Down Syndrome

Author: Sara Demichelis
Date: 18/01/2008



Down syndrome, the most frequent form of mental retardation caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history.


Down syndrome occurs in 1 in 800 to 1,000 births. The risk of having a child with Down syndrome increases as a woman gets older.
Both sexes are affected equally. Down syndrome occurs in all ethnic groups and among all economic classes.


The major features of Down syndrome are as follows:
- Mental retardation - Mild to severe, intelligence quotient (IQ) of 25-50, constant feature
- Characteristic head appearance - Small head (brachycephaly), flat facies with increased interocular distance (hypertelorism), depressed nasal bridge, flat occiput, and broad short neck
- Ocular anomalies - Narrow and upward and outward slating of the rima palpebrarum (80%), white Brushfield spots arranged in concentric rings on the periphery of the iris (60%), medial epicanthal folds, keratoconus, strabismus, cataracta (2%), and retinal detachment
- Oral features - Small mouth (relatively) with protrusion of the tongue (macroglossia) and difficulty in eating and speaking, scrotal tongue, hypoplasia of the maxilla, delayed tooth eruption, hypodontia, juvenile periodontitis, and cleft lip or palate (rare)
- Anomalous auricles - Small ears with anomalies of the folds
- Skeletal anomalies - Short stature,short hands, feet, and digits; short curved fifth finger (dysplasia of the mid phalanx), clinodactyly of the fifth finger; dysplasia of the pelvis (shallow acetabular angle with small iliac wings); joint laxity; a wide gap between the first and second toes; and atlantooccipital instability
- Muscle hypotonia in newborns with decreased response to normal stimuli
- Protuberant abdomen (with or without an umbilical hernia)
- Hypogenitalism (small penis, scrotum, and testes), hypospadia, cryptorchism, and delayed and incomplete puberty (often)
- Congenital defects - Heart or endocardial cushion defects (40%), duodenal atresia, Hirschsprung disease, polydactylia, and syndactylia
- Excess skin on the back of the neck
- Others - Recurrent respiratory infections, leukemia (1%), epilepsy (10%), hypothyroidism (3%), and presenile dementia (development of Alzheimer disease after age 40 y)


One study, carried out in the in United States in 2002, showed an average lifespan of 49 years, with considerable variations between different ethnic and socio-economic groups. However, in recent decades, the life expectancy among persons with Down Syndrome has increased significantly up from 25 years in 1980. The causes of death have also changed, with chronic neurodegenerative diseases becoming more common as the population ages.


- Karyotype on blood cells

- Prenatal Screening and Diagnosis
There are two types of prenatal tests available to detect Down syndrome in a fetus: screening tests and diagnostic tests. Screening tests estimate the risk that a fetus has DS; diagnostic tests can tell whether the fetus actually has the condition.
Screening tests are noninvasive and generally painless. But because they can't give a definitive answer as to whether a baby has DS, mostly they're used to help parents decide whether to have more diagnostic tests.
Diagnostic tests are about 99% accurate in detecting Down syndrome and other chromosomal abnormalities.They are generally recommended only for women age 35 or older, those with a family history of genetic defects, or those who've had an abnormal result on a screening test.

Screening tests include:
- Nuchal translucency testing. This test, performed between 11 and 14 weeks of pregnancy, uses ultrasound to measure the clear space in the folds of tissue behind a developing baby's neck. (Babies with DS and other chromosomal abnormalities tend to accumulate fluid there, making the space appear larger.)

- The triple screen
This test measures the maternal serum alpha feto protein (a fetal liver protein), estriol (a pregnancy hormone), and human chorionic gonadotropin (hCG, a pregnancy hormone)
They are typically offered between 15 and 20 weeks of pregnancy.

- A detailed ultrasound. This is often performed in conjunction with the blood tests, and it checks the fetus for some of the physical traits associated with Down syndrome.

Diagnostic tests include:
- Amniocentesis. This test, performed between 16 and 20 weeks of pregnancy, involves the removal of a small amount of amniotic fluid through a needle inserted in the abdomen. The cells can then be analyzed for the presence of chromosomal abnormalities. Amniocentesis carries a small risk of complications, such as preterm labor and miscarriage. It detects over 99.8% of all numerical chromosomal problems with a very low false positive rate.

- Chorionic villus sampling (CVS). CVS involves taking a tiny sample of the placenta, also through a needle inserted in the abdomen. The advantage of this test is that it can be performed earlier than amniocentesis, between 8 and 12 weeks. The disadvantage is that it carries a slightly greater risk of miscarriage and other complications.

- Percutaneous umbilical blood sampling (PUBS). Usually performed after 20 weeks, this test uses a needle to retrieve a small sample of blood from the umbilical cord. It carries risks similar to those associated with amniocentesis.


It is caused by triplicate state (trisomy) of all or a critical portion of chromosome 21. Most individuals (95%) with trisomy 21 have 3 free copies of chromosome 21; in about 5% of patients, 1 copy is translocated to another chromosome, most often chromosome 14 or 21 . In 2 to 4% of cases with free trisomy 21 there is recognizable mosaicism for a trisomic and a normal cell line

- Trisomy 21 (47,XX,+21) is caused by a meiotic nondisjunction event. With nondisjunction,a gamete produced with an extra copy of chromosome 21; the gamete thus has 24 chromosomes. Trisomy 21 is the cause of approximately 95% of observed Down syndromes, with 88% coming from nondisjunction in the maternal gamete and 8% coming from nondisjunction in the paternal gamete.

- Mosaicism
When some of the cells in the body are normal and other cells have trisomy 21, it is called Mosaic Down syndrome (46,XX/47,XX,+21).This can occur in one of two ways: A nondisjunction event during an early cell division in a normal embryo leads to a fraction of the cells with trisomy 21; or a Down syndrome embryo undergoes nondisjunction and some of the cells in the embryo revert to the normal chromosomal arrangement.

- The extra chromosome 21 material that causes Down syndrome may be due to a Robertsonian translocation. In this case, the long arm of chromosome 21 is attached to another chromosome, often chromosome 14 (45,XX, t(14;21q)) or itself (called an isochromosome, 45,XX, t(21q;21q)). Translocation Down syndrome is often referred to as familial Down syndrome. It does not show the maternal age effect, and is just as likely to have come from fathers as mothers.

In trisomy 21, the presence of an extra set of genes leads to overexpression of the involved genes, leading to increased production of certain products. For most genes, their overexpression has little effect due to the body's regulating mechanisms of genes and their products. But the genes that cause Down syndrome appear to be exceptions.
Which genes are involved? That's been the question researchers have asked ever since the third 21st chromosome was found. From years of research, one popular theory stated that only a small portion of the 21st chromosome actually needed to be triplicated to get the effects seen in Down syndrome; this was called the Down Syndrome Critical Region. However, this region is not one small isolated spot, but most likely several areas that are not necessarily side by side. The 21st chromosome may actually hold 200 to 250 genes (being the smallest chromosome in the body in terms of total number of genes); but it's estimated that only a small percentage of those may eventually be involved in producing the features of Down syndrome.

The following are some of the genes located on chromosome 21:
- APP: amyloid beta (A4) precursor protein
- CBS: cystathionine-beta-synthase
- CLDN14: claudin 14
- HLCS: holocarboxylase synthetase
- KCNE1: potassium voltage-gated channel, Isk-related family, member 1
- KCNE2: potassium voltage-gated channel, Isk-related family, member 2
- LAD: leukocyte adhesion deficiency
- SOD1: superoxide dismutase 1,
- TMPRSS3: transmembrane protease, serine 3
- SLC5A3: sodium/myoinositol cotransporter gene

Down Syndrome Critical Region

Amyotrophic lateral sclerosis in Down Syndrome


Genetic: maternal age

The incidence of this syndrome at various maternal ages is as follows:
15-29 years - 1 case in 1500 live births
30-34 years - 1 case in 800 live births
35-39 years - 1 case in 270 live births
40-44 years - 1 case in 100 live births
Older than 45 years - 1 case in 50 live births
On rare occasions, the disease can be observed in a few members of a family

COMT activity

Gustavson et al. (Catechol-O-methyltransferase activity in erythrocytes in Down's syndrome. 1973) reported that COMT activity was about 40% higher in Down syndrome children than in normal controls. They attributed this to dosage effect owing to a presumed location of the COMT gene on chromosome 21.

Catechol-o-methyltransferase activity in erythrocytes in Down's syndrome: family studies. 1982

  • Catechol-O-methyltransferase (COMT) activity in erythrocytes was measured in six children with Down's syndrome and in their parents to determine if COMT activity is related to a gene on chromosome 21. A gene dosage effect was a possible explanation of the COMT value in three of the children but not in the other three.

Association of anorexia nervosa with the high activity allele of the COMT gene: a family-based study in Israeli patients. 2001

  • Anorexia nervosa (AN) is a common, severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance. Family and twin studies indicate a significant genetic contribution and pharmacological data suggest possible dysfunction of the serotonergic and dopaminergic pathways. Catechol-O-methyltransferase (COMT) is a candidate gene for mediating susceptibility to AN since it is involved in the dopamine catabolism and because its functional polymorphism (Val/Met 158) determines high (H) and low (L) enzymatic activity alleles. Fifty-one Israeli AN patients and their parents were genotyped with the COMT polymorphism. Using the haplotype relative risk (HRR) method it was found that the frequency of the H allele among alleles transmitted to AN patients from their parents was significantly higher than in those not transmitted (68% vs 51% chi(2) = 5.20, df = 1, P = 0.023, odds ratio: 2.01). Transmission disequilibrium test (TDT) revealed that out of 49 heterozygote parents the H allele was transmitted to AN patients 33 times while the L allele was transmitted only 16 (McNemar's chi(2) = 5.90, df = 1, P = 0.015). Our study suggests that the COMT gene is associated with genetic susceptibility to AN, and that individuals homozygous for the high activity allele (HH) have a two-fold increased risk for development of the disorder.
    h3. Alzheimer disease in Down Syndrome

Alzheimer’s disease is far more common in people with Down syndrome than in the general population: the incidence of Alzheimer’s disease in people with Down syndrome is estimated to be three to five times greater than that of the general population. Adults with Down syndrome often are in their mid to late 40s or early 50s when symptoms might first appear, while symptoms first appear in the general population in people in their late 60s.
The percentage of people with DS and AD varies in some of the epidemiologic studies presented. A review of these studies showed that 10-25% of patients had AD when aged 40-49 years, 20-50% had AD when aged 50-59 years, and 60-75% had AD when older than 60 years.

The reason AD is more frequent in individuals with DS is not known All recognized mutations for AD are associated with increased deposition of amyloid beta, a peptide fragment from 39 to 43 amino acids long, which are products of the catabolism of the amyloid precursor protein (APP) molecule.It has been hypothesized that the presence of an extra copy of the amyloid precursor protein gene which is localized to chromosome 21 leads to abnormalities in APP processing in neuronal membranes and to amyloid plaques.

Another possible explanation may involve abnormalitiesin myo-inositol metabolism because the sodium/myoinositol cotransporter gene (SLC5A3) is localized to chromosome 21 over-expression leds to high levels of myoinositol in hippocampal cells.
The presence of inositol 1,4,5-triphosphate (IP3R) receptors on the endoplasmic reticulum membrane could explain the release of Ca2+ and apoptosis which may be incresased in trisomy 21 neurons.

inositol 1,4,5-triphosphate (IP3R) receptors

The roles of calcium and cytochrome c as inter-organellar messengers in apoptosis.

The calcium released from the endoplasmic reticulum causes a global increase in the cytoplasmic calcium concentration , resulting in calcium uptake by mitochondria throughout the cell that triggers the simultaneous release of cytochrome c from all mitochondria . The cytochrome c in the cytoplasm then induces formation of the apoptosome
in which caspases are activated . Caspases and nucleases then finalize the cell death process by cleaving various protein substrates
(caspases) and DNA (nucleases).

An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity

Hippocampal Myo-inositol and Cognitive Ability in Adults With Down Syndrome

Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders

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