Pursuing Elusive Diagnoses for Rare Diseases

Undiagnosed Diseases Program

Laura A. Stokowski, RN, MS; William A. Gahl, MD, PhD


February 26, 2015

Editorial Collaboration

Medscape &

Medscape: What other factors are important in the selection process? Do age, sex, childbearing status, or physical condition of the patient have any bearing on your decision to accept a patient into the program?

Dr Gahl: Sex and childbearing have not had any influence on us, but age has, to a certain extent. Let me give you a couple of examples. When patients are 96 years old, they have complaints. We think that a lot of those complaints can be attributable to their systems breaking down and not to a genetic disorder. We are less likely to accept a 96-year-old than a 50-year-old.

We are actually more inclined to accept a child than an adult. In fact, 40% of our patients are children (under age 18) and our acceptance rate among applicants who are children is about 50%; our acceptance rate among adults is about 20%. Many adults, apparently, especially in the 30- to 60-year age range, have an awful lot of subjective complaints without objective findings. That is the reason for the age skew.

The other possible bias might be to how acutely ill the patient is, but in fact, the more acutely ill patients are, the less likely we are to accept them. The acute illness requires treatment and management that are not part of the mission of the UDP. We could easily become caught up in taking care of 15 patients in a year who would consume all of our resources. Instead we see 150 patients and are able to pursue the diagnosis in those 150. We won't take someone who transfers from another hospital.

Medscape: Let's talk about the inpatient evaluation at the Clinical Center. Patients stay for a week. What is the general approach to seeking a diagnosis?

Dr Gahl: It varies a great deal. Before a patient arrives, we have all of the patient's medical records—the images, the lab reports, the consultations, and sometimes the biopsies—so we know a lot about the patient already. The evaluation plan is established before the patient arrives. It might be to get a specific number of radiographic images or consultations. It might involve taking a skin biopsy, or a plan to get DNA from the patient and family members. That plan is put in place starting on a Monday, and it ends on a Friday when there is a wrap-up with the patient. What happens in between, however, is extremely varied.

Medscape: Are you able to get test results back quickly enough to come up with an answer by Friday, or does the final determination take place after the patient has returned home?

Dr Gahl: We seldom have a diagnosis by Friday, and if we do, generally it's based on the clinical acumen of our consultants and not on having the laboratory test results back. If it were possible to accomplish in 5 days, it would have already been done on the outside.

The case remains open after the patient has left, and our interaction with the family or the doctors after that depends partly on how much interest the family or the patient has, because that's what determines how often they call us back to find out what's up. Some families or patients will call every week, some every month, some not for a year or two, but we have cases that have been open for the past 6 years.

Medscape: How often are you able to find a diagnosis for patients who complete the UDP evaluation?

Dr Gahl: Certain disorders can be diagnosed on genetic grounds, so if the right genetic tests haven't been done, we have a good success rate in those instances. I could quote a success rate ranging from 10% to 40%, and I would be right with any of those percentages depending on the definition of success. What is a diagnosis? If I said that someone had Boucher-Neuhäuser syndrome, would you accept that as a diagnosis, not knowing what the particular genetic defect was in that individual or knowing the mechanism? My point is, you could put a name on it without knowing the entire pathogenesis of the disease. Or let's say we know the biochemical defect. We know that the patient has 3-methylglutaconic aciduria, but we don't know why. We don't know the genetic basis. Or we know the genetics basis—the gene variant that segregates with the disease in the family, and it is 99% likely that it is the cause—but we don't know the mechanism of that gene's action and why it caused this disease.

To have a true diagnosis, we need to put a name on it, put a gene on it, put a biochemical parameter on it, and put a mechanism on it. We do that 10%-15% of the time, but we have some partial diagnosis or basis for a diagnosis 30%-40% of the time.


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