REFINED GENETIC-MAPPING AND PROTEOLIPID PROTEIN MUTATION ANALYSIS IN X-LINKED PURE HEREDITARY SPASTIC PARAPLEGIA

X-linked hereditary spastic paraplegias (HSP) present with two distinc t phenotypes, pure and complicated. The pure form is characterized by spasticity and gait difficulties but lacks the additional features (ny stagmus, dysarthria, mental retardation) present in the complicated fo rm. The complicated form is heterogeneous, caused by mutations of the L1CAM gene at Xq28 (SPG1) or the PLP gene at Xq22 (SPG2) that is allel ic to Pelizaeus-Merzbacher disease (PMD). Since in one kindred (K313) the pure form of HSP was also mapped to Xq22, this raises the issue as to whether a pure form of HSP exists that is allelic to X-linked comp licated HSP (SPG2) and PMD. To answer this question, we carried out li nkage analysis in a new pedigree with pure HSP (K101) and refined link age in pedigree K313. The PLP gene was also screened for mutation by d irect sequencing and reverse-transcriptase polymerase chain reaction ( RT-PCR). In both families, the disease locus mapped to Xq22 with Lod s cores at zero recombination of 5.3 for COL4A5 2B6 in K313 and 2.4 for DXS101 in K101. A T to C transition in exon 5 of the PLP gene was iden tified from affected individuals of K313. This transition causes a Ser to Pro mutation in the major extracellular loop of PLP/DM20. This fin ding demonstrates that a form of X-linked pure spastic paraplegia, X-L inked complicated HSP (SPG2) and PMD are allelic disorders. There was no evidence of mutations in either coding sequences or the intron/exon junctions of PLP in pedigree K101, suggesting that the disease-produc ing mutation may be in the noncoding portions of PLP or in a nearby ge ne.