In 2008, Duygu Selcen, M.D., a pediatric neurologist and research scientist at Mayo Clinic in Minnesota, received a phone call from a pathologist at the University of Manitoba in Winnipeg, Canada. Marc R. Del Bigio, M.D., wanted Dr. Selcen's input in determining the molecular basis of a fatal muscle disease affecting Canadian aboriginal infants of Cree ancestry. The children had rigid muscles and fatal respiratory insufficiency in infancy.
Dr. Del Bigio told Dr. Selcen that the muscle biopsy specimens he had examined appeared to be like those found in a type of muscular dystrophy called myofibrillar myopathy (MFM), even though the disease took a different course. All of the affected children died in infancy except one, who died at 3 years of age.
It is not surprising that Dr. Del Bigio contacted Dr. Selcen. The Muscle Research Laboratory at Mayo Clinic, established more than 40 years ago by Dr. Selcen's mentor, Andrew G. Engel, M.D., receives more than 1,000 muscle biopsy specimens a year for histologic analysis. By the time Dr Selcen received the call, she and her colleagues had already made some important discoveries about the molecular basis and distinctions among types of MFM.
MFM encompasses a group of chronic, slowly progressive diseases of the skeletal muscle, the heart muscle and the peripheral nerves. Signs and symptoms can include:
In most patients, the disease presents in late adulthood, but a subtype of rapidly progressing MFM, identified by Dr. Selcen and her colleagues, can occur in childhood.
The term "myofibrillar myopathy" was coined 15 years ago. It groups together genetically heterogeneous neuromuscular disorders that previously were thought to be distinct but which share common morphological characteristics.
The common pathological features include disorganization and degradation of the contractile filaments of striated muscle (myofibrils) originating at the Z disk. The molecular abnormalities of MFM include the accumulation and aberrant expression of proteins.
Only two of the genes had been identified until 2004, when Drs. Selcen and Engel uncovered two more genes that cause MFM. Both of the newly identified genes were implicated in Z disk structure and biology:
More recently, Dr. Selcen and colleagues discovered a mutation in yet another protein, a product of the BAG-3 gene, which has antiapoptotic features. Their finding isolated a previously unidentified severe, rapidly progressive, fatal childhood type of MFM. It marked the first time that BAG-3, typically associated with cancer, was implicated in human muscle disease.
The finding is of immediate clinical significance because the symptoms of cardiomyopathy often occur before the disease shows up in the peripheral muscles. Affected children and adolescents may be candidates for heart transplantation, but if they have the BAG-3 gene mutation, spine rigidity and respiratory failure will develop eventually, regardless of improved heart function.
Now, under Dr. Selcen's direction, the Mayo team is developing animal models to test anti-apoptotic drugs in an effort to halt the progression of the disease.
What of the Canadian aboriginal infants? Dr. Del Bigio was right: The muscle biopsy specimens shared multiple characteristics with MFM, particularly the abnormal accumulation of specific proteins. When Dr. Selcen conducted further immunostaining tests, however, a protein that is always at increased levels in MFM was totally absent. Its absence provided the clue that led Drs. Selcen and Del Bigio and their colleagues to pinpoint CRYAB as the disease gene — a discovery that will enable genetic testing, genetic counseling and, eventually, disease prevention in this population.
Dr. Selcen is both a clinician and a researcher. She routinely sees patients with MFM and other muscle diseases for clinical assessment and disease management. Her ongoing investigations at Mayo's Muscle Research Laboratory on malfunctioning genes and gene products in muscle disease have led to the identification of specific subtypes of childhood MFM, discoveries that have immediate management implications and hold the promise of identifying therapeutic interventions in the future.