Like other parents of children (young and old) with 22q13 deletion syndrome, I wonder about David’s future. My son was quite ill as an infant and I wonder what wear-and-tear his stay in the neonatal intensive care unit might come back to haunt him later in life. Back when 22q13 deletion syndrome was first identified, I read literature on life expectancy of children with intellectual disability and related problems. There was no equivalent literature just for our syndrome. There is still very little published about what happens when so many genes are lost (from 3 to over 100). However, there has been ample research on individual genes. That research can be a window into the future. Over the next few postings, I will be looking at the genes and what they might tell us about the our children’s futures.
FAM19A5: a cancer gene
There are over 100 genes and gene regulators in the 22q13 region. And, although a very few patients are lucky enough to not worry about the impact of a hundred or more genes, the rest of us face a more daunting reality. One or more of these genes may lead to a chronic condition or life-ending disease. I have chosen the gene FAM19A5 as an example. However, there are 100+ other examples I could have chosen.
In a recent paper by Cornella et. al (2015), they write: “Liver cancer is now the second leading cause of death among cancer patients worldwide. Fibrolamellar hepatocellular carcinoma (FLC) accounts for 0.85% of all primary hepatic malignancies in the United States…” While investigating FLC, these authors discovered two chromosomal regions with mutations most-associated with FLC tumors, 19p13 and 22q13.32. Twentyfive percent of the patients with this cancer had mutations of the gene FAM19A5, which should make this gene of great interest and concern to parents. Ten years ago Diaz de Stahl et al. (2005), showed that this same gene is associated with another cancer, glioblastoma multiforme, a common and aggressive brain tumor.
FAM19A5 and deletion size
Which children might be at risk? FAM19A5 will be missing from patients with a terminal deletion of about 2.5 M bases or larger. Looking at the paper by Sarasua et. al (2014), about 75% of all identified patients will be missing this gene. How many 22q13 deletion syndrome patients will get FLC? There just is not enough data from older patients, yet. However, FLC is not a cancer of old people. It primarily strikes between the ages of 10 and 30. It is not associated with the sorts of liver pathologies seen in other forms of liver cancer. A person’s liver can seem quite normal before the cancer invades it. We will need to keep an eye on our children as they grow up.
Is FAM19A5 associated with other problems?
FAM19A5 produces a substance called TAFA5. TAFA5 is primarily a hormone that is produced in the brain. It is what I call a “22q13 deletion syndrome brain gene”. So much of 22q13 deletion syndrome affects behavioral patterns (chewing, sleep, autistic tendencies, etc.) and many genes in the gene-rich region of 22q13 impact the brain. These brain genes will be the focus of more posts. That is a promise.
Back to the FAM19A5 gene. Its product, TAFA5, is released into the brain and into the bloodstream when needed (Paulsen et al., 2008). It seems to be needed when the body has too little water. That is, TAFA5 production goes up when a person (or animal) is dehydrated. If rats go 48 hours without water, TAFA5 production goes up. As soon as they start drinking, TAFA5 production goes down. What does this mean? It is still anyone’s guess. However, the part of the brain associated with this kind of body fluid and energy regulation (hypothalamus) is also involved in the regulation of body temperature and sweating. TAFA5 is released along with vasopressin, the most important hormone involved with body fluid regulation. It seems to me, if someone wants to study why kids with 22q13 deletion syndrome don’t sweat, they probably should be looking at FAM19A5 and the production of TAFA5. This is sorely needed research. For once, I would like to walk with David on a hot day without carrying a spray bottle.
TAFA5 may have another, perhaps more important, function. It may be important for protecting the brain after a head injury or other insult. There is only a hint of evidence. Animal researchers studying brain injury showed that infusing stem cells into the brain can reduce the amount of brain damage after an interruption of blood flow (e.g., stroke). When the researchers looked at what genes get turned on in brains that have less damage, the FAM19A5 (TAFA5) gene is one of them (Yilmaz et al., 2010). TAFA5 may slow swelling (since it seems to be related to fluid management) or have some other protective role. The increase in TAFA5 may not be important, but if it is, about 75% of 22q13 deletion syndrome kids have an above normal risk for brain injury. My son is prone to falling because of his poor gait. Finding some way to boost TAFA5 may be a way to protect his brain. More research is needed on how TAFA5 might be protecting the brain.
TAFA5 and oxytocin: opinion and science
I have read that one research group plans to study the effects of oxytocin on children with 22q13 deletion syndrome. I am not sure why. There have been lots of studies of oxytocin already. Oxytocin has been studied in rats, voles, monkeys, humans and probably other species. It has been tried in different neuropsychiatric patient and animal populations. Oxytocin can impact behavior. But, except for certain rodents, the influence is very small. Will the researchers see an effect? They probably will find something “statistically significant”. It might be of some help if delivered during ABA. However, it will not make a non-verbal person who avoids eye contact (like David) become suddenly social and personable. If oxytocin comes on the market as a nasal spray, I might try it just once to get an otherwise unexpected hug out of David during the 1-2 hours it lingers in the brain. On the other hand, David is not a little kid anymore (he is 29). Hugs are rare. Even my genetically normal son would need some oxytocin before I get a big hug from him. So, as a parent, I don’t see spending research dollars on oxytocin when there are so many other things that need fixing.
There is a more scientific problem with trying to study oxytocin in children with 22q13 deletion syndrome. TAFA5 is co-released (released simultaneously) with oxytocin in healthy humans. If someone is studying oxytocin, they must consider that oxytocin’s action may, in part, depend upon normal levels of TAFA5. Thus, subjects with small deletions (intact FAM19A5 gene) may have very different responses from the other subjects. It is what scientists call “a confound” and it is an important consideration when so few 22q13 deletion syndrome patients are available for studies. I hope the researchers have taken this into account.
FAM19A5 is a 22q13 gene missing in the overwhelming majority of our kids. It produces a substance called TAFA5 that might be important for regulating body fluids and protecting the brain after injury. FAM19A5 is associated with liver and brain cancers. I have looked carefully at the scientific web sites and read many of the scientific papers on FAM19A5/TAFA5. Not once was 22q13 deletion syndrome or “Phelan McDermid” mentioned. That tells me that parents who live with 22q13 deletion syndrome are not talking to scientists who study FAM19A5. Why parent groups would not pay much attention to a gene that may cause cancer, interfere with fluid balance or may make their child more susceptible to brain injury is difficult for me to understand. The link between 22q13 deletion syndrome and FAM19A5 should be common knowledge. I feel now that I have done my part. The rest is up to the other parents.
22q13 deletion syndrome – an introduction