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.

Why Thousands of 'Penis Fish' Washed Up on a California Beach

Kate Montana, iNaturalist // CC BY-NC 4.0
Kate Montana, iNaturalist // CC BY-NC 4.0

Nature works in mysterious ways. The latest example materialized at Drakes Beach near San Francisco, California, in early December, when visitors strolling along the shore stumbled upon what looked to be the discarded inventory of an adult novelty shop. In fact, it was thousands of Urechis caupo, a marine worm that bears more than a passing resemblance to a human penis.

The engorged pink invertebrate, which is typically 10 inches in length, is native to the Pacific coast and frequently goes by the less salacious name of “fat innkeeper worm.” Burrowing in sand, the worm produces mucus from its front end to ensnare plankton and other snacks, then pumps water to create a vacuum where the food is directed into their tunnel. Since it builds up a small nest of discarded food, other creatures like crabs will stop by to feed, hence the “innkeeper” label.

You can see the worm in "action" here:

Because the worms enjoy a reclusive life in their burrows, it’s unusual to see thousands stranded on the beach. It’s likely that a strong storm broke up the intertidal sand, decimating their homes and leaving them exposed. The event is likely to thrill otters, as they enjoy dining on the worm. So do humans: Penis fish are served both raw and cooked in Korea and China.

[h/t Live Science]

The Horrors of Anglerfish Mating

Masaki Miya et al. "Evolutionary history of anglerfishes (Teleostei: Lophiiformes): a mitogenomic perspective," BMC Evolutionary Biology 10, article number: 58 (2010), Wikimedia Commons // CC BY 2.0
Masaki Miya et al. "Evolutionary history of anglerfishes (Teleostei: Lophiiformes): a mitogenomic perspective," BMC Evolutionary Biology 10, article number: 58 (2010), Wikimedia Commons // CC BY 2.0

When you think of an anglerfish, you probably think of something like the creature above: Big mouth. Gnarly teeth. Lure bobbing from its head. Endless nightmares. 

During the 19th century, when scientists began to discover, describe, and classify anglerfish from a particular branch of the anglerfish family tree—the suborder Ceratioidei—that’s what they thought of, too. The problem was that they were only seeing half the picture. The specimens that they were working with were all female, and they had no idea where the males were or what they looked like. Researchers sometimes found some other fish that seemed to be related based on their body structure, but they lacked the fearsome maw and lure typical of ceratioids and were much smaller—sometimes only as long as 6 or 7 millimeters—and got placed into separate taxonomic groups.

It wasn’t until the 1920s—almost a full century after the first ceratioid was entered into the scientific record—that things started to become a little clearer. In 1922, Icelandic biologist Bjarni Saemundsson discovered a female ceratioid with two of these smaller fish attached to her belly by their snouts. He assumed it was a mother and her babies, but was puzzled by the arrangement.

“I can form no idea of how, or when, the larvae, or young, become attached to the mother. I cannot believe that the male fastens the egg to the female,” he wrote. “This remains a puzzle for some future researchers to solve.”

When Saemundsson kicked the problem down the road, it was Charles Tate Regan, working at the British Museum of Natural History in 1924, who picked it up. Regan also found a smaller fish attached to a female ceratioid. When he dissected it, he realized it wasn’t a different species or the female angler’s child. It was her mate.

The “missing” males had been there all along, just unrecognized and misclassified, and Regan and other scientists, like Norwegian zoologist Albert Eide Parr, soon figured out why the male ceratioids looked so different. They don’t need lures or big mouths and teeth because they don’t hunt, and they don’t hunt because they have the females. The ceratioid male, Regan wrote, is “merely an appendage of the female, and entirely dependent on her for nutrition.” In other words, a parasite.

When ceratioid males go looking for love, they follow a species-specific pheromone to a female, who will often aid their search further by flashing her bioluminescent lure. Once the male finds a suitable mate, he bites into her belly and latches on until his body fuses with hers. Their skin joins together, and so do their blood vessels, which allows the male to take all the nutrients he needs from his host/mate’s blood. The two fish essentially become one.

With his body attached to hers like this, the male doesn't have to trouble himself with things like seeing or swimming or eating like a normal fish. The body parts he doesn’t need anymore—eyes, fins, and some internal organs—atrophy, degenerate, and wither away, until he’s little more than a lump of flesh hanging from the female, taking food from her and providing sperm whenever she’s ready to spawn.

Extreme size differences between the sexes and parasitic mating aren’t found in all anglerfish. Throughout the other suborders, there are males that are free-swimming their whole lives, that can hunt on their own and that only attach to the females temporarily to reproduce before moving along. For deep-sea ceratioids that might only rarely bump into each other in the abyss, though, the weird mating ritual is a necessary adaptation to keep mates close at hand and ensure that there will always be more little anglerfish. And for us, it’s something to both marvel and cringe at, a reminder that the natural world is often as strange as any fiction we can imagine.

Naturalist William Beebe put it nicely in 1938, writing, “But to be driven by impelling odor headlong upon a mate so gigantic, in such immense and forbidding darkness, and willfully eat a hole in her soft side, to feel the gradually increasing transfusion of her blood through one’s veins, to lose everything that marked one as other than a worm, to become a brainless, senseless thing that was a fish—this is sheer fiction, beyond all belief unless we have seen the proof of it.”

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