Of mice & men: advancements in the understanding of Down syndrome

Exceptional Parent, The, July, 2007 by Wayne Silverman

Research Frontiers: Understanding Science, Unlocking Potential--an interesting and enlightening column about current research in the field of intellectual and developmental disabilities.

Down syndrome has been attracting a great deal of recent news coverage. The American College of Obstetricians and Gynecologists (ACOG) published updated practice guidelines targeting prenatal screening for Down syndrome and similar conditions, and this stimulated compelling pieces by George Will in Newsweek and Amy Harman in The New York Times, addressing the moral dilemma presented by prevention methods that involve pregnancy termination and emphasizing the potential for people with Down syndrome to lead happy and fulfilling lives. Both Will and Harman are skilled and eloquent advocates, and their comments elicited a great many highly supportive responses, the vast majority from people having family members with Down syndrome. Pre-natal diagnosis and prevention through abortion remains enormously controversial, raising "pro-life" versus "pro-choice" issues, as well as those explicitly related to disability rights and the inherent value of every individual. These vitally important issues will continue to be debated passionately, and the availability of powerful new technologies for evaluating pre-natal status increases the need for consensus regarding the support of parents facing exceptionally difficult decisions.

Neither the ACOG guidelines nor the reactions to them emphasized science, but we are where we are today because of research. While there seems little doubt that Down syndrome has always been with us, John Langdon Down provided its first "modern" description in 1866, and knowledge has been accumulating ever since. As mentioned in my last column in the May issue of EP, scientific progress can take a considerable amount of time, and while Dr. Down had remarkable powers of observation, the cause of the syndrome wasn't discovered for almost another 100 years. We now know that Down syndrome occurs when an extra copy of an entire chromosome 21 (or its critical parts) is present. Recall that people normally have 46 chromosomes arranged in pairs, but individuals with Down syndrome have three copies of chromosome 21 (or trisomy 21) and a total of 47 chromosomes. (In the vast majority of cases, a complete and separate extra copy of chromosome 21 is present but not always.)

Down syndrome currently affects approximately one in every 700-750 babies born in the United States, and it is, therefore, the most prevalent genetic cause of intellectual disability. The vast majority of cases arise from a chance event (called a nondisjunction) that produces a germ cell, usually an egg, with an extra chromosome 21. Such events are associated with the mother's age, and risk increases dramatically once a woman reaches her mid 30s. Diagnostic procedures are generally quite safe., but they are not entirely without risks. Miscarriage can result in rare instances. Therefore, they should only be used judiciously, and screening and pre-natal diagnostic procedures up until this recent ACOG Procedure Bulletin have targeted pregnant women approximately 35 years of age and older. However, "younger" women have many, many more babies than do "older" women, and while individual risk may be far lower, most babies born every year with Down syndrome will have mothers well under 35. This reality stimulated interest in developing safer and effective methods for pre-natal screening, and a constellation of tests capable of identifying pregnancies at risk has been developed. While these screening procedures are not accurate enough for pre-natal diagnosis, they can provide a basis for identifying increased risk, and these younger families can then be offered the same options available to older women.

Thus, research has brought us a long way with respect to pre-natal diagnosis, but other studies of Down syndrome have other, far less controversial, goals. As George Will mentioned, almost in passing, "better health care, better mental stimulation in schools and homes, and better community acceptance" have had major impacts on the quality of life a newborn with Down syndrome can expect. Research has made critical contributions to these advances. Intellectual disability will be less severe than it would have been even a generation ago, and in that single generation, life expectancy has more than doubled. Serious health concerns associated with Down syndrome can now be addressed with remarkable success, and methods have been developed to identify and correct less severe impairments, like mild hearing and vision problems, with far greater effectiveness. Much more can be envisioned though.

Down syndrome, or trisomy 21, being due to the presence of an entire extra chromosome (or substantial piece of that chromosome), has to be a genetically complex condition. Almost 300 genes have been identified on chromosome 21, each of which provides a code that corresponds to a protein that serves a specific purpose. All of these proteins should be structured in their normal way for individuals with Down syndrome (because no mutations are involved in its cause), but an extra gene copy can result in overproduction. This could have negative consequences in and of itself, or it could cause problems by influencing the activity of other genes (called gene-gene interactions).