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 extracellular matrix protein fibrillin-1. The challenge ahead is to use this 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 theoretical and technological obstacles must be overcome. Among these is an incomplete but expanding comprehension of the pathogenesis of Marfan syndrome. Nevertheless, molecular analysis has led to an increased understanding of the origins of pleiotropy and clinical variability in the Marfan syndrome, a pre-requisite for the development of rationale therapeutic strategies. Of more immediate practical importance, it is now possible to apply molecular methods to the pre-symptomatic and prenatal diagnosis of Marfan syndrome, providing the first opportunity for disease prevention and for presumptive rather than symptomatic intervention. Two genetic methods are routinely applied to determine whether an individual or fetus is at risk for the development of a phenotype concordant with that seen in other affected family members. Linkage analysis is both efficient and accurate, but requires the existence and involvement of many affected and unaffected family members. Direct mutational analysis obviates many of these requirements, but is both time and 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 syndrome or related disorders. It must be stressed that molecular data must always be considered in conjunction with a thorough phenotypic assessment. No test, in isolation, is sufficient for the unequivocal assignment of affected or unaffected status. The Marfan syndrome is now, and shall always remain, a clinical diagnosis. When applied in conjunction with a consideration of each family's beliefs, expectations, resources, and priorities, molecular analysis can be a useful adjunct in patient management and counseling.