Down’s Syndrome, Trisomy 21, or Mongolism is one of the most common causes of mental retardation. The majority of Down’s Syndrome patients have a moderate retardation although it can range from mild to severe. Trisomy 21 occurs in about 1 in 800 live births. This incidence increases markedly as the age of the mother increases over 35. The prevalence in children born to young mothers is 1 in 1000, while it increases to almost 1 in 40 in children born to mothers over 40. Most individuals with Down’s Syndrome have characteristic features such as upward slanted eyes, broad flattened face, short neck, and a prominent tongue. Muscle coordination is often impaired in these individuals, resulting in uncoordinated posture and balance. Congenital heart disease is found in forty percent of these individuals, along with a near twenty fold increase in the risk of kidney malformation, thyroid abnormalities, diabetes, leukemia. Neurological retardation and impaired immune systems render these individuals more susceptible to infection and disease.

In the early l900s, Downs Syndrome patients rarely lived to reach the age of twenty, as they only had a life expectancy of about 10 years. With the advances of modern health care, most individuals, excluding those with irreparable heart damage, live to reach adulthood. Although it is still shorter than normal adults, their life expectancy has increased to about fifty-five.

The disorder was initially described as Mongolism by British physician John Langdon Down. Many theories for the etiology of this condition surfaced, including racial regression, endocrine gland dysfunction, and uterine exhaustion. It was not until the 1930s that Adrian Bleyer hypothesized that the disorder was related to the failure of chromosomes to separate (nondisjunction), resulting in an with an extra copy of one chromosome. This remained only a hypothesis as the exact number of chromosomes had not yet been identified. During the 1950’s the number of chromosomes was identified as forty-six, and Bleyer’s hypothesis was soon supported, as it was verified that individuals with Down’s Syndrome did in fact have 47 chromosomes.

In Down’s Syndrome one pair of chromatics fail to separate during reproductive cell division, resulting in a daughter cell with two chromatics, and the other with none, which then dies. This error is referred to as nondisjunction, and usually occurs during Anaphase I or Anaphase II. It is a result of the failure of spindle fibers to pull the chromatics to their respective poles. Nondisjunction usually occurs on chromosome 21, the smallest of the chromosomes. This abnormal gamete then is then fertilized by the male gamete, resulting in an offspring with chromosome 21 in triplicate, hence the name Trisomy 21.

About three to four percent of patients with Down’s Syndrome have translocation, a slightly different chromosomal abnormality. A portion of chromosome 21 attaches itself to another chromosome during cell division. This results only in part of chromosome 21 being in triplicate, but the offspring once again manifests Down’s Syndrome.

The brain’s of Down’s Syndrome patients show morphological differences when compared to normal individuals. Via magnetic resonance imaging and post mortem examinations it has been determined that the volume of the whole brain is significantly smaller in Trisomy 21 patients. This is due to a reduced volume of cerebral cortex, white matter, and cerebellum, while other structures showed no significant differences from control subjects.

As individuals with Down’s Syndrome approach middle age, their brains begin to show pathological changes similar to Alzheimer Disease. The majority of Down’s Syndrome patients over the age of thirty-five show microscopic senile plaques and neurofibrillar tangles, structures otherwise only seen in Alzheimer patients. Efforts are being made to determine of these changes result in degeneration of neurological function seen in Alzheimer disease. Most patients have developed large enough numbers of amyloid plaques to merit a diagnosis of Alzheimer disease upon their death. These similarities suggest that the pathogenesis of the two diseases may be related.

It is not known whether the formation of neurofibrillar tangles precede the formation of senile plaques, or the plaques form initially, followed by the tangles. One hypotheses suggests that Down’s patients may be predisposed to plaque formation because they possess an extra copy of chromosome 21, which encodes the precursor for the amyloid protein. The duplication may result in overproduction of amyloid protein. Senile plaques have shown high amounts of this amyloid protein. This amyloid protein may in some unknown way lead to the formation of tangles.

Neurofibrillar tangles are flame shaped alterations composed mainly of condensed cytoskeletal proteins. These tangles seem to consistently present in specific locales of neurons. These include projection neurons in defined cytoarchitectural fields within the hippocampus and association cortices, while other neurons in the sensory and motor cortex are spared. The tangles consist primarily of a microtubule associated protein, tau This protein is normally only located in axonal projections. In Alzheimer and Down’s patients tan appears in the somatodendritic compartment within neurofibrillar tangles. Neurons possessing tangles are still capable of synthesizing tau As the proteins build up and are phosphorylated, the cell eventually dies.

Senile plaques demonstrate a similarity to tangles in their topographic hierarchical distribution. Dr. Masters has demonstrated Beta A-4 protein is present in normal individuals by the age of 45, and increases with age. Eighty percent of the population over 80 years of age show significant amounts of amyloid protein. Down’s patients, however, begin to manifest this plaque precursor nearly thirty years earlier. Current investigations are attempting to determine if this amyloid protein is causally related to the formation of neurofibrillar tangles. Evidence is not yet conclusive. Research by Hyman suggests that the first structure to appear, depends upon location; in the hippocampus and entorhinal formation, tangles are first to appear, while in the rest of the cortex senile plaques are the initial presentation.

ALZ-50 is an antibody that is reactive to the neuritic component present in senile plaques and tangles. An investigation was performed by Sparks and Hunsaker to determine the presence of ALZ-50 neurons in Down’s patients verses controls. They discovered that older Down’s subjects did consistently show more ALZ-50 immunoreactive neurons that did age-matched normal controls. Evidence suggested that neuronal degeneration occurred early in Down’s patients in relation to Alzheimer patients. This degeneration continues throughout the life of the individual. Since the same areas of the brain are affected one would think Down’s patients should manifest the progressive cognitive deficits common in Alzheimer Disease. Evidence suggests that this degeneration does occur but may be masked by the mental retardation. Cognitive ability has been shown to decline in individuals with Down’s Syndrome as they reach their late fifties.

In the Down’s patients Hyman demonstrated that the accumulation of ALZ-50 neurons may result in the formation of diffuse plaques, which may be the precursor of further plaque development. Hyman deviates from the current school of thought in that he believed the development of senile plaques is due to the ALZ-50 neurons rather than an over-expression of the amyloid gene. These neurons may contribute dystrophic neurites to the senile plaques. It may also be possible that the AlZ-50 neurons become neuropil threads and are responsible for the formation of neurofibrillar tangles.

Research has indicated a positive correlation between the amount of plaques and tangles, and presence of organic heart disease. Therefore this immunoreactive protein may be due to either the chromosome in triplicate or it could be a result of the heart disease present in most Down’s patients.

Evidence remains inconclusive as to the exact cause of the increase in the Alzheimer type pathologies seen at very early ages in Down’s patients. The triplicate chromosome 21 obviously plays a key role in the etiology of plaques and tangles. Perhaps it is either the increase in the amyloid protein or the AlZ-50 reactive neuron or a combination of the two that results in the formation of the plaques and tangles.

Works Cited:

Sparks and Hunsaker. Down’s Syndrome: occurrence of ALZ-50 reactive neurons and the formation of senile plaques. Journal of the Neurological Sciences, 1992, 109: 593-598.

Raghavan, R. Detection of Lewy Bodies in Trisomy 21. Can. J. Neurol. Sci., 1993, 20:48-51.

Goodison. Neuronal and Glial Gene Expression in Neocortex of Down’s Syndrome and Alzheimer Disease. Journal of Neurol. and Exp. Neurol., 1993, 52 (3) 192-198.

Hyman, B. T. Down Syndrome and Alzheimer disease. Prog. Clin. Biol. Res., 1992, 379: 123-42.

Silverman W. Alzheimer neuropathology in mentally retarded. Acta Neuropathol. Berl., 1993, 85(3):260-6.

Beyreuther, K. Regulation and expression of the Alzheimer’s Beta amyloid protein in Down’s Syndrome. Ann. N.Y. Acad. Sci., 1993, 695: 91-102.

Murata, T. In vivo proton magnetic resonance spectroscopy study on premature aging in Down’s Syndrome. Biol. Psychiatry, 1993, 34(5): 290-7.

Also used articles in the Down’s Syndrome file from previous years.