Silver syndrome (SS) is a complicated form of hereditary spastic paraplegia as sociated with distal wasting of the small muscles of the hands. We have previous ly described a large kindred with SS and mapped a genetic locus (SPG17) to chrom osome 11q12 q14. In the current study we analyse the clinical phenotype and per form linkage analysis in three new SS families. In addition we analyse candidate genes mapping to the SS locus (SPG17). Clinical assessments were performed on 2 5 (15 affected) individuals from each family in which SS segregates with variabl e clinical expression. Neurophysiological studies, performed in the index case o f two families, suggested anterior horn cell or nerve root involvement. Linkage analysis using microsatellite markers mapping to the SPG17 locus was performed a nd only one of the three families had a microsatellite segregation pattern compa tible with linkage. Candidate genes mapping to the SS critical region were analy sed in this and one other SPG17 linked family. Mutation analysis of genes encodi ng calpain 1 (CAPN1), copper chaperone for superoxide dismutase (CCS), ADP ribos ylation factor like 2 (ARL2), LOC120664, a putative homologue of atlastin (ATLS TL 1) and sorting nexin 15 (SNX15) failed to identify any disease specific mut ations. SS therefore exhibits both clinical and genetic heterogeneity and the SP G17 locus may account for a significant proportion of SS mutations in the UK. We have previous ly described a large kindred with SS and mapped a genetic locus (SPG17) to chromosome 11q12 q14. In the current study we analyze the clinical phenotype and per form linkage analysis in three new SS families. In addition we analyze the candidate genes mapping to the SS locus (SPG17). Clinical assessments were performed on 2 5 (15 affected) individuals from each family in which SS segregates with variabl e clinical expression. Neurophysiological studies, performed in the index case of two families, suggested anterior horn cell or nerve root involvement. Linkage analysis using microsatellite markers mapping to the SPG 17 locus was performed a nd only one of the three families had a microsatellite segregation pattern compatiible with linkage. Candidate genes mapping to the SS critical region were analysed in this and one other other SPG17 l inked family. Mutation analysis of genes encodi ng calpain 1 (CAPN1), copper chaperone for superoxide dismutase (CCS), ADP ribosylation factor like 2 (ARL2), LOC 120664, a putative homologue of atlastin (ATLS TL 1) and sorting nexin 15 (SNX15) failed to identify any disease specific muttions. SS therefore both both clinical and genetic heterogeneity and the SP G17 locus may account for a significant proportion of SS mutations in the UK.