Down syndrome: Where are we after 20 years of basic research?

Prenatal diagnostics have led to a significant decrease in the prevalence of Down Syndrome. We take a look at the progress made in the past decades.

Increase in the lifetime prevalence of Down Syndrome

Manifestations of Down Syndrome include congenital heart defects, short stature, muscle hypotonia, reduced neuronal density and atlanto-axial instability. Children and adults with the condition are at increased risk for autoimmune disorders, hypothyroidism, epilepsy, obstructive sleep apnoea, haematological, auditory and visual disorders. They may suffer from increased susceptibility to infections and develop Alzheimer's disease prematurely. Despite these co-morbidities, the life expectancy of individuals with Down Syndrome has increased significantly in childhood due to ameliorative measures.1,2

Another reason, of course, is the growth of the world's population. In the USA, the population prevalence of Down Syndrome increased from around 50,000 people in 1950 (3.3 per 10,000 population) to around 212,000 in 2013 (6.7 per 10,000 population). In Europe, prevalence estimates for Down Syndrome were 4.9 per 10,000 population in 2015. Life expectancy has increased from 26 years (estimated mean in 1950) to 53 years (estimated mean in 2014). The oldest person with Down Syndrome lived to be 83 years old.1,3

Multifactorial factors influencing DS prevalence

The prevalence of Down Syndrome is estimated at 1 per 365 foetuses at the 10th week of pregnancy. However, spontaneous miscarriage occurs in about 32% of cases between the 10th week of gestation and the expected date of birth. Between the 16th week of pregnancy and the expected date of birth, the risk of spontaneous miscarriage is about 25 %. The risk of miscarriage depends on the age of the mother. The prevalence for Down Syndrome also depends on other factors such as the availability of prenatal diagnostics and the decision of the parents. In 2013, these two factors led to a 33-54% reduction in DS prevalence (33% reduction in the USA, 55% in Australia and China, and 54% in Europe).1

The role of mini-brain kinase in Down Syndrome

More than 20 years ago, researchers (Nobel Prize winner Eric Kandel and a team of scientists from the University of Heidelberg, Germany) made an interesting observation: children with Down Syndrome still have "normal" brain structures in the first year of life. The mental disability would only occur after the 1st year of life. At that time, it was hoped to decipher and reverse the pathomechanism responsible for this. Already at that time, researchers suspected the influence of the mini-brain kinase on the pathological process.4

The influence of the Down Syndrome kinase on the nervous system

More than 10 years later, a scientific article was published in the scientific journal Cell that dealt with the Down Syndrome kinase minibrain/DYRK1A. The research team led by Kassandra M. Ori-McKenney concluded that the Down Syndrome kinase MNB/DYRK1A can regulate microtubule dynamics in neurons. Through the phosphorylation of b-tubulin, the Down Syndrome kinase not only influenced microtubule dynamics, but also the morphogenesis of dendrites.5

DYRKs as a target for drugs

Dual-specific tyrosine (Y)-phosphorylation-regulated kinases (DYRKs) are crucially involved in brain development. They thus represent potential targets for drugs against neurodegenerative diseases. Besides the best-known kinase DYRK1A, other kinases belong to the DYRK family: DYRK1B, DYRK2, DYRK3 and DYRK4. The best studied of these is DYRK1A. The reason for this is its role in the pathology of Down Syndrome.6

Dendritic arborisation patterns in DS and autism spectrum disorders

The DYRK1A is necessary to determine the length and composition of the cytoskeleton of the terminal dendrites. This controls the growth of the microtubules. A change in the MNB level disturbs the morphology of the dendrites and thus also the neuronal electrophysiological activity. In 2016, the research team led by Kassandra M. Ori-McKenney was able to show in their scientific work that the direct phosphorylation of b-tubulin by MNB can inhibit tubulin polymerisation.

The phosphoregulation of microtubule dynamics by MNB/DYRK1a is crucial for dendritic patterning and neuronal function. The research group was thus able to uncover a previously unidentified posttranslational microtubule regulation. However, this pathomechanism did not only occur in Down Syndrome, but also in autism spectrum disorders. In both disorders, very specific dendritic arborisation patterns can be identified as consistent anatomical correlates of these genetic disorders.5

Down Syndrome: Potential inhibitor for use in infancy successful in animal model

In 2021, another milestone was reached on the path to treating the intellectual disability of Down Syndrome: In an experimental study on zebrafish, the key protein of Down Syndrome could be inhibited. This represents a potential approach for the development of a new active substance. The zebrafish model of the TU Braunschweig research team (Technical University of Braunschweig, Germany) resembles Down Syndrome for the following reasons: There is an overactivity of the DYRK1A gene.

In Down Syndrome, the presence of 3 instead of 2 DYRK1A genes is responsible for this overactivity. At the TU Braunschweig, various research teams are working on an inhibitor of the DYRK1A protein. In the zebrafish model, they were able to curb congenital nerve cell defects using this inhibitor, which is still experimental, called KuFal194. In a computer simulation, the inhibitor KuFal194 could be integrated extremely precisely at DYRK1A. Currently, this compound is still in the preclinical phase. There is still a long way to go before it can potentially be used in the first year of life of children with Down Syndrome.7

  1. Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW, Sherman SL, Reeves RH. Down syndrome. Nat Rev Dis Primers. 2020 Feb 6;6(1):9.
  2. Valentini D, Di Camillo C, Mirante N, Vallogini G, Olivini N, Baban A, Buzzonetti L, Galeotti A, Raponi M, Villani A. Medical conditions of children and young people with Down syndrome. J Intellect Disabil Res. 2021 Feb;65(2):199-209. 
  3. Brogan Driscoll: World’s Oldest Person With Down’s Syndrome Celebrates 77th Birthday. Auf: vom 23. Februar 2017, Abruf 14. Juli 2017.
  4. (In German only):
  5. Ori-McKenney KM, McKenney RJ, Huang HH, Li T, Meltzer S, Jan LY, Vale RD, Wiita AP, Jan YN. Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis. Neuron. 2016 May 4;90(3):551-63. 
  6. Soundararajan M, Roos AK, Savitsky P, Filippakopoulos P, Kettenbach AN, Olsen JV, Gerber SA, Eswaran J, Knapp S, Elkins JM. Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. Structure. 2013 Jun 4;21(6):986-96.
  7. (In German only):