GENETIC HOMOGENEITY OF PELIZAEUS-MERZBACHER-DISEASE - TIGHT LINKAGE TO THE PROTEOLIPOPROTEIN LOCUS IN 16 AFFECTED FAMILIES

Among the numerous leukodystrophies that have an early onset and no bi ochemical markers, Pelizaeus-Merzbacher disease (PMD) is one that can be identified using strict clinical criteria and demonstrating an abno rmal formation of myelin that is restricted to the CNS in electrophysi ological studies and brain magnetic resonance imaging (MRI). In PMD, 1 2 different base substitutions and one total deletion of the genomic r egion containing the PLP gene have been reported, but, despite extensi ve analysis, PLP exon mutations have been found in only 10%-25% of the families analyzed. To test the genetic homogeneity of this disease, w e have carried out linkage analysis with polymorphic markers of the PL P genomic region in 16 families selected on strict diagnostic criteria of PMD. We observed a tight linkage of the PMD locus with markers of the PLP gene (cDNA PLP, exon IV polymorphism) and of the Xq22 region ( DXS17, DXS94, and DXS287), whereas the markers located more proximally (DXYS1X and DXS3) or distally (DXS11) were not linked to the PMD locu s. Multipoint analysis gave a maximal location score for the PMD locus (13.38) and the PLP gene (8.32) in the same interval between DXS94 an d DXS287, suggesting that in all families PMD is linked to the PLP loc us. Mutations of the extraexonic PLP gene sequences or of another unkn own close gene could be involved in PMD. In an attempt to identify mol ecular defects of this genomic region that are responsible for PMD, th ese results meant that RFLP analysis could be used to improve genetic counseling for the numerous affected families in which a PLP exon muta tion could not be demonstrated.