Huey Jennifer, Gupta Pankhuri, Wendel Benjamin, Liu Teng, Bharadwaj Palash, Schwartz Hillary, Kelly John P, Chang Irene, Chao Jennifer R, Sabesan Ramkumar, Nagiel Aaron, Mustafi Debarshi
Department of Ophthalmology and Roger and Karalis Johnson Retina Center, University of Washington, Seattle, Washington.
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.
Ophthalmol Sci. 2024 May 29;4(6):100560. doi: 10.1016/j.xops.2024.100560. eCollection 2024 Nov-Dec.
To describe the clinical characteristics, natural history, genetic landscape, and phenotypic spectrum of neuronal ceroid lipofuscinosis (NCL)-associated retinal disease.
Multicenter retrospective cohort study complemented by a cross-sectional examination.
Twelve pediatric subjects with biallelic variants in 5 NCL-causing genes (CLN3 lysosomal/endosomal transmembrane protein [], CLN6 transmembrane ER protein [], Major facilitator superfamily domain containing 8 [], Palmitoyl-protein thioesterase 1 ([], and tripeptidyl peptidase 1 []).
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).
Clinical/demographic data, multimodal retinal imaging data, electrophysiology parameters, and molecular genetic testing.
Our cohort included a diverse set of subjects with -juvenile NCL (n = 3), -late infantile NCL (n = 5), -late infantile or juvenile NCL (n = 2), -infantile NCL (n = 1), and /-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 -associated disease revealed significantly different phenotypes of cellular structure and function that could be followed longitudinally.
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.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
描述神经元蜡样脂褐质沉积症（NCL）相关视网膜疾病的临床特征、自然病史、基因图谱和表型谱。
多中心回顾性队列研究，并辅以横断面检查。
12名患有5种NCL致病基因双等位基因变异的儿科患者（CLN3溶酶体/内体跨膜蛋白[]、CLN6跨膜内质网蛋白[]、含主要易化子超家族结构域8[]、棕榈酰蛋白硫酯酶1[]和三肽基肽酶1[]）。
回顾临床记录、视网膜成像、视网膜电图（ERG）和分子基因检测。两名患者接受了横断面检查，包括视网膜自适应光学扫描激光检眼镜成像和视视网膜电图（ORG）。
临床/人口统计学数据、多模态视网膜成像数据、电生理参数和分子基因检测。
我们的队列包括一组多样化的患者，其中青少年型NCL（n = 3）、晚婴儿型NCL（n = 5）、晚婴儿型或青少年型NCL（n = 2）、婴儿型NCL（n = 1）和/-晚婴儿型NCL（n = 1）。鉴定出5种新的致病或可能致病变异。发病年龄范围为2至16岁（平均7.9岁）。患者表现出不同的表型，从严重的神经认知特征（n = 8；67%），包括癫痫发作、发育迟缓和倒退，到非综合征性视网膜营养不良（n = 2；17%）。就诊时的视力范围从光感至20/20。在ERG可记录的患者中，波形为电阴性，提示早期视锥细胞功能障碍。眼底成像和光学相干断层扫描显示外层视网膜缺失，其因潜在基因型而异。对2例非典型相关疾病患者进行的高分辨率自适应光学成像和ORG功能测量显示，细胞结构和功能的表型存在显著差异，可进行纵向跟踪。
我们的队列数据表明，潜在的基因变异驱动了不同形式NCL的表型多样性。基因检测可提供分子诊断，并确保为儿童及其家庭提供适当的疾病管理和支持。随着玻璃体内酶替代疗法即将成为NCL相关视网膜变性的潜在治疗选择，将需要精确的结构和功能测量来更准确地监测疾病进展。我们表明，自适应光学成像和ORG可作为高度敏感的方法来跟踪早期视网膜变化，这可用于确定未来治疗的 eligibility，并提供在细胞水平上确定干预效果的指标。
本文末尾的脚注和披露中可能会发现专有或商业披露信息。
