What Is Hemophilia? Symptoms, Causes, Diagnosis, and Treatment
Trisomy 21
Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy, Down's SyndromeACMG/AMP Pathogenicity Criteria: PS1, PS2, PS3, PS4, PM1Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Down's SyndromeCoding/Non-Coding: BothDNA Change: DuplicationExpected RNA Consequence: DuplicationExpected Protein Consequence: DuplicationGenomic Region: Chromosome 21
The presence of three copies of chromosome 21, which harbors the amyloid precursor protein (APP) gene, is the most common genetic cause of Alzheimer's disease. Carriers of this alteration have Down syndrome (DS), a condition that results in cognitive disability, alterations in craniofacial morphology, increased risk of congenital heart defects, immune disorders, reduced sense of smell, and a very high risk of developing AD (Antonarakis et al., 2020). Most commonly, trisomy 21 arises because of meiotic nondisjunction in which a pair of chromosomes 21 fail to separate in either the sperm or egg. The frequency of this alteration is relatively high, approximately 0.001 worldwide, according to the World Health Organization.
Dating back to 1948, multiple studies have shown that middle-aged individuals with DS are likely to develop AD dementia and pathology, including amyloid plaques, neurofibrillary tangles, and neuronal loss (Jervis, 1948; for review see Lott and Head, 2019). Of note, the original description of amyloid β (Aβ) was in DS (Glenner and Wong, 1984) and contributed to the formulation of the Aβ hypothesis (Lott and Head, 2019).
Mean age at onset of dementia in DS is 55 years (Sinai et al., 2018), by 60 years 70 percent of individuals with DS have been diagnosed with dementia, and by 65, 88 percent (McCarron et al., 2017). Like AD in the general population, AD in individuals with DS is characterized by dementia and can also be accompanied by gait disturbance, sleep disruption, and seizures. The latter are particularly frequent in DS AD, commonly developing after the third decade of life and before the onset of dementia (Lott and Head, 2019).
Overall, AD in DS appears to be the same disease as AD in the general population. Fortea and colleagues, for example, found almost identical AD biomarker trajectories in DS as in autosomal dominant AD (Fortea et al., 2020). In addition, as in sporadic and familial AD, APOE4 accelerates the onset of AD in individuals with DS (Bejanin et al., 2021; Jul 2021 news). Also, AD polygenic risk scores were associated with cognitive phenotypes and cerebrospinal biomarkers in DS adults, suggesting common pathways influence memory decline in both (Gorijala et al., 2023). Interestingly, some studies suggest that, in the general population, trisomy 21 mosaicism in the brain—affecting only a subpopulation of cells—may contribute to AD and other neurodegenerative diseases (for review see Potter et al., 2016).
NeuropathologyAD neuropathology in DS surfaces at a young age. Amyloid plaques can start depositing in carriers as early as during the teen years and 20s (e.G., Lemere et al., 1996; Mori et al., 2002), and are seen routinely after age 30. After age 40, when virtually all DS individuals have AD neuropathology, amyloid accumulation ramps up at an exponential rate (Lott and Head, 2019). Neuropathology is also characterized by Aβ accumulation around the cerebral vasculature. The extent of cerebrovascular disease appears to correlate with the severity of amyloid and tau pathologies, suggesting it is a core feature of DS AD tied to AD progression (Aug 2023 conference news).
The spread of amyloid and tau pathologies in DS AD generally follows the pattern observed in late-onset AD, as do levels of biomarkers in cerebrospinal fluid and blood (e.G., Janelidze et al., 2022; July 2022 news). However, some differences in pathology have been noted (Lott and Head, 2019). For example, in DS, PET imaging suggests the striatum is burdened with amyloid very early on and neurofibrillary tangles are particularly dense in DS brains compared with non-DS brains (Lao et al., 2016, Annus et al., 2016).
Moreover, individuals with DS appear to have a higher frequency and severity of cerebral amyloid angiopathy (CAA) and have a unique neuroinflammatory phenotype possibly due to serum proteins infiltrating the brain via microbleeds. Indeed, microbleeds correlate with CAA in postmortem cortical tissue from individuals with DS beginning in the mid-30s, mirroring the rise in amyloid plaques (Helman et al., 2019). However, compared with CAA in carriers of other APP duplications limited to APP with or without a few neighboring genes, CAA in DS appears to be less severe and individuals with DS have a lower frequency of cerebral hematoma (Mann et al., 2018). This may be due to carriers of APP duplications having higher brain levels of total Aβ and shorter Aβ peptides than individuals with DS (Aug 2023 conference news).
DS AD can present with other neurodegenerative pathologies as well. A post-mortem study of 33 DS AD cases, for example, detected Lewy body pathology in the amygdala of 55 percent of individuals between the ages of 41 and 59, and in 75 percent of individuals aged 61 to 72 (Wegiel et al., 2022). Nine percent of the 33 cases had TDP-43 pathology.
Biological EffectAPP overexpression and the accumulation of Aβ in the brain is considered the primary driver of dementia in individuals with trisomy 21 (for reviews see Wiseman et al., 2015; Lott and Head, 2019). Consistent with this, at least two individuals with partial trisomy 21, carrying three copies of some parts of chromosome 21 but only two copies of APP, have lived past the age of 70 without developing either dementia or AD pathology (Prasher et al., 1998, Doran et al., 2017). Conversely, families with small chromosome 21 duplications consisting of only a few genes including APP have been reported to suffer from early onset AD. Indeed, there are AD families in which APP is the only gene present within the disease-associated duplication or triplication (APP Duplication 1104 [APP-APP]; see also APP Triplication [APP-APP]).
Consistent with the clinical and genetic findings described above, increasing evidence at the cellular and molecular levels indicate DS AD is mechanistically very similar to AD in the general population. For example, a preprint describing spatial transcriptomics and single-nucleus RNA-seq analyses of cortical samples from patients with sporadic AD and DS AD reported broad similarities between the two conditions (Miyoshi et al., 2023). Also, a pathway involving the binding of APP β-CTF to a lysosomal proton pump appears to lead to lysosomal dysfunction in both AD and DS AD (Jul 2023 news, Im et al., 2023).
Nevertheless, the overexpression of non-APP genes on chromosome 21, numbering over 200, may also modify AD risk and presentation (see Lott and Head, 2019 for review). For example, increased expression of DYRK1A, which encodes a kinase that phosphorylates many proteins including tau, and splicing factors that modulate tau mRNA splicing, and RCAN1, which regulates calcineurin, may accelerate the emergence of neurofibrillary tangles. DYRK1A, which also phosphorylates APP, has been reported to increase APP levels as well (e.G., Ferrer et al., 2005, Ryoo et al., 2008, Garcia-Cerro et al., 2017).
On the other hand, some genes on chromosome 21 may delay AD pathology. Age at onset for DS AD varies widely, with many individuals suffering from cognitive decline only after age 55, later than the mean age of onset (~52 years) for APP duplication carriers (Wiseman et al., 2015). One study identified a subregion of chromosome 21 that decreases Aβ accumulation in mouse brain (Mumford et al., 2022). This region included BACE2, previously reported as protective against AD pathology (Feb 2020 news, Alić et al., 2021) and, paradoxically, DYRK1A.
In addition to genetic modifiers of Aβ and tau pathologies, other factors likely modulate the expression of AD in DS individuals. For example, trisomy 21-associated alterations in brain structure, elevated incidence of epilepsy, and disruptions of the immune system that arise during development might increase vulnerability to AD (Lott and Head, 2019).
Several clinical trials for DS are in the works (May 2021a news), including testing of the anti-amyloid vaccine ACI-24 (May 2021b news) and subdermal pulses of gonadotropin-releasing hormone (Sep 2022 news). Of note, anti-amyloid antibodies have yet to be tested in DS AD. Researchers are proceeding cautiously because CAA, very often present in DS AD, is a strong risk factor for amyloid-related imaging abnormalities (ARIA), a side-effect of amyloid antibody treatments (Aug 2023 conference news).
Research Models
Multiple rodent models of DS have been generated (Herault et al., 2017), with a subset being particularly relevant to AD-DS (Farrell et al., 2022). The models have been used for in vivo studies, as well as experiments using cultured cells and organotypic slice cultures.
This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.
PS1-MSame amino acid change as a previously established pathogenic variant regardless of nucleotide change. Trisomy 21: Includes an extra copy of APP like multiple APP duplications known to be pathogenic.
PS2-SDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PS3-SWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PS4-SThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
PM1-SLocated in a mutational hot spot and/or critical and well-established functional domain (e.G. Active site of an enzyme) without benign variation. Trisomy 21: Mutation encompasses the APP gene, a mutational hotspot and a gene known to play a well-established functional role in AD.
Pathogenic (PS, PM, PP) Benign (BA, BS, BP) Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)Trisomy 21 Causes Down Syndrome
One could argue that the presence of extra copies of chromosome 21 in DS patients is only a correlation between an abnormality and the disease. However, scientists have developed trisomic mouse models that display symptoms of human DS, providing strong evidence that extra copies of chromosome 21 are, indeed, responsible for DS. It is possible to construct mouse models of DS because mouse chromosomes contain several regions that are syntenic with regions on human chromosome 21. (Syntenic regions are chromosomal regions in two different species that contain the same linear order of genes.) With mapping of the human and mouse genomes now complete, researchers can identify syntenic regions in mouse and human chromosomes with great precision.
As shown in Figure 4, regions on the arms of mouse chromosomes 10 (MMU10), 16 (MMU16), and 17 (MMU17) are syntenic with regions on the long q arm of human chromosome 21. Using some genetic tricks, scientists have induced translocations involving these mouse chromosomes, producing mice that are trisomic for regions suspected to play a role in DS. (Note that these are not perfect models, because the trisomic regions contain many mouse genes in addition to those that are syntenic to human chromosome 21 genes.) These experiments have shown that genes from MMU16 are probably most important in DS, because mice carrying translocations from MMU16 display symptoms more like human DS than mice carrying translocations of MMU10 or MMU17.
Additional experiments have tried to identify particularly important genes within this region by transferring smaller segments of the interval on MMU16. For example, the three mouse models depicted on the right in Figure 4 carry different portions of MMU16, and all display some symptoms of DS. Of the three, the most faithful model of DS is the Ts65Dn mouse, which carries 132 genes that are syntenic with human chromosome 21. This particular mouse demonstrates many of the symptoms of human DS, including altered facial characteristics, memory and learning problems, and age-related changes in the forebrain.
These results are both daunting and promising. On one hand, they suggest that there will be no magic bullet for treating DS, because large numbers of genes are most likely involved in the condition. On the other hand, the results suggest that mouse models will be useful in developing treatments for the many DS patients around the world.
Figure 4: Regions of synteny between human chromosome 21 (HSA21) and mouse chromosomes (MMUs) 16, 17, and 10.
There are three partial trisomy mouse models of human trisomy 21, all trisomic for a portion of MMU 16. The gene content of these partial trisomies is shown on the right.
Cause Of Leukaemia In Trisomy 21
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03/10/2023 10:00 Cause of leukaemia in trisomy 21People with a third copy of chromosome 21, known as trisomy 21, are at high risk of developing Acute Myeloid Leukaemia (AML), an aggressive form of blood cancer. Scientists led by the Department of Paediatrics at University Hospital Frankfurt have now identified the cause: although the additional chromosome 21 leads to increased gene dosage of many genes, it is above all the perturbation of the RUNX1 gene – a gene that regulates many other genes – that seems to be responsible for AML pathogenesis. Targeting the perturbed regulator could pave the way for new therapies.
FRANKFURT. Leukaemia (blood cancer) is a group of malignant and aggressive diseases of the blood-forming cells in the bone marrow. Very intensive chemotherapy and in some cases a bone marrow transplant are the only cure. Like all cancers, leukaemia is caused by changes in the DNA, the heredity material present in human cells in the form of 46 chromosomes. In many forms of leukaemia, large parts of these chromosomes are altered. People with Down syndrome, who have three copies of chromosome 21 (trisomy 21) are highly vulnerable: the risk of developing aggressive Acute Myeloid Leukaemia (AML) in the first four years of their life is more than 100 times greater for children with Down syndrome. Down syndrome is the most common congenital genetic disorder, affecting about one in 700 newborn babies.
RUNX1 transcription factor is responsible
The research group led by Professor Jan-Henning Klusmann, Director of the Department of Paediatric and Adolescent Medicine at University Hospital Frankfurt, has now discovered how the additional chromosome 21 can promote AML. With the help of genetic scissors (CRISPR-Cas9), they examined each of the 218 genes on chromosome 21 for its carcinogenic effect. It emerged that the RUNX1 gene is responsible for the chromosome's specific carcinogenic properties. In further analyses, the researchers were able to corroborate that only one particular variant – or isoform – of the gene promotes the development of leukaemia. Klusmann explains: "Other RUNX1 isoforms were even able to prevent the cells from degenerating. This explains why RUNX1 has so far not stood out – in several decades of extensive cancer research."
The RUNX1 gene encodes a "transcription factor" – a protein responsible for regulating the activity of other genes. RUNX1 regulates many processes, including embryonic development and early and late haematopoiesis, or blood formation. Disruption of this important regulator is therefore a key event in the development of AML. "Thanks to our research results, we now have a better understanding of what happens in leukemogenesis," explains Klusmann, an expert in paediatric cancer. "The study underlines how important it is to examine all gene variants in carcinogenesis. In many cases, certain mutations in cancer cells alter how these variants form," he says.
Development of more sophisticated therapeutic approaches
These insights are important for a better understanding of the complex mechanisms of carcinogenesis, as Klusmann explains: "In this way, we have laid the groundwork for developing more sophisticated therapeutic approaches. Through our biochemical analyses, we now know exactly how the gene variant alters the blood cells. From there, we were able to use specific substances that block the disease mechanism." The intention now is to further explore the effect of these substances for use in medical care. Klusmann: "On the basis of our expertise, we now want to develop therapies to correct this malfunction. Applying them in clinical practice will certainly take a few more years, but hopefully they will lead in the future to sparing our young patients from intensive chemotherapy."
Contact for scientific information:Professor Jan-Henning KlusmannDirectorDepartment of Paediatric and Adolescent MedicineUniversity Hospital FrankfurtTel.: +49 69 6301-5094kkjm-direktor@kgu.Dewww.Kgu.Dewww.Leukemia-research.De
Original publication:Gialesaki S, Bräuer-Hartmann D, Issa H, Bhayadia R, Alejo-Valle O, Verboon L, Schmell AL, Laszig S, Regenyi EM, Schuschel K, Labuhn M, Ng M, Winkler R, Ihling C, Sinz A, Glaß M, Hüttelmaier S, Matzk S, Schmid L, Strüwe FJ, Kadel SK, Reinhardt D, Yaspo ML, Heckl D, Klusmann JH. RUNX1 isoform disequilibrium promotes the development of trisomy 21 associated myeloid leukemia. Blood (2023) https://doi.Org/10.1182/blood.2022017619
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<Bone marrow smear from a child with Down syndrome who suffers from leukemia. The purple-coloured leu ...Jan KlusmannUniversity Hospital Frankfurt
<Professor Jan Klusmann, MD, University Hospital Frankfurt.Klaus WaeldeleUniversity Hospital Frankfurt
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