CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History

Purpose: To analyze the clinical characteristics, natural history, and genetics of CERKL-associated retinal dystrophy in the largest series to date. Design: Multicenter retrospective cohort study. Subjects: Forty-seven patients (37 families) with likely disease-causing CERKL variants. Methods: Review of clinical notes, ophthalmic images, and molecular diagnosis from 2 international centers. Main outcome measures: Visual function, retinal imaging, and characteristics were evaluated and correlated. Results: The mean age at the first visit was 29.6 +/- 13.9 years, and the mean follow-up time was 9.1 +/- 7.4 years. The most frequent initial symptom was central vision loss (40%), and the most common retinal feature was well-demarcated areas of macular atrophy (57%). Seventy-seven percent of the participants had double-null genotypes, and 64% had electrophysiological assessment. Among the latter, 53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern. Patients without double-null genotypes tended to have fewer pigment deposits and included a higher proportion of older patients with a relatively mild electrophysiological phenotype. Longitudinal analysis showed that over half of the cohort lost 15 ETDRS letters or more in 2: 1 eye during the first 5 years of follow-up. Conclusions: The phenotype of CERKL-retinal dystrophy is broad, encompassing isolated macular disease to severe retina-wide involvement, with a range of functional phenotypes, generally not fitting in the rod-cone/ cone-rod dichotomy. Disease onset is often earlier, with more severe retinal degenerative changes and photoreceptor dysfunction, in nullizygous cases.