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A.V. Cideciyan, T.S. Aleman, M. Swider, S.B. Schwartz, J.D. Steinberg, A.J. Brucker, A.M. Maguire, J. Bennett, E.M. Stone, S.G. Jacobson; Sequence of lipofuscin accumulation, retinoid cycle slowing and retinal degeneration in human ABCA4 disease . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1765.
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Purpose: Mutations in ABCA4 (encoding ABCR) cause autosomal recessive forms of human blindness due to retinal degeneration (RD). 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). The exact pathogenetic sequence leading to photoreceptor and vision loss in human ABCA4–RD is not known. Methods: The study population consisted of 47 patients (age=39+/–16 years) with a wide spectrum of disease severities within the clinical diagnostic criteria of Stargardt disease (STGD) or cone–rod dystrophy (CRD) and one or more changes in the ABCA4 gene considered to be disease–causing variants. We measured dark adaptation kinetics, autofluorescence distribution and absolute psychophysical sensitivities as surrogate measures of retinoid cycle kinetics, lipofuscin accumulation, and photoreceptor loss, respectively. Results: There were different extents of photoreceptor/RPE loss and lipofuscin accumulation in different regions of the retina. Spatially diffuse elevation of lipofuscin could be associated with normal retinoid cycle kinetics and psychophysical sensitivities. 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 estimated from loss of sensitivity. The orderly relationship between these phenotypic features permitted the development of a model of disease sequence in ABCA4–RD. Conclusions: The model confirmed abnormal 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 developing treatment outcomes.
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