CMT + related hereditary polyneuropathies:diagnostics determine management

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Genet Med. 2006 Feb;8(2):86-92.

Charcot-Marie-Tooth disease and related hereditary polyneuropathies:

Molecular diagnostics determine aspects of medical management.

Szigeti K, CA, Lupski JR.

From the Departments of 1Molecular and Human Genetics and

2Pediatrics, Baylor College of Medicine, and 2Texas Children

Hospital, Houston, Texas; 3Departments of Neurology and Pathology,

Tulane University Health Sciences Center, New Orleans, Louisiana.

PURPOSE: 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.

CONCLUSION: 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.