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Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation
Cornelius F Boerkoel1, Hiroshi Takashima, Carlos A Garcia
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Abstract:
Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N-myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N-myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one-third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.
Insights
Genetic testing identified mutations in Charcot-Marie-Tooth disease (CMT) genes, including novel alleles. Molecular diagnosis is crucial for managing inherited and sporadic neuropathies.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Charcot-Marie-Tooth disease (CMT) is a heterogeneous peripheral neuropathy.
- Several genes encoding myelin proteins and other key molecules are implicated in CMT.
- Genetic heterogeneity necessitates comprehensive mutation screening.
Purpose of the Study:
- To determine the frequency of mutations in known CMT-associated genes.
- To identify novel mutations and alleles in patients with CMT and related neuropathies.
- To evaluate the role of de novo mutations in sporadic cases.
Main Methods:
- Screening of 153 unrelated patients for mutations in genes including PMP22, MPZ, and GJB1.
- Identification and characterization of novel mutant alleles.
- Analysis of mutation frequency and inheritance patterns.
Main Results:
- 17p12 duplication (CMT1A) was the most common finding (79 patients).
- Mutations were identified in GJB1 (11), MPZ (5), PMP22 (5), ERG2 (1), PRX (1), and NEFL (1).
- Novel alleles were found for GJB1, MPZ, and PMP22; one PMP22 mutation (W28R) linked to CMT1 and deafness.
Conclusions:
- Molecular diagnosis is essential for accurate clinical diagnosis and management of CMT.
- A significant proportion of mutations arise de novo, contributing to sporadic neuropathy.
- Comprehensive genetic screening aids in understanding CMT pathogenesis and patient stratification.