title: Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence.
abstract: Mutations in ABCA4, which encodes a photoreceptor specific ATP-binding cassette transporter (ABCR), cause autosomal recessive forms of human blindness due to retinal degeneration (RD) including Stargardt disease. The exact disease sequence leading to photoreceptor and vision loss in ABCA4-RD is not known. Extrapolation from murine and in vitro studies predicts that two of the earliest pathophysiological features resulting from disturbed ABCR function in man would be slowed kinetics of the retinoid cycle and accelerated deposition of lipofuscin in the retinal pigment epithelium (RPE). To determine the human pathogenetic sequence, we studied surrogate measures of retinoid cycle kinetics, lipofuscin accumulation, and rod and cone photoreceptor and RPE loss in ABCA4-RD patients with a wide spectrum of disease severities. There were different extents of photoreceptor/RPE loss and lipofuscin accumulation in different regions of the retina. Slowing of retinoid cycle kinetics was not present in all patients; when present, it was not homogeneous across the retina; and the extent of slowing correlated well with the degree of degeneration. The orderly relationship between these phenotypic features permitted the development of a model of disease sequence in ABCA4-RD. The model predicted lipofuscin accumulation as a key and early component of the disease expression in man, as in mice. In man, however, abnormal slowing of the rod and cone retinoid cycle occurs at later stages of the disease sequence. Knowledge of the human ABCA4 disease sequence will be critical for defining rates of progression, selecting appropriate patients and retinal locations for future therapy, and choosing appropriate treatment outcomes.
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA. cideciya@mail.med.upenn.edu
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Swider
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Janet D
authors.initials: JD
authors.lastname: Steinberg
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Brucker
authors.forename: Albert M
authors.initials: AM
authors.lastname: Maguire
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D003623:Dark Adaptation / Q000502:physiology; D018450:Disease Progression; D005453:Fluorescence; D005808:Genes, Recessive; D006801:Humans; D007700:Kinetics; D008062:Lipofuscin / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D008062:Lipofuscin