Locus-phenotype correlations in autosomal dominant pure hereditary spasticparaplegia - A clinical and molecular genetic study of 28 United Kingdom families

This study aimed to describe the clinical phenotype of a large collection o f families with autosomal dominant pure hereditary spastic paraplegia (ADPH SP), to examine the relative frequency of each of the three known ADPHSP ge nes within this population, to assess locus-phenotype correlation in ADPHSP and to ascertain whether there are clinical subgroups within genetically d efined populations of ADPHSP families. We examined 306 family members, 144 affected, from 28 families with ADPHSP, Linkage analysis at the three known ADPHSP loci allowed us to categorize the families into three groups: (i) t hose families showing linkage to the chromosome 2 ADPHSP locus (seven famil ies); (ii) those in which linkage to all known loci was excluded (five fami lies); and (iii) those in which linkage results were inconclusive, There wa s a correlation between linkage group and clinical features, with chromosom e 2-linked families having a later age at onset of symptoms (P = 0.001) and later age before commencing walking stick use (P = 0.007) than those famil ies in which linkage to all known ADPHSP loci was excluded. There were no c linical differences between the families showing linkage to the chromosome 2 locus, but there were clinical differences between the families in which linkage to all of the known loci had been excluded (P < 0.0001). We conclud e that the chromosome 2 ADPHSP gene is a frequent cause of ADPHSP in UK fam ilies, that the responsible gene has not yet been mapped in a significant p roportion of families and that certain clinical features of ADPHSP, includi ng age at onset, are at least in part determined by genetic locus.