A mystery of SIOD is how the mutation of a single gene, SMARCAL1, can wreak so much havoc. One theory is that the SMARCAL1 gene has a role in maintaining telomeres, which are the endcaps of DNA that protect the chromosomes, keeping our genetic material from fraying, much like the cap at the end of a shoelace.

According to the National Human Genome Research Institute, each time a cell divides, the telomeres become slightly shorter, until they are so short that the cell can no longer divide successfully. In this way telomeres are a proxy for the aging process—or for premature aging when the telomeres are shorter than expected in human cells.

Previous scientific literature has some interesting findings along these lines.

A 2012 article in the Orphanet Journal of Rare Diseases shared that older children with SIOD had blood vessels that appeared like those of elderly adults, with defects in the elastin, the protein that keeps the vasculature stretchy like a rubber band, strong yet resisting.

Dr. Lewis shared a general hypothesis of what could be going on: SIOD patients could be experiencing premature aging of their blood vessels, so that their vasculature resembles that of much older individuals who have atherosclerosis and a tendency to get strokes.

In this way, SIOD may be similar to progeria, another rare disease that also seems to have important abnormalities in the endothelial cells.

Then in 2022, the Lewis Lab measured telomeres in SIOD blood samples—the first researchers to check telomere length directly in patients—and confirmed that their blood cells indeed have very short telomeres.

Moving forward, Dr. Lewis hopes that telomeres could provide a useful target for exploring medical interventions. Perhaps drugs could be used to counteract the negative consequences of shortened telomeres, or even to enhance telomere function. For example, danazol, a drug typically used to treat endometriosis, has also shown success counteracting telomere defects.

Dr. Lewis and his team will be continuing to measure telomeres within the SIOD human cell line in collaboration with Stanford’s Steve Artandi, MD, PhD. The Lewis Lab is also in early conversations with Houston Methodist Hospital's John Cooke, MD, PhD, a research physician who has had some success correcting the defects in telomere expression in vitro. Broadly, there has been a groundswell of interest from pharmaceutical companies in exploring the role of telomeres in aging.