![]() ![]() This research might end up concretely improving the life of at least some of the patients most severely affected by statins. Perhaps patients who suffer particularly severe muscle side effects already have less functional versions of the enzyme, which becomes problematic only when they start taking statins, which reduce its function even further. The enzyme, for example, is found in tissues throughout the body, so why do these common side effects show up in muscles specifically?) Rosenson, at Mount Sinai, wondered if variations in this gene could explain why statins don’t affect everyone the same. The enzyme’s role had been suspected, he told me, but “it had never been proven, especially in humans.” (Questions still remain, however. and Israel “really strongly suggests” that statins cause muscle damage via the same HMG-CoA reductase pathway, says Andrew Mammen, a neurologist at the National Institutes of Health who was not involved in either study. When his team saw that this family had the mutations in HMG-CoA reductase, they too immediately recognized the potential link to statins. Another had died in their mid-50s, Ohad Birk, a geneticist and doctor at Ben-Gurion University of the Negev, in Israel, told me. One bedridden woman had to be ventilated full-time through a hole in her windpipe. The oldest family members, in their late 40s or 50s, had lost all movement in their arms and legs. Those afflicted began experiencing minor symptoms in their 30s, such as muscle cramps, that worsened over time. This family also carried mutations in the gene encoding HMG-CoA reductase. Unbeknownst to the Mayo team, a group of researchers halfway around the world was already studying a large Bedouin family with a history of limb girdle muscular dystrophy. (Interestingly, for reasons we don’t entirely understand, they all have normal or low cholesterol.) They too all had mutations in the same gene, and they too were all diagnosed with some degree of limb girdle muscular dystrophy. Six more patients from four other families confirmed the link. So the team looked for genes in which all three brothers had mutations in both copies, which is how they zeroed in on the gene for HMG-CoA reductase. His two brothers had the disease as well. (The disease can also affect large muscles in the torso.) Now in his 30s, he wanted to know the genetic cause of his disease before having children and potentially passing it on to them. The first patient the Mayo team studied had been showing signs of limb girdle muscular dystrophy since he was a child, and his symptoms worsened over time until he lost the ability to walk or breathe with ease. “One of the first things you learn in medical school is association between statins and myopathy.” Now the answer as to why- along with a potential treatment for it-has emerged from the DNA of just a few patients living with a seemingly unrelated genetic disease. “It seemed too good to be true,” says Joel Morales-Rosado, a pathologist who worked on one of the studies as a postdoctoral researcher at the Mayo Clinic. This connection between a rare disease and a common drug stunned the researchers. And so, the answers to two mysteries suddenly became clear at once: Dysfunction in this enzyme causes muscle weakness from both limb girdle muscular dystrophy and statins. It is, in fact, the very enzyme that statins block in the process of halting cholesterol production. ![]() The enzyme is known as HMG-CoA reductase, and to doctors, it is not obscure. and a Bedouin family in Israel, their suspicions separately landed on mutations in a gene encoding a particularly intriguing enzyme. After both teams tracked the disease through a handful of families in the U.S. They were hunting for genes behind a rare disease called limb girdle muscle dystrophy, in which muscles of the upper arms and legs-sound familiar?-become weak and waste away. They weren’t studying cholesterol at all. He’s had patients fall on the street because they couldn’t lift their leg over a curb.īut why should an anticholesterol drug weaken muscles in the arms and legs? Recently, two groups of scientists stumbled upon an answer. A much smaller proportion, less than 1 percent, develop muscle weakness or myopathy severe enough that they find it hard to “climb stairs, get up from a sofa, get up from the toilet,” says Robert Rosenson, a cardiologist at Mount Sinai. Many patients-some 5 percent in clinical trials, and up to 30 percent in observational studies-experience sore and achy muscles, especially in the upper arms and legs. ![]() Statins, one of the most extensively studied drugs on the planet, taken by tens of millions of Americans alone, have long had a perplexing side effect. ![]()
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