Can 22q13 deletion syndrome cause ulcerative colitis?

ItalianoAndrew holding David cropped

David at age 6 months with
with oxygen and feeding tubes

From a parent’s perspective, one the the most challenging and painful experiences is watching your child suffer.  Sometimes, we don’t even know how much distress our child is enduring until after the fact.  Once, when David was quite young, I heard something funny going on in his crib (pictured above).  When I looked closely, he was swallowing over and over, gasping for breath in between each swallow.  I realized his nasogastric feeding tube had slipped partway out and he was doing his best not to choke on the food being pumped into his throat.

Years later, I remember removing David’s shoe after school and discovering that his sock has slipped off his foot.  The sock was scrunching his toes in the shoe.  His toes were very red and swollen.  Every step that day at school must have been painful.

Raising a nonverbal child with multiple problems can be heartbreaking.  How often do our children suffer from painful medical conditions?   How much does undetected pain cause sleep disturbances?  How much poor behavior or failure to learn stem from painful medical conditions? We don’t know, and that keeps me up at night when David does not.

If your child’s deletion size is around 1 M base or larger — about 90% of our children are in this category, he or she is missing at least 30 genes (Sarasua et al., 2014).  That is a lot of genes, considering that damage to only one or two genes can often have devastating consequences!  Our children undoubtedly have things going wrong inside their bodies.  Many of the genes missing in 22q13 deletion syndrome have been studied and the science offers important hints that we should listen to carefully.  Here is a chance to “listen”.

IL17REL and ulcerative colitis

In about 2005, scientists started using relatively new genetic tools to dig into the connection between genes and disease.  22q13 deletion syndrome was discovered using earlier tools that looked at broken chromosomes (Phelan et al., 2001).  Newer tools allow researchers to look at single genes or small regions of the chromosome.  Right around 1 Mbase there a gene that can confer risk for ulcerative colitis (Franke et al., 2010), a form of inflammatory bowel disease closely related to Crohn’s disease.  It is an autoimmune disease, meaning that the body’s own defenses are somehow attacking or otherwise injuring the body itself.  From everything I read, ulcerative colitis is the kind of disease that causes a lot of discomfort: chronic, invisible pain.  How many of our children’s problematic behaviors are not from intellectual disability or autism, but rather, discomfort and lack of communications?  Perhaps, quite literally, we are losing sleep over this gene.

Very little is known about how IL17REL might contribute to ulcerative colitis.  The cases described were gene mutations, not gene deletions. Here is what we do know.  IL1REL probably activates IL-17RE receptors along with the better studied cytokine IL-17C.  IL-17C is associated with psoriasis, another autoimmune disease (Martin et al., 2013).  In healthy animals, IL-17RE receptors operate in colon to defend the body from bacterial infections. In rats, losing the IL-17RE receptors lowered their defenses and lead to infections and death (Song et al., 2011).  One might guess that losing IL17REL, as in 22q13 deletion syndrome, could reduce the body’s ability to fight GI infections.  Thus, problems with IL17REL could lead to ulcerative colitis (overactive) or more frequent GI infections (under active).  Either way, problems with this gene could lead to chronic GI problems with great discomfort.

MAPK11, MAPK12 may make things even worse

What is more disquieting is that not only are 95% of our children missing IL17REL, but almost every one of the same children are also missing MAPK11 and MAPK12. These genes sit side-by-side on chromosome 22.  MAPK11 and MAPK12 are associated with cytokines and, to some degree, ulcerative colitis (see review by Feng and Li, 2011).  Mice lacking MAPK11 do not develop symptoms like ulcerative colitis (Beardmore et al., 2005), but we know that even mice with a SHANK3 mutation don’t have the serious symptoms seen in children with the exact same mutation (Yang et al., 2013).  No one yet knows how much the missing MAPK11 and MAPK12 can exacerbate the loss of IL17REL.

A question of ethics?

So far as I can tell, there has been essentially no targeted spending on IL17REL, MAPK11 or MAPK12 in children with 22q13 deletion syndrome.  Should the potential for chronic, invisible pain be of interest to families with 22q13 deletion syndrome?  It is certainly a topic interesting to me. Does missing all three (IL17REL, MAPK11, and MAPK12) explain recurring symptoms in our children?  I would like to know.  Perhaps the bigger question is, how many other genes could be causing chronic, painful conditions?  From a purely humanitarian point of view, a serious discussion about genes that may cause chronic pain is long overdue.  Thus far, there has not been any talk in the 22q13 deletion syndrome community about identifying or researching “painful genes”.  David cannot tell me what hurts when he does not feel well.  Our children count on us to know when something is hurting, and at least try to fix it.


Previous posts:
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction



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