AUTOSOMAL-DOMINANT CHARCOT-MARIE-TOOTH DISEASE TYPE 1A AND HEREDITARYNEUROPATHY WITH LIABILITY TO PRESSURE PALSIES - DETECTION OF THE RECOMBINATION HOTSPOT IN SLOVENE PATIENTS AND EXCLUSION OF THE POTENTIALLYRECESSIVE THR118MET PMP22 POINT MUTATION

Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy wi th liability to pressure palsies (HNPP) are the most frequent autosoma l dominantly inherited disorders of the peripheral nervous system. The recessive inheritance is observed only exceptionally. Unequal crossin g-over of misaligned flanking CMT1A-REP elements on chromosome 17p11.2 is the most frequent cause of the CMT1A duplication and of the recipr ocal deletion in HNPP patients. Recently a recombination 'hotspot' was noted. In our study 71 Slovene CMT1 patients from 36 families, 12 HNP P patients from 6 families and their 31 healthy relatives were analyse d for the presence of these recombination mutations. In 29 of 36 unrel ated CMT1 (81%) and in all 6 unrelated HNPP patients the duplication o r the deletion, on chromosome 17p11.2-12 was detected. In 26 out of 29 duplication patients (CMT1A) (90%) a 3.2 kb EcoRI/SacI duplication ju nction fragment was observed. The analogous 7.8 kb EcoRI/EcoRI deletio n junction fragment was found in 4 out of 6 unrelated HNPP deletion pa tients (67%). Overall we found a recombination mutation inside the 'ho tspot' in 86% of unrelated Slovene CMT1A and HNPP patients. One hundre d and thirty-six DNA samples of the CMT1 and HNPP patients and of the healthy controls were negative for the potentially recessive Thr118Met PMP22 amino acid substitution. Dominantly inherited CMT1A duplication s and HNPP deletions on chromosome 17p11.2 are thus, as in most other European countries, the most common mutations in Slovene CMT1 and HNPP patients. No signs of polymorphism or of potentially recessive mutati on were found at the specific Thr118Met PMP22 site.