2 NOVEL (M233T AND R278T) PRESENILIN-1 MUTATIONS IN EARLY-ONSET ALZHEIMERS-DISEASE PEDIGREES AND PRELIMINARY EVIDENCE FOR ASSOCIATION OF PRESENILIN-1 MUTATIONS WITH A NOVEL PHENOTYPE

Eleven early-onset dementia families, all with affected individuals wh o have either presented clinical symptoms of early onset familial Alzh eimer's disease (EOFAD) or have been confirmed to have EOFAD by autops y, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of preseni lin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA te mplates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290 -319 of PS-1 (PS-1 Delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pa thogenic PS-2 mutation (M239V), and is characterized by a very early a verage age of onset (before the age of 35). In one early onset case, a nother novel PS-1 mutation was identified in exon 8 (R278T). Of the fi ve remaining families and the other early onset case, none have missen se mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the AP P gene. Moreover, two of the PS-2 mutations, PS-1 Delta 290-319 and R2 78T, are associated with the co-presentation of familial spastic parap aresis (FSP) in some of the affected family members. Our data raise th e possibility that the phenotypic spectrum associated with PS-1 mutati ons may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data su ggest that other novel EOFAD loci, in addition to APP and the presenil in genes, are involved in the aetiology of up to 50% of EOFAD cases.