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It's known that the severity of symptoms caused by a trisomy 21 varies from individual to individual. Part of the explanation for this range of severity is the finding that 94% of Down's syndrome sufferers have a full trisomy, ie., all of the cells in their body have an extra copy of chromosome 21, while others have an underlying translocation (mostly a chunck of chromosome 21 being attached to 14). The last group has mosaic Down syndrome, where just a portion of cells is affected due to errors later in development.

However, this cannot be the only cause of the variation, as it would basically mean that 94% of all Down's syndrome patients should have similar complaints. Indeed, symptom variability is greater, as far as I am aware. I am specifically interested in the range of mental deficits caused by Down's syndrome:

The majority of children with Down syndrome function in the mild to moderate range of mental retardation. However, some children are not mentally retarded at all; they may function in the borderline to low average range; others may be severely mentally retarded.

What is the source of the variability in the neurological deficits? For the sake of answerability it may be best to narrow the scope down to the larger chunk of Down's syndrome sufferers with a full trisomy. Does any, or all of the variability in neurological deficits has to do with the stochastic process of X-inactivation?

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    $\begingroup$ Some useful sources I've read over, section 3 on pg 125 goes over some pathways implicated in intellectual impairment for DS, and more on the 21q22 region. Nothing conclusive yet. $\endgroup$ – CKM Feb 18 '16 at 20:45
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    $\begingroup$ As far as I know, a substantial proportion of the variance within neurological diseases are related to epigenetic marks on the genome. I wouldn't be surprised if this explains some (or perhaps most) of the variability in syndrome severities observed. $\endgroup$ – cagliari2005 May 14 '16 at 19:03
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The symptoms of Down syndrome occur due to overexpression of genes present on the duplicated chromosome.

If possessing an extra chromosome meant an equivalent change in gene expression, one would expect to observe 50% more protein production for having 3 rather than 2 copies of a chromosome. However, due to complexities in regulation at the level of transcription, translation, and protein degradation, the actual expression levels vary substantially. These complexities can arise from alleles present on chromosome 21 or elsewhere on the genome. I will present some examples from three categories of variation that are known to contribute to the spectrum of symptoms in Down syndrome.

1. Complexity of chromosome duplication

Down syndrome is sometimes caused not by a complete, but rather a partial trisomy 21 (Antonarakis et al., 2004). These variations can also partly explain the severity of symptoms because some individuals do not possess a full duplication. You mention this in your question, but as you note, this is a fairly rare occurrence relative to full trisomy, so let us consider other contributions...

2. Variation of expression levels in normal individuals and those with trisomy 21

It turns out that among the genes expressed on chromosome 21, mRNA levels vary between normal individuals by as much as 40-fold! (Deutch, et al. 2005; Stranger, et al. 2005) This expression variability can explain the susceptibility of different individuals to trisomy 21, depending on the expression levels of the alleles they possess.

Among the different genes present on chromosome 21, some expression levels are consistently elevated in Down syndrome across individuals, some have overlapping but significantly different distributions (suggesting some Down syndrome patients have expression levels in the normal range and others do not), and others are indistinguishable between patients and controls (Prandini et al., 2007).

Presumably, genes in the first category contribute most to the shared phenotype of Down syndrome, and genes in the second category contribute most to the variation. Perhaps alleles that produce mRNA transcripts at the low end of normal for those genes are less susceptible to the effects of chromosome duplication.

A case study: Amyloid precursor protein

One protein of interest in particular is the amyloid precursor protein, APP, which is also associated with Alzheimer's disease (which shares some phenotypic characteristics with Down syndrome). APP expression varies widely among tissue types and individuals. Therefore, although APP mRNA levels are significantly elevated in Down syndrome individuals, the distributions between controls and Down syndrome are very overlapping; for example, see Figure 2B from the Antonarakis 2016 review.

3. Interactions with genes on other chromosomes

The third contributor to the variation of symptoms is the interaction of duplicated chromosome 21 genes with alleles located on other chromosomes. Just for an example where some of the genetic basis is understood, Down syndrome individuals are susceptible to certain leukemias, which are also associated with specific alleles on other chromosomes (Antonarakis, 2016). It seems that trisomy 21 affects histone modification in the areas of those alleles (Lane et al., 2014) and promotes proliferation of B-cells. Therefore, Down syndrome interacts with those other oncogenes to produce a greater combined risk. Individual with Down syndrome but not possessing the other alleles are less susceptible to the increased risk of leukemia

Similar interactions are likely with other systems that are influenced by Down syndrome, though the full molecular basis of all of those interactions are not fully understood. The Down Syndrome Genomes Project aims to, among other things, discover these other alleles outside of chromosome 21 that contribute to Down syndrome symptoms, which may also help understanding of the contribution of those alleles to other disorders (Antonarakis, 2016).


References:

Antonarakis, S. E. (2016). Down syndrome and the complexity of genome dosage imbalance. Nature Reviews Genetics.

Antonarakis, S. E., Lyle, R., Dermitzakis, E. T., Reymond, A., & Deutsch, S. (2004). Chromosome 21 and down syndrome: from genomics to pathophysiology. Nature reviews genetics, 5(10), 725-738.

Deutsch, S., Lyle, R., Dermitzakis, E. T., Attar, H., Subrahmanyan, L., Gehrig, C., ... & Antonarakis, S. E. (2005). Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes. Human molecular genetics, 14(23), 3741-3749.

Lane, A. A., Chapuy, B., Lin, C. Y., Tivey, T., Li, H., Townsend, E. C., ... & Yoda, A. (2014). Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation. Nature genetics, 46(6), 618-623.

Prandini, P., Deutsch, S., Lyle, R., Gagnebin, M., Vivier, C. D., Delorenzi, M., ... & Baldo, C. (2007). Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. The American Journal of Human Genetics, 81(2), 252-263.

Stranger, B. E., Forrest, M. S., Clark, A. G., Minichiello, M. J., Deutsch, S., Lyle, R., ... & Deloukas, P. (2005). Genome-wide associations of gene expression variation in humans. PLoS Genet, 1(6), e78.

(note: the two references I have linked here: Antonarakis 2016 and Prandini et al 2007, are, respectively, a nearly direct answer to the posed question that establishes the current state of knowledge about symptom variability, and an original research paper that provides much more detailed genetic analysis of the variability of expression of many relevant genes than would be appropriate for an answer here; I highly recommend them both for further reading on the subject)

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    $\begingroup$ This is really a magnificent and exemplar-styled answer. I'll refrain from either accepting and giving you a well earned bounty until the bounty expires, because I think there may be more to it. This is more of a nature approach and I think the nurture approach may also be an important lead, just as with other mental disorders like schizophrenia and depression. Who knows? Apart from all that, many thanks for this interesting answer. +1 $\endgroup$ – AliceD Mar 14 '17 at 11:54
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    $\begingroup$ @AliceD Styled after your own answers, no doubt. I believe that "early intervention" strategies can improve the functioning and quality of life of affected individuals, but I am more familiar with similar strategies in ASD so I will have to do some reading. I also expect that all of the factors that influence cognition broadly would have an influence on Down syndrome individuals: things like socioeconomic status, and connected with that nutrition and parental care. I'm not sure what empirical research exists but I will check and may update my answer. $\endgroup$ – Bryan Krause Mar 14 '17 at 16:29
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    $\begingroup$ @AliceD (...continued:) I think Parkinsons and Alzheimers might be better analogies than schizophrenia and depression (though all have relevance): both Parkinsons and Alzheimers give some evidence that there can be a fair amount of resilience in the brain, such that symptoms arise not when damage begins, but after damage has accumulated to a sufficient degree. Therefore, I would expect symptoms of Down syndrome to be worse whenever there are other accompanying factors that negatively impact cognitive ability (and vice-versa) and influence the cognitive "ceiling" for that individual. $\endgroup$ – Bryan Krause Mar 14 '17 at 16:34
  • $\begingroup$ please do not feel pushed into doing more reading. This answer is great. I was more of hoping another user may step in and give another answer. But then, of course you're more than welcome to add info but that was not the intention of that comment (-: I really haven't the faintest clue whether nurture is involved $\endgroup$ – AliceD Mar 14 '17 at 17:28
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    $\begingroup$ @AliceD I don't feel pushed at all, I am quite curious myself. :) I am confident that there is a role for nuture to play, though for the types of "nurture" I have in mind there could certainly be a semantic argument about whether it really reflects the severity of the neurological deficits or rather helps compensate for some of the symptoms to improve quality of life (i.e., does "improved vocabulary" mean the severity is lessened, or just mean a DS patient can communicate better despite the challenge they face?). $\endgroup$ – Bryan Krause Mar 14 '17 at 17:38
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The extra genetic material present in DS results in overexpression of a portion of the 310 genes located on chromosome 21. This over expression has been estimated at around 50%. Some research has suggested the Down syndrome critical region is located at bands 21q22.1–q22.3, with this area including genes for amyloid, superoxide dismutase, and likely the ETS2 proto oncogene. Other research, however, has not confirmed these findings. microRNAs is also proposed to be involved.

The dementia which occurs in Down syndrome is due to an excess of amyloid beta peptide produced in the brain and is similar to Alzheimer's disease.This peptide is processed from amyloid precursor protein, the gene for which is located on chromosome 21. Senile plaques andneurofibrillary tangles are present in nearly all by 35 years of age, though dementia may not be present. 

Epigenetics

Down syndrome is associated with an increased risk of many chronic diseases that are typically associated with older age such as Alzheimer's disease. The accelerated aging suggest that trisomy 21 increases the biological age of tissues, but molecular evidence for this hypothesis is sparse. According to a biomarker of tissue age known asepigenetic clock, trisomy 21 increases the age of blood and brain tissue (on average by 6.6 years). Ref-wikipedia.

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    $\begingroup$ An interesting read, thanks for that. But it doesn't really target the question - why the range in severity of symptoms? $\endgroup$ – AliceD Sep 14 '16 at 18:37

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