There is an oft-quoted saying among physicians, “when you hear hoofbeats, think of horses, not zebras.” It’s a gentle reminder to physicians to look for the most obvious cause of a patient’s distress. However with 10 percent of the U.S. suffering some form of rare disease, we wondered if this was as true as it was in the 1950s.
We had the opportunity to speak with Sharon Moalem, MD, PhD geneticist, medical researcher, and New York Times best-selling author about how physicians can integrate rare disease diagnoses into their current practices.
When is a horse a zebra?
Right off the bat the biggest problem is a lack of training when it comes to zebras. It’s through no fault of any physician. It’s just the training. You leave out the things that are rare for things that are actionable.
The biggest key and the highest yield continue to be going back and revisiting the family history. No matter how advanced we get with genomic sequencing, we still are going to be relying on family history to see how all the variations come together in a situation and the best way to do this is always go back to the family.
What’s the best way to gather family history?
Using the standard intake form. They ask about things that run in your family and you have an opportunity to run off a list. Often though, that’s not revisited, and it’s an easy thing to do when you sit down for a yearly physician or whatnot. A lot of what has to do with your own future can be gleaned from your family who are 20 to 30 years down the road from you. From a prevention perspective that’s fantastic. A family history is a moving target, it changes every year but by revisiting that you can start putting together a medical picture of the patient.
They can fill the form out while they’re waiting for the doctor, it doesn’t take that long, it’s not going to eat up the entire visit, it’s a good way to get a snapshot. It’s really easy to do, and the PA, or whoever seeing you can quickly scan whatever you filled out.
Rare disease patients often receive 2 or 3 misdiagnoses before getting the right one. Can you talk about that?
It’s really tough, when you step back it is a misdiagnosis that eventually led to the diagnosis. Sometimes you hit signposts along the way, and it’s just one of those puff things you have to re-examine your differential of what it might be. Getting a misdiagnosis sometimes helps you to get a diagnosis, someone will see you and say I don’t think so and dig deeper.
How has technology helped doctors diagnose and treatrare disease?
Thanks to technology and the internet we have the opportunity to bring patients together. Certain conditions only have a few affected individuals. I was involved in the description of a new syndrome; there were two patients with a 28 year age difference. By reaching out online, we found a connection. To make sure we had the diagnoses we got those cases together side by side, but we wouldn’t have had a clue if we didn’t have the internet.
We can also use bioinformatics. If you have a diagnosis that doesn’t fit, you can go back and revisit and compare confirmed images that are available in databases. If a doctor goes online and tries to mine Google images be careful, often they’re mis-labeled. People are trying to create databases that have confirmed molecular diagnoses so you can use them for a good descriptor. It allows you to rapidlylookforandincludeorexcludeveryrareconditions pretty rapidly by being able to access that information.
There are a few online resources that you can search by feature, and then you can search by putting the features together so you’ll put in a large head, large tongue and freckles and it’ll list out whatever options it might think. It’s good for things that you’ve never seen before in your career.
The average rare disease diagnosis takes 7.6 years in the US but only 5.6 years in the UK. Can you talk about what might be causing the difference?
You hope the numbers shouldn’t be that off. It could be time to referral but different medical systems work in different ways. Sometimes the issue becomes when you’re dealing with a population that is so ethnically mixed, sometimes that can make a diagnosis much harder when you’re dependent on certain features that can be mimicked ethnically. I remember meeting a geneticist who came over from the UK and many of the children that he was saying had things he would flag as dysmorphic we wouldn’t because we’re used to seeing more variability. Ethnic variability can hide certain features.
What about genetic testing and privacy?
I have a verybig problem with the current laws in place because they don’t protect us at all from genetic discrimination. Some state laws provide some coverage, but there’s no federal law in place. The federal law has a loophole allowing for discrimination. I really stress with my patients if you are going to have genetic testing done make sure you have life insurance and disability insurance firmly in place because you might face discrimination.
There are also a lot of issues in how we’re reading the data. Your genome may be accused of harboring a mutation and found out to be benign.
What about others who share your DNA? Could they have consequences if you get your genome sequenced?
That’s, in a way, the most concerning part because never in the past have we had to deal with this. With a cancer syndrome, part of the treatment is the genetic screening. Does that person have a duty to inform or warn all other members of the family they might be harboring that mutation? Should they be screened? Currently, they aren’t forced to do so because of privacy laws. As physicians, we don’t have the right to go against someone’s privacy. It’s the first time in history where you almost feel ethically obliged to encourage people to let other people in the family know that they might be at risk.
Why are rare diseases so important?
I just think raising the issue to the national stage is not just for individuals or their families but an immense opportunity. They provide a window into how our biology works which ultimately leads to treatment for more common conditions.
I discovered a new class of antibiotics that specifically target multi-resistant bacteria by studying a rare disease that involved iron metabolism. No one would have ever made the connection between the two. Sickle cell anemia protects populations against malaria. By understanding diseases through that lens, I can mimic that protection through a new drug.
Mother Nature is the biggest serial killer in the world. If you look at biology in that way most of human death isn’t because we’ve beenrun down and eaten by tigers, it’s by things we can’t see. So many of the evolutionary trade-offs that we deal with ended up causing disease but protecting us from micro-organisms. By understanding that you can then start coming out with new treatments. It brings together history, biology and anthropology on a genetic level.
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We discuss rare disease regularly inside Sermo. If you’re an M.D. or D.O. please join the conversation!
Sharon Moalem, MD, PhD
Bio:
Sharon Moalem, MD, PhD is a geneticist and medical researcher. He focuses on diagnosing and treating orphan diseases, conditions that affect less than 1 in 10,000 persons. He has also been awarded 21 patents for inventions related to biotechnology and human health, and has also cofounded two biotechnology companies. His scientific work has led to the discovery of Siderocillin, a first in class member of a novel class of antibiotic compounds directed against multiresistant or ‘superbug’ microorganisms.
He is also a New York Times and international best-selling author. His writing brings together medicine, genetics, history and biology to explain how the human body functions in new and fascinating ways. Dr. Moalem and his research have been featured in the New York Times, Time Magazine, New Scientist, and on “The Daily Show” with Jon Stewart, Today, and CNN.
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