Alport syndrome and eye
Article information
Abstract
Alport syndrome, characterized by renal failure, hearing loss, and ocular abnormalities due to collagen type IV gene mutations, exhibits distinctive ocular manifestations in the various ocular tissues including the cornea, lens, and retina. Ophthalmological examinations, providing noninvasive visibility of basement membrane anomalies caused by collagen type IV mutations, can have a role in Alport syndrome diagnostics. Lenticonus, macular fleck, and other abnormalities also can serve as indicators of inheritance patterns and predictors of severe mutations or early-onset renal failure. Recognizing these manifestations in advance enables timely surgical intervention, potentially improving long-term visual outcomes. This review highlights the ocular features in Alport syndrome and contributes to the understanding of the relationships among ocular abnormalities as well as the genotype-phenotype correlations in Alport syndrome. In these ways, hopefully, it will guide further research and help to inform the development of clinical strategies.
Introduction
Alport syndrome is a disease characterized by progressive renal failure, sensorineural hearing loss, and distinctive ocular abnormalities. This disease is mostly inherited in an X-linked pattern, but in about 15%, it is inherited in an autosomal-recessive or autosomal-dominant manner [1]. The prevalence of ocular abnormalities in Alport syndrome varies depending on the study or inheritance, but it is known that approximately 11% to 92% of Alport syndrome patients show ocular abnormalities [2]. Specific abnormalities could reflect inheritance or be a predictive factor for early-onset renal failure [1].
Therefore, this review aims to introduce the mechanism by which specific ocular features occur in Alport syndrome and the various types of ocular abnormalities, and further demonstrate the genotype-phenotype correlation. We discuss in detail how to use ocular abnormalities in clinical practice when managing Alport syndrome patients.
Pathophysiology: why do ocular abnormalities often accompany Alport syndrome?
In Alport syndrome, mutations in the collagen type IV genes cause abnormalities in the collagen α3α4α5 network, which plays an important role in the structuring of the basement membrane. Like the kidney’s glomerular basement membrane, there are several types of ocular basement membrane containing the collagen type IV α3α4α5 network. These include Bowman’s membrane and Descemet’s membrane in the cornea, the anterior capsule of the lens, and the internal limiting membrane (ILM) and Bruch’s membrane in the retina (Fig. 1). As a result, many Alport syndrome patients have various accompanying ocular abnormalities.
Various basement membrane structures of the eye and Alport syndrome.
Ocular manifestations
Cornea
Corneal epithelial cells are attached to the Bowman’s membrane through adhesion complexes composed of hemidesmosomes, the lamina densa and the lamina lucida, anchoring fibrils, laminin, fibronectin, and type IV and VII collagen [3]. Damaged type IV collagen in Alport syndrome prevents corneal epithelial cells from properly adhering, causing repetitive epithelial cell loss on the corneal surface, which is the mechanism of recurrent corneal erosion (RCE). In RCE, which occurs in less than 10% of Alport syndrome cases [4], patients complain mainly of ocular pain, redness, photophobia, and excessive tearing. It is especially characteristic that symptoms frequently occur when they open their eyes in the morning [5]. Corneal erosions in their various morphologies such as a loosely adherent epithelium, fluorescein-stained epithelial defect, or corneal infiltrations, can be revealed on slit-lamp examinations.
Posterior polymorphous corneal dystrophy (PPCD), a much rarer complication than RCE, manifests as structural defects in Descemet’s membrane resulting in endothelial cell death or a multilayered endothelial cell form [6]. Diagnosis can be made by observing isolated or coalescent vesicles in the posterior cornea under slit-lamp examination, specular microscopy, or anterior-segment optical coherence tomography (OCT). In most cases, patients are asymptomatic and their visual acuities remain good, though grittiness and/or photophobia may arise.
Another reported complication of Alport syndrome is keratoconus [7,8]. As with PPCD, it has been suggested that abnormalities in Descemet’s membrane may cause this disease. Chugh et al. [9] reported that 6.7% of Alport syndrome patients showed keratoconus-like corneal morphology.
Lens
The lens capsule is a specialized thickened basement membrane, and one of the components of which is collagen type IV [10]. As the lens capsule plays a role in maintaining the shape of the lens, a defective capsule lacking the α3α4α5 network naturally becomes weak. The lens capsule is the basement membrane for the epithelial cells at the front of the lens. Therefore, lens changes occurring in the anterior part of lens can cause the capsule to protrude forward and stretch, thus forming lenticonus in Alport syndrome. Anterior lenticonus, in which the front part of the capsule is stretched, is more common; and in rarer cases, posterior lenticonus also has been reported [11–13].
Anterior lenticonus can be diagnosed by observing the protrusion of the front part of the lens for the “drop of oil in water” shape under slit-lamp examination [14]. Patients might complain of decreased vision due to the changed lens curvature. Additionally, as lenticonus progresses, capsule rupture may occur, and in the process of healing, cataracts can form [15]. Lenticonus is frequently observed in X-linked male or autosomal-recessive Alport syndrome patients after the onset of renal failure [1]. Therefore, if lenticonus is present in a female patient, diagnosis of autosomal-recessive inheritance will be helpful.
Retina
The retina is made up of more than 10 layers, each of which is composed of different cells or tissues [16]. Among them, the α3α4α5 network is a component of the ILM, which is the basal membrane located at the vitreoretinal junction, the innermost part of the retina, and the Bruch’s membrane to which the retinal pigment epithelium is attached [17]. In Alport syndrome, these membranes may become thinner, developing granularity, or deformed, causing functional damage to cells to which they are originally attached, resulting in characteristic retinal changes.
Dot-and-fleck retinopathy is caused by granular changes in the ILM [18] and can be present in the central or perimacular area of the retina [19]. On fundus photography, whitish-yellow dots appear scattered or form an annular band around the fovea (Fig. 2A). Also, on OCT, hyperreflective particles are observed close to the vitreoretinal junction. Dot-and-fleck retinopathy does not affect vision, and in most cases, patients do not complain of any symptoms [17]. It is observed in more than 50% of X-linked males and autosomal-recessive patients and is also a predictive factor for early-onset renal failure [20].
Retinal abnormalities.
(A) Central fleck retinopathy sparing the foveola and located principally in the temporal retina (black arrowheads). (B) Peripheral retinopathy with widespread evenly distributed retinal flecks (white arrowheads) in an ultrawide field scan. (C) Lamellar macular holes (white boxes) as confirmed on optical coherence tomography (OCT) examination. (D) Temporal retinal thinning (white arrows) seen on the cross-section of macular OCT.
Peripheral retinopathy is the most common retinal sign of Alport syndrome. Most X-linked male and autosomal-recessive patients, along with 32% of X-linked female patients, show peripheral retinopathy [21]. Whitish-yellow dots form an asymmetric patch or coalescent pattern (Fig. 2B). Considering that the dots are located beneath the retinal blood vessels on fluorescein angiography, abnormalities in the Bruch’s membrane are possible origins [22].
Temporal retinal thinning refers to a phenomenon in which the temporal area of the macula becomes thinner than normal. It is caused mainly by the thinning of the ILM and the adjacent nerve fiber layer and inner nuclear layer, though in some patients, Bruch’s membrane also becomes thinner [17]. Although the thickness of the retina decreases, findings such as loss of a specific constituent layer are not observed [23]. OCT remains the gold standard for diagnosis of retinal thinning (Fig. 2C); however, retinal “lozenge” or dull macular reflex observed on fundus photography also can be useful diagnostic signs. Temporal retinal thinning alone does not affect vision in most cases. This can be helpful in diagnosing Alport syndrome because it occurs frequently in both autosomal-recessive and X-linked patients regardless of gender [24].
Macular hole or lamellar hole is another ocular abnormality that may accompany Alport syndrome. A number of theories on the pathogenesis of macular hole in Alport syndrome have been presented. Mete et al. [25] stated that Bruch’s membrane dysfunction might advance cystic cavities in the retina, and Ozdek et al. [26] suggested the possibility of a role for chronic hypertensive nephropathy accompanying Alport syndrome. However, as vitreoretinal surgery has been developed, it has become possible to surgically treat macular holes and obtain ILM tissue, leading to the emergence of the hypothesis that macular holes are caused by structural weakness of the ILM, which lacks type IV collagen [27]. Macular holes also can be identified on fundus photography, though full-thickness retinal defects identified on OCT afford easier diagnosis (Fig. 2D). Macular holes are rare complications the prevalence of which is difficult to predict. However, some patients diagnosed with macular hole have been found to already have renal insufficiency as well as other complications of Alport syndrome such as hearing loss and anterior lenticonus [27]. Therefore, the presence of macular hole can be considered a risk factor for severe mutations or early-onset renal failure, not to mention severe visual impairment.
In addition, abnormal macular pigmentation [14], vitelliform lesion [28], stair-case foveal sign, choroidal thinning [29], or retinal detachment [28] may occur as retinal manifestations in Alport syndrome patients.
Genotype and ocular phenotype correlations
Alport syndrome has X-linked, autosomal-recessive and autosomal-dominant inheritance. Mutations in the COL4A3 and COL4A4 genes result in autosomal-recessive or autosomal-dominant-type disease, and mutations in the COL4A5 gene cause X-linked disease [30].
In the case of the autosomal-dominant type, it is very rare for ophthalmologic abnormalities to be reported. According to Furlano et al. [31], ophthalmologic examinations performed on 75 of 270 patients revealed that only two patients had abnormalities, which were corneal erosion and corneal dystrophy, respectively. Colville et al. [32], having investigated four affected patients and nine carriers from two families, found no ocular abnormalities. Kharrat et al. [33] investigated 11 autosomal-dominant Alport syndrome patients and uncovered no ocular abnormalities.
In a study of X-linked Alport syndrome males conducted by Jais et al. [34], 57 of 162 patients (35.2%) showed ocular manifestations: lenticonus (13%), maculopathy (13.6%), both lenticonus and maculopathy (8.6%), and congenital or early-onset cataract (5.6%) (Table 1 [1,4,20,21,24,34–38]). Another interesting by Jais et al. [34] was that lenticonus was more likely to occur in patients with a large deletion or small mutation leading to a premature stop codon than in patients with a missense or splice site mutation. Kim et al. [39] reported similar results, in that the prevalence of ocular problems varied by genotype in a Korean population. In their truncating group, ocular problems were observed in 57.9% of patients, but in the non-truncating group, 4.2%, and in the abnormal splicing group, 36.4%, which findings confirmed that there were relatively few abnormalities.
Prevalence of ocular features and phenotype correlations
X-linked Alport syndrome females also have been reported to have ocular manifestations. According to Jais et al. [35], ocular abnormalities were observed in 15% of patients, most of which were macular flecks, but anterior lenticonus also was found in three patients. In another paper on X-linked Alport syndrome females, it was reported that among 22 patients, no lenticonus was observed, macular flecks were observed in four patients, and peripheral retinopathy was observed in seven patients [20]. Yamamura et al. [40] found that only four of 275 XLAS females (1.5%) showed ophthalmic abnormalities, and they speculated that this may have been due to the young median age of the study subjects.
In a systematic review of autosomal-recessive Alport syndrome, 17% of patients showed ocular manifestations [41]. Similarly to X-linked-type disease, the prevalence of ophthalmic abnormalities in autosomal-recessive-type disease varied by genotype: missense mutations showed a relatively low prevalence (6%) to the other genotypes (29%). Storey et al. [42] observed lenticonus or retinopathy in 56% of 40 patients, while Oka et al. [43] found that only 10% of 30 patients had ophthalmic abnormalities. Notably, the ocular abnormalities paper reported by Oka et al. [43] included those not specific to Alport syndrome, such as retinal degeneration and band-keratopathy.
According to Chen et al. [36], among four patients with autosomal-recessive type Alport syndrome, lenticonus was observed in three, central retinopathy in three, peripheral retinopathy in four, and macular hole in one. Nabais et al. [37] observed anterior lenticonus in three of 34 patients, maculopathy in eight of 41 patients, and cataract in eight of 31 patients. They reported, further, that ophthalmic abnormalities were observed more often in homozygous/compound heterozygous patients than in heterozygous patients. Wang et al. [20] observed lenticonus in 12 of 15 patients, and central and peripheral retinopathy in 13 patients, respectively. These conflicting prevalences across studies may be due to differences in the genotypes included in each study and/or differences in the median age of the study subjects. These various reports regarding ocular abnormalities all suggest that long-term observation is necessary in Alport syndrome.
Ocular examinations in the diagnosis of Alport syndrome
Due to the light transparency of the cornea and lens and the availability of noninvasive microscopic-level techniques, ophthalmological examinations make it possible to observe basement membrane abnormalities caused by type IV collagen mutation in Alport syndrome without biopsy.
Therefore, investigation for ocular abnormalities has an important clinical role in Alport syndrome. First, in the case of specific ocular manifestations, it facilitates inferring of inheritance prior to genetic testing and provides clues to severe mutations and the possibility of early-onset renal failure (Table 2 [1,2,4,14,20–22,24,25,27,29,34,36,39,41,44]). For example, lenticonus has been found to occur more frequently in the autosomal-recessive type and to manifest at a higher prevalence in severe mutations such as large deletions than in missenses. Second, if ocular manifestations affecting vision are detected in advance through ophthalmological examination, surgical treatment at an appropriate time can help to improve the patient’s vision prognosis and overall quality of life.
Utility of ocular features in management of Alport syndrome
Notes
Conflicts of interest
All authors have no conflicts of interest to declare.
Data sharing statement
The data presented in this study are available from the corresponding author upon reasonable request.
Authors’ contributions
Conceptualization, Investigation: YJ, JHJ
Writing–original draft: YJ, JHJ
Writing–review & editing: YJ, JHJ
All authors read and approved the final manuscript.