X-LINKED SPASTIC PARAPLEGIA (SPG2) - CLINICAL HETEROGENEITY AT A SINGLE GENE LOCUS

X linked hereditary spastic paraplegia is a rare condition that has be en divided into two forms (the pure spastic form and the complicated f orm) as a function of clinical course and severity. A gene for pure he reditary spastic paraplegia (SPG2) has been mapped to the proximal lon g arm of the X chromosome (Xq21) by linkage to the DXS17 locus, while a gene for a complicated form of the disease has been mapped to the di stal long arm by linkage to the DXS52 locus (Xq28). Here we report on the mapping of a gene for complicated hereditary spastic paraplegia to the Xq21 region by linkage to the probe S9 at the DXS17 locus (Z = 5 at 0 = 0.04) in a three generation pedigree. Multipoint linkage analys is supports the distal location of the disease gene with respect to th e DXYS1-DXS17 block cen-DXYS1-DXS3-DXS17-SPG2-tel). The observation of a complicated form of spastic paraplegia mapping to Xq21 raises the d ifficult issue of variable phenotypic expression, allelic heterogeneit y, or even close proximity of two genes for hereditary spastic paraple gia in this region. However, since our study provides clinical evidenc e for intrafamilial heterogeneity in complicated X linked spastic para plegia, the present data support the hypothesis of variable clinical e xpression of a single gene at the SPG2 locus, as previously suggested for SPG1. Finally, we report here what we believe to be the first evid ence of clinical expression in heterozygous carriers, a feature that i s relevant to genetic counselling in at risk females.