Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Abstract

Importance: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported.

Objective: To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations.

Design, setting, and participants: A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years.

Main outcomes and measures: Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients.

Results: There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses.

Conclusions and relevance: This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

Figure 1.. Composite of Retinal Imaging From the Left Eyes of Patients With Late-Onset CLN3-Associated Rod-Cone Dystrophy

Imaging from each patient includes color fundus photograph (first panel), fundus autofluorescence (second and third panels), and en face infrared image (fourth panel) demarcating the horizontal optical coherence tomography scan line (fifth panel).

Figure 2.. Composite of Retinal Imaging From the Left Eyes of Patients With Early-Onset CLN3-Associated Rod-Cone Dystrophy

Imaging from each patient includes color fundus photograph (first panel), fundus autofluorescence (second and third panels), and en face infrared image (fourth panel) demarcating the horizontal optical coherence tomography scan line (fifth panel). No color fundus photograph was able to be obtained for patient MEH5 (first panel).

Figure 3.. Full-Field Electroretinograms

Results of full-field electroretinograms under dim scotopic (dark-adapted [DA] 0.01; first panel), bright scotopic (DA 10.0; second panel), photopic flicker (light-adapted [LA] 3.0, 30 Hz; third panel), and photopic single flash (LA 3.0; fourth panel) intensities. Results for patient MEH4 shown from testing performed in his late 30s and 5 years later.

Figure 4.. Electron Microscopy (EM) of Peripheral Lymphocytes

A, A patient with CLN3-associated juvenile neuronal ceroid lipofuscinosis (JNCL). Left and middle panels, Classic EM findings in a patient with CLN3-associated JNCL with foamy vacuoles (yellow arrowheads) and lysosomal storage material forming fingerprint profile structures (blue arrowheads). Right panel, Fingerprint profiles in sagittal (blue arrowheads) and coronal cuts (yellow arrowheads), observed at a high magnification. B, Patient MEH4. The classic EM findings associated with CLN3-associated JNCL were not observed in patient MEH4, who had unremarkable lymphocytes except for the occasional large empty vacuoles (arrowheads). C, Patient CEI1. Classic JNCL findings were also absent in patient CEI1, who had unremarkable-appearing lysosomes (yellow arrowheads) and occasional vacuoles (blue arrowheads) without accumulation of storage material.

Figure 5.. CLN3 Mutations Associated With Isolated Retinal Degeneration

A, CLN3 mutations observed in isolated retinal degeneration in the current series of 10 patients (above) and in the literature (below). Intronic mutations are indicated in green, missense mutations in blue, and truncation mutations in red. Mutations associated with isolated retinal degeneration observed in this series. B, CLN3 mutations associated with isolated retinal degeneration (left panel) compared with juvenile neuronal ceroid lipofuscinosis (JNCL; right panel). Multiple mutations associated with isolated retinal degenerations (left) are in the fifth transmembrane domain compared with more mutations associated with JNCL (right) in the luminal loops. Adapted with permission from Cotman et al (Taylor & Francis Ltd; www.tandfonline.com). ^aMutations also associated with patients with CLN3-associated JNCL with neurological symptoms.