Showing papers by "John B.J. Kwok published in 1997"

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

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.

Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21-22

Abstract: An Australian family with autosomal dominant presenile nonspecific dementia was recently described. The disease results in behavioral changes, usually disinhibition, followed by the onset of dementia accompanied occasionally by parkinsonism. Twenty-eight affected individuals were identified with an age of onset of 39 to 66 years (mean, 53 +/- 8.9 years). We mapped the disease locus to an approximately 26-cM region of chromosome 17q21-22 with a maximum two-point LOD score of 2.87. Affected individuals share a common haplotype between markers D17S783 and D17S808. This region of chromosome 17 contains the loci for several neurodegenerative diseases that lack distinctive pathological features, suggesting that these dementias, collectively referred to as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in the same gene. The entire coding region of five genes, mapped to the FTDP-17 candidate region, were also sequenced. This analysis included the microtubule-associated protein tau that is the major component of the paired helical filaments observed in Alzheimer's disease. No pathogenic mutations were identified in either the tau gene or in any of the other genes analyzed.

Exclusion of linkage between bipolar affective disorder and chromosome 16 in 12 Australian pedigrees.

Abstract: Several recent reports of possible susceptibility loci for bipolar affective disorder (BAD) have identified sites on a number of chromosomes. Specifically, two Danish studies have suggested the presence of a susceptibility locus for BAD on chromosome 16p13. As the first step of a whole genome scan, we screened 12 Australian families with markers at 16p13 and also a number of markers spanning the entirety of chromosome 16. Linkage analysis was undertaken using both the parametric lod score method (two- and multipoint) with different models and diagnostic thresholds, and the nonparametric affected pedigree member (APM) method. Results of lod score analysis convincingly excluded the 16p13 region from linkage to BAD in these families, while APM provided no support for linkage. Furthermore, using the broad definition of BAD, with individuals affected by bipolar I and II and recurrent unipolar disorders included, the entire chromosome was excluded from linkage to BAD with autosomal-dominant transmission at a maximum age-specific penetrance of 60%, and with autosomal-dominant and recessive modes of transmission at a maximum age-specific penetrance level of 90%. Diagnostic thresholds which did not include unipolar affected individuals were somewhat less informative. However, a majority (between 63-96%, depending upon the model) of the chromosome was clearly excluded using narrow diagnostic thresholds. Moreover, no positive lod scores were obtained at theta = 0.00 for any tested model or diagnostic threshold. Our results indicate that no linkage exists between BAD and chromosome 16 markers in this group of Australian families.