TY - JOUR
AU - Brown, Rebecca
AB - Contrary to common expectation, the prevalence of Down syndrome (DS) is increasing. The effect of antenatal diagnosis, and the ensuing termination of many affected pregnancies, is being outweighed by the effects of childbearing later in life and the increased longevity of individuals with DS.1 With no interventions capable of altering the fundamental brain impairments and consequent disabilities of DS, the medical outlook has not been promising. However, several recent developments indicate this may be about to change. The genetic basis of DS—trisomy of chromosome 21—has been a risk for primates for at least 30 million to 50 million years.2 At that time, old world monkeys, with whom humans share ancestry, diverged from new world monkeys. In new world monkeys, the ancestral chromosome 21 was substantially larger with many more genes and, if they had been trisomic, would likely have proven fatal. In human ancestry, chromosome 21 is the smallest chromosome, and this may explain the presumed evolutionary durability of this abnormality.2 It was not until the late 19th century that DS was recognized as a distinct condition. In 1866, John Langdon Down, then medical superintendent of the Earlswood Asylum for Idiots in Surrey, England, published “Observations on an Ethnic Classification of Idiots.”3 He termed the condition mongolism because of apparent facial resemblance to east Asian races. Ninety-three years later, in 1959, the discovery that individuals with DS had trisomy 21 was first reported by Lejeune et al.4 This landmark finding prompted the critical question: what is the mechanism by which an extra chromosome 21 produces the phenotype Down had recognized? Remarkably, this question has defied resolution for 50 years, despite several important observations. One of these observations was the realization that DS could be caused by trisomy of only part of chromosome 21, in the context of translocation. This led to the identification of the distal long arm of chromosome 21 as the region responsible for the DS phenotype. Case reports of individuals with translocations of different portions of the long arm of chromosome 21 described partial or complete DS phenotype, leading to the proposal of a DS critical region (DSCR).5 However, the exact delineation of this region was and remains unclear. In 1971, a strong association between DS and dementia of Alzheimer type was observed; and later, amyloid plaques and neurofibrillary tangles characteristic of Alzheimer dementia were shown to be present in nearly all individuals with DS older than 40 years.6 Another important step was the development of mouse models of DS. Mouse chromosome 16 is homologous with most of the long arm of human chromosome 21, and mice with trisomy 16 have a clinical phenotype that corresponds well with DS, including similar facial abnormalities, learning deficits, and alterations in brain architecture. The Ts65Dn mouse has been most often studied. Despite these developments, an understanding of the pathogenic mechanisms of the effects of the trisomy has only emerged in the last 5 years. More than 450 genes have been identified on human chromosome 21. The development of new mouse models, either trisomic for different chromosome segments or for individual genes, has helped narrow the focus to those genes likely to be important contributors to the DS phenotype. Of particular interest are the findings relating to 2 genes located within the putative DS critical region of chromosome 21. These are dual-specificity tyrosine-regulated protein kinase 1 (DYRK1A) and DSCR1. DYRK1A is particularly expressed in the hippocampus, cortex, cerebellum, and heart—regions affected in DS and overexpressed in fetal DS. Transgenic mice that overexpress DYRK1A show learning and memory deficits. Further, DYRK1A phosphorylates tau protein, and this change is known to be important in initiating the cascade of processes leading to amyloid formation in Alzheimer dementia. DSCR1 is overexpressed in Alzheimer patients and causes abnormalities in synapse function in DS individuals. DYRK1A and DSCR1 act synergistically to regulate the transcription factor NFATc, which plays a critical role in the development of the central nervous system.7 In a provocative report by Guedj et al,8 mice trisomic for DYRK1A were fed green tea from birth to adulthood. Green tea contains the polyphenol epigallocatechin-3-gallate (EGCG), known to be one of the most effective DYRK1A inhibitors. Adult trisomic mice fed with EGCG were found to resemble wild-type mice in both brain morphology and performance in learning tests. Consequently, there will be great interest in studies leading to human trials of EGCG in infants with DS. However, mice with completely deleted DYRK1A are nonviable, implying that establishing a safe and effective therapeutic dose will be a major challenge in its usage. In another study, Costa et al9 reported that memantine, which is currently used as therapy for Alzheimer disease, eliminated deficits in hippocampal learning caused by overexpression of DYRK1A in Ts65Dn mice. Trisomy of DSCR1 also has been shown to have another important property. While DS has been known to be associated with a high incidence of leukemia, individuals with DS also have a decreased incidence of solid tumors. DSCR1 has been shown to encode a protein that suppresses vascular endothelial growth,10 and increased expression of DSCR1 is sufficient to suppress tumor growth in mice. Significantly, up-regulated DYRK1A acts synergistically with DSCR1 to further suppress tumor angiogenesis. This suggests that the low incidence of tumors in humans with DS may be a consequence of inhibited angiogenesis in the tumors. Down syndrome remains a significant medical and social challenge. Yet in the last few years, researchers have finally started to unravel the problem posed by Lejeune et al4 half a century ago. The pathogenic mechanisms connecting the DS phenotype and the genes of human chromosome 21 are increasingly being identified, and now for the first time, the possibility of regulating the function of these genes is a reality. The prospect of improving brain function in individuals born with DS is exciting. Furthermore, given the evidence that tumor growth and Alzheimer dementia are influenced by key chromosome 21 genes, the study of the much-neglected condition of DS also holds promise for the entire community. Back to top Article Information Corresponding Author: Stewart L. Einfeld, MD, Faculty of Health Sciences and Brain & Mind Research Institute, University of Sydney, BMRI Level 3, 94 Mallett St, Camperdown, NSW 2050, Australia (stewart.einfeld@sydney.edu.au). Financial Disclosures: None reported. Additional Contributions: Damian Holsinger, PhD, Brain & Mind Research Institute, University of Sydney; Melanie Pritchard, PhD, Department of Biochemistry and Molecular Biology, Monash University; and Bruce Tonge, MD, School of Psychology and Psychiatry, Monash University, commented on the manuscript. None received compensation for the contributions. References 1. Shin M, Besser LM, Kucik JE, Lu C, Siffel C, Correa A.Congenital Anomaly Multistate Prevalence and Survival Collaborative. Prevalence of Down syndrome among children and adolescents in 10 regions of the United States. Pediatrics. 2009;124(6):1565-157119948627PubMedGoogle ScholarCrossref 2. Richard F, Dutrillaux B. Origin of human chromosome 21 and its consequences: a 50-million-year-old story. Chromosome Res. 1998;6(4):263-2689688515PubMedGoogle ScholarCrossref 3. Down JLH. Observations on an ethnic classification of idiots. London Hosp Rep. 1866;3:259-262Google Scholar 4. Lejeune J, Gautier M, Turpin R. Study of somatic chromosomes from 9 mongoloid children [in French]. C R Hebd Seances Acad Sci. 1959;248(11):1721-172213639368PubMedGoogle Scholar 5. Delabar JM, Theophile D, Rahmani Z, et al. Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur J Hum Genet. 1993;1(2):114-1248055322PubMedGoogle Scholar 6. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol. 1985;17(3):278-2823158266PubMedGoogle ScholarCrossref 7. Rachidi M, Lopes C. Mental retardation and associated neurological dysfunctions in Down syndrome: a consequence of dysregulation in critical chromosome 21 genes and associated molecular pathways. Eur J Paediatr Neurol. 2008;12(3):168-18217933568PubMedGoogle ScholarCrossref 8. Guedj F, Sébrié C, Rivals I, et al. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PLoS One. 2009;4(2):e460619242551PubMedGoogle ScholarCrossref 9. Costa ACS, Scott-McKean JJ, Stasko MR. Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology. 2008;33(7):1624-163217700645PubMedGoogle ScholarCrossref 10. Baek KH, Zaslavsky A, Lynch RC, et al. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature. 2009;459(7250):1126-113019458618PubMedGoogle ScholarCrossref
TI - Down Syndrome—New Prospects for an Ancient Disorder
JF - JAMA
DO - 10.1001/jama.2010.842
DA - 2010-06-23
UR - https://www.deepdyve.com/lp/american-medical-association/down-syndrome-new-prospects-for-an-ancient-disorder-e4SNasaVxt
SP - 2525
EP - 2526
VL - 303
IS - 24
DP - DeepDyve
ER -