Making Sense of Intellectual Disability

Intellectual disability is a diagnosis defined by impaired cognitive and adaptive function with an onset of findings before 18 years of age. Historically, the condition has been referred to as "mental retardation" (the preferred terms nowadays are "intellectual disability" or "cognitive disability"). It is a common condition, affecting 1-3% of individuals and 10% of families, and it is consequently an important public health problem and leads to substantial societal costs.

Advances in the care of persons with intellectual disability have markedly improved survival in some cases, and as these individuals live far into adulthood, the involvement of internists in the care of patients with intellectual disability has expanded. For example, the median survival in Down syndrome in the 1950s was probably less than 1 year; by 1983, survival was 25 years; and, by 1997, it was 59 years (Lancet 2002;359:1019-25).

Because there is no direct correction of the underlying genetic defect in Down syndrome, the observed improvements in longevity have been primarily driven by better pediatric and, more recently, adult care for this population.

Down syndrome remains the most common identifiable genetic cause of intellectual disability with an overall prevalence of 1:800 births (compared with Fragile X syndrome’s prevalence in 1:4,000 males), but hundreds of other described conditions have features of intellectual disability. Overall survival among all individuals with intellectual disability is reduced, and severity of the underlying cognitive defect correlates with reduced survival. Many persons with mild to moderate impairment will survive into adulthood, at which time they generally experience more health problems and hospitalizations and may account for more health care costs than does the cognitively normal adult population.

Genetics and Intellectual Disabilities

Genetic factors are suspected in most cases of congenital intellectual disability, especially when obvious environmental insults have been excluded. In spite of a suspicion for underlying genetic components to intellectual disability, many affected patients lack a specific diagnosis. Some patients may have been evaluated for genetic defects but typically these evaluations were done decades ago during their childhoods, when available testing technology was quite limited. Other patients may never have been evaluated from a genetic perspective. In addition to managing related health issues for these patients, internists may be increasingly called upon to address whether or not a genetic work-up would be fruitful.

Two tools that are gaining diagnostic traction for intellectual disability are array comparative genomic hybridization (aCGH) and intellectual disability genetic testing panels. aCGH is a technology that interrogates the chromosomes for gains or losses of microscopic regions of all 23 chromosomes and the sex-chromosomes. aCGH looks for chromosome abnormalities using a resolution far superior to standard chromosome studies, which are limited by light-microscopy resolution. aCGH technology is rapidly becoming the initial diagnostic test of choice for intellectual disability, and similar aCGH assays are now widely used in cancer diagnostics to look for relevant gains and losses of important oncogenic regions.

One recent study noted aCGH defects in 22% of adult patients with intellectual disability, a rate higher than many studies of pediatric intellectual disability (Genet. Med. 2010;12:32-8).

Gene panels exploit newer high-throughput DNA sequencing to test dozens of "intellectual disability" genes in a single assay. This shotgun approach reflects solutions to the difficulty of distinguishing among the hundreds of different causes of intellectual disability and the continued progression of high-throughput technology. For example, one laboratory offers a test for X-linked intellectual disability that sequences more than 80 genes on the X-chromosome; other similar panels for non–X-linked disease are in development.

Simply, because one can test the several hundred possible genes in a given disorder does not automatically give it clinical value or utility. In the case of many adult patients who are medically stable, the question of what the primary cause of a case of intellectual disability may be largely academic.

The Value of Gene Testing

However, for this population, there are other instances when testing for the purpose of reaching a diagnosis should be considered. Prime among these are patients with intellectual disability who seek reproductive counseling for future or current offspring. Previously, with so few affected patients reaching adulthood this issue was uncommon; now such discussions are increasingly possible and relevant, especially for adults with mild intellectual disability (the largest group) who are likely to consider having children.

Similarly, accurate genetic diagnoses allow for accurate risk-recurrence estimates for other relatives in a family, most notably siblings who often want to know if their future children are at risk. An accurate diagnosis also can be important in cases in which the intellectual disability syndromes carry risks of other medical problems (such as cardiac disease or cancer).