Rare disease researchers notch a win

(Press-News.org) An older medication originally approved to treat heart problems eases the symptoms of a very rare muscle disease that often leaves its sufferers stiff and in a good deal of pain, physicians and researchers report in the Oct. 3 issue of the Journal of the American Medical Association.

The findings are good news not only for the relatively small number of people around the world estimated to have nondystrophic myotonia, but also for many other patients who have one of the thousands of diseases that are very rare, according to neurologists at the University of Rochester Medical Center who took part in the study.

"This study can serve as a blueprint for future rare disease research," said neurologist Jeffrey Statland, M.D., senior instructor in Neurology and the first author of the paper. "This study shows that by bringing together experts and patients around the world and building a common infrastructure, we can tackle rare conditions that have eluded rigorous clinical study up to now."

Rochester neurologist Robert "Berch" Griggs, M.D., another author of the paper and the leader of a Rochester center devoted to studying rare neurological disorders, notes that, ironically, many people suffer from rare diseases.

"Each rare disease might affect only a few thousand people, but there are thousands of rare diseases. Current estimates are that perhaps 30 million people are affected by some form of rare disease," said Griggs.

The corresponding author of the study is Statland's former adviser, Richard Barohn, M.D., the overall principal investigator of the study and chair of the Department of Neurology at the University of Kansas Medical Center.

The study is the brainchild of Griggs and several other investigators who are part of a consortium known as CINCH – the Consortium for Clinical Investigation of Neurologic Channelopathies. Griggs heads the group, which studies neurologic disorders caused by irregularities in the cell gates or channels that regulate levels of crucial substances like potassium, sodium and calcium in our cells. Nondystrophic myotonic is one such condition.

People with nondystrophic myotonia generally have very stiff and painful muscles. Sometimes when they sneeze, for instance, they have trouble opening their eyes afterward, or they might have trouble loosening their hand once they've gripped a doorknob or shaken someone's hand. Usually, sports are very difficult, and sometimes, holding a regular job is impossible.

Since so few people have the disease – neurologists think the incidence is roughly 1 in 100,000 – the disease hasn't captured the attention of the public or researchers in the same way as Parkinson's or Alzheimer's diseases. Without any thorough, reliable studies to go on, physicians have treated patients based on experience or anecdotal evidence.

Statland and Griggs expect that approach to change with the new study, which pulled together doctors and patients from four nations to study whether the generic drug mexiletine alleviates symptoms. The 59 participants received either 200 mg of mexiletine three times daily, or placebo, for four weeks, and then after one week, they received the other treatment for four weeks.

The results show that mexiletine, an anti-arrhythmic medication rarely used for its original indication, significantly improved patient-reported stiffness in nondystrophic myotonia. Participants reported that their stiffness improved by at least 40 percent; pain reported by patients was slashed in half; and patients reported improvements in their everyday quality of life. Testing also showed that mexiletine reduced the abnormal electrical activity in the muscles, and patients were able to relax their grip and open their eyes much faster.

Griggs said the Rare Disease Network begun by the National Institutes of Health, which supported CINCH for 10 years, exists to tackle problems just like this one. There isn't much financial incentive for a pharmaceutical firm to sink money into a study of a disease that affects a small number of people, especially if the medication is generic.

"Pulling off this study is quite an accomplishment when you consider not only the relatively small number of people who have this disease, but also the challenge of getting enough of them together to do a study that is statistically significant," said Griggs.

Statland began working on the project more than six years ago, before his residency at the University of Kansas. His odyssey doing research has included a summer research fellowship at the National Institutes of Health and a Howard Hughes Medical Institute research scholar award. His current work in Rochester doing research and treating patients is funded largely by the Muscular Dystrophy Association. He has been at Rochester since 2010.

Other authors include Rochester neurologist Emma Ciafaloni, M.D.

### In addition to the University of Rochester Medical Center and the University of Kansas, other sites for the study included Brigham & Women's Hospital in Boston, the University of Texas Southwestern in Dallas, the London Health Sciences Center in London, Ontario, University College London Institute of Neurology in London, and the University of Milan in Italy.

The study was supported by the U.S. Food and Drug Administration (RO1 FD 003454) and the National Center for Research Resources of the National Institutes of Health (U54 NSO59065). Statland's work was supported by an NIH experimental therapeutics fellowship (T32 NSO7338-20).