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A network of medical detectives investigating unidentified diseases has diagnosed more than 100 patients with mysterious diseases, a study by scientists at the Stanford University School of Medicine and several collaborating institutes has reported. .
The long-awaited diagnoses are the fruits of the Undiagnosed Disease Network, a program created by the National Institutes of Health in 2014.
"Our goal is to take care of the toughest cases in medicine, to find patients and families with diseases that no one has been able to solve," said Euan Ashley, MD, professor of medicine. at Stanford. "We wanted to provide a place where these people could come, so the network of undiagnosed diseases came together to try to meet that need."
The group, made up of hundreds of doctors across the United States, has so far identified 132 of the 382 previously unknown diseases, or about 35%. "Some of these patients have been waiting for decades before they can name their disease. They tell us how relieved he is to just know what they were facing, "Ashley said. But what is most exciting, he said, is that 80% of network diagnoses are distilling actionable information, such as changes in patient therapy, adjustments to future diagnostic tests, and recommendations for family screening.
"Our findings highlight the impact of a clear diagnosis on clinical decision-making in previously undiagnosed patients," said Kimberly Splinter, Deputy Director of Research Operations for the Network Coordination Center and Genetic Counselor. at Harvard Medical School. "We hope that the results of this analysis will provide a compelling argument for adopting some of the network's diagnostic approaches more broadly, with the goal of clarifying diagnoses and refining the treatment of patients with rare diseases."
An article describing the study was published online on October 11 in The New England Medical Journal. Ashley is the main author and Splinter is the main author.
Cracking the cases
The effort took off four years ago when the NIH asked Ashley to co-chair a consortium of interdisciplinary physicians who would work to resolve some of the most difficult cases of medical treatment – at no cost to the patient. Of the 1,519 patient requests, 601 were accepted because the network would probably be able to help them, given their medical history and available data. The network continues to accept applications. to date, they have received 2,780 requests, accepted 1,179 and reviewed 907.
Ashley and her team of doctors have now seen more than half of these patients, combining traditional medicine with more and more sophisticated diagnostic tests.
"We do this Sherlock Holmes-style detective work by carefully observing, gathering information and asking tough questions, but we also link that with the most advanced genomic technologies to try to solve their case," he said. Ashley.
Some cases are solved simply because we know more today than a year ago.
All patients had their genome sequenced, even those whose genomes had already been sequenced. Ashley explained that the field of genetic and genomic testing is evolving so rapidly that even patients whose genome was sequenced six months ago are getting a new look. In coordination with genome sequencing, doctors looked at patients' RNA profiles, analyzing the precursor molecules of proteins in their bodies. They have also broken down a collection of molecules called metabolites, which form a product of metabolism and can indicate where metabolic processes go wrong.
"Some cases are solved simply because we know more today than a year ago," Ashley said.
Of the people diagnosed, most have presented rare versions of known diseases, thus expanding the symptomatic information that doctors can look for when they evaluate patients for these diseases in the future. But in 31 patients, the network identified previously unknown syndromes.
Matthew Wheeler, MD, an assistant professor of medicine at Stanford and executive director of the Stanford Center for Undiagnosed Diseases, is the case of a patient whom the network has followed for several years. The patient had mysterious and life-threatening episodes of lactic acidosis, a dangerous accumulation of lactic acid in the body.
"It's a bit like an extreme version of the practice of intense physical activity and the burning sensation caused by lactate buildup – it's only your entire body that feels that sensation," said Wheeler. "Lactic acidosis can also unbalance your acid-base balance and, when people have severe acid-base disorders, they are at high risk of arrhythmia or death."
Why did the patient experience these symptoms, which appeared to be caused by a cold or flu? After giving the patient the full range of tests and analyzing the sequencing information, a team of Stanford scientists discovered the culprit: a single mutation in the ATP5F1D gene, which is involved in mitochondria function, central to the cell . Genetic quirks and symptoms had never been officially grouped together, but thanks to connections within the network and, in some cases, by word of mouth, scientists discovered that other doctors around the world had patients affected by this syndrome. By verifying that the mutation causes the syndrome – called the mitochondrial complex V deficiency, the nuclear type 5 nucleus – network collaborators have developed animal models to demonstrate causality.
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"This is a new kind of scientific odyssey," said Ashley. "We are discovering biology in a way that could help not only a family, but potentially dozens, if not hundreds, of families suffering from the same rare disease. This is the main benefit of this network effect: the impact of identifying a patient's illness could become global. "
Even patients who have not been diagnosed benefit from knowing that a team is continuing to study their conditions and that the future may have an answer, even if it does not. This is not the case of the present.
"Patients told us that just knowing that a team was looking at their health, that there was someone in the world who was not leaving them, scientists still keeping an eye on the literature – which gives hope, "Ashley said.
Ashley and her colleagues are now entering the second phase as they develop network sites and continue to accept requests and see patients.
"Let's face it, the resolution of one-third of these cases in the first phase was excellent: when they walked through the door, it was 0%. So, to reach more than 30%, we are satisfied, but this still leaves the majority of unsolved cases and many patients still suffering. So we have to do better, "said Ashley.
The other authors of the Stanford study are Jonathan Bernstein, MD, PhD, professor of pediatrics; and Chloe Reuter, genetic counselor.
Ashley is a member of the Stanford Cardiovascular Institute, Stanford Bio-X and the Stanford Child Health Research Institute.
Researchers from Harvard University, the NIH Clinical Center, Baylor University, the University of Maryland, Vanderbilt University, HudsonAlpha Institutes of Biotechnology, the University of California 39; University of Oregon, Brigham and Women's Hospital, Northwest Northwest Laboratory, University of California at Los Angeles, Duke University, Massachusetts General Hospital and the National Human Genome Research Institute contributed to this study.
The study was funded by the NIH (grants U01HG007709, U01HG007672, U01HG007690, U01HG007708, U01HG00773, U01HG007674, U01HG007942, U01HG007943, U01H000095, U01H000095 and woodlots).
The Stanford Department of Medicine also supported the work.
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