Their mission, like detectives tackling a stack of cold case files, was to determine the genetic underpinnings of disease in patients who had been undiagnosable, sometimes for years.
But the team of Duke researchers – whose methods involved painstaking, one-by-one examination of perhaps thousands of mutations in the genes of the individual patients – needed something more in the unique case of tiny Bertrand Might: a father who is unusually skilled with social media.
What happened is a tale of medicine at its most modern.
Bertrand was born seemingly healthy in 2007 in Georgia, where his parents, Matt and Cristina Might, were in graduate school. But by the time he was 6 months old, they couldn’t help but notice that he couldn’t yet crawl. He also was doing what they began to call jiggling, almost never stopping the odd motions, particularly with his hands.
By then, the young family had moved to Salt Lake City, where Matt Might had a new job as an assistant professor of computer science at the University of Utah. Cristina Might had an MBA and had been running two small startup companies. Bertrand’s problems, though, meant that she quickly became a full-time caregiver and advocate for her son.
Bertrand’s doctor recommended a developmental pediatrician, who made the first wrong and frightening guess at the problem. It could be brain damage, she said.
They didn’t know it, but the Mights had begun a frustrating and expensive odyssey that is familiar to the parents of many children with mysterious diseases. It would take them all over the country, including three trips to Durham to explore the possibilities with doctors at Duke. But mainly it took them on a seemingly endless and emotional ride.
First, the brain damage diagnosis. Then an MRI that showed no problems.
Bad news, then good news. It was a pattern that would come to dominate their lives.
Was it a degenerative, fatal disease? Some thought so. Was his liver failing? Doctors thought that for a while, too. Yet another test revealed high levels of sugars in his urine, which suggested an illness that could be treated via a bone marrow transplant.
So when Bertrand was about 1 year old, the Mights flew to Durham, where he underwent elaborate testing so that Dr. Joanne Kurtzberg could be sure about his condition before committing to a transplant. Among the team there was a medical geneticist, Dr. Vandana Shashi.
The Mights learned from examinations of Bertrand’s brain waves that many of his odd motions were seizures, and they began trying various medicines and a special diet to try to control them.
The Duke team, like so many other doctors before them, couldn’t determine the precise cause of Bertrand’s illness. And in any case, it had progressed too much for a marrow transplant to help, Kurtzberg said.
Disappointed, the Mights boarded a plane and headed back to Utah – back to their frustrating search.
Dr. Shashi, though, didn’t forget them.
One of Bertrand’s most distinctive symptoms, an inability to produce tears, led the family to Maryland to the National Institutes of Health to investigate another possibility. That guess was wrong, too, as were more guesses at other diseases from the NIH panel.
But Bertrand’s eyes were dry when he cried, and that would turn out to be a crucial clue.
Meanwhile, one of his three types of seizures were getting worse, and the drug for that type had severe side effects. When Bertrand came off that drug, he briefly showed his parents a glimpse of normalcy: He laughed at a television program.
Bertrand had never spoken. He was nearly 3.
Cristina began crying, and, in his personal blog, Matt Might called it the most direct sign of Bertrand’s humanity they had yet seen.
But it was just a sign. The testing and guessing continued. He had potentially fatal liver problems, and an electrocardiogram found a rare heart condition called long QT syndrome that can be fatal.
“During this time, there seemed to be a grim race between Bertrand’s brain, heart and liver to kill him,” his father wrote in his blog.
Then, when Bertrand was 4, they got another call from Dr. Shashi. She had often called to check in and offer ideas. This time, though, she had something better: Duke’s Center for Human Genome Variation was starting a study that would focus on patients whose illnesses had defied diagnosis but that seemed likely to be genetic. Researchers were doing it with elaborate analysis of each patient’s genetic material and that of some of the patients’ relatives. Would Cristina and Matt be willing to have their exomes, and Bertrand’s, mapped and analyzed?
The couple eagerly agreed. The whole family, including Bertrand’s younger sister, Victoria, flew to Durham.
The researchers were blunt. Even if they were able to pin down the cause of Bertrand’s symptoms, there was no guarantee that would point the way to effective treatments.
Invariably though, when families are told this, they still want to be a part of the study, David Goldstein, the director of the Center for Human Genome Variation, said in a recent interview.
“The value that the families place (on) simply knowing, it’s just hugely important to them,” Goldstein said. “This is one of, if not the most important things in their lives, and it’s of huge personal utility to them to know.”
Making some progress
A person’s genome is the full set of instructions for building, operating and maintaining their body. The exome, the protein-encoding part, makes up only about 1 or 2 percent of it, but is believed to contain about 85 percent of the genetic mutations responsible for disease. It’s also much quicker and cheaper to map, or sequence, than the full genome.
Using powerful computers, the Duke researchers sequenced the Mights’ exomes, then compared them with each other and with those of about 9,000 people that Duke has sequenced. They compared millions of mutations, eliminating from consideration those that were unlikely to be at fault.
The basic idea, Goldstein said, is to get the genetic information and use it to think really, really hard about individual cases.
As the researchers worked, the Mights began to get some good news. Bertrand’s heart problem wasn’t congenital but instead had been caused by the hormone drug, and it cleared up. Another drug helped his liver problems.
But his eyes’ perpetual dryness – caused by an inability to produce hardly any fluid – began to trigger all kinds of problems, including eye infections that left his corneas scarred. Every two hours, the couple learned, he would need ointment and drops in his eyes.
The family flew to the Cleveland Clinic in Ohio to see if treatments offered there could improve his epilepsy. The doctors said a type of surgery that worked in some cases wouldn’t work for Bertrand, but they were able to come up with a drug regimen that was effective, sharply reducing his seizures.
A new disease
Meanwhile, at Duke, the researchers had begun focusing on a set of two mutations in one of Bertrand’s genes, a gene known as NGLY1.
That gene had never been associated with disease, but the scientists couldn’t find similar mutations of it in any of the thousands of sets of human genes they were using for comparison. And an earlier research paper showed that it was responsible for the creation of an enzyme called N-glycanase 1, which plays a role in breaking down defective bits of protein. If these misshapen proteins aren’t broken down for recycling, they can accumulate and trigger health problems.
Bertrand’s symptoms suggested a group of disorders long associated with problems in properly creating N-glycanase 1 – so much so, in fact, that he had already been tested for them twice.
It made sense to the Duke researchers that if he had a new form of disease related to degrading the misshapen proteins, his symptoms would seem similar.
His mother and father had one mutation each in the NGLY1 gene, though the mutations were different from each other. It appeared that Bertrand had inherited both.
Testing showed that production of N-glycanase 1 was below normal in each parent, but not enough to affect either’s health. By getting a mutation from each of them, though, Bertrand couldn’t produce any.
That was the theory, one that the researchers grew increasingly confident about as they thought deeply about the case. They also consulted with Dr. Hudson Freeze at Sanford-Burnham Medical Research Institute in La Jolla, Calif., one of the world’s top experts in the biology of the proteins involved.
What it meant, though, was that Bertrand was different from the typical cases being solved. Many of the other research subjects’ genes were found to carry mutations already known for causing a specific disease, though they were presenting in ways somewhat different from normal.
They were claiming to have found an entirely new disease, and they had no other patients whose genes could be matched to confirm the diagnosis.
In 2012, the Mights got another call from Duke. The study was done, and the research team wanted to talk to them in person.
“It was tremendously exciting, because we knew they were calling us out because they had some kind of answer, and they wouldn’t have called otherwise,” Matt Might said.
The family was ushered into a room at Duke’s Lenox Baker Children’s Hospital. Then Dr. Shoshi, Goldstein and two other members of the team Bertrand had been working with walked in.
“They said, ‘Here’s what we found, and here’s why we think this is causing your son’s problems,’ ” said Might. “They took us through the whole process and told us what they found and why they think they found it.”
Dad goes to work
The good news, as usual for Bertrand, came with caveats. Potential treatments were unclear.
And without at least a second patient, there was no way to definitively confirm the diagnosis.
“I remember Cristina and I saying to them at that point, ‘Well, we will find you another patient,’ ” Matt Might said.
And he knew just how to do so.
Might, who had a blog that tries to use simple metaphors to explain complex topics in computer science and academia, knew all too well that the parents of children with strange illnesses quickly turn to their computers in hopes of answers.
He would write about the case on his blog to leverage his readership. Might would use key phrases that would make his blog pop up high on any Google search of the more distinctive symptoms, phrases such as “inability to produce tears,” “dry eyes” and “lack of tears.”
And it would have to be dramatic, something that people would read and link to so that the net could grow.
He posted a picture of actor Liam Neeson, who held a role in “Taken” as a father who hunts down and kills his daughter’s kidnappers, pointing a gun directly at the camera. Then he began typing:
Might’s metaphors and compelling language reads like a genetics whodunnit narrated by a computer geek.
He had to learn as he went about the long string of medical issues. Having no training in biology – let alone genetics – since his last high school biology class, Might wrote that if he made mistakes, readers should help him fine-tune his words.
Making Bertrand happy
The dramatic approach, and the blog’s existing readership in the tech community, helped it spread quickly. Within 48 hours, it had piled up more than 1 million hits.
Other parents quickly began contacting him. There weren’t many, since the nature of the disease means there are only a handful of cases worldwide. But he had built an effective net that ended up catching a significant percentage of them.
The researchers, meanwhile, were starting to find a couple of likely cases via doctors who worked with illnesses involving the same N-glycanase 1 mutation.
They and the patients whose families contacted Might were evaluated – and in some cases sequenced – in their own countries. So far, more than a dozen people have been identified with the disease, most of them after reading Might’s blog and contacting him.
All of this means that not only does Bertrand have a solid diagnosis, there is now a tiny but growing community of parents around the world who help each other by sharing information about things such as symptoms, what to expect and treatments that help with things such as reducing seizures.
The scientists at Duke are still trying to learn more about how mutations work in the NGLY1 gene.
“Just getting an answer has been an immeasurable comfort for the families,” Matt Might said. “Otherwise you just never stop the search.”
The Mights, both 32, don’t feel like they’re finished, either. The end of one search meant the start of another: They’re working with Dr. Freeze to fight the disease and are raising money for that battle .
Insurance from Matt Might’s university job has covered much of Bertrand’s diagnostic costs but not the travel or all of the therapy. They have paid much of that themselves, including using some money that they had begun saving for Bertrand to go to college, some from relatives and some from sales of an online booklet Matt Might wrote. And when they could, Cristina Might said, they pick research programs – such as the one at Duke – providing testing that was free to patients.
Bertrand still can’t walk, speak or feed himself. He is still “jiggly.” His cognitive development plateaued at about 8 months, but he’s in school, attending a full day “life skills” program that includes various kinds of therapy every day. And one characteristic of the disease is that its victims are generally cheerful as long as their simple needs are met.
“The goal for us, first and foremost, is make sure Bertrand stays happy,” said Matt Might. “As parents, you just want your kids to be happy.
“But if we’re going to dream, then we’d like to see Bertrand walk; we’d like to see him talk; we’d like to see him feed himself. We’d like to see him go to school, not in a special needs class.”
In December, Bertrand turned 6.