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One Gene Mutation Links Three Mysterious, Debilitating Diseases

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On a good day, my shoulders, knees, and hips will dislocate two to five times apiece. The slightest bump into a table or door will bloom new bruises on my arms and legs or tear a gash in the thin skin on my hands. My blood pressure will plummet each time I stand, making me feel woozy, nauseated, and weak. I’ll have trouble focusing and remembering words. I’ll run my errands from underneath an umbrella to prevent an allergic reaction to the Sun.

I have Ehlers-Danlos Syndrome (EDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS)—a trifecta of weird diseases. POTS, EDS, and MCAS are so obscure that many doctors have never even heard of them. But a 2016 study published in Nature Genetics might help change that: Researchers have found a genetic mutation that links all three conditions.

There are at least six types of EDS, all caused by defective connective tissue. I’ve got the most common form, Hypermobility Type (EDS-HT), also known as EDS-III. EDS-HT is considered the most “benign” form—that is, it’s generally not fatal—but the chronic pain, injuries, and other symptoms it causes can easily take over a person’s life.

POTS is a form of dysautonomia, or dysfunction of the autonomic nervous system (ANS). The ANS manages all the things your body does without thinking, from breathing and pumping blood to digesting food. My POTS is pretty mild; at the moment, the hardest parts are the fatigue and the cognitive issues caused by decreased blood flow to my brain. Other people are not so lucky and may need feeding tubes or constant bed rest.

MCAS, also called Mast Cell Activation Disease, is the newest and potentially the trickiest of the three. Mast cells are generally heroes in the body, helping keep the immune system alert and responsive. But some people have paranoid mast cells that can perceive just about anything (foods, medications, temperatures, deep breathing) as a threat. And when they go off, there’s no telling what will happen; researchers have implicated mast cell activation issues in dozens of symptoms and conditions, from anaphylactic shock to irritable bowel syndrome as well as dysautonomia and connective tissue problems.

People who have EDS-HT often also have POTS or MCAS or both, yet the relationships between the three remain murky. Some scientists think EDS causes POTS. Others think MCAS causes POTS and EDS. But we don’t really know, because there’s been barely any research on any of them. It’s hard to study conditions that look different in every patient (I've never met anyone else with one of these conditions who has a sunlight allergy) and have few, if any, quantifiable symptoms. Another reason for the lack of scientific interest? All three conditions are far more common in women, a trait long associated with meager research funding and minimal medical concern.

Consequently, there are no FDA-approved tests for these diseases, and there are certainly no cures. People with EDS-HT wear joint braces to reduce dislocations and are taught to manage their pain. People with POTS are prescribed beta blockers, high-sodium diets, and compression gear to keep up their blood pressure. People with MCAS are given antihistamines.

EDS-HT is typically passed from parent to child, and scientists have found genetic markers for other types of EDS, so it’s not unreasonable to think that it could be caused by mutated DNA.

Fortunately, the cost of DNA sequencing has continued to drop, and clusters of researchers around the world are beginning to take a look. The latest study, led by Joshua Milner at the National Institute of Allergy and Infectious Diseases, involved 96 people with EDS-HT and mast cell issues. POTS symptoms were common, especially gut problems like Irritable Bowel Syndrome.

The study participants had another thing in common: higher-than-normal levels of a protein called tryptase in their blood. Tryptase is part of the immune system’s reaction and has been linked to a handful of core EDS-HT and POTS symptoms, Milner says.

"Tryptase can contribute to pain sensitivity," he told me. "It can contribute to blood vessels doing funny things, and it can contribute to how your connective tissue, your bones and joints, are made."

Most people with mast cell issues actually have normal levels of tryptase, so the group Milner and his colleagues tested represented just a small subset of mast cell patients. But that subset did seem to have a unique genetic signature: an extra copy of a gene called TPSAB1. Under normal circumstances, TPSAB1 makes a form of tryptase called alpha-tryptase. People with a double dose of the gene are getting a double dose of the protein, too.

Armed with this clue, the researchers then went back through thousands of patient records for healthy people. When they looked at the DNA results of people with high tryptase levels, they found that all of them also had the TPSAB1 mutation. The scientists then interviewed a number of these supposedly hearty specimens and found that all of them were living with symptoms that sounded suspiciously similar to those of EDS-HT, POTS, and MCAS. They'd just never been diagnosed. (This is unsurprising—the average time to diagnosis for a person with EDS-HT is 10 years.)

In short, Milner and his team had discovered a genetic biomarker for Ehlers-Danlos Syndrome. Now, EDS-HT is a very variable condition, and the few experts that do exist suspect it's actually a bunch of different diseases called by the same name. Still, this finding represents one possible clinical test for what has been an un-testable illness.

Alpha-tryptase is a funny thing. About 30 percent of people don't make it at all, and they seem just fine without it, which means that a potential treatment pathway for the EDS-HT/MCAS/POTS hat trick could involve simply shutting down the alpha-tryptase factory.

It’s "interesting work," says Lawrence Afrin, a hematologist at the University of Minnesota. He told me the study represents "early progress toward further unraveling these illnesses." And Afrin should know: he's one of the leading MCAS experts in the country.

He agrees that alpha-tryptase could be a promising avenue for treatment. "But if I've learned anything about [MCAS]," he says, "it's that it's incredibly complex. Hopefully, with another 10,000 studies, we'll make 10,000 more bits of progress."

In the meantime, people with EDS, POTS, and MCAS have found other ways to cope. Communities of patients have popped up in cities across the globe and all over Twitter, Tumblr, and elsewhere on the web. These illnesses can be incredibly isolating and lonely—but, as I've learned, none of us are alone.

If you recognize yourself or your symptoms in this story, read up on the basics of EDS, MCAS, and POTS, and brace yourself for an uphill battle.

"Find a local physician who’s willing to learn," Afrin advises.

"And try to be patient," Milner says. "I know it's hard, but stick with it. We're all figuring this out together."

Know of something you think we should cover? Email us at tips@mentalfloss.com.

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Animals
How a Pregnant Rhino Named Victoria Could Save an Entire Subspecies
Sudan, the last male member of the northern white rhino subspecies, while being shipped to Kenya in 2009
Sudan, the last male member of the northern white rhino subspecies, while being shipped to Kenya in 2009
Tony Karumba, AFP/Getty Images

The last male northern white rhino died at a conservancy in Kenya earlier this year, prompting fears that the subspecies was finally done for after decades of heavy poaching. Scientists say there's still hope, though, and they're banking on a pregnant rhino named Victoria at the San Diego Zoo, according to the Associated Press.

Victoria is actually a southern white rhino, but the two subspecies are related. Only two northern white rhinos survive, but neither of the females in Kenya are able to reproduce. Victoria was successfully impregnated through artificial insemination, and if she successfully carries her calf to term in 16 to 18 months, scientists say she might be able to serve as a surrogate mother and propagate the northern white rhino species.

But how would that work if no male northern rhinos survive? As the AP explains, scientists are working to recreate northern white rhino embryos using genetic technology. The San Diego Zoo Institute for Conservation Research has the frozen cell lines of 12 different northern white rhinos, which can be transformed into stem cells—and ultimately, sperm and eggs. The sperm of the last northern white male rhino, Sudan, was also saved before he died.

Scientists have been monitoring six female southern white rhinos at the San Diego Zoo to see if any emerge as likely candidates for surrogacy. However, it's not easy to artificially inseminate a rhino, and there have been few successful births in the past. There's still a fighting chance, though, and scientists ultimately hope they'll be able to build up a herd of five to 15 northern white rhinos over the next few decades.

[h/t Time Magazine]

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entertainment
Why Our Brains Love Plot Twists
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From the father-son reveal in The Empire Strikes Back to the shocking realization at the end of The Sixth Sense, everyone loves a good plot twist. It's not the element of surprise that makes them so enjoyable, though. It's largely the set-up, according to cognitive scientist Vera Tobin.

Tobin, a researcher at Case Western Reserve University, writes for The Conversationthat one of the most enjoyable moments of a film or novel comes after the big reveal, when we get to go back and look at the clues we may have missed. "The most satisfying surprises get their power from giving us a fresh, better way of making sense of the material that came before," Tobin writes. "This is another opportunity for stories to turn the curse of knowledge to their advantage."

The curse of knowledge, Tobin explains, refers to a psychological effect in which knowledge affects our perception and "trips us up in a lot of ways." For instance, a puzzle always seems easier than it really is after we've learned how to solve it, and once we know which team won a baseball game, we tend to overestimate how likely that particular outcome was.

Good writers know this intuitively and use it to their advantage to craft narratives that will make audiences want to review key points of the story. The end of The Sixth Sense, for example, replays earlier scenes of the movie to clue viewers in to the fact that Bruce Willis's character has been dead the whole time—a fact which seems all too obvious in hindsight, thanks to the curse of knowledge.

This is also why writers often incorporate red herrings—or false clues—into their works. In light of this evidence, movie spoilers don't seem so terrible after all. According to one study, even when the plot twist is known in advance, viewers still experience suspense. Indeed, several studies have shown that spoilers can even enhance enjoyment because they improve "fluency," or a viewer's ability to process and understand the story.

Still, spoilers are pretty universally hated—the Russo brothers even distributed fake drafts of Avengers: Infinity War to prevent key plot points from being leaked—so it's probably best not to go shouting the end of this summer's big blockbuster before your friends have seen it.

[h/t The Conversation]

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