All over the country, specialized teams of doctors are giving hope to families who are desperately searching for a diagnosis.
The medical sleuths, scattered across 12 clinics nationwide, form the Undiagnosed Disease Network. Since the program began in 2014, they've identified 31 previously unknown syndromes and they've cracked more than a third of their cases, according to a recent paper in the New England Journal of Medicine.
"It was like Sherlock Holmes," says Euan Ashley, a professor of medicine at Stanford University." Patients would come with mystery diseases and we would try to solve them."
Although rare diseases are individually very uncommon, collectively they are surprisingly pervasive. In fact, if grouped together into a single category, they afflict between 25 to 30 million Americans.
For people coping with mystery conditions, finally getting a diagnosis can be life-saving or life-changing. Take the perplexing case of the two Miller boys from Marin County.
A Four-Year Diagnostic Odyssey
Five-year-old Chase and 7-year-old Carson have alert minds and radiant smiles but very uncooperative bodies. The blond, blue-eyed brothers are not able to sit, stand, speak, or feed themselves. They've spent their lives in wheelchairs.
Even though they attend a mainstream elementary school and are cognitively functioning on par with their peers, they are both still in diapers. The boys require constant care at home and attentive individual aides in the classroom.
The boys' parents, Nikki and Danny Miller, first noticed a problem seven years ago when their first son wasn't reaching typical milestones like rolling over or crawling. Instead, they witnessed spastic movements and tiny hands repeatedly balling into fists. Babbling never turned into words.
When Carson was about a year old, he was misdiagnosed with cerebral palsy. Then when the same developmental delays emerged in the Millers' second-born, the parents started asking more questions, which led to a four-year diagnostic odyssey with countless inconclusive lab tests. One after another, specialists shrugged their shoulders.
"It's really tough because as a parent you blame yourself," says Danny. "What did I do wrong? Is there something wrong with my genes?"
Cracking the Case
Finally, two years ago Danny applied to the clinic at the Stanford Center for Undiagnosed Diseases. After reviewing the boys' medical history, researchers ordered full genome sequencing for all four family members. Until recently this type of extensive testing was prohibitively expensive.
"We're rapidly moving to the point where it makes more sense to go straight to the genome rather than measuring one gene, then another, then another," says Ashley as he pulls out his laptop to point out the clue within the family's genetics.
The screen is divided into several rows and columns with long strings of letters that represent the human DNA code. Ashley points to a section in the MECR gene, which, when disrupted, alters the part of the brain that controls movement.
"You can see in the colored section the same gene was hit by two variants, one from mom and one from dad," he says. There is an incorrect letter in the boys' genetic code. "One letter of 6 billion can cause these incredibly devastating diseases," Ashley says.
Neither of the boys' two copies of the gene works properly, which is why Carson and Chase have a brain disease called MEPAN syndrome. Only 13 people in the world are currently known to have it, and there is only one published scientific paper on it, says Ashley.
"Currently, there is no treatment for MEPAN, but Danny and Nikki are hoping a heavy cocktail of vitamins and supplements will slow down the disease from progressing and further limiting the boys' ability to move. The parents also take the boys to physical, occupational, and speech therapy to strengthen their muscles and teach them life skills. The boys communicate with computers attached to their wheelchairs.
Discovering what was wrong was only a single step on the family's journey, though a crucial one. A diagnosis is key to refining treatment and potentially attracting more scientific interest, which may someday lead to a cure.
Father Danny Miller's voice cracks as he contemplates the road ahead.
"Recently at school Carson built a sentence that said, 'I hate my wheelchair,' " recalls Danny. "Because I know that he wants to be up running around, playing tag, and hide and seek with the other kids. That may not be the way things work out. But I'm going to do everything in my power to try and make sure that does happen."
STEVE INSKEEP, HOST:
Doctors are solving health mysteries for families who've run out of options. These specialists across the country form what is called the Undiagnosed Disease Network. This sounds almost like a television drama, but this is very real life. They recently cracked the perplexing case of two boys in Northern California. Lesley McClurg from member station KQED has the story.
LESLEY MCCLURG, BYLINE: On a cold, dark morning, Chase Miller peeks out from under his covers, and he peers curiously at my microphone with a big smile.
NIKKI MILLER: Chasey-pie? Chase? You want to say hi? This is Lesley.
MCCLURG: Nikki, Chase's mom, gently lowers the thin boy to the floor. He's 5. She lays him on his back because he can't sit or stand. Then Nikki goes to the same routine with her other blue-eyed, blond son, Carson. He's 7.
N MILLER: Carson. There we go.
MCCLURG: Carson's legs jerk randomly, and Nikki struggles to pull on a stiff leg brace. She wipes her brow.
N MILLER: This is a workout. This life is a workout for sure.
MCCLURG: Nikki never imagined their morning routine would include electric lifts and two boys strapped into wheelchairs who still require spoon-feeding.
N MILLER: OK, guys. It's 7:40. So about a couple more minutes, and then I'm going to start getting you guys cleaned up.
DANNY MILLER: It is much easier when you wake up to those beautiful, brilliant smiles every morning - every morning.
MCCLURG: That's Danny Miller, the boys' father. Seven years ago, he and Nikki began noticing their first son wasn't reaching milestones like rolling over or crawling. Instead, their baby was...
D MILLER: Fisting, spastic movements, tight movements.
MCCLURG: And then at about a year, their son was misdiagnosed with cerebral palsy. And then when the same developmental delays emerged in their second newborn, they started asking more questions. And they spent the next four years getting test after test after test.
D MILLER: It can be a very lonely experience.
MCCLURG: Each specialist shrugged their shoulders.
D MILLER: It's really tough because as a parent, you blame yourself. What did I do wrong? You know, is there something wrong with my genes?
MCCLURG: Finally, two years ago, the family heard about a group of doctors known for sleuthing the toughest cases, the Undiagnosed Disease Network. It's funded by the National Institutes of Health. Euan Ashley heads up one of the country's 12 clinics at Stanford University.
EUAN ASHLEY: It was like "Sherlock Holmes." Patients would come with mystery diseases, and we would try to solve them.
MCCLURG: And how common are these patients that you're seeing?
ASHLEY: The remarkable thing is that although individually rare diseases are rare, collectively they're very common. In fact, 1 in 20 people in the population has a rare disease.
MCCLURG: To unlock the Miller case, Ashley recommended a complete genome sequencing for each family member. He pulls out his laptop to point out what the test revealed.
ASHLEY: So what you're looking at, four genomes on one screen.
MCCLURG: Each is a long string of letters that is code for our DNA. He's looking for a letter where it shouldn't be, what they call a variant.
ASHLEY: And you can see in the colored section, same gene was hit by two variants, one from Mom, one from Dad.
MCCLURG: So their whole lives are affected by a misspelling.
ASHLEY: Yeah. One letter out of 6 billion can cause these incredibly devastating diseases.
MCCLURG: The misspelling is why Carson and Chase have a brain disease called MEPAN syndrome. Their genetic mutation affects the part of the brain that controls movement. There's only one scientific paper that's been published about it.
D MILLER: And aside from that, there was nothing else out there.
MCCLURG: Danny has only found 13 other people in the world who have it. There's no current treatment for the degenerative disease. And even though the boys' minds are cognitively sound, their bodies will eventually fail them, so doctors hope a hefty dose of daily vitamins and supplements will slow their brain decline. The boys are also in therapy to strengthen muscles and to give them life skills.
D MILLER: We have PT and OT and speech.
MCCLURG: Recently, on a computer which helps the boys communicate, Carson...
D MILLER: He built a sentence that said, I hate my wheelchair because I know that he wants to be up running around, playing tag and hide-and-seek with the other kids. That might not be how things work out, but I'm going to do everything in my power to try and make sure that that does happen.
MCCLURG: The first step was knowing what was wrong. The network of disease detectives have solved about a third of their patient cases and named 31 new syndromes in the first few years of the program. And once there's a diagnosis, then it's a lot easier to attract scientific interest and someday potentially more cures. For NPR News, I'm Lesley McClurg in Marin County. Transcript provided by NPR, Copyright NPR.