Genetics and therapy for pediatric eye diseases

Abstract

Ocular morphogenesis in vertebrates is a highly organized process, orchestrated largely by intrinsic genetic programs that exhibit stringent spatiotemporal control. Alternations in these genetic instructions can lead to hereditary or nonhereditary congenital disorders, a major cause of childhood visual impairment, and contribute to common late-onset blinding diseases. Currently, limited treatment options exist for clinical phenotypes involving eye development. This review summarizes recent advances in our understanding of early-onset ocular disorders and highlights genetic complexities in development and diseases, specifically focusing on coloboma, congenital glaucoma and Leber congenital amaurosis. We also discuss innovative paradigms for potential therapeutic modalities.

Keywords: Congenital disorders; Eye organogenesis; Ocular diseases; Retinal development; Therapy; Vision impairment.

Fig. 1

Cross-sectional images of the human eye (A) and the light-sensitive retina (B). (C) Development of the human eye. Eye field specification starts at around three weeks gestation in the anterior neural plate, followed by the formation of optic vesicle, lens, cornea and retina at various stages. ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer.

Fig. 2

Etiology and phenotypes of pediatric eye diseases. (A) Coloboma. Optic fissure closure defects affecting the formation of the optic nerve (upper) and iris (lower) as shown by graphic illustration (left), clinical images (middle) and fundus images (right). The blue circles and arrows highlight the approximate location of the optic fissure closure defects in the eye. In the upper panel, there is colobomatous enlargement of the optic nerve without iris involvement. In contrast, both the iris and the retina are impacted in the lower panel. (B) Congenital glaucoma. Increased intraocular pressure causes corneal enlargement with splits in Descemet's membrane. Also present are a detached posterior embryotoxon (white arrow) and irido-corneal adhesions (middle and right). (C) Leber congenital amaurosis (LCA) is characterized by dysfunction or loss light-sensitive photoreceptors. In this patient, the death of photoreceptors is caused by a loss-of-function mutation of RPE65 leading to visual cycle defect in the retinal pigment epithelium. White arrows in the fundus images (middle and right) indicate the affected regions.