An introduction to Down’s syndrome

This is another archival repost from the old blog — this one from march 2007.

I wrote this for a one hour timed essay for the “medical genetics” module and the lecturer picked it out for special commendation for its “novel and elegant organisation and presentation,” so I thought I’d stick it on the weblog. Because of the situation in which it was written, I haven’t included any references, but I have them to hand and can add them if people are interested in them. I’m slowly getting back into enjoying writing, and considering it as a career again.

A major branch of medicine is concerned with congenital diseases, a large amount of which are caused by chromosomal abnormalities. The most frequently occurring of these is Down’s syndrome (DS), accounting for 1 in 700 live births, and an estimated 1 in 200 conceptions (the discrepancy caused by unusually high spontaneous abortion—66%—and still birth—21%—rates). DS is characterised by mild to moderate mental retardation (MR), abnormal skeletal and facial development, and reduced life expectancy.

DS is an example of an autosomal aneuploid condition. In aneuplody, the number of chromosomes present differs from the normal 46, in this case trisomy (one extra copy) or partial trisomy of chromosome G21. This is the smallest chromosome in humans, which is why DS is better tolerated, and more frequent in live births, than most chromosome abnormalities. There are several known mechanisms by which DS can arise. During anaphase of cell division, sister chromatids (the two copies of a duplicated chromosome) separate and are pulled to opposite poles of the cell, ultimately ending up in separate daughter cells after telophase. If the sister chromatids fail to separate—non-disjunction (N-D)—one of the daughter cells will be trisomic for that chromosome. If this occurs during gametogenesis (sperm and egg formation), any resulting baby will have DS. If it occurs during early development, a mosaic condition may arise, in which which some of the individual’s cells are trisomic, with a potentially less severe phenotype. Additionally, partial trisomy can occur by centric fusion translocation. Accrocentric chromosomes (of which G21 is one) can break at the centromere, losing their short p arms (which contain nucleolar organiser regions, whose loss can be tolerated), and the long q arms join together to form a fusion chromsome. If this occurs, a balanced translocation carrier arises, with no phenotypic abnormality, but if it occurs in the germ-line, gametogenesis could result in some cells with an extra copy of G21q. A region of G21—21q22.2, the DS critical region (DSCR)—of 20-40 genes (compared to 200+ total on G21) has been identified as required for developing DS, so it is also possible that duplication of the DSCR alone could give rise to some or all of the DS traits.

Amongst the genes found in the DSCR are DYRK, which has been implemented in MR—DS sufferers typically have an IQ between 25 and 80, and a child-like personality; DSCR1 and ETS2, implemented in skeletal abnormalities, such as short statue; and SOD, COL6A1 and IFNAR, implemented in reduced immune system efficiency and heart disease, plus GART, CAF1A and CBS involved in DNA repair, which together may account for the reduced life expectancy, averaging around 40. Additional aspects of the phenotype include facial abnormalities, with a broad flat face with hypertelorism (abnormal spacing) of the eyes and small nose and chin; epicanthal folds; oversized tongue, lips and teeth; a single palmar crease on the hands; under developed genitalia; and individuals are often slightly overweight relative to height. These characteristics are not universal, and the phenotype may be influenced by complete or partial trisomy, and mosaic cell lines.

DS is correlated with maternal age, with a risk of less than one in 1000 for mothers under 30, and above one in 40 for those above 40 years old. 25% of DS babies are born to mothers over 35 years old, even though this accounts for only 5% of total pregnancies. It is thought that N-D may be affected by time spent suspended in meiosis, due to errors in spindles, kinetochores or centromeres—the machinery which separates sister chromatids. However, older women are also likely to have had higher exposure to teratogens, such as radiation and free radicals, which can damage DNA and the cellular machinery, and there may be a variety of factors involved. Additionally, it has been suggested that, rather than a higher number of DS conceptions being to blame, older women have a higher proportion of DS babies to surviving to term, and lower spontaneous abortion rate. It has been speculated that this is an evolutionary adaptation, with older mothers risking a baby with birth defects, rather than risk losing their last chance to reproduce.

The DS phenotype first becomes apparent at eight weeks from gestation, but can not usually be picked up until between 10-14 weeks, when in many cases the nuchal folds of the neck are abnormally large (>5mm), which can be detected by ultrasound. Generally, DS is caused by an imbalance of gene products, rather than by an all-or-nothing presence, or absence of expression. No single test has therefore been developed which can detect DS with low false positive and negative rates. However, the triple and quadruple tests (15-18 weeks), when maternal age and nuchal fold transparency are factored in, can give false positive and negative rates of around 80% and 7% respectively. These tests look at two molecules down regulated in DS—alpha-feta-protein in maternal serum, and serum unconjugated estriol—plus two which are up regulated in DS—human chorionic gonadotrophin, and (in the quadruple test) inhibin A. Modern procedures are seeking to use genes of the DSCR, such as DYRK, in addition to the above. Other tests can detect DS—and are often performed when the above tests are positive for confirmation—for example by producing metaphase spreads, which will show the presence of an extra chromosome. However, these require invasive procedures, such as amniocentesis, which come with a chance of inducing miscarriage, and require time consuming processes, such as cell culture.

Prenatal testing gives parents time to prepare for a DS baby, plus the option of therapeutic abortion if the economic burden of a severely disabled child is too high. Future developments in gene therapy may be able to target the genes of the DSCR, or perhaps to ‘switch off’ one of the G21 chromosomes. However, this would likely require very early intervention to avoid the technical difficulties and dangers likely from in utero gene therapy on an individual already composed of millions of cells. As current available tests take place at 10-20 weeks, this may remain impossible.

As the most common genetic disorder, studied for a century and a half, the phenotypes and cytogenetics of DS are well understood. Modern advances are making it possible to determine how the phenotypes develop from the genes of chromosome G21, and how maternal age affects DS, plus the mechanisms by which N-D occurs and is detected. While no ‘cure’ is available, it is not impossible that one could be developed in the distant future, though it is unrealistic in the short term.

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