Atypical Karyotypes

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The high risk of AD in DS is also associated with early mortality, with an average life expectancy at birth of only 56 years (Baird and Sadovnick,1988). Karyotypic analysis of adults aged over 70 years with DS can provide an opportunity to identify genetic factors associated with longevity. While these cases are rare, they are highly informative and suggest that karyotypes that decrease pAPP load are associated with improved survival and reduced risk of AD. Prasher and colleagues determined the clinical and molecular correlates of partial trisomy 21 in a 78-year-old woman with DS [46,XX,rec(21)dup q, inv(21) (p12q22.1)] (Prasher et al., 1998). Although she did not display the full range of stigmata associated with the DS phenotype, she developed several of the characteristic age-related medical conditions, including hypothyroidism, cataracts, hypotonia, and hearing impairment. Analysis of gene sequences on chromosome 21 using fluorescent in situ hybridization showed that the partial trisomy excluded the region containing the gene for pAPP, which was present in only two copies. There was no evidence of decline in cognitive or adaptive competence for the five years preceding her death, and no evidence of AD-associated plaque and tangle formation was found at autopsy. Similarly, there have been case reports of two women with DS with respectively 25% and 97% disomy for chromosome 21 (Chicoine and McGuire, 1997; W. B. Zigman, personal communication). Both women had a characteristic DS phenotype and some of the typical age-related medical conditions, including hypothyroidism and cataracts. One woman (with 25% disomy) died without any evidence of dementia at age 83, while the other woman (with 97% disomy) is still living and shows no evidence of decline in either cognitive or adaptive behavior.

In turn, adults in the general population with mosaicism or translocations involving chromosome 21 may be informative for factors that accelerate the development of AD. There have been several case reports of women without mental retardation and without apparent phenotypic features of DS who developed dementia at very early ages and were shown to be mosaic for DS. One 45-year-old woman who had developed dementia at age 43 was shown on cytogenetic analysis to have a low-grade (1-5%) translocation trisomy 21 in peripheral lymphocytes [mos46,XX/46,XX, —21,+(21q;21q)], and varying degrees of trisomy (ranging from 0 to 100%) in skin fibroblast lines (Shapiro et al., 1990). She had several stigmata of DS, but was never diagnosed with DS. Follow-up neuropsychological assessments over the next two years showed progressive cognitive decline, with radiological evidence of increasing ventricular volumes and significant reductions in regional cerebral glucose metabolism. The cytogenetic findings showed that the region trisomic for chromosome 21 included the locus for pAPP. Another case of presenile dementia with onset at age 41 was observed in a mother of a child with DS who had trisomy 21 in 10% of her peripheral blood lymphocytes (Rowe et al., 1989). The early onset of dementia in these women is consistent with the hypothesis that an increased dose of APP plays a key role in increasing risk.

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