Profile: NIH's disease detectives

Abstract

Listen

Translate article

The Undiagnosed Diseases Program (UDP) at the National Institutes of Health (NIH), MD, USA, sounds like it was lifted straight from a television programme: a team of physicians works to identify their patients' mysterious, life-threatening ailments. Led by William Gahl, Clinical Director of the National Human Genome Research Institute, the UDP is often the last hope for hundreds of Americans whose diseases have escaped diagnosis. Although diagnosing just one person's disease may seem like an odd investment for America's national medical research agency, the NIH announced in July, 2012, that it will provide additional funding to the 4-year-old UDP to aid the establishment of similar programmes at six universities around the USA. The UDP began in May, 2008, with a nationwide call for physicians to send in their most challenging and mysterious cases and an initial budget of US$280 000. In the first 2 years of the programme, the UDP physicians were called upon to review 1191 patient files. Most of these patients suffer from extremely rare diseases, meaning that their condition affects less than 10 000 people in the USA. However, regardless of how rare the disease is, patients still want answers. “There are patients who come and we give them a diagnosis that is essentially a death sentence, and they are still incredibly appreciative”, Gahl said. “The need to know is as important as living.” Since the first call for applications more than 4 years ago, Gahl and his colleagues have invited more than 400 patients to spend a week as inpatients at the NIH hospital for a battery of intensive tests and DNA screenings. Advances in DNA sequencing technologies have probably had the biggest effect on the UDP, and is one of the main reasons behind the programme's success, says Manfred Boehm, a geneticist at the NIH who works with the UDP. The scientists at the UDP frequently analyse a patient's DNA for single nucleotide polymorphisms (SNPs), as well as sequencing their entire genome or just the protein-coding regions for any mutations. Thus far, the UDP has identified 15 new genetic mutations associated with previously recognised diseases and discovered two new diseases. The discovery of a new vascular disease—arterial calcification due to CD73 deficiency (ACDC)—has been one of the highlights of the UDP. Members of two different American families presented to the UDP with pain in their legs and feet caused by poor circulation. X-rays and MRIs showed extensive calcium deposits in their arteries, but the UDP researchers could not match their symptoms and DNA with any known mutations. Because all five siblings in one of these families had symptoms of this disease, Gahl and colleagues hypothesised that the disorder might be an inherited, recessive condition. Genetic sequencing revealed a mutation in the NT5E gene in all three families, which codes for the CD73 protein. Without CD73, crystals of calcium phosphate accumulate in arteries and joints, causing the pain and poor circulation associated with ACDC. “This is the cutting edge of the application of genomic science”, said Barry Coller, a medical geneticist at Rockefeller University in New York City. “It's a very powerful proof of concept of the utility of this approach to identify new abnormalities.” Although only a small portion of patients receive a definitive diagnosis, Gahl estimates that around 10% of patients receive a full diagnosis, and an additional 30% get a partial diagnosis. Furthermore, the UDP researchers believe that insights into rare diseases will give scientists improved understanding of more common diseases, as well as providing new ways to treat these illnesses. “You see vascular calcification in atherosclerosis, diabetes, and end-stage renal disease. Identifying the phenotype in a small group of individuals may help us better understand the disease mechanism that is actually quite common”, says Boehm. The success and popularity of the programme has led to marked increases in funding. In 2009, the budget was increased to $3·5 million annually, where it remained until 2012. Funding was again increased for the 2013 fiscal year. Instead of increasing the scope of the intramural programme at the NIH, however, administrators decided to create six extramural programmes at hospitals and universities around the USA. The NIH has committed $145 million over 7 years from the NIH Common Fund (a $557 million programme for cross-cutting initiatives) to the creation of these six programmes. The UDP is currently accepting applications from interested research centres. In the end, what really drives the UDP and the general public's fascination with the programme is the very human instinct to ask “why?”, Gahl says. “Every case that comes to us is a human interest story that deals with desperation and uncertainty”, he noted. “It's bringing people together and opening up the question of what it means to be a human.”