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.

Stargardt Disease: towards developing a model to predict phenotype

“…Such products can trigger RPE dysfunction through various mechanisms, consequently leading to degeneration of photoreceptors and ultimately vision loss. 3,13 A high level of allelic heterogeneity is displayed in arSTGD, as over 600 mutations in ABCA4 have been identified. 14 The vast number of identified mutations in ABCA4, their respective effects on the protein and the combination of mutations within a particular individual are largely accountable for the phenotypic heterogeneity in arSTGD patients.…”

Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics

“…Visual field testing was performed with kinetic and static perimetry as published (3,(23)(24)(25)(26)(27)52). For kinetic perimetry, white (318 cd⅐m Ϫ2 ) targets of Goldmann sizes III (patient 1) or V (patients 2 and 3) were used on a 10 cd⅐m Ϫ2 achromatic background.…”

“…Normal human vision becomes more sensitive to light after an instantaneous decrease in ambient illuminationthe process is known as dark adaptation. Normally, full dark adaptation can require up to 1 hour for rod photoreceptor-based night vision (18,(23)(24)(25)(26)(27); further changes in light sensitivity after 1 hour are insignificant in normal eyes. Accordingly, initial testing in all patients was performed after a standard dark adaptation period of 1 to 2 h. Clues to the inadequacy of this period were suggested from reports by the subjects of noticeably increased brightness in their treated eye when they awoke from sleep in their darkened rooms.…”

Novel mutations in of the ABCR gene in italian patients with Stargardt disease

“…All-trans-retinal is then converted into a substance called A2-E, a major component of lipofuscin, which determines a toxic effect leading to the disruption of the RPE and the overlying photoreceptors. 8 Several series of mutation analyses have confirmed that homozygous and compound heterozygous mutations in ABCR are responsible for recessive STGD. [9][10][11][12][13] ABCR has also been singled out as a possible cause of other diseases with similar clinical macular abnormalities.…”