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Late-Onset Retinal Degeneration Caused by C1QTNF5 Mutation Sub–Retinal Pigment Epithelium Deposits and Visual Consequences

Samuel G. Jacobson, MD, PhD1; Artur V. Cideciyan, PhD1; Alexander Sumaroka, PhD1; Alejandro J. Roman, MSc1; Alan F. Wright, MB, PhD2
[+] Author Affiliations
1Scheie Eye Institute, University of Pennsylvania, Philadelphia
2Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland
JAMA Ophthalmol. 2014;132(10):1252-1255. doi:10.1001/jamaophthalmol.2014.2059.
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Two decades ago, a postmortem eye donor study identified a unique autosomal dominant disease and named it late-onset retinal degeneration (L-ORD).1 The distinguishing feature of L-ORD was a retina-wide thick layer of extracellular deposit between the retinal pigment epithelium (RPE) and Bruch membrane. A founder mutation, p.Ser163Arg, in C1QTNF5 was causative.2 Recent study of the crystal structure of C1QTNF5 suggested that L-ORD may be caused by reduced adhesion of the RPE.3

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Figure 1.
Outer Retinal Structure and Visual Function in Patients With C1QTNF5 Disease

A, Vertical optical coherence tomographic scan (57° span) in a healthy participant. Yellow marks the sub–retinal pigment epithelium (RPE) to Bruch membrane (BrM) space. B, Magnified images at 11° to 13° superior retina (brackets in full scans in A and C) compare normal laminar architecture with that in patient 1. Longitudinal reflectivity profiles are overlaid on scans to show basis of labeling. Yellow marks the sub-RPE to BrM space, which has abnormal hyperreflectivity in patient 1. COST indicates cone outer segment tips; ISe, ellipsoid region of photoreceptor inner segments; OLM, outer limiting membrane; ONL, outer nuclear layer; OST, outer segment tips; and ROST, rod outer segment tips. C-G, The results for patient 1 are shown in the left panels, and the results for patient 2 are shown in the right panels. C, Scans across the right eye of patient 1 and the left eye of patient 2 with highlighted sub-RPE to BrM abnormality (yellow) and ONL (blue). The ONL thickness includes anatomical layers of photoreceptor nuclei and Henle fiber layer. D, Thickness of the ONL in the patients (lines) compared with normal limits (±2 SDs; shaded areas). E, Outer segment lamination (OS+) in the patients (lines) plotted across eccentricity and compared with normal findings (shaded areas). F, Thickness of the sub-RPE to BrM lamina in patients 1 and 2 using the RTVue-100 (Optovue, Inc). Dashed line indicates maximum intervening space in healthy individuals. G, Rod sensitivity with a 500-nm stimulus (rod-mediated by dark-adapted 2-color chromatic perimetry) and cone sensitivity with a 600-nm stimulus (light-adapted), in log units. Patient data are dark bars, superimposed on the normal mean for each locus (light bars). Insets between rod and cone function are graphs of ONL thickness (expressed as a fraction of normal at 10°-16.5° eccentricity vertically) vs rod sensitivity loss (RSL) at the same eccentricities. Gray regions outlined by dashes show the predicted relationship in an idealized photoreceptor degeneration.

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Figure 2.
Autofluorescence Imaging in Patients With C1QTNF5 Disease

Autofluorescence imaging (HRA2; Heidelberg Engineering) from a representative healthy participant (aged 59 years) (A), the right eye of patient 1 (B), and the left eye of patient 2 (displayed as the right eye) (C). Larger panels showing near-infrared reflectance (NIR-REF) and near-infrared reduced-illuminance autofluorescence imaging (NIR-RAFI) are digital mosaics obtained from multiple overlapping 30° views. Insets, Short-wavelength reduced-illuminance autofluorescence imaging (SW-RAFI). Images are contrast stretched and gamma corrected for visibility of features in brighter and dimmer parts of the images.

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