In-Depth Review Ocular Features in Alport Syndrome: Pathogenesis and Clinical Significance

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result in absenceof the collagen IVa3a4a5network fromthebasementmembranesof the cornea, lens capsule, and retinaand are associatedwith corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning. Typically, these features do not affect vision or, in the case of lenticonus, are correctable. In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giantmacular hole, andmaculopathy all produce visual loss. Many of the ocular features of Alport syndrome are common, easily recognizable, and thus, helpful diagnostically, and in identifying the likelihood of early-onset renal failure. Lenticonus and central fleck retinopathy strongly suggest the diagnosis ofAlport syndromeand are associatedwith renal failure before the age of 30 years, inmaleswith X-linked disease. Sometimes, ophthalmic features suggest the mode of inheritance. A peripheral retinopathy in the mother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a female means that recessive disease is likely. Ocular examination, retinal photography, and optical coherence tomography are widely available, safe, fast, inexpensive, and acceptable to patients. Ocular examination is particularly helpful in the diagnosis of Alport syndrome when genetic testing is not readily available or the results are inconclusive. It also detects complications, such as macular hole, for which new treatments are emerging. Clin J Am Soc Nephrol 10: 703–709, 2015. doi: 10.2215/CJN.10581014 Introduction Alport syndrome is characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities affecting the cornea, lens, and retina (1,2). Corneal scarring, temporal retinal thinning, giant macular hole, and maculopathy are recently described features that extend the ophthalmic phenotype (Figures 1–3) (3–7). Alport syndrome affects at least one in 10,000 individuals, and the diagnosis is important because of the risk of disease in other family members; also, early treatment with angiotensin-converting enzyme inhibitors delays the onset of end stage renal failure (8,9). Inheritance of Alport syndrome is X-linked in nearly all families (85%), and mutations affect the COL4A5 gene, which codes for the collagen IV a5-chain (10,11). The diagnosis of X-linked Alport syndrome is often overlooked, especially in women, who are affected three times as often as men. Inheritance in the other 15% of Alport families is autosomal recessive with homozygous or compound heterozygous mutations in trans in the COL4A3 or COL4A4 gene, which corresponds to the collagen IV a3or a4-chain (12,13). The occurrence of an autosomal dominant form of Alport syndrome is controversial. Thin basement membrane nephropathy represents the carrier state for autosomal recessive Alport syndrome, and affected individuals have a heterozygous COL4A3 or COL4A4 mutation (13,14) but no ocular or other extrarenal abnormalities (15). The characteristic ocular features of Alport syndrome are corneal opacities, anterior lenticonus and cataract, central perimacular and peripheral coalescing fleck retinopathies, and temporal retinal thinning. Rarely, posterior polymorphous corneal dystrophy, a macular hole, or a maculopathy impairs vision. Lenticonus, corneal dystrophy, central and peripheral fleck retinopathies, temporal retinal thinning, and giant macular hole are all highly suspicious for the diagnosis of Alport syndrome. Biochemistry of Collagen Type IV Collagen IV is the most abundant protein found in basement membranes and is responsible for the membrane’s strength and integrity. It also contributes to many biologic functions through its interactions with other proteins and cells (16). Collagen IV occurs as three heterotrimers (a1a1a2, a3a4a5, and a5a5a6) that form distinct networks (17). Individual chains have an intermediate collagenous sequence with glycine as every third amino acid, because it is the only residue small enough to fit inside the collagen helix. The collagen IV a1a1a2 network predominates in embryonic membranes and the adult vasculature. It is replaced by the a3a4a5 network in the adult glomerulus (glomerular basement membrane), cochlea (stria vascularis), cornea (Descemet’s and Bowman’s membranes) (18), lens capsule, and retina (inner limiting membrane and Bruch’s membrane) (19), and by the a5a5a6 network in the skin (17). *Department of