Down syndrome

Abstract

Trisomy 21, the presence of a supernumerary chromosome 21, results in a collection of clinical features commonly known as Down syndrome (DS). DS is among the most genetically complex of the conditions that are compatible with human survival post-term, and the most frequent survivable autosomal aneuploidy. Mouse models of DS, involving trisomy of all or part of human chromosome 21 or orthologous mouse genomic regions, are providing valuable insights into the contribution of triplicated genes or groups of genes to the many clinical manifestations in DS. This endeavour is challenging, as there are >200 protein-coding genes on chromosome 21 and they can have direct and indirect effects on homeostasis in cells, tissues, organs and systems. Although this complexity poses formidable challenges to understanding the underlying molecular basis for each of the many clinical features of DS, it also provides opportunities for improving understanding of genetic mechanisms underlying the development and function of many cell types, tissues, organs and systems. Since the first description of trisomy 21, we have learned much about intellectual disability and genetic risk factors for congenital heart disease. The lower occurrence of solid tumours in individuals with DS supports the identification of chromosome 21 genes that protect against cancer when overexpressed. The universal occurrence of the histopathology of Alzheimer disease and the high prevalence of dementia in DS are providing insights into the pathology and treatment of Alzheimer disease. Clinical trials to ameliorate intellectual disability in DS signal a new era in which therapeutic interventions based on knowledge of the molecular pathophysiology of DS can now be explored; these efforts provide reasonable hope for the future.

Fig. 1 |. Symptoms and manifestations in Down syndrome.

Individuals with trisomy 21 (the presence of a supernumerary chromosome 21; also known as Down syndrome (DS)) present with a distinct collection of symptoms and manifestations that affect multiple body systems, although variation exists between individuals. Individuals with DS are generally of short stature, with short fingers, hypotonia and atlantoaxial instability. Facial characteristics include the presence of epicanthic folds, flat nasal bridge and occiput, small mouth and ears, and up-slanting palpebral fissures. Congenital heart defects are common, particularly atrioventricular septal defect (AVSD). Individuals with DS are also more likely to develop certain health conditions compared with the general population, including hypothyroidism, obstructive sleep apnoea, epilepsy, hearing and vision problems, haematological disorders (including leukaemia), recurrent infections, anxiety disorders, and early-onset Alzheimer disease.

Fig. 2 |. Prevalence of DS and pregnancy outcomes in the USA.

a | Prevalence of Down syndrome (DS) in the USA for the period 1950–2013. This graph combines the prevalence data for 1950–2010 in the USA with unpublished prevalence data for 2011–2013 for the same region. b | Pregnancy outcomes in the USA for the period 1974–2013. This graph combines estimates of live births, natural losses and elective terminations in women carrying a fetus with DS after 10 weeks gestation for the period 1974–2010 in the USA with unpublished data for 2011–2013 (REF.). GA, gestational age. Part a adapted from REF., Springer Nature Limited. Part b adapted with permission from REF., Wiley-VCH.

Fig. 3 |. Conserved synteny of human chromosome 21 with mouse chromosomes and mouse models of trisomy 21.

Down syndrome (DS) results from the presence of a supernumerary Homo sapiens chromosome 21 (HSA21). More than 20 mouse models of DS have been created, which are designed to overexpress part of or a complete HSA21, or the orthologous mouse genomic regions^,,. Mouse orthologues of HSA21 genes occur on Mus musculus chromosome 16 (MMU16), MMU17 and MMU10. Tc1 mice carry a mutated HSA21 and are mosaic animals, with a mix of trisomic and euploid cells that is unique to each individual, apparently due to suboptimal function of the human centromere in mice. Ts65Dn animals contain a duplication of ~140 genes on MMU16, some of which are not orthologous to HSA21^, (dashed line). TcMAC21 animals contain the long arm of HSA21 (HSA21q) as a mouse artificial chromosome (that is, with a mouse centromere to ensure that the chromosome is retained in every cell); however, this artificial chromosome contains deletions that affect ~8% of HSA21q genes. All of these models except Ts65Dn are direct duplications; that is, the genes in each are trisomic but they do not contain an extra chromosome or centromere. Ts1Rhr, Ts1Cje, Ts1Yey and Ts65Dn mouse models are discussed in the text.

Fig. 4 |. Mechanisms of Alzheimer disease in Down syndrome.

The increased gene dosage of APP (encoding amyloid precursor protein (APP)) and DYRK1A (encoding dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)) on Homo sapiens chromosome 21 (HSA21) in individuals with Down syndrome (DS; trisomy 21) increases their risk of developing Alzheimer disease (AD). APP can undergo non-amyloidogenic processing (not shown) and amyloidogenic processing by β-secretase 1 (β-sec) and γ-secretase (γ-sec) to produce the neurotoxic Aβ42 peptide. The increased APP levels result in higher levels of Aβ42, and phosphorylation of APP at Thr668 by DYRK1A increases the amyloidogenic processing of APP. DYRK1A has other targets in the cell, including splicing factors and the microtubule-binding protein tau. DYRK1A phosphorylation of splicing factors alters the splicing of the MAPT mRNA (encoding tau), resulting in increased levels of tau containing three microtubule-binding domains (three-repeat (3R) tau) and reduced levels of 4R tau. This imbalance leads to neurofibrillary tangle (NFT) formation, possibly due to the lower binding affinity of 3R tau for microtubules. Furthermore, DYRK1A phosphorylation of Thr212 in tau alters the conformation of the protein, reducing the affinity of tau for microtubules and leading to NFT formation. The presence of the ε4 allele of APOE (APOE^⋆ε4) alters the processing, deposition and clearance of Aβ, and is therefore a major risk allele for AD. AICD, APP intracellular domain; APOE, apolipoprotein E; CNS, central nervous system; P_i, inorganic phosphate; sAPP, soluble amyloid precursor protein.

Fig. 5 |. Alzheimer disease prevalence and cognitive decline in Down syndrome.

a | Distribution of age at dementia diagnosis in individuals with Down syndrome (DS). The risk of developing Alzheimer disease in individuals with DS is closely related to age. The mean age of dementia diagnosis is 55 years, although some individuals already show cognitive decline starting from 40 years of age, whereas others are not diagnosed until after 60 years of age. b | Cognitive decline in individuals with DS, measured by performance (z score) in a memory test. Cross-sectional data from the London Down Syndrome Consortium showing the distribution of test scores on an object memory task by age and apolipoprotein E (APOE) genotype in individuals with DS. The task is a measure of short-term and delayed memory, adapted for individuals with DS. Participants are instructed to name and recall seven objects with two immediate recall trials, and one delayed recall trial after 5 minutes. The data are split by APOE genotype to compare the effect of the ε4 allele of APOE (APOE^⋆ε4; which increases the risk of late-onset sporadic Alzheimer disease) with that of the APOE^⋆ε2 allele (which decreases AD risk) and APOE^⋆ε3 allele (which has a neutral effect on AD risk) on cognitive performance. Cognitive performance in individuals with an APOE^⋆ε3/APOE^⋆ε4 or APOE^⋆ε4/APOE^⋆ε4 genotype declines from 40 years of age, noticeably earlier than the average age of dementia diagnosis and earlier than in individuals with an APOE^⋆ε2/APOE^⋆ε2, APOE^⋆ε2/APOE^⋆ε3, APOE^⋆ε2/APOE^⋆ε4 or APOE^⋆ε3/APOE^⋆ε3 genotype. Part a is adapted from REF., CC-BY-4.0 (https://creativecommons.org/licenses/by/4.0/). Part b adapted with permission from REF., Elsevier.