A chromosomal abnormality that is the commonest cause of MENTAL HANDICAP in children, affecting 1 in 600 live births. Once known as mongolism, Down syndrome is characterized by distinctive morphological features in the development of the face and neck, a shortened stature, immune deficiency, and a developmental heart defect that is the commonest cause of early death, as well as the marked sub-normality. The risk of having a Down syndrome child increases in mothers older than 30 and fathers older than 60. The mental subnormality involves a wide range of social and intellectual functions, and can vary widely in severity. The most severely affected do not acquire the ability to speak, dress or feed themselves, and require total lifelong care, whereas with family support the less affected can develop good language skills, begin to read, maintain good social interactions, and undertake simple work.
Down syndrome is in most cases due to the embryo acquiring an extra copy (trisomy) of chromosome 21 at MEIOSIS (see CHROMOSOMES; CELL DIVISION). In rare cases, the syndrome may also arise from chromosomal translocations in which only a fragment of chromosome 21 is carried in triplicate, implicating the distal part of the long arm of chromosome 21 as the obligate region that determines the syndrome. This segment of the chromosome is associated with genes for SUPEROXIDE DISMUTASE, important in regulating developmental cell death (see APOPTOSIS), and the AMYLOID PRECURSOR PROTEIN implicated in the development of the pathology of Alzheimer’s disease. The chromosomal abnormalities can be detected in utero by amniocentesis or the newer techniques of chorionic villa sampling, and routine prenatal screening allows the parents, with counselling, to decide whether to terminate the pregnancy.
Until recently, the majority of Down syndrome cases died in childhood and young adulthood, in particular due to the atrioventricular septal heart defect and an impaired immunological response. In the last three decades improved health care has markedly increased the life span of affected individuals, commonly into their 50s.
This has revealed an additional burden of an Alzheimer-like dementia with onset at 40–50 years of age, and the same pathology as Alzheimer disease is seen at post mortem of senile PLAQUES and NEUROFIBRILLARY TANGLES. Since all affected individuals ultimately develop this pathology and dementia several decades earlier than its occurrence in spontaneous Alzheimer’s disease, Down syndrome has become an important source of information for studying the development of Alzheimer-like pathology. It turns out that the first detectable pathological event is the deposition of the β/A4 amyloid protein in the brains in teenage cases. The association of this primary pathology with triplication of a particular chromosome was the critical clue enabling the search for the amyloid precursor protein gene to focus on chromosome 21, leading to its rapid identification and sequencing in 1987.
Trisomy of different chromosomes can be selectively bred in various strains of mice having acrocentric chromosomes by cross-breeding between parents with different Robertsonian translocations. Most trisomies in mice are lethal, as in humans, including trisomy of murine chromosome 16 (syntenic to chromosome 21 in humans) which die in utero of a septal heart defect. The murine models have proved useful for detailed analysis of pathology in the development of systems in the brain as well as of peripheral organs. It has been shown that trisomy 16 mouse brain tissues will also develop an Alzheimer-like pathology by transplantation of embryonic cortical donor tissue into the brains of normal host mice.
Reference
Holland A.J. & Oliver C. (1995) Down’s syndrome and the link with Alzheimer’s disease. Journal of Neurology, Neurosurgery and Psychiatry 59:111–114.
STEPHEN B.DUNNETT
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