RESULTS Five of the 12 AD-HSP probands were found to have spastin gene mutations (table 1). The five mutations responsible for HSP included three missense mutations (R499C, Q347K, and K388R) and two splice site mutations (1370+ 1g-t and 1742-1g-t). The proband of the 2p linked family had no mutations in any of the exons or splice junction sites, 5′ upstream 4.8 kb region from the initiator ATG codon or the 3′ non-coding region from the stop codon to the polyadenylation site. In the subjects with spastin mutation, the mean age at onset was 31.8 years (SD 18.1, n= 5), the range being 10-54 years. There was no significant difference in the mean age at onset between the probands with and without spastin mutation by Student’s t test (p= 0.53).

DISCUSSION The present study showed that five out of 12 probands with AD-HSP (41.6%) had spastin gene mutations. In the remaining AD-HSP probands (58.4%), such mutations were not detected. This is the first report on the frequency of spastin gene mutation among Japanese patients with AD-HSP. Three out of five mutations, including Q347K and the two splice site mutations, were novel mutations. 10 14–20 Each of these novel mutations was segregating with affected members in each family (data not shown). The variety of mutations in our subjects indicates that each pedigree had a different founder. Recently, Fonknechten et al14 analysed 17 exons of the spastin gene in 87 AD-HSP probands from around the world, but mainly from Europe. They reported that SPG4 accounted for 37% of all AD-HSP. Our estimation of the prevalence of SPG4 in Japanese AD-HSP patients is compatible with their finding. As in previous reports, the three missense mutations that we found were localised within the functional domain of spastin (the AAA cassette) and were therefore considered to interfere with the functioning of spastin. Two splice site mutations were also detected in the present study. Fonknechten et al14 suggested that the frequency of spastin splice site mutations