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.

Some Mathematicians Think the Equal Sign is On Its Way Out

Paperkites/iStock via Getty Images
Paperkites/iStock via Getty Images

A growing number of mathematicians are skeptical that the equal sign, traditionally used to show exact relationships between sets of objects, holds up to new mathematical models, WIRED reports.

To understand their arguments, it’s important to understand set theory—a theory of mathematics that’s been around since at least the 1870s [PDF]. Take the classic formula 1+1=2. Say you have four pieces of fruit—an apple, an orange, and two bananas—and you put the apple and the orange on one side of a table and the two bananas on the other. In set theory, that’s an equation: One piece of fruit plus one piece of fruit on the left side of the table equals two pieces of fruit on the right side of the table. The two sets, or collections of objects, are the same size, so they’re equal.

But here’s where it gets complicated. What if you put an apple and a banana on the left side of the table and an orange and a banana on the other side? That’s clearly different from the first scenario, but set theory writes it as the same thing: 1+1=2. What if you switched the order of the first set of objects, so instead of having an apple and an orange, you had an orange and an apple? What if you had only bananas? There are potentially infinite scenarios, but set theory is limited to expressing them all in only one way.

“The problem is, there are many ways to pair up,” Joseph Campbell, a mathematics professor at Duke University, told Quanta Magazine. “We’ve forgotten them when we say ‘equals.’”

A better alternative is the idea of equivalence, some mathematicians say [PDF]. Equality is a strict relationship, but equivalence comes in different forms. The two-bananas-on-each-side-of-the-table scenario is considered strong equivalence—all of the elements in both sets are the same. The scenario where you have an apple and an orange on one side and two bananas on the other? That’s a slightly weaker form of equivalence.

A new wave of mathematicians is turning to the idea of category theory [PDF], which is based in understanding the relationships between different objects. Category theory is better than set theory at dealing with equivalence, and it’s also more universally applicable to different branches of mathematics.

But a switch to category theory won’t come overnight, according to Quanta. Interpreting equations using equivalence rather than equality is much more complicated, and it requires relearning and rewriting everything about mathematics—even down to algebra and arithmetic.

“This complicates matters enormously, in a way that makes it seem impossible to work with this new version of mathematics we’re imagining,” mathematician David Ayala told Quanta.

Several mathematicians are at the forefront of category theory research, but the field is still relatively young. So while the equal sign isn’t passé just yet, it’s likely that an oncoming mathematical revolution will change its meaning.

[h/t Wired]

7 Facts About Blood

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Moussa81/iStock via Getty Images

Everyone knows that when you get cut, you bleed—a result of the constant movement of blood through our bodies. But do you know all of the functions the circulatory system actually performs? Here are some surprising facts about human blood—and a few cringe-worthy theories that preceded the modern scientific understanding of this vital fluid.

1. Doctors still use bloodletting and leeches to treat diseases.

Ancient peoples knew the circulatory system was important to overall health. That may be one reason for bloodletting, the practice of cutting people to “cure” everything from cancer to infections to mental illness. For the better part of two millennia, it persisted as one of the most common medical procedures.

Hippocrates believed that illness was caused by an imbalance of four “humors”—blood, phlegm, black bile, and yellow bile. For centuries, doctors believed balance could be restored by removing excess blood, often by bloodletting or leeches. It didn’t always go so well. George Washington, for example, died soon after his physician treated a sore throat with bloodletting and a series of other agonizing procedures.

By the mid-19th century, bloodletting was on its way out, but it hasn’t completely disappeared. Bloodletting is an effective treatment for some rare conditions like hemochromatosis, a hereditary condition causing your body to absorb too much iron.

Leeches have also made a comeback in medicine. We now know that leech saliva contains substances with anti-inflammatory, antibiotic, and anesthetic properties. It also contains hirudin, an enzyme that prevents clotting. It lets more oxygenated blood into the wound, reducing swelling and helping to rebuild tiny blood vessels so that it can heal faster. That’s why leeches are still sometimes used in treating certain circulatory diseases, arthritis, and skin grafting, and helps reattach fingers and toes. (Contrary to popular belief, even the blood-sucking variety of leech is not all that interested in human blood.)

2. Scientists didn't understand how blood circulation worked until the 17th century.

William Harvey, an English physician, is generally credited with discovering and demonstrating the mechanics of circulation, though his work developed out of the cumulative body of research on the subject over centuries.

The prevailing theory in Harvey’s time was that the lungs, not the heart, moved blood through the body. In part by dissecting living animals and studying their still-beating hearts, Harvey was able to describe how the heart pumped blood through the body and how blood returned to the heart. He also showed how valves in veins helped control the flow of blood through the body. Harvey was ridiculed by many of his contemporaries, but his theories were ultimately vindicated.

3. Blood types were discovered in the early 20th century.

Austrian physician Karl Landsteiner discovered different blood groups in 1901, after he noticed that blood mixed from people with different types would clot. His subsequent research classified types A, B and O. (Later research identified an additional type, AB). Blood types are differentiated by the kinds of antigens—molecules that provoke an immune system reaction—that attach to red blood cells.

People with Type A blood have only A antigens attached to their red cells but have B antigens in their plasma. In those with Type B blood, the location of the antigens is reversed. Type O blood has neither A nor B antigens on red cells, but both are present in the plasma. And finally, Type AB has both A and B antigens on red cells but neither in plasma. But wait, there’s more! When a third antigen, called the Rh factor, is present, the blood type is classified as positive. When Rh factor is absent, the blood type is negative.

Scientists still don’t understand why humans have different blood types, but knowing yours is important: Some people have life-threatening reactions if they receive a blood type during a transfusion that doesn’t “mix” with their own. Before researchers developed reliable ways to detect blood types, that tended to turn out badly for people receiving an incompatible human (or animal!) blood transfusion.

4. Blood makes up about 8 percent of our total body weight.

Adult bodies contain about 5 liters (5.3 quarts) of blood. An exception is pregnant women, whose bodies can produce about 50 percent more blood to nourish a fetus.)

Plasma, the liquid portion of blood, accounts for about 3 liters. It carries red and white blood cells and platelets, which deliver oxygen to our cells, fight disease, and repair damaged vessels. These cells are joined by electrolytes, antibodies, vitamins, proteins, and other nutrients required to maintain all the other cells in the body.

5. A healthy red blood cell lasts for roughly 120 days.

Red blood cells contain an important protein called hemoglobin that delivers oxygen to all the other cells in our bodies. It also carries carbon dioxide from those cells back to the lungs.

Red blood cells are produced in bone marrow, but not everyone produces healthy ones. People with sickle cell anemia, a hereditary condition, develop malformed red blood cells that get stuck in blood vessels. These blood cells last about 10 to 20 days, which leads to a chronic shortage of red blood cells, often causing to pain, infection, and organ damage.

6. Blood might play a role in treating Alzheimer's disease.

In 2014, research led by Stanford University scientists found that injecting the plasma of young mice into older mice improved memory and learning. Their findings follow years of experiments in which scientists surgically joined the circulatory systems of old and young mice to test whether young blood could reverse signs of aging. Those results showed rejuvenating effects of a particular blood protein on the organs of older mice.

The Stanford team’s findings that young blood had positive effects on mouse memory and learning sparked intense interest in whether it could eventually lead to new treatments for Alzheimer’s disease and other age-related conditions.

7. The sight of blood can make people faint.

For 3 to 4 percent of people, squeamishness associated with blood, injury, or invasive medical procedures like injections rises to the level of a true phobia called blood injury injection phobia (BII). And most sufferers share a common reaction: fainting.

Most phobias cause an increase in heart rate and blood pressure, and often muscle tension, shakes, and sweating: part of the body’s sympathetic nervous system’s “fight or flight” response. But sufferers of BII experience an added symptom. After initially increasing, their blood pressure and heart rate will abruptly drop.

This reaction is caused by the vagus nerve, which works to keep a steady heart rate, among other things. But the vagus nerve sometimes overdoes it, pushing blood pressure and heart rate too low. (You may have experienced this phenomenon if you’ve ever felt faint while hungry, dehydrated, startled, or standing up too fast.) For people with BII, the vasovagal response can happen at the mere sight or suggestion of blood, needles, or bodily injury, making even a routine medical or dental checkup cause for dread and embarrassment.

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