Down Syndrome

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DS Is the most common genetic cause of MR and the leading known cause of severe MR in developed countries (Nicholson & Alberman, 1992). All cases of DS result from partial or complete duplication of chromosome 21 in the genome (Epstein, 1986). The most common form (95% of cases at birth) is standard trisomy, involving duplication of chromosome 21. In over 90% of these cases, the extra chromosome is of maternal origin, due to nondisjunction during meiosis (Hassold, Chiu, & Yamane, 1984; Sherman et al., 1991; Stewart et al., 1988). Translocation of chromosome 21 material to another chromosome (usually 13 or 18) and mosaicism (transmission of a cryptic trisomy 21 cell line from an unaffected parent) are rare causes of DS (Hook, 1982; Staples, Sutherland, Haan, & Clisby, 1991).

The most striking epidemiological characteristic of DS is the marked increase in risk with increasing maternal age, from 1 per 1550 live births at ages 20-24 years to 1 per 700 live births at ages 30-34 years to 1 per 50 live births at ages 41-45 years (Cuckle, Wald, & Thompson, 1987). Despite this strong association with maternal age, most DS births are to women aged less than 35 years because younger women contribute the great majority of births. Thus, the crude birth rate of DS in a population will depend on the maternal age distribution and the availability and use of prenatal diagnosis followed by selective abortion.

Except for advanced maternal age, factors that increase risk for having a child with DS are not well established. Recently, variants in two folate metabolizing enzymes, the 677C ^ T polymorphism in the gene for methylenetetrahydrofolatereductase (MTHFR) and the 66A ^ G polymorphism in the gene for methionine reductase (MTRR), have been found to be more prevalent among mothers of children with DS than among control mothers (Hobbs et al., 2000; James et al., 1999; O'Leary et al., 2002). The combined presence of both the MTHFR and MTRR polymorphisms increased risk of having child with DS to a greater extent than either polymorphism alone (Hobbs et al., 2000; O'Leary et al., 2002). The MTHFR 677C ^ T mutation affects both folate metabolism and cellular methylation reactions. James and colleagues hypothesized that gene-nutrient interactions associated with abnormal folate metabolism and reduced DNA methylation might increase risk of nondisjunction DS (Hobbs et al., 2000; James et al., 1999). As Hobbs has noted, the reduction in enzyme activity in carriers of the 677C ^ T mutation may raise dietary requirements for folic acid. This is the first risk factor to be identified for DS in young women and raises the possibility of intervention and prevention for DS (Hassold et al., 2001).

Virtually all persons with DS have a cognitive impairment, with the majority functioning in the moderate to profound range of MR. Observations of children living at home with their families or enrolled in infant stimulation programs suggest that the cognitive intellectual potential of children with DS may have been underestimated (Bennett, Sells, & Brand, 1979; Centerwall & Centerwall, 1960; Clements, Bates, & Hafer, 1976; Connolly, Morgan, & Russell, 1984; Melyn & White, 1973; Rynders, Spiker, & Horrobin, 1978; Sharav & Shlomo, 1986). However, early intervention has not been effective in altering the trajectory of development for all children who receive it, and some children with severe MR do not benefit substantially from it.

Adults with DS show a variety of age-related changes in physical and functional capacities suggestive of premature or accelerated aging (Martin, 1978), including changes in skin tone, hypogonadism, increased frequency of cataracts, increased frequency of hearing loss, hypothyroidism, seizures, degenerative vascular disease, and Alzheimer's disease (AD) (Oliver & Holland, 1986; Sare, Ruvalcaba, & Kelly, 1978; Schupf & Sergievsky, 2002; Wisniewski, Wisniewski, & Wen, 1985; Zigman, Schupf, Sersen, & Silverman, 1996). The most extensively studied aspect of aging in DS is their high risk for the development of AD. Virtually all individuals with DS have key neuropathological changes consistent with a diagnosis of AD by the time they reach 40 years of age, including deposition of beta amyloid (Aß) in diffuse and neuritic plaques (Wisniewski, Wegiel, & Popovitch, 1994), and most will develop dementia by the end of their seventh decade of life (Lai et al., 1999). The neuropathological manifestations of AD in DS have been attributed to triplication and overexpression of the gene for amyloid precursor protein (APP) located on chromosome 21 (Rumble et al., 1989). The increased risk of dementia in DS may be mediated by an increased substrate for cellular production of Aß. Neuropathological studies have shown that diffuse plaques, the most prevalent "Alzheimer-type'' lesion seen in individuals with DS before age 50, are not associated with dementia. In contrast, increase in the numbers of neuritic plaques, containing substantial amounts of fibrillized Aß peptides, is observed in adults with DS predominantly after 50 years of age (Wisniewski et al., 1994) and all incidence studies agree that risk of AD increases primarily after 50 years of age (Holland, Hon, Huppert, & Watson, 1998; Lai et al., 1999; Visser et al., 1997). In addition, not all adults with DS will develop dementia even if they reach ages when the presence of high densities of neuritic plaques and neurofibrillary tangles can be presumed. Thus, factors, which modify the rate and degree of Aß deposition, rather than overexpression of APP, may be the important determinants of risk for dementia in DS (Schupf & Sergievsky, 2002).

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