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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 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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Medicine
New Technique Can Spot a Heart Attack in the Making Long Before It Happens
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Cardiology experts have developed a noninvasive way of measuring the fat around a person's blood vessels, which could help determine their risk for dangerous cardiac events. The researchers described their technique today in the journal Science Translational Medicine.

Heart attacks are incredibly common, affecting around 750,000 Americans every year. Heart disease is the number one cause of mortality in the U.S., responsible for one out of every four deaths. There are many reasons for this. Among them is the difficulty of identifying at-risk patients before it's too late.

Cardiologists' current method of choice uses a metric called coronary calcification score (CCS) to measure the hardening of a patient's arteries. CCS is a reliable way to predict future heart problems, paper co-author Charalambos Antoniades said in a statement, but it has its limitations.

"When coronary calcification is detected," he said, "it is already too late, as the calcification is not reversible."

And so, rather than measuring calcification, many researchers have begun looking for a way to measure blood vessel inflammation, which is usually a pretty good—and early—predictor of heart disease.

The inflammation itself can be hard to see without entering a patient's body. But recent studies have shown that it rarely travels alone: Blood vessels that are inflamed are also often wrapped in larger fat cells than healthy vessels. 

With this link in mind, Antoniades and his colleagues decided to try measuring the fat cells instead. They reviewed computed tomography scans from 453 patients about to undergo heart surgery, and used these data to create what they call the fat attenuation index (FAI). The higher a patient's FAI, the more inflammation they had, and the more advanced or severe their heart disease. 

The researchers then compared the FAI of 40 additional patients with the results of invasive scans of the inflammation in their hearts. Sure enough, each patient's FAI matched the swelling onscreen.

There are many benefits to using FAI, the authors say. Not only is it noninvasive and accurate, but it can be used in tandem with CCS and other methods for an even more complete picture. The next step will be validating the test's safety and accuracy in clinical trials.

FAI scans "could help direct these new types of treatments to the appropriate subgroups of patients at greatest risk," Antoniades says, "reducing costs and targeting more powerful drugs to the patients who will benefit most."

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Health
Don't Panic About the Plague
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If reports of measles and whooping cough making a reappearance aren't alarming enough, the news that three people in New Mexico have contracted plague this year might have you on edge. But these aren't the only recent cases of plague in the state—the disease appeared in both 2016 and 2015, causing one death—or even in the U.S.

In 2015, a child contracted the plague in Yosemite National Park, and so did a tourist from Georgia; park officials closed a campground where they discovered two dead squirrels infected with the disease. That same year in Colorado, a pitbull infected four humans with pneumonic plague before being put down, and two other Colorado residents died from plague, including a 16-year-old boy.

It all seems very scary, but don't go sealing yourself in protective gear yet. There's less to fear about plague than you may think. While the public is prone to panic that a medieval illness, which wiped out a quarter of Europe in the Middle Ages during the Black Death, has suddenly arisen from obscurity, the truth is: Plague never left.

Though we haven't seen a widespread epidemic of plague since the early 20th century, thanks to advances in sanitation and medicine, and there hasn't been a human-to-human case of transmission in America since 1924, an average of seven new cases are reported every year in the U.S. From 2010 to 2015, there were 3248 cases, including 584 deaths, reported worldwide, according to the World Health Organization.

Yersinia pestis, the flea-borne bacteria that's most often responsible for plague, infects rodents; humans are “incidental hosts,” who can acquire the infection if bitten by an infected flea or rodent. Compared to the 14th century, when the Black Death spread wildly, or the late 19th century, when 10 million people died of the disease after it traveled from Hong Kong to port cities worldwide, most people today live in more sanitary conditions and have less frequent contact with the rodents most likely to carry the infected fleas. Today, 95 percent of plague cases originate in parts of sub-Saharan Africa and Madagascar.

The most common of the three strains of plague is the notorious bubonic plague, which causes painful swollen lymph nodes (also called buboes) and was responsible for Europe's Black Death—so named because internal hemorrhages caused by the infection make the skin appear black. But the pitbull that infected four Colorado residents carried the rarer respiratory strain of pneumonic plague, which is contagious when the infected person coughs up infected particulates. There is also septicemic plague, the most lethal form, which infects the blood, and most often occurs when plague virus has gone undetected and is allowed to spread.

In the U.S., you're generally only at risk of contracting plague in late spring to early fall if you've been in a rural or semi-rural area of the West, especially New Mexico, Arizona, or Colorado, and have had contact with fleas or rodents including ground squirrels, chipmunks, prairie dogs, or rats. And even then, the risk is low.

Only the pneumatic version of plague is contagious from human to human (though untreated bubonic plague can become pneumonic), but you have to be coughed upon, or receive fluid from an infected person upon an open wound or directly into your mouth or nose.

Plague symptoms mimic any flu—fever, chills, headache, difficulty breathing or coughing—but people have been known to cough up blood with the pneumonic variety. If you've been in a rural area, or camping, and come down with these symptoms two to three days later, it's best to go to a hospital.

Now for some good news: While untreated plague is quite deadly, people with plague who are treated with antibiotics within 24 hours of infection have strong recovery rates.

So while it's good to be aware and take precautions, the chances of another plague pandemic remain slim.

This story was originally published in 2015 and has been updated. 

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