Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease)

Abstract

Juvenile neuronal ceroid lipofuscinosis (JNCL; also known as CLN3 disease) is a devastating neurodegenerative lysosomal storage disorder and the most common form of Batten disease. Progressive visual and neurological symptoms lead to mortality in patients by the third decade. Although ceroid-lipofuscinosis, neuronal 3 (CLN3) has been identified as the sole disease gene, the biochemical and cellular bases of JNCL and the functions of CLN3 are yet to be fully understood. As severe ocular pathologies manifest early in disease progression, the retina is an ideal tissue to study in the efforts to unravel disease etiology and design therapeutics. There are significant discrepancies in the ocular phenotypes between human JNCL and existing murine models, impeding investigations on the sequence of events occurring during the progression of vision impairment. This review focuses on current understanding of vision loss in JNCL and discusses future research directions toward molecular dissection of the pathogenesis of the disease and associated vision problems in order to ultimately improve the quality of patient life and cure the disease.

Keywords: CLN3; juvenile neuronal ceroid lipofuscinosis; ocular pathologies; retina; vision loss.

Figure 1

Fundoscopy of JNCL patient eyes. (A) Posterior pole of the left eye of an 8-year-old female JNCL patient with the common 1 kb deletion showing bull’s eye maculopathy, attenuated vessels, and pale optic discs. Reproduced, with permission, from Ref. . (B) Angiogram with diffuse stippled hyperfluorescence in the eye of a 9-year-old JNCL patient. Reproduced, with permission, from Ref. .

Figure 2

Fluorescence microscopy of far peripheral retina with 4′,6′-diamidino-2-phenylindole (DAPI)-stained nuclei (in blue) showing reduced RPE autofluorescence and retinal degeneration in JNCL. (A) Healthy control and (C) JNCL retinal sections treated with no primary antibody. Yellow: autofluorescent lipofuscin granules; arrowheads: ganglion cells. (B) Healthy control and (D&E) JNCL retinal sections labeled with anti-rhodopsin (in red). Arrowheads: retained rhodopsin⁺ rods; the one in (E) has a long, beaded neurite. Reproduced, with permission, from Ref. . Abbreviations: C, choroid; RPE, retinal pigment epithelium; O, outer nuclear layer; N, inner nuclear layer; IS, rod inner segments; OS, rod outer segments; G, ganglion cell layer.

Figure 3

Electron micrographs of retinal ganglion cells containing inclusions with (A) curvilinear and (B&C) fingerprint features. (A) An inclusion found in a JNCL patient ganglion cell with trilaminar membranes (arrows), some of them arranged in a curvilinear fashion (arrowheads) surrounded by a trilaminar unit membrane (×31,000). (B) A rare fingerprint body found in the cytoplasm of a JNCL patient ganglion cell (×51,000). A and B are reproduced, with permission, from Ref. . (C) Perinuclear inclusions with fingerprint profiles are abundant in the cytoplasm of a retinal ganglion cell from a 10-month-old Cln3^Δex7/8 homozygous mouse. Reproduced, with permission, from Ref. .

Figure 4

ISCEV standard ERGs of three JNCL patients. The tracings from each patient’s right and left eyes are shown in black. The tracings in red are for normal subjects of the same age range. Reproduced, with permission, from Ref. .