MOLECULAR ANALYSES OF UNRELATED CHARCOT-MARIE-TOOTH (CMT) DISEASE PATIENTS SUGGEST A HIGH-FREQUENCY OF THE CMT-IA DUPLICATION

Charcot-Marie-Tooth disease (CMT) is the most common inherited periphe ral neuropathy. One form of CMT, CMT type 1A, is characterized by unif ormly decreased nerve conduction velocities, usually shows autosomal d ominant inheritance, and is associated with a large submicroscopic dup lication of the p11.2-p12 region of chromosome 17. A cohort of 75 unre lated patients diagnosed clinically with CMT and evaluated by electrop hysiological methods were analyzed molecularly for the presence of the CMT1A DNA duplication. Three methodologies were used to assess the du plication: measurement of dosage differences between RFLP alleles, ana lysis of polymorphic (GT). repeats, and detection of a junction fragme nt by pulsed-field gel electrophoresis. The CMT1A duplication was foun d in 68% of the 63 unrelated CMT patients with electrophysiological st udies consistent with CMT type 1 (CMT1). The CMT1A duplication was det ected as a de novo event in two CMT1 families. Twelve CMT patients who did not have decreased nerve conduction velocities consistent with a diagnosis of CMT type 2 (CMT2) were found not to have the CMT1A duplic ation. The most informative molecular method was the detection of the CMT1A duplication-specific junction fragment. Given the high frequency of the CMT1A duplication in CMT patients and the high frequency of ne w mutations, we conclude that a molecular test for the CMT1A DNA dupli cation is very useful in the differential diagnosis of patients with p eripheral neuropathies.