New ABCR mutations and clinical phenotype in Italian patients with Stargardt disease

PURPOSE. TO assess the mutation spectrum in the ABCR gene and clinical phen otypes in Italian families with autosomal recessive Stargardt disease (STGD 1) and fundus flavimaculatus (FFM). METHODS. Eleven families from southern Italy, including 18 patients with di agnoses of STGD1, were clinically examined. Ophthalmologic examination incl uded kinetic perimetry, electrophysiological studies, and fluorescein angio graphy. DNA samples of the affected individuals and their family members we re analyzed for variants in all 50 exons of the ABCR gene by a combination of single-strand conformation polymorphism analysis and direct sequencing t echniques. RESULTS. Ten ABCR variants were identified in IG (73%) of 22 mutant alleles of patients with STGD1. Five mutations of 10 that were found had not been previously described. The majority of variants represent missense amino aci d substitutions, and all mutant alleles resegregate with the disease in the respective families. These ABCR variants were not detected in 170 unaffect ed control individuals (340 chromosomes) of Italian origin. Clinical evalua tion of these families affected by STGD1 showed an unusually high frequency of early age-related macular degeneration (AMD) in parents of patients wit h STGD1 (8/22; 36%), consistent with the hypothesis that some heterozygous ABCR mutations enhance susceptibility to AMD. CONCLUSIONS. Patients from southern Italy with Stargardt disease show exten sive allelic heterogeneity of the ABCR gene, concordant with previous obser vations in patients with STGD1 from different ethnic groups. Half the mutat ions identified in this study had not been previously described in patients with STGD1. Screening of increasingly large numbers of patients would help to determine whether this can be explained by ethnic differences, or is an indicator of extensive allelic heterogeneity of ABCR in STGD1 and other ey e diseases. in 6 (55%) of 11 families, the first-degree relatives of patien ts with STGD1 were diagnosed with early AMD, supporting the previous observ ation that some STGD1 alleles are also associated with AMD.