Histopathology and Functional Correlations in a Patient with a Mutation in RPE65, the Gene for Retinol Isomerase

Leber congenital amaurosis (LCA) comprises a group of genetic disorders in which visual loss or dysfunction is present at birth. Patients typically have hyperopia and nystagmus and reduced electroretinograms (ERGs). The extent of visual loss varies from patient to patient but is usually severe. Mutations have been identified in 15 genes in persons with LCA, each of which is a recessive disorder.1,2 Mutations in the RPE65 gene account for approximately 7% of LCA. RPE65 is uniquely expressed in the retinal pigment epithelium (RPE), where the protein, an enzyme, binds and converts all-trans retinyl ester to 11-cis retinol.3–5 Retinol isomerization is an essential enzymatic step required for functional vision to occur in rod and cone photoreceptors.6,7 More than 60 mutations in the RPE65 gene have been documented in LCA patients. Mutations have been reported in each of the 14 exons of the RPE65 gene and its boundaries.8–14 Typically, mutations in the RPE65 gene result in impaired vision from birth and typically progress to legal blindness in the third decade of life.9,11,12,15,16 Mutations in RPE65 do not necessarily result in early loss of photoreceptors. For example, studies of dog retinas with a naturally occurring RPE65 mutation and mouse retinas that are missing the RPE65 gene show structurally intact photoreceptors visible by optical coherence tomography that appear nonfunctional because of the inability of the RPE to generate 11-cis retinal. The sparing of photoreceptors has allowed RPE65 gene replacement therapy to restore this critical retinol isomerase activity to the RPE with the accompanying restoration of visual function.17,18 In this report we describe the pathology and clinical findings in a woman with a homozygous mutation (Ala132Thr) in the RPE65 gene.12 Unlike most persons with RPE65 mutations, this patient retained some vision into her early fifties. To our knowledge this is the first study of adult postmortem donor eyes from a patient with a homozygous recessive mutation in the RPE65 gene.