Down Syndrome

Overview of Down Syndrome

Down syndrome (DS), so-called trisomy 21, is a genetic disorder with a substantial medical and social cost. It is the most common chromosomal disorder in the world and the prevalent genetic cause of intellectual disability. DS patients typically have physical and intellectual disabilities, including learning and memory, growth retardation, cancers, congenital heart diseases (CHD), characteristic facial features, gastrointestinal (GI) tract abnormalities, seizures, Alzheimer's disease (AD), hypotonia, and leukemia.

Until now, there is still no medical cure for DS. What we can do is screen all pregnant women for DS. Amniocentesis and chorionic villus sampling (CVS) are reliable but risky prenatal diagnoses for DS. It has a risk of a miscarriage of between 0.5 to 1%.

Key Factors in Down Syndrome

Research shows the cause of DS is the trisomy of the whole or part of chromosome 21(Hsa21). Over 95% of DS cases have a triplication of Hsa21 in every cell of the body. Another 1 to 2% of the cases have only partial cells carries one extra Hsa21. Others have a condition when two long arms of a chromosome separate together instead of the long and short arm while in Robertsonian translocation.

The most accepted theory for the pathogenesis of DS is that the genetic material present in the extra copy of chromosome 21 results in around 50% overexpression of the partial genes located on Hsa21. Some research has suggested that about 30 genes, located on a region of 3.8-6.5 Mb on 21q22.1-q22.3, are responsible for the common DS phenotypes. Much research, based on studies on humans and DS mouse models, shows that it is the over expression of multiple genes instead of one critical gene that results in partial phenotypes associated with DS.

Critical Genes in Clinical Conditions associated with Down Syndrome

As we all know, there are many clinical conditions associated with DS with its causative genes, such as neurological problems, cardiac problems, hematological problems, hypertension, and gastrointestinal problems.

• Neurological problems

Research shows DS patients have a significantly high risk of developing early-onset AD. Around 50% to 70% of DS patients developing AD after the age of 50. Researchers have found gene APP (Amyloid precursor protein), which is associated with Alzheimer's disease, is encoded on Hsa21. It suggests that the high-level protein expression of APP was responsible for the risk of DS patients developing AD. Besides, other genes like BACE2 (beta secretase 2), PICALM (Phosphatidylinositol binding clathrin assembly protein), and APOE (Apolipoprotein E) are also found to be associated with AD developing in DS patients. Besides, almost 100% of DS patients have learning and memory disabilities. Recent studies in the mice model showed a significant correlation between the high expression of the gene DYRK1A and SIM2 and the learning and memory defects in mice.

• Cardiac problems

Newborn babies with DS are up to 50% likely to develop CHD, especially the atrioventricular septal defect (AVSD). Research on AVDS shows that it is associated with the mutation of the non-Hsa21 CRELD1 gene.

• Hematological problems

Patients with Down syndrome are more likely to develop leukemia, especially acute megakaryoblastic leukemia (AMKL). AMKL is reported to be associated with the presence of somatic mutations involving the GATA 1 gene. Besides, 30% of cases with acute lymphoblastic leukemia (ALL) in DS have an association with function mutation in Janus Kinase 2 gene.

• Gastrointestinal problems

Patients with DS have many structural and functional disorders related to the gastrointestinal (GI) tract. About 12% of patients with Hirschsprung disease (HD) have DS. Hirschsprung disease is a form of functional lower intestinal obstruction which fails normal defecation reflex. Several pieces of research have suggested that HD patients are associated with the presence of the DSCAM gene expressed in the enteric nervous system.

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