene (611101) on chromosome 1p36; and CMTRID (616039), caused by mutation in the COX6A1 gene (602072) on chromosome 12q24.
Nelis et al. (2002) reported a consanguineous Turkish family in which 2 sisters had a mixed form of axonal and demyelinating autosomal recessive Charcot-Marie-Tooth disease. Onset was at the age of 4 years in both with foot deformity. At ages 12 and 13 years the sisters were still walking independently with ankle-foot orthosis. No muscle weakness was recorded in the arms or legs but there was sensory loss. In both, the reflexes were normal in the arms but absent at the ankle. Nerve conduction velocities (NCV) were normal.
Senderek et al. (2003) reported a consanguineous Turkish family in which 2 cousins had a severe form of intermediate CMT. Onset was in early childhood (2-3 years) after normal early motor development. Features included foot deformities, lower and upper limb muscle weakness and atrophy, steppage gait, decreased or absent reflexes, and distal sensory impairment. Motor NCVs were decreased (26-31 m/s), and nerve biopsy showed features of both demyelination and axonal degeneration.
Kabzinska et al. (2011) reported 2 Polish sisters with a severe, early-onset form of CMT due to a homozygous missense mutation in the GDAP1 gene (G327D; 606598.0016). The proband showed awkward gait and foot deformity at age 2 years. At age 5, physical examination showed distal muscle atrophy of the lower limbs, with foot drop, pes equinovarus, areflexia, scoliosis, and inability to walk without aid. Sensory modalities were preserved. Motor nerve conduction velocity of the median nerve was decreased at 31.2 m/s, and sural nerve biopsy showed a chronic mixed axonal and demyelinating neuropathy, with loss of myelinated fibers, thin myelin sheaths, segmental demyelination, regenerating clusters, and small onion bulbs. The disorder was progressive, later involving the upper limbs, and she lost the ability to walk at age 13 years. At age 29, distal joint position was affected. Her sister had a similar phenotype, with distal muscle weakness and atrophy of the upper and lower limbs, areflexia, scoliosis, Achilles tendon contractures, and loss of ambulation at age 13 years. Nerve conduction velocities were normal.
Nelis et al. (2002) reported 7 families with autosomal recessive CMT linked to chromosome 8q21 who demonstrated variable NCVs and nerve biopsy findings, suggesting both demyelinating and axonal phenotypes.
The transmission pattern of CMTRIA in family CMT-136 reported by Nelis et al. (2002) was consistent with autosomal recessive inheritance.
In a consanguineous Turkish family (CMT-136) in which 2 sisters had a mixed form of axonal and demyelinating autosomal recessive CMT disease, Nelis et al. (2002) identified a homozygous mutation in the GDAP1 gene (R282C; 606598.0006).
In affected members of 2 families with CMTRIA, Senderek et al. (2003) identified homozygous mutations in the GDAP1 gene (606598.0007-606598.0008).
Kabzinska et al. (2006) identified a homozygous mutation in the GDAP1 gene (L239F; 606598.0011) in a 39-year-old Polish woman with intermediate CMT. The patient had early onset of a motor and sensory neuropathy leading to severe disability in the third decade of life. Sural nerve biopsies showed mild loss of myelinated fibers, small onion bulb formations, and occasional wrinkled and focally folded myelin fibers. Motor NCVs were consistently above 38 m/s.
Kabzinska et al. (2011) reported 2 Polish sisters with a severe, early-onset form of CMT due to a homozygous missense mutation in the GDAP1 gene (G327D; 606598.0016).
See comments of Nicholson and Ouvrier (2002) concerning the mixed axonal and demyelinating type of CMT resulting from GDAP1 mutations.
Kabzinska, D., Drac, H., Rowinska-Marcinska, K., Fidzianska, A., Kochanski, A., Hausmanowa-Petrusewicz, I. Early onset Charcot-Marie-Tooth disease caused by a homozygous leu239phe mutation in the GDAP1 gene. Acta Myol. 25: 34-37, 2006. [PubMed: 17039978, related citations]
Kabzinska, D., Niemann, A., Drac, H., Huber, N., Potulska-Chromik, A., Hausmanowa-Petrusewicz, I., Suter, U., Kochanski, A. A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe from of AR-CMT2C disease. Neurogenetics 12: 145-153, 2011. [PubMed: 21365284, related citations] [Full Text]
Nelis, E., Erdem, S., Van den Bergh, P. Y. K., Belpaire-Dethiou, M.-C., Ceuterick, C., Van Gerwen, V., Cuesta, A., Pedrola, L., Palau, F., Gabreels-Festen, A. A. W. M., Verellen, C., Tan, E., Demirci, M., Van Broeckhoven, C., De Jonghe, P., Topaloglu, H., Timmerman, V. Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. Neurology 59: 1865-1872, 2002. [PubMed: 12499475, related citations] [Full Text]
Nicholson, G., Ouvrier, R. GDAP1 mutations in CMT4: axonal and demyelinating phenotypes? (Editorial) Neurology 59: 1835-1836, 2002. [PubMed: 12499472, related citations] [Full Text]
Senderek, J., Bergmann, C., Ramaekers, V. T., Nelis, E., Bernert, G., Makowski, A., Zuchner, S., De Jonghe, P., Rudnik-Schoneborn, S., Zerres, K., Schroder, J. M. Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain 126: 642-649, 2003. [PubMed: 12566285, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 217055; DO: 0110201;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q21.11 | Charcot-Marie-Tooth disease, recessive intermediate, A | 608340 | Autosomal recessive | 3 | GDAP1 | 606598 |
A number sign (#) is used with this entry because autosomal recessive intermediate Charcot-Marie-Tooth disease A (CMTRIA) is caused by homozygous mutation in the GDAP1 gene (606598) on chromosome 8q21.
Mutations in the same gene cause several forms of autosomal recessive Charcot-Marie-Tooth disease (see CMT4A, 214400).
Autosomal recessive intermediate Charcot-Marie-Tooth disease A (CMTRIA) is a peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. Onset is usually in early childhood (summary by Senderek et al., 2003).
Genetic Heterogeneity of Recessive Intermediate Charcot-Marie-Tooth Disease
See also CMTRIB (613641), caused by mutation in the KARS gene (601421) on chromosome 16q; CMTRIC (615376), caused by mutation in the PLEKHG5 gene (611101) on chromosome 1p36; and CMTRID (616039), caused by mutation in the COX6A1 gene (602072) on chromosome 12q24.
Nelis et al. (2002) reported a consanguineous Turkish family in which 2 sisters had a mixed form of axonal and demyelinating autosomal recessive Charcot-Marie-Tooth disease. Onset was at the age of 4 years in both with foot deformity. At ages 12 and 13 years the sisters were still walking independently with ankle-foot orthosis. No muscle weakness was recorded in the arms or legs but there was sensory loss. In both, the reflexes were normal in the arms but absent at the ankle. Nerve conduction velocities (NCV) were normal.
Senderek et al. (2003) reported a consanguineous Turkish family in which 2 cousins had a severe form of intermediate CMT. Onset was in early childhood (2-3 years) after normal early motor development. Features included foot deformities, lower and upper limb muscle weakness and atrophy, steppage gait, decreased or absent reflexes, and distal sensory impairment. Motor NCVs were decreased (26-31 m/s), and nerve biopsy showed features of both demyelination and axonal degeneration.
Kabzinska et al. (2011) reported 2 Polish sisters with a severe, early-onset form of CMT due to a homozygous missense mutation in the GDAP1 gene (G327D; 606598.0016). The proband showed awkward gait and foot deformity at age 2 years. At age 5, physical examination showed distal muscle atrophy of the lower limbs, with foot drop, pes equinovarus, areflexia, scoliosis, and inability to walk without aid. Sensory modalities were preserved. Motor nerve conduction velocity of the median nerve was decreased at 31.2 m/s, and sural nerve biopsy showed a chronic mixed axonal and demyelinating neuropathy, with loss of myelinated fibers, thin myelin sheaths, segmental demyelination, regenerating clusters, and small onion bulbs. The disorder was progressive, later involving the upper limbs, and she lost the ability to walk at age 13 years. At age 29, distal joint position was affected. Her sister had a similar phenotype, with distal muscle weakness and atrophy of the upper and lower limbs, areflexia, scoliosis, Achilles tendon contractures, and loss of ambulation at age 13 years. Nerve conduction velocities were normal.
Nelis et al. (2002) reported 7 families with autosomal recessive CMT linked to chromosome 8q21 who demonstrated variable NCVs and nerve biopsy findings, suggesting both demyelinating and axonal phenotypes.
The transmission pattern of CMTRIA in family CMT-136 reported by Nelis et al. (2002) was consistent with autosomal recessive inheritance.
In a consanguineous Turkish family (CMT-136) in which 2 sisters had a mixed form of axonal and demyelinating autosomal recessive CMT disease, Nelis et al. (2002) identified a homozygous mutation in the GDAP1 gene (R282C; 606598.0006).
In affected members of 2 families with CMTRIA, Senderek et al. (2003) identified homozygous mutations in the GDAP1 gene (606598.0007-606598.0008).
Kabzinska et al. (2006) identified a homozygous mutation in the GDAP1 gene (L239F; 606598.0011) in a 39-year-old Polish woman with intermediate CMT. The patient had early onset of a motor and sensory neuropathy leading to severe disability in the third decade of life. Sural nerve biopsies showed mild loss of myelinated fibers, small onion bulb formations, and occasional wrinkled and focally folded myelin fibers. Motor NCVs were consistently above 38 m/s.
Kabzinska et al. (2011) reported 2 Polish sisters with a severe, early-onset form of CMT due to a homozygous missense mutation in the GDAP1 gene (G327D; 606598.0016).
See comments of Nicholson and Ouvrier (2002) concerning the mixed axonal and demyelinating type of CMT resulting from GDAP1 mutations.
Kabzinska, D., Drac, H., Rowinska-Marcinska, K., Fidzianska, A., Kochanski, A., Hausmanowa-Petrusewicz, I. Early onset Charcot-Marie-Tooth disease caused by a homozygous leu239phe mutation in the GDAP1 gene. Acta Myol. 25: 34-37, 2006. [PubMed: 17039978]
Kabzinska, D., Niemann, A., Drac, H., Huber, N., Potulska-Chromik, A., Hausmanowa-Petrusewicz, I., Suter, U., Kochanski, A. A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe from of AR-CMT2C disease. Neurogenetics 12: 145-153, 2011. [PubMed: 21365284] [Full Text: https://doi.org/10.1007/s10048-011-0276-7]
Nelis, E., Erdem, S., Van den Bergh, P. Y. K., Belpaire-Dethiou, M.-C., Ceuterick, C., Van Gerwen, V., Cuesta, A., Pedrola, L., Palau, F., Gabreels-Festen, A. A. W. M., Verellen, C., Tan, E., Demirci, M., Van Broeckhoven, C., De Jonghe, P., Topaloglu, H., Timmerman, V. Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. Neurology 59: 1865-1872, 2002. [PubMed: 12499475] [Full Text: https://doi.org/10.1212/01.wnl.0000036272.36047.54]
Nicholson, G., Ouvrier, R. GDAP1 mutations in CMT4: axonal and demyelinating phenotypes? (Editorial) Neurology 59: 1835-1836, 2002. [PubMed: 12499472] [Full Text: https://doi.org/10.1212/wnl.59.12.1835]
Senderek, J., Bergmann, C., Ramaekers, V. T., Nelis, E., Bernert, G., Makowski, A., Zuchner, S., De Jonghe, P., Rudnik-Schoneborn, S., Zerres, K., Schroder, J. M. Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain 126: 642-649, 2003. [PubMed: 12566285] [Full Text: https://doi.org/10.1093/brain/awg068]
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