Ocular features in Alport syndrome: pathogenesis and clinical significance

Abstract

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 absence of the collagen IV α3α4α5 network from the basement membranes of the cornea, lens capsule, and retina and are associated with 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, giant macular hole, and maculopathy 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 of Alport syndrome and are associated with renal failure before the age of 30 years, in males with 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.

Keywords: Alport syndrome; extracellular matrix; genetic renal disease.

Figure 1.

Collagen IV molecule—location and nature of mutations causing X-linked Alport syndrome.

Figure 2.

Corneal abnormalities. (A) Mild scarring caused by recurrent corneal erosions shown on slit-lamp examination in a man with X-linked Alport syndrome (arrow), renal failure, and perimacular retinopathy. The patient’s mother is also affected with renal disease and similar corneal changes. (B) Posterior polymorphous corneal dystrophy (arrow) with diffuse and vesicular lesions posteriorly at the level of Descemet’s membrane on slit-lamp examination in a man with X-linked Alport syndrome, renal failure, lens replacement for lenticonus, and perimacular retinopathy. (C) A slit-lamp view of posterior polymorphous corneal dystrophy showing the characteristic doughnut-like vesicles posteriorly (arrow). (D) Specular microscopy of the corneal endothelium in the patient in C showing that the doughnut-like lesions are vesicles with thick dark borders around clusters of endothelial cells (arrow).

Figure 3.

Lens abnormalities. (A) Lenticonus appearance on slit-lamp examination showing an anterior dimple or oil droplet (arrow) in a man with X-linked Alport syndrome, renal impairment, and posterior polymorphous corneal dystrophy. The oil droplet is also obvious on direct ophthalmoscopy. (B) Anterior segment view showing the anterior bulging of the lens (arrows) with a Scheimpflug camera (Pentacam) in the patient from A. (C) Electron microscopy of an anterior lens capsule obtained at surgery showing the thinned capsule (arrow) and vertical tears (upper panel) compared with normal (arrow in lower panel). The abnormal lens was from a man with X-linked Alport syndrome, renal failure, lenticonus, and retinopathy.

Figure 4.

Retinal abnormalities. (A) Central or perimacular fleck retinopathy sparing the foveola and located principally in the temporal retina (arrow) in a man with X-linked Alport syndrome, renal failure, and lenticonus. (B and C) Perimacular fleck retinopathy in a woman with X-linked Alport syndrome, renal impairment, and hearing loss (arrows). The flecks are pronounced in the temporal retina. They are more obvious and can be distinguished from the normal retinal sheen on the redfree image (arrows). (D and E) Peripheral coalescing fleck retinopathy in a woman with X-linked Alport syndrome, normal renal function, and hearing loss. The flecks are >2 disc diameters from the foveola and more obvious on the redfree image (arrows). (F) Peripheral retinopathy with widespread evenly distributed retinal flecks (arrows) in an ultrawide field scan (Optos camera) in a man with X-linked disease. The lozenge and central fleck retinopathy are not obvious in this view. (G) Pigment disturbance with bull’s eye maculopathy. There is a ring of hypopigmentation with central hyperpigmentation in a woman with X-linked Alport syndrome, renal impairment, and peripheral retinopathy (arrow). (H) Lozenge from temporal extension of the normal round foveolar reflex (arrow) caused by retinal thinning in a man with X-linked Alport syndrome, renal failure, hearing loss, lenticonus, and perimacular fleck retinopathy. (I) Temporal retinal thinning seen on a cross-section of the retina from a man with X-linked Alport syndrome, renal failure, and hearing loss. (J) Temporal thinning confirmed in the patient from I indicating that the temporal thickness is in the <5th percentile (red). (K–N) Retinal shadow suggesting (K) macular hole in a woman with autosomal recessive Alport syndrome, hearing loss, and lenticonus. (L) The holes are more obvious on a black and white image of the macula and temporal retina. (M) The lamellar holes are confirmed with three well demarcated areas of thinning seen on optimal coherence tomography (OCT) (<200-µm thick). (N) These correspond to three areas of lamellar thinning on OCT. (O) Full-thickness giant macular hole in a woman with Alport syndrome and renal failure.