Genes Help Unravel Marfan Pathology, Point Way to Potential New Therapies

Abstract

MODERN GENETIC TECHNIQUES are providing new insights into the pathogenesis of Marfan syndrome, a genetic disorder that can cause skeletal malformations and abnormalities of the heart and other organs. In the process, these insights are challenging long-held beliefs about the disease and related disorders and raising hope for better treatments. Such hope counters the pessimism that accompanied the 1991 discovery that Marfan syndrome is caused by mutations in the gene that encodes fibrillin-1, a component of the extracellular matrix (Dietz et al. Nature. 1991; 352:337-339). After all, defects in structural proteins throughout the body would be nearly impossible to correct. But more recent discoveries suggest that fibrillin-1 regulates transforming growth factor(TGF) and show that excessive activity of this protein appears to play an integral role in the pathogenesis of Marfan syndrome and some related disorders. The finding regarding of TGF’s role in the disease also points to potential targets for future therapies. Peter H. Byers, MD, medical geneticist and professor in the departments of pathology and medicine at the University of Washington, in Seattle, said the discoveries mark a dramatic shift in the understanding of Marfan syndrome and bolster a long-standing theory that extracellular matrix proteins play a regulatory role as well as a structural one. “It has opened up the door to many new opportunities for therapeutic treatments,” said Josephine Grima, PhD, director of research and legislative affairs at the National Marfan Foundation, in Port Washington, NY. Marfan syndrome is an autosomal dominant disorder that affects an estimated 1 in 5000 people worldwide. Affected individuals are often, but not always, very tall, slender, and loose jointed, according to the Foundation. Limbs and digits may be disproportionally long and malformations of the sternum or scoliosis may be present. The disorder also affects the cardiovascular system, eyes, skin, and nervous system. If left untreated, individuals with Marfan syndrome may develop aortic dissections and many die before age 40. However, with early diagnosis and proper management, individuals can have nearly normal lifespans. Current therapies for Marfan syndrome aim to decrease stress on the aorta. Intervention strategies include the use of -blockers and certain exercise restrictions to reduce cardiovascular stress, said Harry C. Dietz, MD, director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins University School of Medicine, in Baltimore. Physicians also closely monitor the condition of the aortas of individuals with Marfan syndrome and make surgical corrections when there is a risk of rupture.