Two-year-old Vanessa had survived the unthinkable: two massive cerebral hemorrhages, nine days apart. Katherine Bell and her wife Nancy Mendoza felt immense relief at their daughter’s close call. But they wanted to know more. What had caused Vanessa’s strokes? Would there be more? Was the cause treatable?
The strokes were the culmination of a mysterious illness that had started with a rash. Because of high levels of inflammatory proteins in her blood, Vanessa’s rheumatologists, Pui Lee, MD PhD and Robert Sundel, MD, had given her a provisional, somewhat vague diagnosis of periodic fever syndrome.
“In rheumatology, we have to be comfortable with operating with a lot of unknowns,” Lee says.
But the strokes occurred despite three different anti-inflammatory treatments, which worked only temporarily. Bell, less comfortable with the unknowns, began searching the medical literature.
“It helped me feel calmer,” Bell says. “The more information I have, the less out of control I feel.”
A rare enzyme deficiency
The persistent inflammation, together with the strokes, suggested that Vanessa had vasculitis, meaning her immune system was attacking her blood vessels. But why?
While Vanessa was still in the ICU, her doctors began discussing a paper that had come out the prior year in The New England Journal of Medicine. It described a rare condition called DADA2, deficiency of the adenosine deaminase 2 (ADA2) enzyme.
The National Institutes of Health had a protocol for DADA2 and agreed to test Vanessa for ADA2 mutations. “We were told there’s one disease that’s very, very rare, an inflammatory disease that causes stroke in children,” says Bell.
Vanessa tested positive — the 16th child diagnosed by the NIH. Per the NIH experience, doctors started her on a fourth rheumatology drug: Enbrel, an inhibitor of tumor necrosis factor (TNF), also originally approved for arthritis.
“The NIH had found that once they start patients on TNF inhibitors, they no longer have any strokes,” says Lee.
Vanessa immediately began doing better, and her parents still inject her once a week. Enbrel manages most of her symptoms, but it isn’t a cure for DADA2, and many questions remain. No long-term data exist for this use of the drug, which can cause side effects like an increased risk for infections.
“It’s really unclear exactly what ADA2 is doing in the body, and how ADA2 deficiency causes inflammation and strokes is a big mystery,” says Lee.
A foundation and a conference
Once Vanessa left the hospital, Bell attended Boston Children’s Hospital’s 2015 pediatric innovation summit, primarily for business reasons (she is an editor for the Harvard Business Review). There, she connected with Matt Might, a rare disease parent who took part in one of the summit panels and had been profiled in the New Yorker.
Amazingly, just the night before, Might had spoken with a father of two children with DADA2, a surgeon at Vanderbilt University named Chip Chambers.
“Chip was in touch with almost every doctor in the world who had patients with DADA2,” Bell says. “He would talk to doctors on behalf of patients and advocated for them. As a doctor, he could basically call anybody.”
Chambers had floated the idea of an academic conference on DADA2 with the NIH. When they spoke, he told Bell, “I need a partner.”
The two formed the DADA2 Foundation. Chambers organized the conference; Bell handled the communications and built a website. Together, they raised funds to help bring in doctors and families from overseas. To maximize attendance, they held the conference near NIH headquarters in Bethesda, the day before a big rheumatology conference.
The DADA2 conference, in November 2016, drew 136 doctors and scientists from 16 countries, representing 26 different specialties. The experts shared scientific abstracts and took part in panels, while 70 patients and family members compared notes on DADA2 at a concurrent patient conference.
Bell and Chambers believe the event represents the shortest time between the reported discovery of a disease and the convening of a large-scale scientific conference.
Investigating the ADA2 mutation
At the conference, Lee learned that ADA2, the missing enzyme, is made by the white blood cells known as monocytes and macrophages. “That’s intriguing because there is no other condition where a defect in a gene expressed in monocytes or macrophages is associated with vasculitis and stroke,” he says. “Being a monocyte biologist, I was interested in what this enzyme has to do with a monocyte’s natural function, and how its absence causes disease.”
Vanessa has two different ADA2 mutations. One hasn’t yet been defined, but it somehow prevents the gene from being transcribed to RNA, so the enzyme is never made. The other causes ADA2 to get stuck inside the cell.
Interestingly, deficiency of ADA1, a closely related protein, is a common cause of severe combined immune deficiency (a.k.a. “bubble boy disease”). ADA2 seems to have a similar enzymatic function to ADA1 — only it’s 100 times weaker.
Lee recently received a Boston Children’s Hospital career development grant for a project to investigate the mutations’ effects. It’s titled, “Mechanism of Inflammation in Systemic Vasculitis Caused by Deficiency of Adenosine Deaminase 2.”
He plans to directly investigate the effects of ADA2 mutations in human cells. He can produce them through gene editing or by introducing patients’ DNA — then do tests on the cells and investigate the effects of TNF inhibitors. Bell and Lee remain in close contact, texting frequently.
DADA2: A work in progress
Vanessa, now age 4, is doing remarkably well. But her parents still worry about the long term. Bone marrow transplant could offer a permanent cure, replacing Vanessa’s immune system with a new one. Some children with DADA2 have had it, but it’s a very toxic and risky procedure.
Other possibilities to be explored are enzyme replacement therapy, or perhaps gene therapy to correct the mutation. The DADA2 Foundation has formed a patient registry that could help lay the groundwork for such efforts and is raising money to support new research.
Since the conference in 2016, at least four independent medical collaborations have been launched.
“This is just the beginning,” says Bell.