The AAMR 2002 states "etiology is a multifactorial construct composed of four categories of risk factors (biomedical, social, behavioral, and educational) that interact across time, including across the life of the individual and across generations from parent to child'' (p. 123). Even gross genetic factors such as DS or mutation of a gene, can be viewed as highly associated with MR although not absolutely causal. In fact, with early intervention services some children with DS function in the low normal range on tests of IQ are not classified as having MR until they qualify for services later in childhood. Even more importantly, the cause of many genetic impairments remains unknown even when the underlying molecular pathways that cause neuronal processes involved in cognitive functions are understood.

In approximately half of the cases of MR the cause is unknown. Algorithms have been suggested for the evaluation of individuals that rely on family history, physical findings, and neurological functioning. The evaluation should include karyotyping and identification of anomalies. Then depending on the resources available to pursue the investigation there are a growing range of methods and technology available to make a diagnosis. Diagnostic techniques include chromosome microdissection, fluorescence in situ hybridization (FISH), interferometer spectral karyotyping (SKY), primed in situ labeling (PRINS), subtelomeric screening, magnetic resonance spectroscopy (MRS) of the brain, and other techniques in molecular genetics, neuroimaging and dysmorphology (Battaglia & Carey, 2003). The time when an insult occurs and leads to MR ranges from the time of conception through late childhood. A range of conditions associated with, and less often causally linked to MR, are described below in Table 1.2, in chronological order of occurrence.

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