Genetic Reasons for Phenotypic Diversity in Neuronal Ceroid Lipofuscinoses and High-Resolution Imaging as a Marker of Retinal Disease.

Purpose: To describe the clinical characteristics, natural history, genetic landscape, and phenotypic spectrum of neuronal ceroid lipofuscinosis (NCL)-associated retinal disease. Design: Multicenter retrospective cohort study complemented by a cross-sectional examination. Subjects: Twelve pediatric subjects with biallelic variants in 5 NCL-causing genes (CLN3 lysosomal/endosomal transmembrane protein [ Methods: Review of clinical notes, retinal imaging, electroretinography (ERG), and molecular genetic testing. Two subjects underwent a cross-sectional examination comprising adaptive optics scanning laser ophthalmoscopy imaging of the retina and optoretinography (ORG). Main Outcome Measures: Clinical/demographic data, multimodal retinal imaging data, electrophysiology parameters, and molecular genetic testing. Results: Our cohort included a diverse set of subjects with Conclusions: Our cohort data demonstrates that the underlying genetic variants drive the phenotypic diversity in different forms of NCL. Genetic testing can provide molecular diagnosis and ensure appropriate disease management and support for children and their families. With intravitreal enzyme replacement therapy on the horizon as a potential treatment option for NCL-associated retinal degeneration, precise structural and functional measures will be required to more accurately monitor disease progression. We show that adaptive optics imaging and ORG can be used as highly sensitive methods to track early retinal changes, which can be used to establish eligibility for future therapies and provide metrics for determining the efficacy of interventions on a cellular scale. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.