Molecular genetics of macular dystrophies.

Macular dystrophies represent a heterogeneous group of disorders spanning a broad spectrum of clinical, histopathological, and laboratory findings. Despite this variability, funduscopic changes involving the macula and retinal pigment epithelium (RPE) and clinically significant loss of central or functional vision are characteristic of these disorders. As a group of diseases with a strong genetic component, many macular dystrophies are excellent candidates for study using molecular biological techniques such as genetic linkage analysis, positional cloning, and the candidate gene approach. Such molecular investigations have been successful, and genes for several inherited maculopathies including Stargardt's macular dystrophy,'" North Carolina macular dystrophy,45 Best's vitelliform macular dystrophy,6 and Sorsby's macular dystrophy78 have been mapped to specific chromosomal loci. In addition to elucidating the aetiology and pathogenesis of these rare heritable disorders, it is hoped that the identification of individual genes and molecular pathways involved in inherited macular dystrophies will give greater insight into the more complex aetiology of age-related macular degeneration (ARMD). ARMD is the most common cause of blindness among the elderly in many Western countries including the UK and the USA.9-"' By 1996, it is estimated that over two million people in the USA alone will have ARMD, and more than 100 000 will probably be blind from the disease.'2 Despite its prevalence, the aetiology and molecular pathogenesis of ARMD are poorly understood." This finding makes a rational approach to treatment difficult, and therapeutic options for ARMD limited. Direct application of molecular genetic techniques to ARMD is hindered by two major factors. Firstly, the late onset ofARMD makes genetic linkage experiments difficult because the parents of affected individuals are often deceased and the children of affected members are often too young to express the ARMD phenotype. Secondly, although genetic studies involving monozygotic twins suggest a major genetic component,'"" ARMD in most patients is probably multifactorial including both genetic and environmental factors. For example, a high dietary intake of carotenoids has been associated with a lower risk of ARMD,'8 whereas a high risk of ARMD has been associated with atherosclerosis in