The Athena Diagnostics database is one of the world’s largest repositories of clinically important human genetic variation in neurogenetic disorders. Athena Diagnostics has uncovered hundreds of thousands of genetic variants across a wide range of diseases, from the most common to the rarest. For Matthew Wicklund, MD, working in conjunction with scientists at Athena Diagnostics has provided the opportunity to analyze the full spectrum of mutations responsible for limb girdle muscular dystrophy (LGMD), and to develop recommendations for other physicians when confronting a patient suspected to have LGMD. Dr. Wicklund is Professor of Neurology and Pediatrics at Penn State Hershey Medical Center in Hershey, Pennsylvania, and is an expert in the genetics of muscle diseases.
“There are over 35 different forms of limb girdle muscular dystrophy,” Dr. Wicklund says, “and for the average neurologist, and even the average neuromuscular specialist, it can be very challenging to deliver a specific diagnosis on clinical grounds alone. Although each form has distinct characteristics, patients often present with similar features. While there are some clinical features that will help you, they don’t get you to the right answer all the time.” All forms of LGMD share the cardinal feature of predominant weakness in the hip and shoulder girdles. Some forms include cardiorespiratory muscle weakness, while others are usually limited to skeletal muscle involvement alone, a difference with obvious prognostic and management implications.
Dr. Wicklund is working with colleagues to develop a practice guideline for LGMD diagnosis to improve the clinical care of patients. But little is known about the relative prevalence of the various types of LGMD in the United States population, and without that information it has been difficult to give physicians insight into the range of patients they are likely to encounter.
To overcome that challenge, Dr. Wicklund approached Athena scientists to collaborate on an analysis of almost 500 cases of LGMD from the Athena database. The sample is approximately five times larger than any other group of patients previously analyzed.
In a poster presented in March 2013 at the Annual Meeting of the American Academy of Neurology, Dr. Wicklund reported that mutations in the gene for calpain accounted for 30% of cases, with dysferlin mutations at 18 percent, and fukutin-related protein at 17 percent , with 6 other genes accounting for an additional 31 percent.
Remarkably, Dr. Wicklund says, the genes responsible for LGMD have little in common, with effects on the nuclear envelope, the sarcolemma, the plasma membrane, cytoskeleton, and a variety of other cell processes. They are a group of “bewildering complexity, with no one common pathway.” Nonetheless, “availability of this data will help guide investigators in future epidemiological, clinical and treatment trials.”
Better diagnosis and treatment is the ultimate goal of the work, he says. For a patient whose LGMD is due to a calpain or dysferlin mutation, together accounting for almost half the sample, it can be reassuring to know that they are unlikely to develop respiratory or cardiac involvement. On the other hand, those with lamin A/C mutations often do have heart rhythm abnormalities, and closer monitoring is advisable. A precise genetic diagnosis allows the physician to know which patients would benefit from intervention versus watchful waiting.
The study is also gratifying to the Athena Insight team, according to co-author Izabela Karbassi, PhD, Senior Scientist at Athena Diagnostics. “The Athena Insight group is the curator of the data at Athena, and it is always important to have our fingers on the pulse of that data. Understanding how our variants fall into various categories allows us to pull out the meaning of each variant on an individual level.” More such fruitful collaborations are on track for the future, she says.