MOLECULAR ETIOLOGY, PATHOGENESIS AND DIAGNOSIS OF THE MARFAN-SYNDROME

It is now known that most, if not all cases of classic Marfan syndrome are caused by primary mutations in the gene (FBN1) encoding the extra cellular matrix protein fibrillin-1. The challenge ahead is to use thi s information in a responsible manner to improve the lives of affected patients and families. While the prospect for gene therapy, the most dramatic potential application, is now exciting and real, many theoret ical and technological obstacles must be overcome. Among these is an i ncomplete but expanding comprehension of the pathogenesis of Marfan sy ndrome. Nevertheless, molecular analysis has led to an increased under standing of the origins of pleiotropy and clinical variability in the Marfan syndrome, a pre-requisite for the development of rationale ther apeutic strategies. Of more immediate practical importance, it is now possible to apply molecular methods to the pre-symptomatic and prenata l diagnosis of Marfan syndrome, providing the first opportunity for di sease prevention and for presumptive rather than symptomatic intervent ion. Two genetic methods are routinely applied to determine whether an individual or fetus is at risk for the development of a phenotype con cordant with that seen in other affected family members. Linkage analy sis is both efficient and accurate, but requires the existence and inv olvement of many affected and unaffected family members. Direct mutati onal analysis obviates many of these requirements, but is both time an d cost intensive. In selected circumstances, protein analyses, such as immunohistochemistry and metabolic labeling studies, may be useful in the evaluation of individuals at risk for the development of Marfan s yndrome or related disorders. It must be stressed that molecular data must always be considered in conjunction with a thorough phenotypic as sessment. No test, in isolation, is sufficient for the unequivocal ass ignment of affected or unaffected status. The Marfan syndrome is now, and shall always remain, a clinical diagnosis. When applied in conjunc tion with a consideration of each family's beliefs, expectations, reso urces, and priorities, molecular analysis can be a useful adjunct in p atient management and counseling.