Retinal dystrophies caused by mutations in the ABCA4 gene. An evaluation of the clinical spectrum.

In the past seven years, the ABCA4 gene has emerged as the most prominent gene in inherited retinal disease. Pathogenic ABCA4 mutations are the cause of all cases of Stargardt disease, and a portion of the cases of autosomal recessive retinitis pigmentosa and cone-rod dystrophy. Moreover, specific heterozygous alterations in this gene have been associated with age-related macular degeneration, although this role has been disputed by others. The papers in this thesis, joined in the six appendices, address the clinical findings in ABCA4 retinal dystrophies and attempt to correlate these findings with the underlying genetic abnormalities. Mutation analysis of a cohort of autosomal recessive cone-rod dystrophy patients revealed that mutations in the ABCA4 gene are responsible for the majority of the cases of recessive cone-rod dystrophy. A surprising heterogeneity in clinical expression exists between the cone-rod phenotypes caused by ABCA4 mutations. Evaluation of larger cohorts of patients with autosomal recessive cone-rod dystrophy and retinitis pigmentosa lead to the conclusion that causative ABCA4 mutations will be present in approximately two-third of the autosomal recessive cone-rod dystrophy cases and less than 5% of the cases with autosomal recessive retinitis pigmentosa. The carrier frequency of pathologic ABCA4 mutations in the general population is high and this may lead to the occurrence of different ABCA4-associated phenotypes in one family. Several of these families are described in this thesis; such combinations may not be as uncommon as once believed. Review of the phenotypic spectrum of retinal dystrophies caused by mutations in the ABCA4 gene reveals a continuum that includes both typical and intermediate forms. With the prospect of future therapeutic approaches, early recognition of these phenotypes by the general ophthalmologist will become increasingly important