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CERKL Mutations Cause an Autosomal Recessive Cone-Rod Dystrophy with Inner Retinopathy

From the ¹Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania; the ²SNONGC (Sankara Nethralaya Oil and Natural Gas Corporation) Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India; the ³Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, United Kingdom; ⁴Howard Hughes Medical Institute and Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, Iowa; and the ⁵Department of Ophthalmology and Visual Sciences, University of IIlinois at Chicago, Chicago, Illinois.

Corresponding author: Tomas S. Aleman, Scheie Eye Institute, University of Pennsylvania, 51 N. 39th Street, Philadelphia, PA 19104; aleman{at}mail.med.upenn.edu.

Purpose. To define the phenotype of the retinal degeneration associated with mutations in the CERKL gene.

Methods. Six patients (ages, 26–54 years) from three unrelated families with CERKL mutations were studied clinically and by electroretinography, kinetic, and chromatic static perimetry, autofluorescence (AF) imaging, and optical coherence tomography (OCT).

Results. Three siblings were homozygotes for p.R257X mutation; two siblings were compound heterozygotes for p.R257X and a novel p.C362X mutation; and one patient had only p.R257X mutation identified to date. There was a spectrum of severity: from mild visual acuity loss to light perception; from full kinetic fields with relative central scotomas to remnant peripheral islands; from reduced ERGs (some with negative waveforms) to nondetectable signals. Maculopathy showed residual foveal islands or extensive central rod and cone scotomas. With AF imaging, there was evidence of hyperautofluorescence at earlier and hypoautofluorescence at later disease stages. Peripheral function was generally less affected than central function. With OCT there were small foveal islands of outer nuclear layer (ONL) in those with preserved acuity. Eccentric to an annular region with no discernible ONL, there could be ONL in the midperiphery. At early disease stages, ganglion cell layer thickness was less affected than ONL. Later disease stages were accompanied by inner nuclear layer and nerve fiber layer abnormalities.

Conclusions. CERKL mutations are associated with widespread retinal degeneration with prominent maculopathy. The clinical presentation is that of an autosomal recessive cone–rod dystrophy. Photoreceptor loss appears at all stages of disease and inner laminopathy complicates the phenotype at later stages.