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Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. NeuroReport 8:1537-1542

Garvan Institute of Medical Research, Sydney, NSW, Australia.
Neuroreport (Impact Factor: 1.64). 05/1997; 8(6):1537-42.
Source: PubMed

ABSTRACT Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates 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 pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.

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    • "twenties ( Taddei et al . 1998 ) . At age 34 , the patient had a moderate dementia , abnormal gait , and brisk reflexes with bilateral extensor plantar responses , although tone was normal . As the dementia progressed , the patient became physically more disabled with increasing spasticity , pseudobulbar palsy and rigidity , and died at 40 years ( Kwok et al . 1997 ; Taddei et al . 1998 ) . Since these reports , other PSEN1 mutations in AD / SP pedigrees have been reported , in particular in patients with PSEN1 exon 9 deletions . Known AD / SP pedigrees are described below and reviewed in further detail by Karlstrom et al . 2005 and summarized in Table 2 ."
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