PAULA MARKET
Down’s syndrome is the most commonly identified cause of mental retardation occurring in 1 out of
700 live births. In addition to mental deficiency, characteristics of the disease include epicanthic
folds of the eyes, flattened facial features, unusual palm creases, short stature, open mouth,
protruding tongue and poor posture. A twenty-two to fifty fold increase in risk of the development
of leukemia along with congenital heart defects in forty percent of these individuals is also seen.
The increased level of purines often found can lead to mental retardation itself. Neurological
impairment and immune system deficiencies make these individuals more susceptible to infection.
Also noted are increased risk for cataract development and vision impairment due to defects in the
lenses of the eyes.
Evidence for the disease can be found as far back as the nineteenth century with many theories for
the etiology of the disease. Early hypotheses include links to endocrine gland malfunction,
tuberculosis, syphilis and "uterine exhaustion". The idea of uterine exhaustion was based on the
observation that many children with Downs Syndrome (DS) tended to be the last born members of
large families. This was later accounted for as mere coincidence. The first formal reference to the
anomaly came in 1866 in England by a physician at the Earlewood Asylum noting the distinct
physical characteristics of this group of individuals. In the 1930’s, Adrian Bleyer hypothesized that
the condition was caused by a failure of the chromosomes to separate but could provide no proof
for this since an accurate human chromosome count had not yet been obtained by anyone.
The correct number of 46 chromosomes was obtained in Sweden in the 1950’s, and shortly
thereafter a total of 47 was verified in a Down’s individual confirming non-disjunction as the
mutation occurring. When non-disjunction occurs, the chromatics do not separate so one of the
daughter cells receives two chromatics and the other none. The daughter cell in which the
chromatic is absent will die and the other will receive a third copy upon fertilization resulting in a
variety of defects. This non-disjunction can occur during anaphase I or anaphase II when the
chromatics are pulled to opposite poles by the spindle fibers of the centromere. Trisomy, having
three copies of a chromosome, most commonly occurs in chromosome 21, the smallest of the 23
human chromosomes. The process showing normal meosis, non-disjunction occurring in meosis I
and non-disjunction occurring in meosis II is illustrated on the following figure.
In 1929, the average life span of an individual with Down’s syndrome was 9 years. Due to advances in medical care allowing for treatment of factors such as congenital heart disorders and leukemia, this has now increased to more than 30 years with 25% reaching the age of 50. Morphologically, the brain of a Down’s individual is smaller than a normal individual’s with a reduction in the size of both cerebral and cerebellar components. The brain continues to change with age, also showing widening of the temporal horns of the lateral ventricles as is seen in patient’s with Alzheimer’s disease (AD).-
Virtually all individuals over age 35 with Down’s Syndrome have been shown to have some kind of microscopic senile plaques and neurofibrillar tangles as seen in victims of Alzheimer’s disease. Using methenamine silver staining techniques with a Nissl counterstain, facilitates the detection of pre-plaques or presumed early senile plaques. These are of unknown origin and composed of amyloid fibrils {homogenous protein), degenerating neurites and reactive filial cells. The plaques are classified on the basis of the morphological arrangement of the amyloid fibrils and degenerating neurites as to whether they are primitive, typical (mature) or compact (burned out). Large plaques are found to be in the localization of glial nuclei, capillaries and neuronal perikarya. Smaller plaques tend to be localized around neuron cell bodies. Senile plaques have amyloid "cores" which have been shown to give the same amino acid sequence as beta protein which was first isolated from amyloid found in a meningeal vessel. It is believed to be from a larger amyloid precursor protein (APP). The gene encoding for this is thought to be on chromosome 21 producing at least three different forms of APP mRNA expressed in the brain, spleen, heart and kidney. It is still unknown whether or not a plasma precursor exists. Pre-plaque or "pre-amyloid deposits" areas cannot be detected by conventional antigen or Congo Red stains but are seen as granular staining areas using an immunohistochemical reaction and the anti-beta protein antibody. In DS people over 40, features of AD including senile plaques and neurofibrillary tangles are seen as well as the development of dementia. In younger individuals they are not. Using the above mentioned staining technique, a large number of pre-plaques can be seen in the younger individuals suggesting that the deposition of amyloid precedes the degeneration of neurites and may originate from proximal dendrites of morphologically normal neurons. The development of the pre-plaques into the typical plaque structure is still not clear yet and is being studied.
Experiments have been done involving murine embryonic brain development, in which murine trisomy 16 is considered to serve as a model of the human trisomy 21. The same phenotypic features are observed in a mouse as seen in human Down’s syndrome. At day 17 of embryonic development, retardation is noted to occur in the murine embryo. The results are a reduction in brain size and cortical thickness. Also observed in this murine model is a great reduction of muscarinic receptors showing selective retardation of some neuronal systems that appear to be deficient in Down’s adults. Evidence for this in human species is the increased mydriatic or pupillary dilation response to tropicamide, an anticholinergic. The noted increased response seen in people with Down’s indicates a peripheral cholinergic/adrenergic imbalance.
Other studies have investigated the electrical properties in cultured human fetal dorsal root ganglion neurons when trisomy 21 is present. Compared to diploid cells, action potentials and depolarization/repolarization are faster with decreased spikes seen. It was found that the degree of inactivation of fast sodium channels was decreased in trisomic 21 cells by comparison of normal control cells, which showed complete inactivation of these channels at resting potential. The cells were stimulated by a sodium current containing a slow and a fast current. The slow sodium current generated slower reaction time in trisomic cells than was seen in the controls. When stimulated with the fast current, the trisomic neurons exhibited accelerated activation kinetics believed to be attributed to the activation of residual fast sodium channels that were not inactivated, and thus allowed for a faster time course of the action potentials
The cerebellar basket cells, corpus callosum and internal capsule axons stain much more intensely in the nervous tissue of Down’s postmortem obtained tissue. This could suggest an aberrant expression of a neurofilament subunit now associated with DS and chronic heart failures. An aberrant neurofibril expressed in the first few months of life in Down’s Syndrome may be associated with the eventual development of Alzheimer’s Disease leading to the presumption that AD is a congenital disease. This could also implicate the lack of cytoskeletal integrity and an axoplasmic transport deficiency to account for malfunction in DS. Aberrant expression of a normal cytoskeletal component may be the predisposing factor of AD, and may be from chromosome 21. Other possible proteins on chromosome 21 are SOD-1 and interferon alpha and beta receptor. Down’s individuals have a 3 to 8 fold increased response to interferon.
In the organization of the cell, there are three polymeric protein systems - microtubules, intermediate filaments and microfilaments. These elements are responsible for the cytoskeleton and shape of the cell, its motility, cytoplasmic flow of the organelles, and in the nerve cell, axoplasmic flow. Some evidence indicates that these proteins may also be a part of the process of learning at the synaptic level and partially responsible for the mental retardation found in Down’s Syndrome. Employment of the Golgi stain on autopsies tissue of Down’s individuals shows them to have an abnormal dendritic arborization, spine shape and distribution. This is suggestive of an underlying cytoskeletal abnormality associated with mental retardedness The basis for abnormal cytoskeletal interactions, in DS is a decrease in the number of cortical neurons resulting in slowed neurogenesis.
This decrease in dendritic spines and arborization is present in young victims of DS with a topography that mimics normal morphology of earlier development, indicating neuronal maturational arrest. Their decreased presence on the pyramidal cells of the hippocampus indicate that the cells haven’t reached normal dendritic spine values, in contrast to Alzheimer’s Disease in which there is a shortening and reduction in the number of dendritic spines with a loss in cortical and hippocampal neurons. In those DS individual’s which have developed AD, the number of dendritic spines falls even lower.
Many of the deficits in trisomy 21 are believed to be related to abnormal expression of a particular protein or proteins. Various mapping techniques are being utilized to search for the location of these genes on the 21st chromosome in hopes of finding out exactly which portion of the gene is responsible for the Down’s related defects. One method would be to look for a protein expressed at one and a half times the normal level, since there is a fifty percent increase in the amount of the gene available for transcription. This is not a fool proof method due to the fact that it could be expressed in low levels, or an autoregulating protein with a feed-back mechanism used in keeping the amount down to normal levels at any given time. For these reasons, it is best to use another method in conjunction with this theory. Also used in the hunt for these genes are Genetic markers, especially the restriction length fragment polymorphism’s (RLFP), which are pieces of DNA that have been cleaved with restriction endonucleases. The DNA is consistently cleaved looking for an alteration in the pattern that may be indicative of a mutation occurring. Finding the location of the genes which cause the mental retardation or other defects, could prove to be a valuable tool in treating or even preventing some of these problems.
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