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Peter Charbel Issa, Philipp Mueller, Martin Gliem, Elisabeth Mangold, Hanno Joern Bolz, Frank G Holz; Monoallelic mutations in ABCA4 are not associated with abnormal lipofuscin accumulation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3820.
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Bi-allelic mutations in the ABCA4 gene cause Stargardt disease and cone-rod dystrophy. A very early finding in ABCA-related retinopathy is a diffuse increase of lipofuscin in the retinal pigment epithelium (RPE), which can now be assessed using quantitative fundus autofluorescence (qAF) imaging. We used this sensitive technique to investigate if mono-allelic ABCA4 mutations would result in a retinal phenotype.
Individuals with mono-allelic ABCA4 mutations were selected by investigating genotyped parents (n=21) of patients with retinal disease due to bi-allelic ABCA4 mutations. Fundus AF images were acquired with a scanning laser ophthalmoscope (Spectralis HRA-OCT, Heidelberg Engineering, Heidelberg, Germany) equipped with an internal fluorescent reference. For every subject, the mean gray value of a circular region at an eccentricity of approximately 7° to 9° centered on the fovea was determined. The qAF value was calculated after adjustment to the reference, the optical magnification, the density of the ocular media, the laser offset and a device-specific correction factor. Data were compared to normative qAF-values derived from 90 healthy subjects.
In each parent, segregation analysis revealed one of the two pathogenic mutations identified in the index patient. The parents’ mean±SD age was 52±8.3 years. The spectrum of mutations included frequent missense mutations (p.Gly1961Glu, p.Gly863Ala), and 7 out of the 21 parents carried a null mutation. All index patients with bi-allelic mutations revealed qAF intensity measures above the age-related 95% confidence interval (CI) of the control group. All parents with mono-allelic ABCA4 mutations showed normal findings on ophthalmoscopy, OCT- and conventional fundus AF- imaging. Lipofuscin-related qAF levels were not significantly different between carriers of mono-allelic ABCA4 mutations and controls, independent from the type of mutation. QAF levels were within the age-adjusted 95% CI of normal controls in 19 subjects, and were slightly above or below this range in 1 subject each.
Absence of a phenotype based on qAF in parents of patients with bi-allelic ABCA4 mutations makes it unlikely that mono-allelic ABCA4 mutations are disease causing. The finding that one normal ABCA4 allele is sufficient to prevent retinal disease may be important for the required transduction efficiency in gene therapy for ABCA4-related retinopathy.
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