Inflammatory bowel disease (IBD), which affects more than 200,000 Canadians and is more common than multiple sclerosis and almost as prevalent as Type 1 diabetes and epilepsy, used to be known as a disease that typically developed in adolescents and young adults. However, over the past decade the medical community has seen a dramatic increase in the number of young children including infants diagnosed with a particularly severe form of the disease termed “very early onset IBD.” It is suspected that the onset of such severe IBD in especially young children may be explained by genetics.

A new study led by The Hospital for Sick Children (SickKids) validates this suspicion. Researchers not only identified a gene that causes very early onset IBD, but they also uncovered a new form of the disease that has yet to be described in medical literature. The study is published in Gastroenterology.

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This research began with the genetic analysis of a single patient at SickKids. Dr. Yaron Avitzur, lead author of the paper, Staff Gastroenterologist and Medical Director of Intestinal Rehabilitation and Transplantation at SickKids, was caring for a baby who was born with extremely severe IBD. “The case was very unusual; not something I had ever seen before, and I couldn’t find a description of it anywhere. Diagnostic tests presented very unique features, so this really got the ball rolling to do a genetic analysis,” says Avitzur.

The researchers identified a gene called TTC7A and through further investigation found that it was expressed in the bowel.  “We determined that this gene is involved in a signalling network that is important in maintaining the healthy intestine. The protein it makes is supposed to bind to another protein that is very important for cell survival and proper orientation within the bowel,” says Dr. Aleixo Muise, principal investigator of the study, Co-Director of the IBD Centre and Staff Gastroenterologist and Scientist in Cell Biology at SickKids. “If this doesn’t happen, the result is a very serious intestinal disease.”

After the gene was discovered in this single case, the research team connected with the interNational Early Onset Pediatric IBD Cohort Study (NEOPICS; www.NEOPICS.org) and were soon able to find four other patients with mutation in the same gene – two in Germany and two in Iran (both sibling pairs).

NEOPICS is an international research group that was started by Muise in 2012. It is devoted to discovering all the genes that cause very early onset IBD to ultimately develop new treatments for all young children with IBD. “When you identify a mutation in a single patient, you can’t be fully certain that it is the causative gene, but when you have five patients with mutations in the same gene, we are much more confident that defects in this gene do, in fact, cause disease,” says Muise.

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“The fact that we were able to find four other patients so quickly tells me that there are more patients out there,” says Avitzur. The discovery of this gene and the description of this new form of the disease will help clinicians identify and diagnose this disease in young children around the world.

The international team of investigators termed the new disease TTC7A-deficiency. Previous SickKids research into the genetic causes of very early onset IBD demonstrated that children with a different gene mutation could be treated, and cured, with a bone marrow transplant. This current study identifies a different genetic defect, and Muise explains that because this newly-identified gene is expressed in the bowel, a bone marrow transplant would not be effective for patients with this genetic alteration. “This is a prime example of the value of individualized medicine. There are unique genetic causes for what on the surface appears to be the same disease, but genetic analysis tells us that there are specific differences that will affect the way we can treat these patients,” says Muise. “A bone marrow transplant isn’t the answer for patients with the TTC7A-deficiency, but the good news is that we now know this, and are already screening existing drugs that may be able to treat this defect”

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This study speaks to the strength of SickKids collaborative research. “The ongoing communication between the scientists and clinicians gives us the ability to make discoveries that go from the bedside to the lab and back to bedside,” says Avitzur. “Ultimately, we are impacting children’s health, not only in Canada, but around the world.”

The study demonstrates one genetic cause for one form of infantile IBD, but researchers believe that this growing knowledge on the genetic factors behind infantile IBD will not only help treat young patients, but may also provide insight into the cause of IBD in adolescents and adults.

The paper was supported by CIHR, Leona M. and Harry B. Helmsley Charitable Trust and SickKids Foundation.