Triplet repeat expansion mutations: the example of fragile X syndrome.

Mental retardation represents a deficiency in intelligence, as measured by IQ, with limited adaptive behavior that is normally reflected in maturation, learn­ ing, or social adjustment (American Psychiatric Association 1987). Approxi­ mately 1 to 3% of the population, depending upon definitions of adaptive behavior, is mentally retarded (Popper 1988). The etiologies and determinants of mental retardation are diverse and include socioeconomic influences leading to extreme malnutrition and/or inadequate prenatal care; toxic insults, such as that leading to fetal alcohol syndrome; trauma and infection; and genetic factors (Popper 1988). At least 300 genetic disorders include mental retardation as part of the phenotype, and genetic components are considered important influences on related disorders such as attention deficit disorder and learning disability (Smith et al 1983, Biederman et al 1987, McKusick et al 1992). Since the early twentieth century a male predominance at all levels of mental retardation, ranging from 1.5 to 3 times the incidence in females, has been acknowledged (Penrose 1938). Although a variety of explanations have been put forth, including the probable ascertainment bias of mentally retarded males being more frequently institutionalized because of uncontrollable or violent behavior, there is good reason to believe X-linked loci contribute significantly to this gender inequity (Opitz 1986). Perhaps as many as 95 genes have been tentatively assigned to the X chromosome where mutations lead to mental retardation as at least part of the phenotype (Schwartz 1993). As the vast