New research solves the medical mystery of why a 2-year-old child — seemingly healthy at birth — succumbed to an undiagnosed, rare illness.

Interstitial lung disease is a generic term describing a condition in which the lungs gradually degenerate, resulting in scarring that makes breathing more difficult.

Interstitial lung disease in newborns and children has been linked to several gene abnormalities, although some people get the condition despite having none of the known genetic abnormalities.

In the new paper, the team from Washington University School of Medicine in St. Louis were presented with the case of a 2-year-old child with interstitial lung disease of unknown cause. The child later died as a result of the illness.

The researchers looked at the child’s DNA code as well as both parents’ DNA codes. A team of Baylor College of Medicine bioinformatics experts then filtered down the initial huge list of DNA code variations or genetic variants detected — many of which are innocuous — to a smaller list of likely culprits.

The child’s lung tissue revealed evidence of a surfactant abnormality in the lungs. Surfactant is a complex mixture of proteins and lipids found in the air sacs of the lungs.

It lowers surface tension in the air sacs and keeps them open, facilitating the exchange of oxygen and carbon dioxide during breathing. Surfactant protein genes can be messed up in a lot of people who have interstitial lung disease.

However, there were no genetic variations in the code of the surfactant protein genes in this child.

Rather, the researchers discovered a mutation in a gene that produces a protein called RAB5B, which eventually turned out to be part of the cellular machinery that processes surfactant proteins.

They discovered that the RAB5B protein is essential for packaging surfactants into vesicles and transporting them to their right sites. The genetic variation in this example did not merely prohibit the protein from operating; it also caused the protein to be actively destructive.

“When mutations happen that break a protein, usually the protein just doesn’t work anymore — its function is missing,” says co-senior author Tim Schedl. “But this is a case where the broken protein is not only not working, it’s actively poisoning other processes. This results in the loss of the surfactants in the lungs.”

By examining the genetic mutation in roundworms known as C. elegans, the researchers were able to determine the existence of this anomaly. Even having one normal copy of the gene could not compensate for the deadly protein produced by the mutant copy, as the child only had one abnormal copy.

According to research conducted by first author Huiyan “Winnie” Huang, worms with one defective copy required three normal copies to restore normal function, confirming the abnormal copy’s deadly activity.

Moreover, the researchers discovered that neither of the child’s parents had the genetic aberration, implying that the variant was only present in the child’s genes by chance and was thus a novel variant in the DNA that originated during embryonic development.

“In so many cases, we don’t know why a patient has a particular disease,” adds co-senior author Steven L. Brody. “But we were able to solve this case, and there’s a real satisfaction in that. Potentially, this could lead to finding answers for other people who have diseases similar to this.”

According to co-author Jennifer A. Wambach: “This gene, RAB5B, is now associated with interstitial lung disease in children. There are patients with a clinical diagnosis of interstitial lung disease without a genetic explanation. For these patients, sequencing RAB5B may reveal changes in their DNA code that could account for their disease. Knowing the underlying genetic cause and identifying other patients with the same genetic problem can help us better predict the course of the disease, so we can better prepare patients and their families for what is to come, such as whether the patient may respond to treatments, or worsen to needing a lung transplant, or whether it may be appropriate to begin discussing compassionate care.”

While the diagnosis could not help the patient in this situation, knowing the underlying reason allowed the parents to know that the genetic mutation was not inherited and that their future children would have a very low probability of developing the disease.

Image Credit: Getty

You were reading: New study reveals cause of deadly rare, undiagnosed lung disease in children