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Published On April 6, 2017

TECHNOLOGY

Where Lost Diseases Go

A new, nationwide team of experts gives the toughest medical cases a chance at a breakthrough.

Almost from the moment their son Zach was born, the Nichols knew that something wasn’t right. He had wide-set and downward-slanting eyes, loose joints and an extra set of ribs. He also didn’t hear or see well, and had trouble breathing and eating.

Hundreds of medical visits have followed over the eight years since. Zach depends on a tracheostomy tube to breathe and a wheelchair to get around. But because doctors couldn’t identify what caused his condition, they were unable to treat its root causes and such efforts might cause more harm than good. Zach’s parents worried about having more children in case the condition turned out to be genetic.             

Then, in November 2015, Zach’s case was one of the first accepted by the Undiagnosed Diseases Network. The UDN, which grew out of a 2008 initiative from the National Institutes of Health, was designed to serve as a broad, national brain trust for cases like Zach’s. It links the resources of seven noted medical clinics across the country and six additional research sites to look for the root causes of puzzling diseases.

There’s no lack of demand for such help. As of early March, the UDN has received 1,274 applications, accepted 511 and was reviewing another 302. UDN scientists have diagnosed 53 diseases that were previously unknown—most of them caused by genetic mutations, though some by environmental factors, bacteria or viruses. These diagnoses, once they are pinned down, may prove useful for future patients.

“We have been able to resolve diagnostic odysseys that have gone on for decades,” says David Sweetser, chief of medical genetics at Massachusetts General Hospital, which participates in the network.

For these patients, the diagnosis is a critical first step. Once physicians and researchers know what’s causing a disease, they can begin to move beyond treating symptoms and on to seeking cures, though in many cases that may take many years. A diagnosis can also help families find others with closely related conditions, creating a de facto support network that can share ideas and resources.

Sometimes the search begins with sequencing the patient’s entire genome. A major challenge, however, is determining whether any variants and mutations they find are actually causing the symptoms. Zach turned out to have variations in his genome similar to those that cause Marfan syndrome, a disorder of the connective tissue that strengthens blood vessels and links bones, tissues and organs. Some of Zach’s symptoms, such as abnormally flexible joints and dilation of his aorta, also overlap with that disease. But Zach lacks some key features of that condition, such as tall stature and long fingers, and has others that aren’t part of Marfan syndrome, including his seizures and facial appearance.

The UDN researchers speculate that Zach may have a new disorder, caused by the Marfan mutation in conjunction with two other genetic variations that were also found. The UDN is especially well equipped to parse the finer points of the patient’s genome. While many clinics are able to perform basic gene sequencing, UDN researchers have the time, funding and resources to explore mutations in genes that no one knows much about.

In the UDN’s Model Organism Screening Center, the team can replicate Zach’s mutations in zebrafish and fruit flies to see whether the animals develop similar symptoms. Or it might tap its metabolomics unit. “This team can identify a large set of small molecules that are found in body fluids, and see if they match known disease states. This can yield further clues as to what the underlying problem might be,” says Sweetser. “In some cases interactions between genes and the environment may be important. Each family is also asked to complete a detailed environmental survey, looking at anything people have been exposed to or places where they’ve lived that could account for features of the disease.”

All of the UDN’s cases generate data, and lots of it. This is stored in a secure databank to protect the identity of patients, but de-identified data can be provided to researchers outside the network. The hope is that breakthroughs could create applications useful to other cases and teams.

Although the researchers looking at Zach’s case have yet to reach a definitive diagnosis, Sweetser is confident that the UDN will eventually shed some light that could lead to a more sure-footed course of treatment for Zach and for other children who might have the same condition. “Just knowing the causes may direct you to better therapies,” says Sweetser. “Even if a treatment is not forthcoming, the value of finally having a diagnosis cannot be underestimated.”