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The Zebra Hunter

By Eva Hagberg Fisher
Ada Hamosh is on a quest to find—and treat—some of the rarest genetic diseases known to man. Writer Eva Hagberg Fisher, who recently learned that she has a rare disease of her own, knows firsthand the value of a diagnosis.

"I like zebras," Ada Hamosh tells me. A physician and geneticist, Hamosh isn't talking about a zoological enthusiasm. She is talking, instead, about the elusive diagnostic zebra, medical patients who have a rare, difficult-to-identify disease. Zebras get their name from the old medical school adage, “When you hear hoofbeats, think of horses, not zebras.” Physicians are taught in medical school that the most likely answer to a patient’s symptoms is usually the most common one. If a patient presents with flu-like symptoms, it’s probably influenza and not a rare disorder. Occasionally, though, there are outliers: patients with a multitude of ailments and no clear diagnostic answer. “As a medical student, I liked rare diseases,” says Hamosh, 55. “I liked the unusual patient, the sleuthing of figuring out what the diagnosis is.”

Having a diagnosis matters. I know this because I’m a zebra. Since birth, I’ve experienced various symptoms, strange rashes and weaknesses and eczema, and then, in my late 20s, ongoing and insoluble dizziness and thirst and cognitive problems. In my early 30s, I got so sick that I ended up in the hospital, which kick-started a three-year process of misdiagnosis after misdiagnosis after excruciating surgery. I saw about 26 doctors until one of them, finally, diagnosed me with mast cell activation syndrome, a rare and multisystem disease only recently named. I read the article he sent me—“See if you relate, at all,” he’d said—and then I cried for four days. From relief. From the knowledge that I hadn’t made it all up. From the understanding that my symptoms were, and had always been, real. Finally, someone had described me. I was no longer alone. I was no longer without a name. I knew where I fit. After years of hopelessness, I felt hope.

And so, in the present, when I interview Hamosh, I try to be the removed reporter, professional and detached, but I can’t, not completely, because I don’t quite believe this person really exists. Hamosh has specialized in rare diseases for much of her career, and she is, like the patients she treats, a zebra: one of the few doctors in the world seeking to research, identify, and treat rare genetic diseases.

She does this through the Johns Hopkins McKusick-Nathans Institute of Genetic Medicine, where she sees patients, as well as through her collaborative research into the origins and treatment of genetic disorders. Hamosh is on a quest not just to help patients but to connect those of us with rare diseases to others like us and to aid researchers and families around the world in doing the detective work behind humanity’s most unusual diseases.

As a geneticist and the clinical director at the institute, Hamosh works with patients to find an answer to their ailments. She focuses largely on pediatrics because most genetic diseases first announce themselves in childhood, but she also sees adults who’ve suffered from symptoms that can’t be explained by a diagnostic horse, or whose “zebra” first appeared in childhood and remains. Her patients often have a bevy of symptoms, many of which tend to appear in their families, and they’ve frequently been to a host of specialists first. They come to her undiagnosed, or with conflicting conclusions from other doctors, or with constellations of symptoms that seem to point to one particular genetically influenced disease. Hamosh is often their last hope. “In one clinic day, I might see eight patients with eight alleged diagnoses,” Hamosh says. And sometimes “they leave with eight other diagnoses than what they came in with.”

Hamosh works in uncharted territory, where there aren’t always clear protocols of treatment. She remembers one patient, several years ago, who was admitted to the institute’s genetics department. “I was making a plan for what to do, and a third-year medical student asked, ‘What’s the evidence base for that?”' Hamosh says. “I said, ‘There are 20 people in the world with this—there is no evidence base for this.’”

The disease? Methylmalonic acidemia, a disorder in which the body can’t break down certain fats and proteins. Her treatment: fixing the patient’s electrolytes and then checking six hours later to see if his vitals had improved. What Hamosh wanted to do, most of all, was get the patient feeling better. It may not have been evidence-based or a particularly dramatic treatment, but the electrolytes helped. He felt better.

In this case, Hamosh knew the underlying condition. In many cases, though, she must hunt for the disease and find a name for what’s ailing her patient, and further, the gene that’s causing it. Unusual conditions and ailments come in many forms, but Hamosh focuses primarily on Mendelian diseases, or inherited genetic diseases. These were named for Gregor Mendel, a monk who in the 1860s observed that a single gene variant in a pea plant could cause tremendous downstream mutations. In a human being, a Mendelian disease is one where a single gene mutation can trigger an inherited disease, such as cystic fibrosis, sickle-cell anemia, or Tay-Sachs disease.

Not every rare disease is a Mendelian disease; not every genetic disease is Mendelian. What makes a disease a Mendelian disorder is its relationship to heritability—the fact that the genetic mutation responsible for the symptom is found along a parental line, or shared across siblings. For Hamosh’s research purposes, the unit of investigation is always the family; the individual patient is one branch on a complex and multivalent tree of symptoms and genetic tendencies.

Hamosh came to focus on Mendelian diseases through Victor McKusick, who founded Johns Hopkins’ Division of Medical Genetics in 1957. McKusick rigorously studied these rare genetic diseases and began to catalog them, first in a hardbound book called Mendelian Inheritance of Man, and later online in the Online Mendelian Inheritance of Man, or OMIM. There are about 8,000 conditions now listed in OMIM, but only about 3,500 known genes that cause these conditions.

The unit of investigation is always the family; the individual patient is one branch on a complex and multivalent tree of symptoms and genetic tendencies.

In medical school at Georgetown in the mid-1980s, Hamosh found herself drawn to the then strange subworld of genetic codes and chromosomal errors. She came to Johns Hopkins to work as a pediatric physician and to earn a master’s in public health at the Bloomberg School. Her mentor and colleague David Valle, director of the McKusick-Nathans Institute, remembers when Hamosh arrived at Johns Hopkins in 1985 to practice pediatrics. By 1989, “she was finishing up her Master of Public Health and trying to decide where to go next,” Valle recalls. Valle encouraged her to specialize in genetics, what he called “the way of the future” and that’s what she did.

Hamosh’s love for the hunt, dedication to research, and compassion for the patient caught McKusick’s attention, according to Valle, and when it came time for McKusick to turn the work of the OMIM over to somebody, he picked Hamosh. Since 2002, part of her job has been to oversee the continual update of OMIM, introducing new genes whenever they’re discovered.

In 2010, Hamosh and Valle partnered with physician James Lupski at the Baylor College of Medicine in Texas to apply to the National Institutes of Health for funding of the Baylor-Hopkins Center for Mendelian Genomics. The goal: Find those genes responsible for the thousands of conditions that are recognized in OMIM but that don’t yet have an identified gene as the cause.

In 2015, the center released Gene-Matcher, a website that allows investigators to post a gene they believe may be an underlying cause of a Mendelian disease to a shared database. If two or more investigators post the same gene, they’re introduced so that they can share the information they have, adding to the universal wealth of medical knowledge.

The team also created PhenoDB, a secure, web-based portal that allows clinicians and researchers to post information that may prove to be genetically useful. This online database helps clinicians and patients analyze and track particular gene variants associated with both known and as-yet-unidentified rare diseases. The hope is that amassing all of this data will help patients and researchers put together pieces of a puzzle much faster. Users upload everything they have, including photos, X-rays, MRIs, and videos. That information then goes to Hamosh’s team for review, and they decide if they want to sequence a family’s genes for further study. “PhenoDB grew out of the desire for a standardized way to collect complex information in a head-to-toe way,” Hamosh explains.

François Schiettecatte, a member of the PhenoDB team, programmed the site; his mandate was to create a database that allows for the easy entry, storage, and analysis of genetic information. Schiettecatte’s programming turned a potential minefield of gene letters and numbers into a searchable website. Hamosh and her team knew that they would have three kinds of families under analysis through the database. The family would have either a known Mendelian disease described in OMIM, where one or more genes have been identified; or a known Mendelian disease described in OMIM that doesn’t yet have an identified gene; or something totally unknown. “We have families that have something no one’s ever seen before,” Hamosh says.

Sometimes, clinicians have a hunch but need confirmation. One example she gives is of a family that believes they suffer from Dubowitz syndrome—a disorder that presents with, among other things, a high or sloping forehead, thin hair, and flat, underdeveloped bones above the eyes. “Maybe the physician is pretty sure, but other experts would say they weren’t sure.” Hamosh says. The only way to know, she says, is to analyze phenotypic features, which is the goal of PhenoDB.

The hope is that amassing all of this data in a standardized way will help patients and researchers put together pieces of a puzzle much faster.

A phenotypic feature is a visible trait—such as hair color, eye color, a sloping forehead, or curled fingers. PhenoDB filters the massively complex genome into a few easily understandable elements. The program assesses which particular gene might be causing a rare disease down to fewer than four, then links to any animal studies that have been done, and searches for any papers that mention these particular variants. This information opens the possibility for better understanding of recurrence risk in subsequent generations, as well as informed genetic counseling. Patients can also request insurance approval for certain treatments.

While there isn’t always a known cure or treatment, there is a benefit in knowing a disease. “What’s the value of a diagnosis?” Hamosh says. “Even if you can’t do a thing for someone, having a name to put on a condition is helpful because people need closure, a label.”

Before I got my diagnosis, I kept thinking that there must be a reason that I can smell mold or eat a strawberry or be in the sunshine or exercise too hard and my cognitive function goes out the window; that my throat closes up; that my skin breaks out in hives. For a few months in 2015, during a severe flare-up, I was reacting to everything. I couldn’t go anywhere without my brain feeling like it was warming and swelling, without feeling my ability to think drain away. It was terrifying, but the most terrifying part was that I couldn’t figure out why.

When I told my mother I was sick, she said that for 10 years, in her 30s, she suffered from excruciating allergies. And my cousin on my father’s side has this thing where she breaks out in hives whenever she gets too cold. Could my symptoms be inherited? I sent away and tested my genes as best I could. I went down a rabbit hole of research.

“What’s the value of a diagnosis? Even if you can’t do a thing for someone, having a name to put on a condition is helpful because people need closure, a label.”

And then, I had a name. Mast cell activation syndrome. My mast cells, which are a type of white blood cell that mediate allergic reactions, are forever wired to “degranulate”—leaking histamine, cytokines, serotonin, who knows what else—into my blood, affecting my brain, my nervous system, my respiratory system, my heart rate, my melatonin production, my GI tract, my tongue, my mouth, my nose, my eyes—and the only thing I can do is give them treatment. I’m on a protocol of pills where I take antihistamines and mast cell stabilizers that patch the vulnerabilities, but sometimes they’re not enough and I have to do other stuff—weird experimental stuff that may be working because of placebo and may be working because of some type of magic, but either way, it’s working.

During our interview, Hamosh tells me: “No one can take pills more than twice a day.”

I wait for a break in the conversation. “I take pills five times a day,” I tell her. I have a pill case I carry everywhere. I have to, or we don’t know what will happen.

I expect Hamosh to brush off my contribution to the pill conversation; we’re talking about her, her work, her clinic, not me. And instead, a pause, which is rare for Hamosh, and then: “I’m so sorry.”

I’m so used to people laughing at how many pills I have to take, or marveling at the size of my pill case. I’m used to people believing that I was going to die. And here I am, alive. People in my life don’t really acknowledge that we all thought I was going to die, except sometimes. And almost no one ever says to me, “I’m so sorry.”

I have been the zebra among my friends for so long that it is just how it is to be me, but here, this doctor who runs a clinical research institute almost 3,000 miles away from where I live is the person who makes me stop and realize that having a rare disease is terrible. It isn’t a cool, strange thing, even though my best friend got me a Don’t Talk To Me, My Mast Cells Are Degranulating T-shirt for Rare Disease Day, which, appropriately, falls every four years on February 29. That having a rare disease is a horrible burden to carry. It is an excruciatingly vulnerable way to live.

Searching OMIM and PhenoDB and GeneMatcher isn’t just about discovering new diseases. It’s based on the idea that at least one other human out there will have whatever disease you have, and with that can come so much: comfort, mutual recognition, new avenues for research. Through Hamosh’s work, zebras around the world can find one another. “If you have a label that no one else has, it leaves you with uncertainty,” Hamosh says. “But if you have one that other people share, from a prognostic perspective, that’s very powerful.”

Through Hamosh’s work, zebras around the world can find one another. “If you have a label that no one else has, it leaves you with uncertainty. But if you have one that other people share, from a prognostic perspective, that’s very powerful.”

Hamosh’s compassion for her patients and her zeal for research extend to the next generation of geneticists. She’s a professor of pediatric genetics at the Johns Hopkins University School of Medicine, where she’s been a faculty member since 1992. Nara Sobreira is a physician who has worked with Hamosh at the institute for the last eight years, ever since she came to do a quick rotation with Hamosh and never left. “I cannot say what she did supporting me through this time emotionally, helping me forward, understanding when I could not do something, just being there and saying, ‘You will do it; you can do it.’ She calls me her daughter,” Sobreira says. “I see her trying to help everyone, from the patients to the people who work with her.”

There are, in Hamosh’s research, even rarer zebras than people like me. Between 5 and 6 percent of those tested through the Baylor-Hopkins Center have “two or more rare, single-gene Mendelian disorders, which is why it couldn’t be figured out,” Hamosh says. Hamosh will look for something that might tie these disparate diseases together, but just as people may have both hypertension and arthritis, patients can have multiple extremely rare genetic conditions simultaneously. “Bad luck happens,” she says.

This doesn’t deter her. “I think all good health care is individualized,” Hamosh says. A doctor takes care of individuals, and every individual is unique. “Even if you’re the gallbladder in room 57, you’re a person with a family, and a social construct, and a social history,” Hamosh says.

Even more, “we’re unique over time,” she points out—something that is so often lost in diagnostic maps and ruling-out processes and the desire, on so many people’s parts, to have the problem be a simple and easily treatable horse. But that uniqueness is part of what draws Hamosh here and what keeps her in the clinic and on call, even as research demands attention and so many genes need to be looked at. She tells me about one patient whom she’s admitted 20 times. “People would say to me, ‘Aren’t you tired of admitting this patient?’ —but every time, she comes in with something different.” Hamosh is ready for zebras. And all their stripes.

zebra illustration by Joey Guidone
Illustration by Joey Guidone

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