Phenotype of AD-HSP due to mutations in the SPAST gene: Comparison with AD-HSP without mutations

Background: "Pure" autosomal dominant hereditary spastic paraparesis (AD-HSP) is clinically and genetically heterogeneous. There are at least seven genetic loci with varying ages at onset and disability. The SPAST gene at the SPG4 locus on chromosome 2p is the major disease gene for AD-HSP. Objectives: To investigate whether there are distinct clinical features among families with AD-HSP due to SPAST mutations compared with families excluded from SPG4. Methods: Nineteen families with"pure" AD-HSP were identified, and the clinical features of family members were compared using a standard protocol. With use of genetic studies, the families were divided into two groups for comparison: Those with mutations in SPAST, the "mutation-positive" group, and those excluded from SPG4 on the basis of linkage studies, the "SPG4-excluded" group. Results: Twenty-nine individuals from four families had mutations in SPAST, whereas 22 individuals from three families comprised the SPG4-excluded group; in 11 families, the pattern of linkage was unknown. In the one remaining family, no mutations were found despite strong linkage to SPG4. Different mutations were identified in the four SPAST pedigrees, but the clinical picture was similar in each. Comparison of the mutation positive group with the SPG4-excluded group revealed an older age at onset (p = 0.03), more disability (p = 0.001), more rapidly progressive paraparesis (p = 0.044), and more cognitive impairment (p = 0.024) among affected individuals with SPAST mutations, not confounded by disease duration. Conclusion: Despite different mutations, SPAST families have a similar phenotype that can be distinguished from other genetic groups.