At first, Corrie and Adam Mendes thought their daughter Emmie had an inner ear problem. She was late with several early milestones, including walking, and when she did walk, she often lost her balance. The family pediatrician sent them to a neurologist, who ordered a brain MRI and diagnosed her with pachygyria, a rare condition in which the brain is smoother than normal, lacking its usual number of folds.
Additionally, Emmie’s ventricles, the fluid-filled cushions around the brain, looked enlarged, so the neurologist recommended brain surgery to install a shunt to drain off fluid. He advised Corrie and Adam that Emmie’s life expectancy would be greatly reduced.
As Corrie recounts on her blog, Emmie’s Story, she went online and came across the research laboratory of Christopher Walsh, MD, PhD, at Boston Children’s Hospital. The lab does research on brain malformations and has an affiliatedBrain Development and Genetics Clinic that can provide medical care.
After Walsh’s team reviewed Emmie’s MRI scan, genetic counselor Brenda Barry invited the family up from Florida. In Boston, Emmie received an alternate diagnosis—far from lacking folds, her brain had an excess of small, thin folds, a condition known as polymicrogyria. Her parents also learned the cause: a rare recessive mutation in GPR56—a gene previously found by the Walsh Lab to help drive folding of the brain’s cortex.
With a proper diagnosis, Emmie’s projected life expectancy shot up into the normal range, and her ventricles, though larger than usual, didn’t require a shunt. Now age 6, Emmie is about to enter kindergarten, where her parents feel she’ll be able to function with some extra help.
“We couldn’t afford to pay for genetic testing at the time—insurance doesn’t cover it—but we were tested as part of a study, and that’s how we got the diagnosis,” says Corrie.
Connecting with experts
For many families who don’t connect with the right physicians and researchers—or even those who do—answers are far harder to get. Some families can go a decade or more not knowing what’s causing their child’s symptoms or whether future children will be at risk. Misdiagnoses, treatment delays and repeated, often unnecessary and costly diagnostic tests are often the norm.
That may now change. The National Institutes of Health (NIH) just expanded itsUndiagnosed Disease Network (UDN), adding six new clinical sites around the country, including a Boston consortium comprised of Boston Children’s Hospital, Brigham and Women’s Hospital and Massachusetts General Hospital. The Boston site alone, known as the Harvard Center for Integrated Approaches to Undiagnosed Diseases, is receiving a $7.19 million, four-year grant. Nationally, it is a $43 million initiative.
In its first year, the Boston center will enroll and care for 12 patients, both children and adults, increasing to 50 per year by the summer of 2017. Essentially, a team of experts will converge on each patient, providing a detailed clinical evaluation, cutting-edge genetic and genomic analysis, environmental exposure analysis, proteomics, metabolomics, systems biology and network medicine analysis. The center will tap the three hospitals’ strengths, such as Brigham and Women’s expertise in cardiac genetics and Boston Children’s knowledge of neurogenetics and rare diseases. Physicians can refer patients to the UDN, and patients can also seek UDN services on their own.
“One thing that’s very important to us is keeping the patient at the center of what we do,” says Walsh, who is also chief of the Division of Genetics and Genomics at Boston Children’s and a co-principal investigator on the grant. “All patients enrolled in the Center will have access to specialty care and genetic counseling as we work to solve their diagnostic ‘mystery.’ This isn’t just research, it’s also clinical care.”
The NIH decided to create a network of six locations when it found that its own Undiagnosed Disease Program received so many applications that it couldn’t keep up. (To date, it’s provided services to about 600 patients and diagnosed about 100.) To create uniformity and help figure out workflows, the agency designated Harvard Medical School (HMS) in December to be the UDN Coordinating Center, naming Isaac Kohane, MD, PhD, of HMS and Boston Children’s as principal investigator.
“We can match patients with the right experts, establish best practices and really design a clinical diagnosis network that looks like it belongs to the new millennium,” Kohane said in a press release.
To Brenda Barry, the genetic counselor who worked with Emmie’s family, the UDN is a greatly scaled-up version of what the Walsh Lab and the Brain Development and Genetics Clinic do for patients with neurologic conditions. “If Emmie had gone to a place with less experience in brain malformations like polymicrogyria, her condition likely would have remained a mystery no matter how many second opinions the family pursued,” Barry says.
The Manton Center for Orphan Disease Research, which will be a major part of the UDN at Boston Children’s, does similar work across the spectrum of rare diseases, and sees the UDN as an opportunity to scale up its efforts.
The other UDN Centers are:
Baylor College of Medicine, HoustonDuke University, Durham, North CarolinaStanford University, Stanford, CaliforniaUniversity of California, Los AngelesVanderbilt University Medical Center, Nashville