"Disease detectives" present cases in 130 patients with mysterious diseases

A national network of "disease detectives" has uncovered the complex medical mysteries of more than 130 previously unidentified rare disease patients, although the majority of cases referred to them remain unresolved, according to a network analysis released on Wednesday.

According to the analysis published in the New England Journal of Medicine, the network of undiagnosed diseases – which currently has 12 clinics across the country, including one at Stanford – has a resolution rate of about 35%. Considering that all the cases studied by the network concern patients with extremely complex diseases for which they have spent years – sometimes decades – without diagnosis, this is an impressive result, said the authors of the report.

Most patients have been diagnosed after a thorough analysis of their genome revealing a rare genetic mutation. Some were diagnosed only after the network was able to find one or two other patients in the world with similar symptoms and a diagnosis.

The researchers diagnosed 31 patients with diseases never observed before.

"They are people with mysterious syndromes who have not had answers from the mainstream health system. They are referred to one doctor and another, they pass from experts to experts. They carry medical odysseys. And what these patients are going through, they're going through terrible times, "said Dr. Euan Ashley, professor of medicine at Stanford, co-chair of the national network for two years and author of the new analysis.

"For many patients, it's very important to know what's the enemy – to give it a name -" said Ashley.

The Undiagnosed Diseases Network was established in 2014 by the National Institutes of Health, which had launched a similar, much smaller program at its clinic in Bethesda, Maryland, in 2008. The network, funded by the NIH, should cost about $ 100 million over the next four years. Patients do not pay any of the services necessary for their diagnosis.

The network has been developed largely to help patients with rare diseases. But it is also planned to improve large-scale research on rare diseases and in particular genetic diseases that can be identified by genome sequencing. Each new diagnosis potentially adds to the overall understanding of human biology and where systems can malfunction.

Especially with genome sequencing, the more information collected, the easier the future diagnoses will be. The human genome is huge and, with some rare diseases, doctors are looking for a mutation in a single gene – it's like "looking for a needle in a needle stack," Ashley said.

But if doctors can access previous research that associates certain symptoms with specific parts of the genome, they can at least give them an idea of ​​where to look for a diagnosis. The network of undiagnosed diseases, which often relies on sequencing the genome to diagnose patients, could be a major contributor to this better understanding, Ashley said.

The same is true for patients with conditions not caused by a gene with misfires. The greater the number of people with similar identifiable symptoms, the more doctors can approach a diagnosis.

"We are essentially looking for a place to light," Ashley said.

For the newspaper published Wednesday, the Ashley group reviewed the 1,519 patients who applied to the national network from September 2015 to May 2017. Of these patients, 601 were accepted for study by the network. The doctors evaluated 382 of them during the period analyzed by Ashley's group.

Of the 132 people who were finally diagnosed, 21% were asked to change their treatment plan – take a new medicine, for example – based on the diagnosis. 37% of respondents were asked to undergo new, more disease-specific tests to better monitor their symptoms. And in 36% of cases, the diagnosis led to genetic counseling among family members who could carry the same mutation causing the disease.

In a few cases, the diagnosis has changed life. A man suffering from severe recurrent fevers for years began taking a new drug after being diagnosed with rare immune disease. The drug has significantly reduced the frequency and intensity of its symptoms.

However, even among patients diagnosed, discovering the mystery has done little to change their treatment or improve their symptoms. Identifying the disease, however, can at least convince patients, their families and doctors that they are getting the best possible care, said Dr. Jon Bernstein, pediatric medical director of the Stanford Center for Undiagnosed Diseases.

"For many families, it feels like fighting an enemy and not knowing what it is. When you have a diagnosis, you know, "said Bernstein. "A key step in taking the best care of someone you can is to know what is going on."

Anahi Villanueva, a 10-year-old Pittsburg girl who began to experience the symptoms of a severe metabolic disorder as early as a few days old, is one of Bernstein's most memorable cases. Her body was not good for energy production and her body systems slowed or stopped working under the slightest stress – a simple viral infection, a long day at school. Some times she has been in a state of coma.

She jumped from one expert to the other, but none could diagnose her. She even underwent genome sequencing, but no one could find the gene to blame. When the network of undiagnosed diseases was opened, his family immediately asked for an assessment.

The first step taken by the investigators was to reanalyze the genome sequencing she had already done, Bernstein said. Every month or so, a new discovery of the genome analysis can help the experts read the results – they were hoping for such an advance for Anahi.

Indeed, the researchers discovered a mutation in a single gene that had been associated with energy production in the body. There was no known case of serious illness caused by a variation of this gene, but it was a clue to Anahi's doctors. The investigators began to contact other doctors around the world, wondering if there were other patients. After a few months, they found a boy in the UK.

It turned out that he had the same genetic mutation as Anahi. After this discovery, the US investigators conducted an experiment on fruit flies: they inserted the mutation of the gene into the flies and discovered that they also had problems of energy production.

It was good enough for a diagnosis: mitochondrial complex deficiency of V due to mutation of ATP5F1D. "Yes, it's a mouthful," Bernstein said.

For the moment, Anahi is doing well, said her mother, Maria Villanueva. She goes to school. She is a bit small for her age and she gets tired easily. Although she goes to the emergency room about once a year when her condition is clear, it is an improvement over her youth and hospitalization every few months.

Not knowing what was wrong with her daughter was frustrating, Villanueva said. She had so many questions to ask Anahi's doctors, and they never had answers.

"At least the doctors know exactly what she has and can perhaps better treat her now," she said. "I still have questions. They still can not answer it. But it's not like before.