Clinical Characterization, Natural History, and Detailed Phenotyping of NMNAT1-Associated Leber Congenital Amaurosis

Purpose

To characterize the clinical phenotype and disease progression in patients with NMNAT1-associated Leber congenital amaurosis (LCA) within the Korean population.

Design

Retrospective, observational case series.

Subjects

Fourteen patients with LCA with biallelic variants of NMNAT1 at a single tertiary referral center.

Methods

Electronic medical records were reviewed for medical history, ophthalmic examinations, and molecular diagnoses, both cross-sectionally and longitudinally.

Main Outcome Measures

Ophthalmic examination findings were evaluated and retinal phenotypic characteristics were assessed using multimodal imaging.

Results

All patients exhibited early-onset, rapidly progressive bilateral retinal degeneration with pronounced central involvement. The condition was characterized by multiple atrophic lesions that coalesced into a large central retinal scar by age 2. The condition stabilized around 4 years of age. Fluorescein angiography demonstrated central hypofluorescence with visible choroidal vasculature. Optical coherence tomography showed significant retinal thinning, outer retinal layer disruption, and retinal pigment epithelial atrophy. Most patients maintained light perception vision or better, with minimal deterioration of visual acuity after the age of 2. All patients were hyperopic and exhibited undetectable electroretinography and visual-evoked potential responses.

Conclusions

NMNAT1-associated LCA is characterized by severe, early-onset retinal degeneration with rapid progression, followed by stabilization. This distinct temporal pattern of disease progression suggests a potential therapeutic window in early childhood, emphasizing the importance of early diagnosis and regular monitoring for potential interventions.