Wednesday, August 31, 2011

Why is There Such a Huge Range in People with Down Syndrome?

A mom, Nina R, on the Einstein-Syndrome list asked why there is such a range of symptoms in people with Down Syndrome. Why do some people with DS seem to be "severely affected" why do others with DS seem to be "higher functioning."

It's an interesting question. Another mom, Kris B, responded with a very in-depth answer that hit the nail right on the head.

With Kris' permission, I am posting her reply here.

Going way back to the cob web corners of my mind, I can pull out some ideas from my freshman genetics course that may answer this.  There is is a huge range of features/symptoms/abilities because there's huge variation in genetic make-up.  Genes exist in many different forms, called "alleles", and there are hundreds of genes on that chromosome.  No two people's genetic make-up is identical (except for identical twins of course).

There are so many alleles and so many genes that the combination possibilities are probably close to infinite.  Genetic variation is what makes us all so amazingly and dramatically different. So an extra chromosome disorder is going to express differently in every single person because of their unique combination of genetic alleles on that chromosome.  There are similarities in symptoms/features because each chromosome has a specific set of genes, so for the most part, the same "things" (proteins, hormones, chemicals, cellular processes) are affected, but how they are affected is dependent upon the alleles on that chromosome and the genes/alleles responsible for how that chromosome is expressed.

For example, say the extra chromosome contained the gene for hair color. Now, everyone with that extra chromosome is not going to have the same hair color.  If my son had the gene alleles for blond hair, then maybe with that extra chromosome, the hair color gene expresses twice as much and he has super blond hair or maybe that extra expression causes the release of more pigment so that his hair is much darker than it might have been.  But (without a completely unrelated mutation) his hair is not going to be black because he had no gene alleles for that.

Even more variation is added in when you take into account mutations that can occur when genes are in the wrong place on a chromosome or are switched between chromosomes.  All of this adds infinite variation into the genetic makeup of the baby even before he/she is born.  And the variation doesn't stop there, once born, there are tons of environmental and natural factors that also have an effect.  Maybe the extra chromosome causes an imbalance so that the child is severely depleted in Vitamin D, but that child lives in Florida and spends tons of time in the sun - that imbalance may never be expressed and/or known because it is already being fully compensated for just by lifestyle.

There is so much variation built into our genes that it is somewhat surprising that people with DS have so many "features" in common.  That is indicative of the 21st chromosome being pretty well conserved - meaning that the genes that are on that chromosome do not change position and/or swap out with genes on other chromosomes very frequently.
There are actually some of the chromosomes for which genes are routinely swapped around, which adds even more variation - because what chromosome and even where on a chromosome a gene is, highly effects how often it is going to be expressed.  So to clarify the difference between genes being swapped within a chromosome, genes being swapped being chromosomes, and chromosome duplication (T21), we can use a cake baking analogy:

Say there is a cabinet with 3 shelves on it and all of the ingredients to bake the cake are placed in specific locations on the shelves.  The cabinet is the chromosome, the ingredients are the genes, and the shelves represent the positions of the genes on the chromosome.

The first shelf i has butter and sugar, the second shelf has eggs and flour, and the third shelf has the flavoring and baking soda.  For a "normal" cake, the ingredients on the first shelf are "expressed" or used first and 1 cup of sugar and 2 sticks of butter are added.  Then the second shelf ingredients are expressed and 2 eggs added and 3 cups of flour.  Then the 3rd shelf is expressed and a tsp of each flavor and the baking soda is added.  Then the cake is baked and turns out as expected.

A gene switch within a chromosome would equal the locations of baking soda and flour being switched.  The baker doesn't know to grab the flour on the 3rd shelf - they just grab whatever's on the second shelf and add it in the amounts told to.  So now 3 cups of baking soda are added with the eggs, and then, when the third shelf ingredients are expressed, only 1 tsp of flour is added.  This would be a bad mutation.  A less obvious mutation would be that maybe two of the flavorings switch places on the 3rd shelf.  This may not even be noticed at all.

A gene switch between chromosomes would equal butter being replaced by something not found in this cabinet - something like carrots.  Two sticks of carrots are added from the first shelf instead of butter.  This would be a pretty destructive mutation.  Maybe instead carrots, the butter switches with lard - that might not be as bad of a mutation and may never be noticed and maybe it might end up being even better.

An extra chromosome would be like adding another second shelf (and second shelf ingredients) so now twice as many eggs and flour is added as the second step.  Therefore, the ingredients are out of balance and the cake does not turn out as expected.  Depending on what ingredients in what ratios are on that shelf will affect how "mild" or "severe" the cake turns out.  That is why people think that there are grades of Down Syndrome, when it's really just a yes/no question. Do you have an extra chromosome?  yes or no.  You can't have a little or a lot of DS.  You have it or you don't.  It's just the resulting problems that are so variable due to inherent genetic variability as well as environmental, parental, and other external influences.

Where TNI comes in is the theory that if you know what ingredients were added in duplicate, then adding in twice of the rest of the ingredients (or removing half of the extra ingredients) should create the proper balance leading to proper baking and development of the cake. I believe that by doing this, it is possible to achieve typical development and above because we are working so much harder at achieving the right balance for growth and development. Everybody - normal and DS alike - have genetic mutations that throw off balances here and there on the cellular level (genetic variation and mutations), most of us do not eat right or take the right vitamins, so these imbalances, which are usually not severe, are not corrected and cause limitations in some microscopic way.  By focusing so much on every aspect of nutrition and cellular balance, we are fine tuning our kids bodies to function at their highest possible level.

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