Down syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]


Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability. Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome. Mechanisms leading to trisomy 21 include meiotic non-disjunction during meiosis I (majority) and meiosis II, Robertsonian translocation and mosaicism (rare). In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle. Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21.Immaturity of the feto-placental unit has been proposed as an explanation for the reduced maternal serum alpha fetoprotein (AFP) and unconjugated oestriol (UE3) levels and increased hCG levels in Down’s syndrome pregnancies. Reduced synthesis of AFP by the fetal liver is also thought to contribute to low AFP in Down’s syndrome pregnancies. Robertsonian translocation occurrs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromeres and the 2 short arms are lost. Mosaicism does not have any maternal association and it is a post-fertilization mitotic error. Disbilities found in Down syndrome patients are thought to arise secondary to varied genetic expression associated with the presence an extra 21st chromosome.


Mechanisms of trisomy 21

Meiotic non-disjunction

Robertsonian translocation


Effects on increased gene dosage

Learning and memory


  • DS patients have increased rates of neuronal apoptosis related to oxidative stress.[30]
  • Brain size of fetuses carrying trisomy 21 is smaller than euploid fetuses.
  • Murine models have suggested that disruption in expression of the following genes may play key roles in affecting neurodevelopment in DS patients:

Alzheimer's disease

Cancer and leukemias


Expression of the following genes may be disturbed in trisomy 21:

Table 1: Some genes located on the long arm of chromosome 21[50]
Gene OMIM Reference Location Purported Function
APP 104760 21q21 Amyloid beta A4 precursor protein. Suspected to have a major role in cognitive difficulties. One of the first genes studied with transgenic mice with Down syndrome.[51]
SOD1 147450 21q22.1 Superoxide dismutase. Possible role in Alzheimer's disease. Anti-oxidant as well as possible affects on the immuno-system.
DYRK 600855 21q22.1 Dual-specificity Tyrosine Phosphorylation-Regulated Kinase 1A. May have an effect on mental development through abnormal neurogenesis. [52]
IFNAR 107450 21q22.1 Interferon, Alpha, Beta, and Omega, Receptor. Responsible for the expression of interferon, which affects the immuno-system.
DSCR1 602917 21q22.1–21q22.2 Down Syndrome Critical Region Gene 1. Possibly part of a signal transduction pathway involving both heart and brain.[53]
COL6A1 120220 21q22.3 Collagen, type I, alpha 1 gene. May have an effect on heart disease.
ETS2 164740 21q22.3 Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have "demonstrated that overexpression of ETS2 results in apoptosis. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome."[54]
CRYA1 123580 21q22.3 Crystallin, Alpha-A. Involved in the synthesis of Crystallin, a major component of the lens in eyes. May be cause of cataracts.

Associated Conditions

The following conditions may be associated with Down's syndrome:

Gross Pathology

There are no gross pathological findings associated with Down syndrome.

Microscopic Pathology

There are no microscopic findings associated with Down syndrome.


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