Hope springs eternal

NIH names new clinical sites for Undiagnosed Diseases Network and provides $43 million

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BETHESDA, Md.—Since the age of 25, Louise Benge has suffered from a blood blockage to her legs and hands, turning her calves rock-hard and making the act of even walking across a room painful, notes the National Institutes of Health (NIH), looking to the past to help frame its current efforts in rare and undiagnosed diseases. Her younger sister Paula, once a tomboy, began feeling the same symptoms at age 18. Doctors were baffled, but after countless tests, could find nothing wrong. It would only get worse over the next 20 years for Benge, Allen and their three siblings.
With no diagnosis in sight for the Kentucky-born kin, there seemed no hope for recovery.
That is, until May 2008, when the NIH and its National Human Genome Research Institute (NHGRI) launched its Undiagnosed Diseases Network (UDN), and one year later took the family under its wing, soon diagnosing the five adult siblings with arterial calcification due to deficiency of CD73 (ACDC), a rare genetic disorder that was explained for the first time in the Feb. 3. 2010 issue of the New England Journal of Medicine. ACDC is caused by a gene defect that permits calcium to build up in arteries below the waist and in the hands.
Clinical investigators from the NHGRI and the National Heart, Lung and Blood Institute identified the rare disorder in May 2009, of which just nine cases from three families are known, according to the NIH. The genetic condition is recessive, meaning that it is caused by a gene variant that is present in one copy of the two genes passed down by each of her parents.
Fast-forward to 2014.
To expand the scope and efforts of the UDN network, the NIH recently awarded six grants to medical centers, charging them to choose from among the most difficult-to-solve medical cases and then diagnose, conduct clinical evaluations and investigate patients with prolonged undiagnosed conditions.
The institutions awarded grants this year to establish UDN clinical sites were the Baylor College of Medicine in Houston; Duke University in Durham, N.C.; Stanford University in California; the University of California, Los Angeles; Vanderbilt University Medical Center in Nashville, Tenn.; and—grouped together as a trio—Boston Children’s Hospital, Brigham and Women’s Hospital in Boston and Massachusetts General Hospital.
The network builds on a program at the NIH Clinical Center in Bethesda, Md., that for the past six years has evaluated hundreds of patients and provided many diagnoses, often using genomic approaches for rare conditions.
“Newly developed methods for genome sequencing now provide us amazingly powerful approaches for deciphering the causes of rare undiagnosed conditions,” Dr. Eric D. Green, director of the NHGRI, stated in a news release. “Along with robust clinical evaluations, genomics will play a central role in the UDN’s mission.”
The NIH Common Fund awarded four-year grants of approximately $7.2 million (pending available funds) to each of the six awardees, said Dr. James M. Anderson, director of the NIH Division of Program Coordination, Planning and Strategic Initiatives. In addition, this past December, NIH selected Harvard Medical School as the UDN Coordinating Center for the multi-institution network.
“The NIH Undiagnosed Diseases Network has the potential to transform medicine and serve as a catalyst for new discoveries,” Anderson stated. “It is an ideal NIH Common Fund program—the only one focused on diagnoses of rare disorders.”
This type of program “can invigorate a medical center anywhere in the country and in the world,” Dr. William A. Gahl, clinical director at NHGRI, stated. “Often, patients have a lot of physical complaints and no objective diagnoses. Our goal is to use the latest tools to make a diagnosis that spans the clinical, pathological and biochemical spectrum to uncover the basic genetic defect.”
Since 2008, the NIH’s Undiagnosed Diseases Program (UDP) has enrolled approximately 600 undiagnosed children and adults in its clinical protocols. The multidisciplinary clinical and research team diagnosed approximately 100 patients (20 to 25 percent of those evaluated), discovered two unknown diseases and identified 15 genes not previously associated with any other human disease.
The additional six clinical sites and the UDN will all draw upon the expertise of new clinical research groups and cultivate opportunities for collaboration among a larger group of expert laboratory and clinical investigators, the NIH stated. Physicians within the network will collect and share clinical and laboratory data, including genomic information, clinical observations and documentation of environmental exposures. Each site will also benefit from common protocols designed to improve the level of diagnosis and care for patients with undiagnosed diseases.
“The UDN will look at diseases across all clinical specialties using new tools and methods of analysis for the identification of new diseases,” stated Anastasia L. Wise, a program director in NHGRI’s Division of Genomic Medicine.
“We believe that there is a substantial unmet demand for the diagnoses of conditions that have perplexed skillful physicians,” stated Dr. Isaac Kohane, professor of pediatrics at Harvard Medical School and Boston Children’s Hospital. “We want to address inquiries from physicians and patients throughout the country who require these services and create a 21st-century model for diagnosis and treatment in this genomic and information-intensive era.”
The network will start up and test its operating procedures during its first year. It will progressively expand recruitment of patients so that by the summer of 2017, the rate of admissions at each new clinical site will be about 50 patients per year.
The caseload of the UDP is steadily growing, with more than 100 pediatric and adult patients added each year, the NIH stated. The volume of applications from patients across the country, and abroad, has exceeded expectations, reflecting that the UDP fills an unmet need for undiagnosed patients, according to the NIH.
“In the last 30 years, we have made significant strides in molecular diagnosis of undiagnosed and rare diseases with the advancement of research and implementation of next-generation genetic testing,” noted Dr. Brendan Lee, professor and interim chair of molecular and human genetics at Baylor, who will lead his institution’s UDN study site. “We are able to make a diagnosis (identify a potential molecular DNA lesion) in approximately 25 to 30 percent of cases, whereas before it was less than 1 to 2 percent. Baylor and Texas Children’s Hospital have been pioneers in this effort and have robust research and clinical programs focused on improving this field,” he continued, adding that the network will address both childhood and adult cases.
“The UDP responds to a critical unmet need, with compassion, clinical expertise and state-of-the-art genomic technologies,” said Dr. Daniel Kastner, scientific director at the NHGRI. “A patient who cannot be diagnosed may cycle through the medical system with no satisfactory treatment plan or be abandoned by the medical system. Through the UDP, NIH provides a glimmer of hope to patients and their families, while at the same time gaining remarkable medical insights.”
More than half of the 326 current accepted patients had undiagnosed neurological problems, the NIH said. Other prominent disorder categories include gastrointestinal disease; fibromyalgia and chronic fatigue syndrome; immune-mediated and rheumatic illnesses; psychiatric conditions; pain; dermatologic disorders and cardiovascular disease.
As for Louise Benge, for the past several years she has received therapy that helps her kidneys flush calcium from her blood. Though she has received recommendations for activities such as water aerobics, nothing currently has been offered to eliminate the painful effects of ACDC. Back in Kentucky, she remains hopeful that doctors will develop a treatment now that the disorder is identified and understood at the molecular level.
In the early days of seeking treatment for her painful affliction, some medical professionals “suggested we should just go about our business,” Benge said. “It has impressed me that at NIH, they wanted to do something to help us.”

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