Thirty Year Clinical Follow-Up of a Patient with Novel RPE65 Mutations and Leber Congenital Amaurosis

Abstract

Abstract: : Purpose: To report a North American family with heterozygous compound mutations in the RPE65 gene associated with Leber Congenital Amaurosis, and to present a long-term follow-up of the ocular findings in the proband Methods: RPE65 mutation screening was performed on 30 patients with Leber Congenital Amaurosis (LCA) using PCR amplification of the 14 exons of RPE65, and search for sequence changes using SSCP and direct sequencing of abnormal bands. Ophthalmic examinations included visual acuity testing, ophthalmoscopy, color vision testing, dark-adapted threshold perimetry, and electroretinography. Results: The proband, a 35 year-old female carried two RPE65 mutations in a compound heterozygous fashion: a maternal K303X (A961T) nonsense mutation and a paternal Y431C (A1346G) missense mutation. She had severe visual deficits and an absence of rod and cone electroretinographic responses. Visual acuity of 20/60 and color recognition during early childhood declined over time to 20/100 OD and 20/50 OS with total absence of color recognition during the teenage years, and only 2/200 OD and 1/200 OS at the age of 30. She graduated from high school in regular classroom setting. Both parents had normal visual function and a sister carried one of the mutations. Conclusions: The RPE65 mutations K303X and Y431C in compound heterozygous form cause progressive visual compromise that starts in childhood and advances to almost total visual loss by the fourth decade of life. The identification and characterization of the clinical course of patients with RPE65 mutations is important in preparation for future trials of gene therapy for retinal degeneration.

Keywords: candidate gene analysis • genetics • retinal degenerations: hereditary