Clinical, Ophthalmic, and Genetic Characterization of RPGRIP1-Associated Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy

• Published in: American journal of ophthalmology 2024-10, Vol.266, p.255-263
• Main Authors: Daich Varela, Malena, Jeste, Mrunmayi, de Guimaraes, Thales A.C., Mahroo, Omar A., Arno, Gavin, Webster, Andrew R., Michaelides, Michel
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Child; Child, Preschool; Cross-Sectional Studies; Cytoskeletal Proteins - genetics; DNA Mutational Analysis; Electroretinography; Eye Diseases, Hereditary; Female; Fluorescein Angiography - methods; Humans; Infant; Leber Congenital Amaurosis - diagnosis; Leber Congenital Amaurosis - genetics; Leber Congenital Amaurosis - physiopathology; Male; Mutation; Proteins - genetics; Retinal Dystrophies - diagnosis; Retinal Dystrophies - genetics; Retinal Dystrophies - physiopathology; Retrospective Studies; Tomography, Optical Coherence; Visual Acuity - physiology; Young Adult
• ISSN: 0002-9394; 1879-1891; 1879-1891
• DOI: 10.1016/j.ajo.2024.05.007

To present the clinical characteristics, retinal features, natural history, and genetics of RPGRIP1-associated early-onset severe retinal dystrophy (EOSRD)/Leber congenital amaurosis (LCA). Retrospective case series. Review of clinical notes, multimodal retinal imaging, and molecular diagnosis of 18 patients (17 families) with EOSRD/LCA and disease-causing variants in RPGRIP1. The mean age of visual symptoms onset was 0.87 ± 1 year (birth to 3 years), and the mean age at baseline visit was 11.4 ± 10.2 years (1-39 years). At the baseline visit, 44% of patients were legally blind (range, 2-39 years), and there was no significant association found between age and best-corrected visual acuity (BCVA) in cross-sectional analysis. Retinal evaluation showed an abolished electroretinogram or a cone-rod dystrophy pattern, no or minimal pigment deposits, a hyperautofluorescent ring at the posterior pole, and a largely preserved central macular architecture, with retained outer nuclear layer and ellipsoid zone island into adulthood. Eleven variants (48%) were previously unreported, and 13 families (76%) had a double-null (DN) genotype. Twelve patients (67%) had follow-up assessments over a 15.7 ± 9.5-year period. The rate of BCVA decline was 0.02 logarithm of the minimum angle of resolution (1 letter)/year. RPGRIP1 EOSRD/LCA often presents at birth or early infancy, with nystagmus, decreased visual acuity, hyperopia, and photophobia. Patients with a DN genotype may develop symptoms earlier and have worse vision. Multimodal imaging may show a hyperautofluorescent posterior pole ring and relatively preserved central macular architecture, suggesting that the condition is a promising candidate for gene supplementation.