Charcot-Marie-Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management.
OBJECTIVE
An evidence-based approach was used to determine the frequency distribution of genes contributing to the Charcot-Marie-Tooth (CMT) disease phenotype.


METHODS
We performed a combined analysis of 11 population-based studies from various ethnic backgrounds to generate an evidence-based testing scheme. To estimate the relative frequencies of the responsible genes for which population-based studies are not available, we used our cohort of clinically classified patients with CMT and related neuropathies collected before the availability of genetic testing.


RESULTS
Similar mutation frequencies were detected in the various studies, revealing a uniform distribution of pathogenic mutations. In CMT1 70% of patients harbor the CMT1A duplication, followed by GJB1 mutations at 8.8%. MPZ and PMP22 mutations are less common, identified on average in 2.9% and 1.5% of patients, respectively. Other genes not tested in population-based studies contribute to less than 1% of disease individually. In CMT2 MFN2 mutations are the most common, although population-based studies are not yet available.


CONCLUSIONS
CMT represents a heterogeneous group of disorders at the molecular level. Nevertheless, testing for the CMT1A duplication (i.e., duplication of PMP22) alone yields an accurate molecular diagnosis in approximately half of all patients. If one further specifies the clinical type (demyelinating vs. axonal), the yield of detecting a molecular defect increases to 75% to 80% in the demyelinating or CMT1 group with a screening test that evaluates for CMT1A duplication/hereditary neuropathy with liability to pressure palsies deletion and GJB1 point mutations.
Szigeti
Kinga
K
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Garcia
Carlos A
CA
Lupski
James R
JR
D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002886:Chromosomes, Human, Pair 17; D015331:Cohort Studies; D017630:Connexins / Q000235:genetics; D004252:DNA Mutational Analysis; D005006:Ethnicity / Q000235:genetics; D019317:Evidence-Based Medicine; D005787:Gene Frequency; D006801:Humans; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D009185:Myelin Proteins / Q000235:genetics*; D010641:Phenotype; D011115:Polyneuropathies / Q000175:diagnosis* / Q000235:genetics; D011159:Population Surveillance; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D009185:Myelin Proteins; D000097002:Gap Junction beta-1 Protein; C073687:PMP22 protein, human