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Advanced Neurology Improving cognitive development in Down syndrome

contains 225 protein-coding genes and some 400 non- 2. Chromosome correction
coding genes regulating gene expression. 3
Several techniques have been tested for reducing
Screening for trisomy 21 is possible from the 11 week supernumerary chromosomes. Amano et al. claim to have
th
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of pregnancy with 95% accuracy in analyzing a sample of normalized up to 40% of iPSCs generated from fibroblasts
maternal blood to isolate fragments of DNA from the fetus. obtained from persons carrying a standard trisomy 21.
About 99% accuracy is reached in combining the analysis They suggest that introducing a ZSCANA-mRNA into
of maternal blood with measures of cardiac rhythm and aneuploid cells allows to detect unpaired chromosomes
nuchal translucency of the fetus. However, the screening during cell division and eliminate them.
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test is not diagnostical. It cannot substitute more invasive Li et al. introduced a TKNEO fusion transgene at the
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techniques such as amniocentesis and chorionic villus locus 21q21.3 of the gene APP in iPSCs generated from
sampling. 5 fibroblasts of persons with DS. This resulted in the loss of
Present-day legislation in many countries allows medical an entire copy of Hsa21 in a large majority of the treated
termination of pregnancy if the health of the mother is at clones.
stake or if the fetus presents a strong likelihood to bear an The most promising correction technique may be the
incurable pathology leading to a major handicap. one experimented by Jiang et al. involving the use of a
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According to de Graaf et al., the European mean of XIST gene. In humans, the male Y chromosome contains
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medical termination of pregnancy in cases of trisomy a few dozen genes compared to about 3000 for the X one.
21 is 54% with huge variations between countries As females have two X chromosomes, a dosage reduction
(from 0% in Malta to 83% in Spain). In spite of these is needed to maintain a balance. Natural X dosage
negative indications, the prevalence of persons with reduction is driven by a non-coding RNA, named XIST,
DS in Western countries is important. De Graaf et al. produced from the inactive X chromosome. Jiang et al.
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report estimations of 419,000 people living with DS in reprogrammed fibroblasts from male persons with DS
the European countries in 2015 and around 250,000 in into iPSCs through genetic engineering. They inserted a
the United States in 2014. Decrease in natal prevalence transgene XIST at locus 21q22 of the gene DYRK1A in one
of trisomy 21 due to early diagnosis and medical of the three Hsas21. This silenced this chromosome in 85%
interruption of pregnancy is compensated by improved of the treated clones.
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medical care along the lifespan. Most importantly, Czerminsky and Lawrence report
that epigenetic plasticity in DS iPSCs is retained at least
Life expectancy in persons with DS is close to 65 years
and increases regularly. It is reduced by too high a mortality 35 days beyond the pluripotent stage. At that time, it is still
strong enough to initiate chromosome-wide repression in
in the first years due to life-threatening comorbidities NSC differentiating into neurons. Correcting a deficiency
like congenital cardiopathies and by the early deaths of in the process of differentiation of neural stem cells into
persons with DS developing a form of Alzheimer’s disease, neurons could be possible by inducing XIST at different
a casualty several times more prevalent in DS than in the stages in neurogenesis. However, it is unclear how such
rest of the population. 8 corrected cells would behave in vivo.
Current work in biomedical sciences and Full chromosome correction requires intervening in
pharmacotherapy aims at improving the phenotype of the very first days of life. A plausible scenario involves
the persons with DS. The question is whether it has the blastomere biopsy and genetic analysis to ascertain trisomy
power of normalizing the cognitive phenotype of these 21 before inserting the biologic agent able to normalize
children. As will be argued, the answer to this question the aneuploidy and reimplanting the treated cells into the
is likely to be negative. This should not be taken to mean embryo expecting cell proliferation to proceed normally. 14
that experimental and clinical works in these domains are
useless. Even if not able to cure the condition, they may To cure DS all of the eight cells at day 3 post-insemination
end up setting a more robust neurophysiological apparatus would have to undergo chromosome correction. At this
in DS children better suited for potentiating the effects of stage, embryonic cells are multipotent. They no longer
associated behavioral interventions. 9 have the power to generate a complete organism but can
differentiate into any organic tissue. An intervention
The paper is divided in four sections: (1) Chromosome on fewer stem cells at that stage would induce a mosaic
correction; (2) epigenetic reduction of gene overexpression; of cells, some with the normal number of chromosomes
(3) brain pharmacotherapy; and (4) cognitive behavioral and others with three copies of Hsa21. Chromosome
interventions. correction at day 2 after syngamy would not need to be

Volume 4 Issue 1 (2025) 2 doi: 10.36922/an.3785