Where People Turn When Nobody Can Diagnose Their Illness

"I spent hours and hours and hours researching and trying to find anyone or anything that might get us down the right path to figuring out what was going on with the boys."

by Shayla Love
Oct 19 2018, 2:55pm

Quinn Mills was born in September 2014 to Liz Aronin and Jamie Mills, after an unremarkable pregnancy. He had a normal delivery, normal blood tests, and was, Mills tells me, a normal little boy. “There was nothing that you could point to and say: That's different.”

But around three to six months, Quinn stopped meeting his milestones. During a baby’s first year of life, they grow physically—baby’s weight should double around five to six months—and developmentally. Babies learn how to roll over, sit up, and hold things. They also learn to prefer human faces over objects, recognize their parents’ voices, show an interest in mirrors, and produce that characteristic baby babble.

By seven months, Quinn’s daycare was concerned that he was having trouble seeing. Mills and Aronin weren’t sure if he could hear them. Quinn wasn’t sitting up by himself. He could scoot a little, but not crawl. He couldn’t hold onto objects for longer than a few seconds. His doctors, who previously said not to worry, now referred them to specialists: Ophthalmology, audiology, and neurology. At nine months old, an ophthalmologist found that Quinn had cataracts in both eyes.

“That was when we're like, ‘That's odd,’” Mills says. “Usually when there's cataracts there's something wrong at a deeper level.” Suddenly, Mills and Aronin’s “normal” little boy had a condition that no one could find an explanation for.

When something in the body goes wrong, we see a doctor, get examined, get swabbed or draw blood, and usually leave with an answer. But for many patients and families, medical examination doesn’t lead to a diagnosis—and what do they do then?

A paper published in the New England Journal of Medicine last week covers the progress of the Undiagnosed Disease Network (UDN), a collection of sites around the country where people can turn when there are no more specialists to see and no more conventional tests to run, to find answers to their health mysteries.

The UDN was inspired by a 2008 program called the Undiagnosed Diseases Program (UDP) at the National Institutes of Health (NIH) Clinical Center, which was quickly overwhelmed by patients seeking their services. The UDN was formed in 2014 and is made of 12 sites across the country. They also have two sequencing centers, a group of people who do metabolomics, or study the small molecules made by cells, and a model organisms core, which is a group of people who check genes that might be causing disease in organisms like flies and fish.

Since its inception, 1,519 patients have been referred to the UDN and 601 were accepted for evaluation. A large bulk of them, 40 percent, had a neurological condition, like Quinn. Of the 382 patients who got a complete evaluation, 132 got a diagnosis, about 35 percent. Most of those diagnoses were found through genetic testing. 21 percent of those who were diagnosed were able to make changes to their therapy, specific to their condition. As of today, the UDN has defined 31 new syndromes.

Two days before his neurology appointment in June 2015, Quinn had his first seizure at 9 months old. The family was at home, and Quinn was being put to bed around 11 PM. “He started to stiffen up, kind of like a sumo wrestler with his arms out and his legs bent a little bit,” Mills tells me.

Quinn stiffened, and then let out a scream—“a much more exaggerated scream than anything I'd ever heard him do," Mills says. "The frequency was like, every 15 seconds. He would scream, stiffen for about five seconds, it would lessen, and then he would do it again another 15 seconds later.”

At the hospital, they confirmed that Quinn had had a seizure, but his diagnosis was still murky. It didn’t look exactly like infantile spasms, a form of childhood epilepsy, but that was the closest diagnosis they could arrive at. A brain MRI showed that Quinn had low myelination, or white matter, in his brain.

After six weeks in hospital, a number of feeding tubes and infections, Quinn returned home with no answers, but worse symptoms. His sleeping schedule was erratic: Sometimes he would sleep all day and be up all night, or the opposite. He had seemingly chronic, un-soothable full-body pain. “It could last for days to weeks where he's just screaming inconsolably,” Mills says. “Nothing that we did could help calm him down.”

Aronin essentially had to stop working to care for Quinn, and both parents' lives revolved around trying to make him feel better, even though they didn't know what was wrong. "I love my son, but there were days where it was extremely challenging," Mills says. "It's just hard. It's hard to leave your house. It's hard to make plans because you'd make plans and then you'd have to cancel because he's having a bad day. I mostly felt upset for him when he's having miserable days."

In December 2015, results from exome sequencing they had ordered came back. (In exome sequencing, only the genes that encode for proteins are sequenced.) “Unfortunately, it was inconclusive," Mills says. The results had picked up a change in a gene called NACC1, but nothing was known about it, and this gene hadn't been associated disease before.

At that point, Mills and Aronin had exhausted every medical option available to them. “It was one of the lowest moments of our lives together as a family,” Mills says. “Because it was like, ‘Well, what do we do now?’”

Many of the people who come to UDN, about a third, already have some kind of genetic sequencing, says Euan Ashley, a professor of medicine and genetics at Stanford University and the first co-chair of the UDN. And still, they still don’t get a diagnosis. Sometimes, it's because the full genome needs to be sequenced and the explanation lies between the protein-coding genes. Or large segments of the genome are changed, and that’s hard to see in an exome sequence, which only sequences about 2 percent of the genome.

The UDN can go deeper. It also sequences the parents, and sometimes siblings, which adds power to the results. They can also look for genetic abnormalities, like mosaicism, which is when patients have more than one genome in different parts of their bodies. “We're able to drill down a bit further in a way that can be harder for regular doctors in a clinic," Ashley tells me. And sometimes, they just get lucky. If it's been a year or two years since a patient’s original sequencing, "there’s a year's worth of genetic knowledge out there that wasn't there before," he says. "So just being able to do it later can be helpful and can get us to the diagnosis.”

For Danny Miller’s children, Carson and Chase, there was just one paper on their mutation, published right around the time they were accepted to UDN. Miller’s son Carson had originally been diagnosed with cerebral palsy at 14 months old, to explain movement problems. But when his second son, Chase, was born, he started to have the same issues.

“He also had trouble pulling himself up to standing, and not following the usual progression that a young child would in learning how to crawl, learning how to walk, learning how to move their bodies and so forth,” Miller says. This brought doubt to the cerebral palsy diagnosis: It’s rare that two children in one family would get it.

Their first neurologist visit was in May of 2103, and for three years they went to four different neurologists, had multiple MRIs, two rounds of exome sequencing done, but nothing was conclusive. The MRIs showed changes in the boys' basal ganglias, a part of the brain important more movement, but didn’t lead to a diagnosis.

“There are many moments where, you think, what did we do wrong?" Miller tells me. "You know, why is this happening? I'm a big researcher and so I spent hours and hours and hours researching and trying to find anyone or anything that might get us down the right path to figuring out what was going on with the boys. That's how I learned about the UDN program. I knew that it was sort of the end of the line. It's for the toughest cases that are out there.”

Carson and Chase were accepted to the UDN in December 2016, and towards the end of 2017 the UDN decided to do whole genome sequencing. In February of this year, their genetic counselor called and told them, "I think we have something."

Carson and Chase
Carson and Chase. Photo courtesy of Danny Miller.

“We didn't know what to expect, it's kind of a mixed bag," Miller says. "Because on the one hand, great, we've got some clarity on what might be going on but what if it's something that's fatal? What if it's something that's so devastating that they're going to be intubated by the time they're ten, or something like that?”

Chase and Carson were both diagnosed with a disease called MEPAN, short for the wordy mitochondrial enoyl CoA reductase protein-associated neurodegeneration. It’s a disorder caused by a mutation in the MECR gene, which makes fatty acids for mitochondria, the power sources of a cell. With the mutation, the mitochondria can’t function properly, and leads to the problems the boys had in walking and talking. MEPAN affects the mitochondria in the cells in the basal ganglia and the optic nerve, but very few other systems.

There are only 13 known MEPAN patients, but Miller has been encouraged to see that they are doing well aside for an inability to walk or talk. In MEPAN, comprehension is intact, as well as cognitive development. Carson and Chase, now 6 and 5, are in regular schools, and at the same reading and math levels as their peers, though they still can’t walk or speak. Carson is really into Harry Potter, Miller tells me, and loves YouTube videos about bodily functions, like the digestive system.

“He's going to be a doctor for Halloween this year, and who knows, maybe it's because of everything we've gone through," he says.

Ashley says matching these rare cases together is fundamental to defining an actual new disease. “We'll do the sequencing and we'll find maybe five or 10 candidates, we think any one of these could cause the condition," he tells me. "And then what do you do? How do you get down to one? If you find a second case and they have five or 10 candidates, then you can compare the two lists and sometimes there is only one gene that's in common between those two unrelated people, and that can help solve the case.”

Rare diseases are individually rare, yes, but collectively common. There are between 1 in 10 and 1 in 20 people in the world who have a rare disease, Ashley tells me, which is about as common as diabetes. There’s not a big wall or barrier between a rare and common disease either; it’s more like a spectrum, and a gradation between the two.

“Every time we find something out about a rare disease, it is relevant for everybody," Ashley says. "We learn about new biology. We learn, say, how the mitochondria or the powerhouse of the stem cell actually works when we find a new metabolic disease. And that can be relevant then to everyone.”

Ashley also runs the genome program at Stanford hospital and envisions a day where genetic testing could be more available to all patients, not just those with rare diseases. “I wish it were easier," he says. "I wish we didn't have to get on the phone every time and justify paying for an exome.”

This is the promise of precision medicine, where each disease is considered individually, and treated as such. Groups like the UDN show how efficacious it could be, and even potentially more cost-effective. For patents who got a diagnosis, their average cost of care before UDN was $305,428, and the average cost of the UDN evaluation was $18,903.

“These cost estimates suggest that the UDN approach has the potential to cut short an expensive medical diagnostic odyssey, and they are consistent with recent cost-effectiveness analyses for genome sequencing,” the paper says.

Ashley thinks genetic information will one day be as common as any other lab test, like a cholesterol test. Not everyone may want to know the information stored in their DNA, but for those that do, you could discover risks or predispositions for cancer or heart disease, and make choices accordingly.

“We could start to understand even more common disease at a deeper level, and think about targeting each of the subgroups of that more precisely," he says. "This is really the essence of precision medicine, the idea of using molecular techniques to understand the disease at a deeper level, subcategorize it, and then target those subcategories with much more precise therapies.”

Mills and Aronin applied to the UDN in January of 2016, and Quinn was accepted a few months later. By that summer, they had determined it was the variant in the NACC1 gene causing his disease, which usually encodes for a protein that binds to DNA and is involved in gene expression. They then found a handful other individuals with similar symptoms as Quinn and the same mutation.

Quinn Mills and his mom
Quinn Mills. Photo courtesy of Jamie Mills.

The UDN was also able to determine that Quinn’s mutation was de novo—meaning it didn’t come from recessive genes in Mills and Aronin, but that it had spontaneously occurred on its own. If they wanted to have another child, the chances were extremely low that it would be sick too. Their daughter, Josie, was born in June of last year and is completely healthy.

Quinn’s grandparents, Aronin's parents, are research scientists who have spent their careers studying Huntington’s Disease. When Quinn got his diagnosis, they started to research his mutation, and the family is now fundraising to hire a postdoc at The Laboratory of Cellular Neurobiology at Massachusetts General Hospital to study the mutation full time for a year. While they hope that the grandparents’ efforts will spearhead the research to find treatments for Quinn, just knowing the diagnosis provides more comfort than they've had for the last several years.

"Before, I felt like we were just surviving," Mills says. "I had let go of the idea of wanting him to be like all the other kids. My wife and I just wanted him to be happy and comfortable. That's an interesting transition to make in your brain when you go from 'Oh, what college are they gonna go to and what are they gonna be when they grow up?' to 'I just want him to smile today.'"

But Quinn is like some other kids, at least a few.

There are currently a dozen people known to have the NACC1 mutation and Mills tells me he’s in touch with six other families. They’re all over the world: Canada, Ireland, Finland, France. Another child was just diagnosed in Australia.

"I remember the first time we talked to the first two families, I remember it being really monumental for all of us," Mills says. "To know that there's somebody else out there that's going through extremely similar situations, It's been really helpful to have that, and to be able to understand what everybody's going through. It's been remarkable. We have a name, and something we can put our hands around.”

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