Genetic intellectual disability (GID), what we used to call mental retardation, is defined as a neurodevelopmental disorder that results in an IQ of 70 or below. A GID may be inherited, or not inherited. Down syndrome is the most common form of non-inherited genetic intellectual disability and it is caused by an extra copy ofchromosome 21 in the genome of individuals. GID can also be the result of a single gene disorder, like fragile X syndrome, the most common inherited GID. Intellectual disability is thought to affect 1% to 3% of the population worldwide, and intellectual disability that has a genetic origin to be 25% to 50% of those cases. The human genome is incredibly complex, and GID can be caused by a number of factors from whole chromosome disorders like Down syndrome, to microdeletion syndromes like Angelman, DiGeorge, or Williams syndrome where a particular chromosome is missing a small piece.
The Jerome Lejeune Foundation is interested in and funds research into all genetic intellectual disabilites, but the majority of our funding is provided to research on the most common form of GID, Down syndrome.
Down syndrome is a congenital genetic disorder in which individuals are born with an extra copy of chromosome 21. The presence of an extra chromosome causes mild to moderate intellectual disability, as well as increased risk for certain medical conditions, such as congenital heart defects, leukemia, various autoimmune disorders, vision and hearing problems, digestive problems, sleep disorders, and others. For reasons no one yet understands, the severity of these conditions varies among individuals. The extra copy of chromosome 21 is the result of an error in cell division, usually on the maternal side, prior to fertilization, but what causes that error is also still unknown. Sometimes people will talk about a "Down syndrome gene" but there is no such thing. People who have Down syndrome have an extra copy of EVERY gene on that chromosome, or 50% more genetic material on the 21st chromosome than what is typical.
The live birth incidence of Down syndrome varies across the world. In the United States, the newest research indicates that the live birth incidence is approximately 1 in 792 births, or about 5,300 births each year. In some parts of the world, such as Islamic countries where abortion is not permitted for Down syndrome, the birth incidence is much higher - about twice that of the United States. In some countries like those of Northern Europe and Australia, however, the birth incidence is much lower. We don’t know for certain how many people are living in the United States with Down syndrome, but the number is estimated to be somewhere between 250,000 and 400,000 individuals. The world-wide population is estimated to be about 6 million individuals.
There are three types of Down syndrome:
As stated above, the only kind of Down syndrome that can be inherited is a translocation. The majority of cases of Down syndrome are not inherited, rather they occur as random events during the formation of the sperm and egg cells. Trisomy 21 and mosaic Down syndrome cannot be inherited. In perhaps one third of cases of translocation Down syndrome, a parent of the individual carries what is called a balanced translocation, a rearrangement of genetic material between chromosome 21 and another chromosome.1 Although these carriers do not have signs of Down syndrome themselves, it has been found that those that carry this balanced translocation have an increased risk of having children with Down syndrome.
It is unlikely that there will ever be a “cure” for Down Syndrome. Down syndrome is an incredibly complex genetic disorder. Cystic fibrosis, sickle cell disease, fragile X syndrome, muscular dystrophy, and Huntington disease are all examples of single gene disorders and they continue to puzzle researchers searching for cures. Individuals living with Down syndrome don’t just have an extra copy of a single gene. Individuals with Down syndrome have an entire extra chromosome containing at least 160 genes called protein encoding genes, or genes that make the proteins responsible for all of the human organism's entire observable characteristics! While some remarkable developments have taken place in research labs that theoretically show Down syndrome can be "cured", doing so in humans is a much different possibility. Rather than seeking a cure, most researchers are trying to find ways to rebalance the metabolic imbalance caused by all these extra genes making proteins on the 21st chromosome. That said, and perhaps to risk being overly simplistic, research can be divided into at least 2 broad categories: those who are attempting to shut down the extra 21st chromosome; and, those who are working to rescue cognition and memory through drugs that regulate the proteins encoded on the 21st chromosome.
Research on Down syndrome focuses on the investigation of therapeutic treatments to improve cognition, memory and speech, as well as a resolution of the many coexisting medical conditions that result from the metabolic imbalance caused by an extra copy of chromosome 21. The Jerome Lejeune Foundation supports both fundamental and clinical research with these targets. Fundamental research works to better understand the biological mechanisms and metabolic imbalance that results from trisomy 21. Clinical research tests the safety and effectiveness of treatments to improve the lives of those living with genetic intellectual disabilities with the goal of bringing targeted treatments through the drug development process to patients. The Jerome Lejeune Foundation funds clinical research projects that show particular promise in the treatment of patients, and projects that it anticipates will provide valuable data for further investigation and refinement. Understanding the function and interaction of genes on chromosome 21, as well as the impact of those genes on the entire genome, will help researchers to develop trageted medical treatments for individuals living with Down syndrome.
If one were to bake a cake that called for 2 cups of sugar and added 3 instead, the flavors in the cake would be out of balance. It may be a poor analogy, but the third copy of chromosome 21 in individuals living with Down syndrome has an analogous effect. The body’s metabolic system is too rich with genetic activity on the 21st chromosome. Just as you can’t remove the extra cup of sugar from a recipe, at this point in time you can’t remove the extra chromosome that is present in every cell of the body. Instead, you may add other ingredients to try to rebalance the recipe.
Researchers investigating treatments for Down syndrome are attempting to rebalance the genetic recipe by searching for drug molecules that can regulate the extra genetic activity on chromosome 21, and restore the delicate balance the body needs to function well. This may involve searching for drugs that inhibit the over excitation of neurons in the delicate excitatory – inhibitory balance in typical neurotransmission. They also may try to restore what has been lost due to a degeneration of neural pathways. There are a variety of ways researchers are attempting to address the problem of intellectual disability in Down syndrome.
There are specific families of drugs and gene targets that have been isolated as primary suspects in intellectual disability. As one example, neurons rely on something called GABA (Gamma-aminobutyric acid) to fine-tune neurotransmission, or the communication of signals in the brain. In 2011 the Roche pharmaceutical company initiated a clinical trial on a drug they hope will be effective in regulating the activity of GABA and that clinical trial continues today. The Jerome Lejeune Foundation has been involved in supporting research on the DRK1A and CBS genes.
As fundamental research continues to inform investigators on the biological mechanisms of Down syndrome, new drug targets will continue to be developed and tested. The Jerome Lejeune Foundation is funding the development of a new drug that we anticipate having in clinical trial by 2017. With the accelerated pace of developments in recent years, it is not unreasonable to expect there will be some treatment available to improve the lives of individuals living with Down syndrome within the next 5 to 10 years.
Studies have shown that by age 40, the brains of all individuals with Down syndrome have significant levels of plaques and tangles, or abnormal protein deposits considered to be features of Alzheimer’s disease.2 Researchers suggest that more than from 50% to 80% of individuals with Down syndrome will develop demetia in their 40s or beyond, nearly 6 times the percentage of individuals in this age group who do not have Down syndrome.3
Like other health risks and issues associated with Down syndrome, researchers believe that the increased risk of Alzheimer’s disease is a result of the extra genes present on the extra chromosome 21, and in particular APP, the amyloid precursor protein. APP’s function remains largely unknown, but it has been found that day-to-day brain activity involves processing (cleaving) APP into shorter pieces. One of the products of APP is beta-amyloid, a toxic fragment found to be a primary component of plaques, and a prime suspect in Alzheimer’s-related brain changes. Having an extra copy of the APP gene on the extra chromosome 21 increases production of beta-amyloid, activating the chain of events leading to Alzheimer’s disease and eventually dementia.
More information on the link between Down syndrome and Alzheimer's disease can be found here.
While those with Down syndrome do have an increased risk for leukemia, it has been found that individuals with Down syndrome have a much lower incidence of other types of cancer, including breast cancer.4 It has been suggested that the decreased incidence is caused by the over production of some product on the extra copy of chromosome 21. Recent studies have shown that breast, lung, and mouth cancer are sometimes associated with loss of certain regions of chromosome 21. This indicates that these specific regions may contain tumor suppressor genes.5 Furthermore, studies of the activity of several genes have revealed that individuals with Down syndrome typically experience 50% more activity of genes on chromosome 21 than individuals without Down syndrome. Therefore, it is possible that high-level activity of tumor suppressor genes on this extra chromosome may protect against cancer.
More information on the link between Down syndrome and breast cancer can be found here.
Currently, there are no commercially available drugs that will improve cognition in those with Down syndrome. In recent years, a number of researchers have uncovered critical drug targets within disabled chemical pathways in the brains of individuals with Down syndrome, especially within the hippocampus and cerebellum.6 It has been suggested through the use of animal models that these pathways may be restored with drug treatments. There are also a number of trials currently studying the effects of such treatments on individuals with Down syndrome. As research and trials progress, the Jerome Lejeune Foundation remains hopeful for future drug treatments for individuals with Down syndrome, and continues to fund research that will contribute to the development of drug treatments.
Occasionally we hear of treatments that families give their children that they claim to be effective. As research in Down syndrome intensifies, we are also seeing different drugs mentioned in the news that are already FDA approved for another medical problem that researchers believe may have some benefit to those with Down syndrome. The Jerome Lejeune Foundation cannot make any recommendation of treatments that have not been proven safe and effective through carefully controlled clinical trials. While we appreciate parents' concern for the welfare of their children, we would caution any family against pursuing any kind of vitamin therapy or other medication without first consulting a physician well acquainted with individuals living with Down syndrome and their healthcare needs. Any substance may have unintended side effects, especially when taken in large doses. Any potential rumored benefit is not worth the risk to the health of our loved ones.