Thursday, December 18, 2014

New cause found for muscle-weakening disease myasthenia gravis

MeiresearchwebAn antibody to a protein critical to enabling the brain to talk to muscles has been identified as a cause of myasthenia gravis, researchers report.

The finding that an antibody to LRP4 is a cause of the most common disease affecting brain-muscle interaction helps explain why as many as 10 percent of patients have classic symptoms, like drooping eyelids and generalized muscle weakness, yet their blood provides no clue of the cause, said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics at the Medical College of Georgia at Georgia Regents University.

“You end up with patients who have no real diagnosis,” Mei said.

The finding also shows that LRP4 is important, not only to the formation of the neuromuscular junction – where the brain and muscle talk – but also maintaining this important connection, said Mei, corresponding author of the paper in The Journal of Clinical Investigation.

Mei and his colleagues first reported antibodies to LRP4 in the blood of myasthenia gravis patients in the Archives of Neurology in 2012. For the new study, they went back to animals to determine whether the antibodies were harmless or actually caused the disease. When they gave healthy mice LRP4 antibodies, they experienced classic symptoms of the disease along with clear evidence of degradation of the neuromuscular junction.

LRP4 antibodies are the third cause identified for the autoimmune disease, which affects about 20 out of 100,000 people, primarily women under 40 and men over age 60, according to the National Institutes of Health and Myasthenia Gravis Foundation of America, Inc.

An antibody to the acetylcholine receptor is causative in about 80 percent of patients, said Dr. Michael H. Rivner, MCG neurologist and Director of the Electrodiagnostic Medicine Laboratory, who follows about 250 patients with myasthenia gravis. Acetylcholine is a chemical released by neurons which act on receptors on the muscle to activate the muscle. More recently, it was found that maybe 10 percent of patients have an antibody to MuSK, an enzyme that supports the clustering of these receptors on the surface of muscle cells.

“That leaves us with only about 10 percent of patients who are double negative, which means patients lack antibodies to acetylcholine receptors and MuSK,” said Rivner, a troubling scenario for physicians and patients alike. “This is pretty exciting because it is a new form of the disease,” Rivner said of the LRP4 finding.

Currently, physicians like Rivner tell patients who lack antibody evidence that clinically they appear to have the disease. Identifying specific causes enables a more complete diagnosis for more patients in the short term and hopefully will lead to development of more targeted therapies with fewer side effects, Rivner said.

To learn more about the role of the LRP4 antibody, Mei now wants to know if there are defining characteristics of patients who have it, such as more severe disease or whether it’s found more commonly in a certain age or sex. He and Rivner have teamed up to develop a network of 17 centers, like GR Medical Center, where patients are treated to get these questions answered. They are currently pursuing federal funding for studies they hope will include examining blood, physical characteristics, therapies and more.

Regardless of the specific cause, disease symptoms tend to respond well to therapy, which typically includes chronic use of drugs that suppress the immune response, Rivner said. However, immunosuppressive drugs carry significant risk, including infection and cancer, he said.

Removal of the thymus, a sort of classroom where T cells, which direct the immune response, learn early in life what to attack and what to ignore, is another common therapy for myasthenia gravis. While the gland usually atrophies in adults, patients with myasthenia gravis tend to have enlarged glands. Rivner is part of an NIH-funded study to determine whether gland removal really benefits patients. Other therapies include a plasma exchange for acutely ill patients.

The Journal of Clinical Investigation study was funded by the NIH and the Muscular Dystrophy Association. Mei is a Georgia Research Alliance Eminent Scholar in Neuroscience.


  1. I would like to find out how to become a participant/candidate for one of the 17 centers that will be studying MG patients.

  2. Marina Tressler-Tangonan

    I am a double negative Myasthenia Gravis patient. Diagnosis based on clinical, response to Mestinon and a positive EMG. I recently found out my grandmother was 1/2 Cherokee Indian and my grandfather 1/4 Cherokee, both were from Georgia. I also have Lupus, Sjogrens, Pernicious anemia, hypothyroidism, and fibromyalgia, My daughter has s morphea and Sjogrens. My daughters 4 year old girl was diagnosed with Juvenile Rheumatoid Arthritis. Could there be this many autoimmune issues in one family due to being Native American? How would I find a lab for the LRP4 test? I am on federal disability, are there gene test that our family could participate in for research?

  3. As a patient with seronegative generalized Myasthenia Gravis, I cannot tell you how great this development is. I’ve been treated as if I’m ‘just crazy’ by more than one neurologist as I lay in hospital beds, near crisis. I even had a neurologist tell me, “I don’t believe in seronegative MG.” I don’t know how to tell them that I don’t want to feel like this. I have three children and a wonderful husband. I’ve lost the career I love and every ability to do anything I enjoy, right down to brushing my own hair. I cannot imagine what these doctors must be thinking, or not thinking, to treat patients like this. I am printing this article for any instance that I may need it in the future, as well as to send it to the neurologists I’ve seen that obviously need further education.
    Thank you so much, your work is so very important to so many of us!

  4. I am also a double negative Myasthenia Gravis patient. I am a 24 year old male and thankfully, my symptoms are only ocular. Over the past 3 years, since my initial diagnosis, prednisone has been able to keep my symptoms in check. Most of the time I am on a very low dose or totally off the drug. Although Myasthenia is a fairly rare disease among healthy individuals I believe my case is extraordinary because of my age, family history, and lifestyle. My family has never had any history of Myasthenia and we are healthy individuals (good diet and exercise frequently). It is also unusual in that my symptoms are only present in my right eye (the eye muscle does not allow for full range of motion causing double vision…this eyelid also droops). You can imagine how difficult the diagnosis was considering my history. Luckily I am being treated by one of the best doctors in the country. At any rate, this new development must be considered a possibility in the cause of my symptoms. I am so thankful for all the research and hard work that continues to be done in order to treat this disease. If I can be of any assistance in this research please let me know. I will continue fighting this disease and I am eager to help those who are in need of support!!

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