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 [CLN3], CLN6 transmembrane ER protein [CLN6], Major facilitator superfamily domain containing 8 [MFSD8], Palmitoyl-protein thioesterase 1 ([PPT1], and tripeptidyl peptidase 1 [TPP1]).

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 CLN3-juvenile NCL (n = 3), TPP1-late infantile NCL (n = 5), PPT1-late infantile or juvenile NCL (n = 2), CLN6-infantile NCL (n = 1), and CLN7/MFSD8-late infantile NCL (n = 1). Five novel pathogenic or likely pathogenic variants were identified. Age at presentation ranged from 2 to 16 years old (mean 7.9 years). Subjects presented with varying phenotypes ranging from severe neurocognitive features (n = 8; 67%), including seizures and developmental delays and regressions, to nonsyndromic retinal dystrophies (n = 2; 17%). Visual acuities at presentation ranged from light perception to 20/20. In those with recordable ERGs, the traces were electronegative and suggestive of early cone dysfunction. Fundus imaging and OCTs demonstrated outer retinal loss that varied with underlying genotype. High-resolution adaptive optics imaging and functional measures with ORG in 2 subjects with atypical TPP1-associated disease revealed significantly different phenotypes of cellular structure and function that could be followed longitudinally.

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 Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.