Autosomal dominant Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies: detection of the recombination in Slovene patients and exclusion of the potentially recessive Thr118Met PMP22 point mutation

Abstract

Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsies (HNPP) are the most frequent autosomal dominantly inherited disorders of the peripheral nervous system. The recessive inheritance is observed only exceptionally. Unequal crossing-over of misaligned flanking CMT1A-REP elements on chromosome 17p11.2 is the most frequent cause of the CMT1A duplication and of the reciprocal deletion in HNPP patients. Recently a recombination was noted. In our study 71 Slovene CMT1 patients from 36 families, 12 HNPP patients from 6 families and their 31 healthy relatives were analysed for the presence of these recombination mutations. In 29 of 36 unrelated CMT1 (81%) and in all 6 unrelated HNPP patients the duplication or 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 junction fragment was observed. The analogous 7.8 kb EcoRI/EcoRI deletion junction fragment was found in 4 out of 6 unrelated HNPP deletion patients (67%). Overall we found a recombination mutation inside the in 86% of unrelated Slovene CMT1A and HNPP patients. One hundred 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 duplications 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 mutation were found at the specific Thr118Met PMP22 site.