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Winston Lee, Jana Zernant, Stephen Tsang, Janet R Sparrow, Rando Allikmets; Do Mutations in ABCA4 Really Cause Retinitis Pigmentosa?. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1052.
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© ARVO (1962-2015); The Authors (2016-present)
To re-evaluate the connection between variation in the ABCA4 gene and retinitis pigmentosa (RP).
A comprehensive review of the literature was conducted to evaluate the characteristics of ABCA4-associated RP (retinitis pigmentosa 19, MIM# 601691). Retrospective analysis of a large clinically diagnosed and genetically confirmed (≥2 ABCA4 mutations) cohort (n=350) identified seven patients exhibiting RP-like characteristics. Data evaluated for these patients included clinical history, multimodal imaging and full-field electroretinogram (ffERG) testing.
Forty-nine peer-reviewed articles have been published describing patients with ABCA4-associated RP between 1998 and 2019. Clinical data of the described cases were evaluated when available. A retrospective screening of our ABCA4-confirmed cohort identified 7 patients matching the clinical characteristics described. All 7 patients reported a history of central vision loss from childhood and presented to the clinic at an already advanced disease stage. Consistent amongst all cases were RP-like characteristics in the fundus, including widespread outer retinal degeneration, distinctive bone-spicule pigment (BSP) deposition, waxy disc pallor and profound vessel attenuation. Notably, severe atrophic changes and choroidal scarring of the central macula was noted in all cases. Wide-field autofluorescence (AF) imaging of the posterior pole revealed a notably less affected periphery covered with autofluorescent flecks. Photopic 30 Hz and single flash responses on ffERG were non-recordable in all cases. Scotopic and maximal responses were also non-recordable in all except one patient, in whom an appreciable, but attenuated waveforms were detected. All patients exhibited variable attenuation of maximal responses although the rod amplitudes of P3 were found to be within normal range. The majority of ABCA4 alleles in the cohort were deleterious including nonsense, canonical splice site, and severe missense variants.
The overwhelming majority of patients reported in the literature reported as having ABCA4-associated RP, as well as the cases presented in this study, likely have a severe form of cone-rod dystrophy with RP-like changes such as BSP deposition due to a rapid progression of rod photoreceptor degeneration. A clear connection between ABCA4 and “true” RP remains to be proven and the present findings of this study challenge this long-established paradigm.
This is a 2020 ARVO Annual Meeting abstract.
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