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Published on: April 19, 2012
Genetic Reasons for Phenotypic Diversity in Neuronal Ceroid Lipofuscinoses and High-Resolution Imaging as a Marker of
Jennifer Huey1, Pankhuri Gupta2, Benjamin Wendel1
1Department of Ophthalmology and Roger and Karalis Johnson Retina Center, University of Washington, Seattle, Washington.
Insights
Neuronal ceroid lipofuscinosis (NCL) shows diverse retinal disease phenotypes driven by genetic variants. Advanced imaging like adaptive optics scanning laser ophthalmoscopy and optoretinography can track early retinal changes for future NCL therapies.
Area of Science:
- Ophthalmology
- Genetics
- Neurology
Background:
- Neuronal ceroid lipofuscinoses (NCL) are a group of rare genetic disorders.
- These disorders are characterized by progressive neurodegeneration and vision loss.
- NCL-associated retinal disease presents a spectrum of clinical manifestations.
Purpose of the Study:
- To delineate the clinical characteristics, natural history, genetic landscape, and phenotypic spectrum of NCL-associated retinal disease.
- To investigate the genotypic-phenotypic correlations in pediatric subjects with NCL.
Main Methods:
- A multicenter retrospective cohort study with a cross-sectional examination.
- Analysis included clinical notes, retinal imaging, electroretinography (ERG), and molecular genetic testing.
- Advanced imaging techniques such as adaptive optics scanning laser ophthalmoscopy and optoretinography (ORG) were utilized in a subset of subjects.
Main Results:
- Twelve pediatric subjects with biallelic variants in five NCL-causing genes (CLN3, CLN6, MFSD8, PPT1, TPP1) were studied.
- Phenotypes ranged from severe neurocognitive features to nonsyndromic retinal dystrophies.
- Electronegative ERG traces indicated early cone dysfunction, and outer retinal loss varied by genotype.
Conclusions:
- Genetic variants are key drivers of phenotypic diversity in NCL-associated retinal disease.
- Genetic testing is crucial for diagnosis, management, and family support.
- High-resolution imaging (adaptive optics, ORG) shows promise for monitoring disease progression and evaluating therapeutic efficacy for emerging treatments like intravitreal enzyme replacement therapy.
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 Disclosures:
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
