Improved Method for Diagnosis of Charcot-Marie-Tooth Type 1A: Patent Pending?

Abstract

In this issue of Clinical Chemistry , two groups, Badano et al. (1) from Baylor College of Medicine and Latour et al. (2) from France, report on PCR of short tandem repeats (STRs) for the diagnosis of Charcot-Marie-Tooth type 1A (CMT1A). CMT1A is caused by the duplication of a 1.4-Mb region on chromosome 17p12 that includes the peripheral myelin protein 22 (PMP22) gene. The increased gene dosage of PMP22 caused by the duplication event is thought to be responsible for the pathogenesis of CMT1A, producing a peripheral neuropathy. When the duplication was reported in 1991, the method developed for diagnosis was densitometric analysis of a Southern hybridized with a region-specific probe, allowing assessment of the presence of one to four copies of the 17p12 region. For diagnostic laboratories that began testing for CMT1A, the method was laborious and time-consuming. Other methods for diagnosis of CMT1A subsequently were developed, including pulsed-field gel electrophoresis for detection of recombination-specific junction fragments, fluorescent in situ hybridization using a PMP22 probe, and several PCR methods. Initial use of STR PCR of a single locus looking for the presence of three different alleles for diagnosis of CMT1A was able to diagnose only approximately one-third of cases. Use of additional STR loci increased the detection rate to ∼85%. Although the STR PCR method was easier for the laboratory, it could not be done without the back up of a second more sensitive method [see Refs. (1)(2) for methods]. Both reports in this issue describe improved STR PCR methods with the ability to diagnose 100% of CMT1A cases tested. The Baylor group (1) identified a larger set of 42 STR loci in the duplicated region and defined a subset of 15 STRs that can be amplified in two multiplex PCRs. The panel was tested on 39 …