Down Syndrome (DS) or Trisomy 21 is a disorder which occurs in approximately 1 in 691 births. It is the result of a triplication (3 copies) of all or part of chromosome 21 (see More about genetics below). This causes an excess of genetic material and the over-expression of the genes contained therein. The over-expression of certain genes on chromosome 21 causes the impairments in DS; however, it remains unclear which of the approximately 250 genes causes the core features of DS. Several genes have been correlated with certain features – for example, DSCAM and COL6A2 (as well as COL6A1) have been associated with the increased risk of heart abnormalities1. Approximately 50% of children with DS have some type of heart defect. The gene CRYA1 may cause premature cataract formation, another common ailment in DS. The gene SOD1, which alters the function of superoxide dismutase, may be associated with premature development of Alzheimer’s disease. Also, the gene encoding for pre-A4, the precursor the amyloid protein, is overactive in those with DS. Over-expression of the gene DYRK1A has been associated with mental retardation2. Abnormalities in the immune system make persons with DS more vulnerable to infections, possibly related to the IFNRA gene.
A number of medical challenges are frequently experienced by persons with DS, although in many instances the causal gene is not known. Slowed growth or delayed growth often leads to smaller stature. Soft tissue and skeletal alterations and a tendency to be more obese than the general population all contribute to an increased risk for obstructive sleep apnea. People with DS tend to have higher cholesterol, possibly directly related to a specific gene. Problems with vision (cataracts, amblyopia, myopia) and hearing (fluid build up in inner ear) are common. Complications in the gastrointestinal system are much more frequent for people with DS, including GI blockage and intestinal infarction. Lastly, because of increased amyloid production and possibly compromise in the immune system, people with DS tend to develop Alzheimer’s disease much younger – often in their 40’s.
Recent studies have shown that the DNA of Herpes-1 virus (the cold sore virus) is located in the pathological plaques in Alzheimer’s disease3. Cultured brain cells with the genetic material of the Herpes-1 virus inserted into their DNA accumulate amyloid abnormally4. Transgenic mice containing the Herpes-1 virus genetic material develop the mouse equivalent of Alzheimer’s disease far more rapidly5. As time goes on, research may confirm that infectious elements contribute to Alzheimer’s disease and other neuropsychiatric illnesses6,7,8, including the neurodevelopmental variation in DS7. Because people with DS have compromised immune function, they may be at increased risk for acquiring these infectious elements. Combined with the genetic overproduction of amyloid, increased cholesterol, malfunction of superoxide dismutase, and abnormalities in neuroglial function9, this compromise in the immune system may represent “the perfect storm” for Alzheimer’s disease.
Physicians treating children and adults with DS must be mindful of this wide range of significant medical issues. Dr. Henderson does not focus only on the behavioral or academic struggles that a patient with DS might have. He is mindful that certain medications used to treat these problems may increase cholesterol, which would increase the risk for cardiac problems and accelerate premature Alzheimer’s disease. Targeting sleep apnea can be very important for people with DS, as repeated apnea impairs cognitive function and mood stability. Some medications used to treat anxiety can impair memory, learning, and cognitive function. With his thorough grasp of the research literature, Dr. Henderson is able to bring a safer and more holistic treatment approach to those affected by DS.
More about genetics
The chromosomes are the structures that carry genetic information and are composed of DNA and proteins. Over 95% of cases of DS result from a process called nondisjunction, which is a failure of the chromosome pair to separate during the formation of eggs or sperm. The great majority of cases arise from abnormal chromosomes in the egg and maternal age is a contributing factor.
Approximately 3-4% of DS cases results from Translocation, wherein a fragment of the chromosome 21 becomes attached to another chromosome. Thus, only a portion of chromosome 21 is triplicated. This form of DS can be inherited. If a father is a carrier for the translocation, the chance of having a child with DS is about 3%. If the mother is the carrier, then the chance is between 10 and 15%. Maternal age also contributes to risk. At age 30, the likelihood that a woman will have a child with DS is 1 in 900. This increases to 1 in 350 by age 35, 1 in 100 by age 40 and 1 in 35 by age 45. Woman who have had one child with DS have a 1 in 100 chance of have another child with DS.
1) Grossman TR, et al. Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects. PLoS Genet. 2011 Nov;7(11):e1002344.
2) Wegiel J, Gong CX, Hwang YW. The role of DYRK1A in neurodegenerative diseases. FEBS J. 2011 Jan;278(2):236-45
3) Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J Pathol. 2009 Jan;217(1):131-8.
4) Wozniak MA, et al. Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett. 2007 Dec 18;429(2-3):95-100.
5) Itzhaki RF, Wozniak MA. Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer’s disease and other disorders. Prog Lipid Res. 2006 Jan;45(1):73-90.
6) Carter CJ. Alzheimer’s disease plaques and tangles: cemeteries of a pyrrhic victory of the immune defence network against herpes simplex infection at the expense of complement and inflammation-mediated neuronal destruction. Neurochem Int. 2011 Feb;58(3):301-20
7) Cheon MS, et al. Evidence for the relation of herpes simplex virus type 1 to Down syndrome and Alzheimer’s disease. Electrophoresis. 2001 Feb;22(3):445-8.
8) Miklossy J. Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med. 2011 Sep 20;13:e30
9) Nelson PG, et al. Glial-neurotrophic mechanisms in Down syndrome. J Neural Transm Suppl. 2001;(61):85-94.