ARTICLE IN BRIEF
The article features the NIH Undiagnosed Disease Program, which has seen up to 50 percent of cases that involve neurological complaints.
DR. WILLIAM A. GAHL ...Image Tools
Three years ago, federal investigators decided to put their collective resources together to help patients with undiagnosed disorders figure out what is wrong with them. With no promise that they will deliver, and certainly no guarantee that a diagnosis will lead to a treatment, the program is proving that there can't be enough cooks in the proverbial kitchen.
“The NIH Undiagnosed Diseases Program [UDP] combines the best of medicine and science, the best of compassion and discovery,” said NIH Director Francis S. Collins, MD, PhD. “When we started this effort, our goal was to provide answers to patients afflicted by mysterious disorders that had long baffled the medical field. But, as it turns out, some of the answers themselves have proven to be rather surprising, opening unexpected windows into biology as a whole.”
The numbers of calls has been steady for around two years with a total of 5,000 inquiries and over 1,800 medical records logged since the launch of the program in May 2008. The clinicians examining the patients and pouring through their charts are finding that the majority — up to 50 percent — involve unexplained neurological symptoms, according to a commentary published in May in the Journal of the American Medical Association.
The neurological symptoms include seizures, ataxia, neuropathic pain, abnormal movements, and cognitive disturbances for which traditional medicine seemed to have no answers.
William A. Gahl, MD, PhD, clinical director of the National Human Genome Research Institute, and also the director of the new program, described the various neurological complaints in a telephone interview with Neurology Today.
For example, one 47‐year‐old man had a long list of bladder and bowel problems and neuropathic pain in the legs and feet — for five years prior to coming to the NIH. He was no longer sweating and he had balance and gait problems and garbled speech. By the time he showed up at the NIH Clinical Center, the once athletic man was in a wheelchair. He had been to numerous doctors, including neurologists, all of whom were stumped. Previous MRIs of the brain showed a progressive leukoencephalopathy, but that broad category did not constitute a diagnosis, said Dr. Gahl.
A long list of tests came back normal. But a single nucleotide polymorphism (SNP) analysis found duplication on chromosome 5q23, a region containing a gene recently found to cause autosomal dominant leukodystrophy. A history revealed that the patient's father died in his 40s with some neurological issues but no one remembered much more than that. This diagnosis was of interest because this patient has a child, who may also be at risk of this rare disease.
“Neurologists are generally focused on genetic testing around specific symptoms,” said Dr. Gahl. Using some of the more modern genetic technology, including SNP arrays, has a greater chance of identifying a genetic defect. There are fewer than 200 [published] patients worldwide with this condition, he said.
The other mysterious set of neurological symptoms involved two brothers with symptoms of ataxia, epilepsy, and paraplegia. One of the boys died of pneumonia before the NIH work‐up. UDP physicians conducted a long list of neurologic and genetic tests and added whole exon sequencing that found a homozygous missense mutation in a gene called AFG3L2.
Studying how the gene worked allowed the clinicians to put the puzzle pieces in place. The gene product, the AFG3L2 protein, interacts with another AFG3L2 molecule and, separately, with a second protein called paraplegin. The AFG3L2 mutation disrupts both of these interactions. AFG3L2 is a subunit of mitochondrial protease in the inner mitochondrial membrane that removes damaged or misfolded proteins.
“Sometimes just having a diagnosis is a great comfort,” said Dr. Gahl. “And patients can go home to their doctors who no longer have to keep looking for an explanation.”
Dr. Gahl said that the program was initially started with $280,000 from the NIH Office of Rare Diseases Research but that funding has increased to $3.5 million a year from 2010 to 2012.
He added that they delivered diagnoses to 25 percent of the patients who have been through the extensive clinical assessment.
TWO NEW DISORDERS
The NIH team has identified two disorders that have never been described before. One of the conditions was reported extensively in a study the group published in February in the New England Journal of Medicine.
The patients in the study are from Kentucky and the NIH researchers uncovered a metabolic pathway not previously known to be involved in calcification of blood vessels. The calcifications are linked to an increased risk of vascular disease. The NIH clinician‐scientists performed SNP analysis, targeted gene sequencing, quantitative PCR assays, Western blots, enzyme measurements, transduction rescue experiments and in vitro calcification assays.
They identified nine people from three families with these calcifications and the affected members of one family shared a single 22.4‐Mb region of homozygosity that was not shared by their parents. This led to the identification of a nonsense mutation in NT5E. The other family had a different missense mutation in the same NT5E gene. It encodes CD73 that coverts AMP to adenosine, which inhibits ectopic tissue calcification. This was an adult‐onset disease whose cause had never been described before. The patients had widespread calcifications of the lower extremity arteries and small joint capsules.
“Better understanding of this mechanism may guide the development of treatments not only for the Kentucky family but for people suffering from far more common conditions,” said Dr. Collins.
In addition to discovering the new diseases, the NIH team has have given 15 patients answers to conditions that are considered ultra‐rare, which means that there are perhaps 50 reports of similar cases worldwide. Many of the patients so diagnosed are children.
Dr. Gahl added that many of these patients have been handed too many diagnoses, all of them wrong. “They arrive here feeling helpless,” he said. “It is fascinating listening to their stories. Many people have felt abandoned by the medical system.”
On a recent day he examined a young woman in her 30s who a decade ago began having uncontrollable flushing. She has carried around a fan ever since and no one can tell her what is wrong. “If you find something, is there something you can do to help me?” she asked Dr. Gahl. The young woman was exhausted from all of the unsuccessful examinations of the last 10 years. Sitting before Dr. Gahl, she had tears in her eyes.
“The experience is always emotional,” said Dr. Gahl. It may take months to figure out what is triggering the flushing. He said that even a diagnosis without a treatment is solace to these patients. He tells the story of a man in his 40s who had to quit his job after he began losing strength and mobility in his legs and had trouble speaking. He'd been to major medical centers and neurologists could not provide a definitive diagnosis. At the end of a week of testing they discovered a familial form of amyotrophic lateral sclerosis.
“When I gave the patient and his wife the diagnosis, she hugged me,” Dr. Gahl said. “It was so important to have resolution of a diagnosis.”
NIH neurologist Camilo Toro, MD, a member of the program, said that he often consults with an outside advisory panel of clinicians to help solve these puzzle cases. “It harkens back to when medicine was medicine,” said Dr. Toro, “and physicians sat around discussing symptoms. It is a real feeling of discovery.”
He said that it is difficult when they must send a patient home without an answer. He recently assessed a 30‐year‐old woman with an adult onset of myoclonus, Parkinson disease, and severe dystonia. She progressed rapidly. Now, she can no longer speak. They collected blood samples from the patient and her parents. They found increased iron in the young woman's brain and a scan revealed severe cortical atrophy. They also found a significant deficiency in a co‐factor involved in the function of enzymes that synthesize dopamine. This had all the hallmarks of a metabolic disease, Dr. Toro said. But even after a tremendous effort, they have not found a genetic culprit.
“This is a very unique patient population,” said Dr. Toro. “The patients have been through a lot before they come here. Their resiliency is striking.”
No one in the program was really surprised that there were so many neurological cases. Thomas D. Bird, MD, professor of neurology at the University of Washington and a member of the Neurology Today editorial advisory board, said that it “is not unusual that neurologists can't come up with a diagnostic conclusion. There is a lot we don't know about the causes of neurological diseases. And there is a lot we have to learn.”
Dr. Bird said that there are some general rules of thumb that he follows when stumped by a patient's symptoms. “Always be willing to get a second opinion. Thoroughly review the medical information every year and don't give up.”
He said that sometimes the technology is just not available when a patient first presents with complaints. He knows. In the last two years he has finally given two patients a diagnosis after decades of caring for them. Both had rare forms of ataxia.
UNRAVELING RARE DISORDERS: WHAT IT TAKES
The Office of Rare Diseases Research estimates that it can take anywhere from one to five years for a proper diagnosis in 33 percent of people with rare diseases and more than five years for 15 percent of these patients. And the federal institute estimates that about 6 percent of inquiries to the Genetic and Rare Disease Information Center are from patients whose symptoms remain undiagnosed.
The selection process is based on the puzzle put before a group of consultants. Patients must get their physicians to write a summary referral letter and send copies of their medical records, along with images and biopsies, if pertinent, to the federal sleuths. Clinicians from all walks of medicine, selected based upon the patients' manifestations, examine the records to decide who among the patients will be selected for a five‐day inpatient stay at the NIH Clinical Center. There is no charge to the patients. They go through whatever tests are ordered, including state‐of‐the‐art genetic studies. Often, family members also undergo genetic testing to see whether there are mutations that have never been identified before and that could explain the mysterious symptoms that have plagued many of them for years and some for decades.
Said NIH Director Francis Collins, MD, PhD: “I think the Undiagnosed Diseases Program is a most compelling example of the ‘virtuous circle’— the oft‐discussed loop from basic research to clinical research and back again. The work of this dedicated team truly shows how advances made at the bedside can serve to stimulate exciting new ideas in the lab. Biomedical research can learn a lot from their spirit of collaboration and innovation.”
For more information about the Undiagnosed Diseases Program, visit http://1.usa.gov/itNyp4.