Objective: To evaluate the phenotype of affected and carrier members of a family with mutations in RPE65 (a retinal pigment epithelium gene). Methods: RPE65 mutation screening was performed on DNA from 2 affected brothers, 1 unaffected brother, both parents, and 3 surviving grandparents using cycle sequencing. Ophthalmic examinations included ophthalmoscopic fundus examination; visual function testing; 2-color, static, dark-adapted threshold perimetry; and rod electroretinographic a-wave phototransduction analysis. Results: The 2 affected brothers carried RPE65 mutations in compound heterozygous form: a maternal Y368H (1156T→C) missense mutation and a paternal IVS1 + 5g→a splice-site mutation. Severe visual deficits and an absence of rod and cone electroretinographic responses were diagnosed in both affected boys before the age of 5 years. Visual acuities of about 20/100 during grade school declined to hand movements by the teenage years, and only a rudimentary peripheral temporal visual field remained by the ages of 25 and 29 years. Both parents had normal central visual function, as measured by visual acuity, contrast sensitivity, color vision, and Humphrey 10-2 fields. However, the 50-year-old father showed hundreds of tiny whitish hard drusen in both eyes and had abnormal peripheral function on dark-adapted perimetry, with extended field defects of 15 to 20 dB outside 30° eccentricity. His rod photoreceptor sensitivity and amplitude, calculated by fitting the rod a waves by a model of activation of phototransduction, were normal, but the flicker electroretino-graphic response was delayed. Conclusions: The RPE65 mutations Y368H and IVS1 + 5g→a present in compound heterozygous form cause severe visual compromise in childhood and progress to nearly total vision loss by the second to third decades of life. The retinal and functional changes in the father carrying a presumed functional null allele suggest that some RPE65 heterozygous carriers may manifest visual symptoms.
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