The Ultrastructure of the Lens Capsule Abnormalities in Alport’s Syndrome

doi:10.1016/S0021-5155(98)00031-8

Japanese Journal of Ophthalmology

Volume 42, Issue 5, September–October 1998, Pages 401-405

https://doi.org/10.1016/S0021-5155(98)00031-8 Get rights and content

Abstract

The ultrastructure of lens capsule abnormalities in Alport’s syndrome is reported. An anterior lens capsule from a 29-year-old patient with lenticonus who was affected by Alport’s syndrome was obtained at the time of surgery. The histopathologic findings showed the thickness of the anterior lens capsule was decreased and there were many vertical capsular dehiscences localized at the inner part of the lens capsule. Almost every dehiscence was limited to the inner two thirds of the capsule. One should be cautious in attempting intraocular lens implantation into the lens capsule of patients with Alport’s syndrome, because the lens capsule may be fragile in this disease.

Introduction

Alport’s syndrome is a hereditary nephritis often accompanied by hearing impairment. This disease is primarily X-chromosome–linked, but autosomal forms have also been described. It is generally accepted that abnormalities in the type IV collagen molecule may play a causative role in the development of this syndrome. In recent years, many studies involving biochemistry and molecular biology have greatly improved our understanding of this disease. In some instances, the gene locus of gene mutation has already been identified. Because a diversity in modes of inheritance and clinical findings has been described, this syndrome is currently considered as a group of similar hereditary diseases.

Although anterior lenticonus is the most commonly reported ocular abnormality in Alport’s syndrome, little is known about the histopathologic changes in this disorder. As for the histologic findings of lenticonus, Brownell and Wolter¹ have demonstrated the thinning of the lens capsule by means of a light microscope. Electron microscopic study has demonstrated the marked thinning and vertical dehiscence of the anterior lens capsule in Alport’s syndrome.²

Here, we describe the detailed histopathologic and ultrastructural findings in the lens capsule obtained from an Alport’s syndrome patient at the time of surgery.

Section snippets

Case Report

A 29-year-old man came to our clinic on January 31, 1994, with the complaint of decreased vision in his left eye. At the age of 18, he had developed irreversible renal failure, and eventually he required hemodialysis. His mother and elder sister were diagnosed as having Alport’s syndrome, but they were not available for ophthalmic examination.

Gross examination did not show any abnormal findings. Slit-lamp examination disclosed there was lenticonus accompanied by a subcapsular faint opacity in

Discussion

In 1927, Alport³ reported a familial disorder characterized by progressive nephritis associated with nerve deafness. This syndrome causes recurrent hematuria with progression to renal failure; men are more frequently and severely affected than women. It is often accompanied by sensorineural hearing loss and ocular abnormalities. Some previous studies described that lenticonus was present in about half the cases.4, 5 The other ocular changes, arcus juveniles, posterior polymorphous dystrophy,

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Clear lens extraction in Alport syndrome with combined anterior and posterior lenticonus or ruptured anterior lens capsule
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Citation Excerpt :
Ohkubo et al.17 reported that the anterior capsule of a patient with Alport syndrome was 3 μm thick in the central portion and noticeably thinner than the anterior capsule of the controls (20 μm). In addition to the histological changes of the anterior capsule, the weakened structure is stressed during accommodation, as the anterior lens curvature becomes more convex centrally.16 The combination of these factors might lead to rupture of the anterior lens capsule, as seen in one of our patients.
We describe the results of clear lens extraction in 7 eyes of 4 Alport-syndrome patients. Three patients (6 eyes) had both anterior and posterior lenticonus; the fourth patient had spontaneous rupture of the anterior lens capsule, resulting in an acute drop in vision. Clear lens extraction was an effective method for visual rehabilitation in Alport syndrome patients.
No author has a financial or proprietary interest in any material or method mentioned.
Wavefront analysis and ultrastructural findings in an eye with posterior lentiglobus
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The reason for the limited improvement in the best-corrected visual acuity after occlusion treatment may be that the patient was already beyond the age limit for amblyopia treatment. We did not find discontinuous portions or disruptions in the posterior lens capsule, as has been described previously.6-8 To our knowledge, the unusual nodular structures and variations in electron density of the posterior lens capsule have not been reported previously in posterior lentiglobus; they could represent pathological changes of the posterior lens capsule in the current case.
An 8-year-old girl with unilateral posterior lenticoglobus underwent lens aspiration and intraocular lens implantation. Wavefront analysis performed before surgery to assess the surgical indication showed a higher-order aberration of 0.502 μm root mean square. After surgery, the value decreased to 0.132 μm root mean square. Preoperative best-corrected visual acuity of 0.1 improved to 0.3 postoperatively. Electron-microscopic examinations of the posterior capsule revealed unusual nodular structures and variations in capsular density.
Abnormal expression of collagen IV in lens activates unfolded protein response resulting in cataract
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Stickler and Marshall syndromes are two disorders caused by mutations in the COL2A1 gene that are associated with the early onset of distinctive cataracts (10, 11). Alport syndrome, caused by mutations in either the COL4A3, COL4A4, or COL4A5 genes, is also associated with lens capsule abnormalities and cataract formation (12–14). Humans carrying mutations in the COL4A1 locus often exhibit lens abnormalities and cataracts along with porencephaly and sporadic intracerebral hemorrhage (15–19).
Human diseases caused by mutations in extracellular matrix genes are often associated with an increased risk of cataract and lens capsular rupture. However, the underlying mechanisms of cataract pathogenesis in these conditions are still unknown. Using two different mouse models, we show that the accumulation of collagen chains in the secretory pathway activates the stress signaling pathway termed unfolded protein response (UPR). Transgenic mice expressing ectopic Col4a3 and Col4a4 genes in the lens exhibited activation of IRE1, ATF6, and PERK associated with expansion of the endoplasmic reticulum and attenuation of general protein translation. The expression of the transgenes had adverse effects on lens fiber cell differentiation and eventually induced cell death in a group of transgenic fiber cells. In Col4a1^+/Δex40 mutant mice, the accumulation of mutant chains also caused low levels of UPR activation. However, cell death was not induced in mutant lenses, suggesting that low levels of UPR activation are not proapoptotic. Collectively, the results provide in vivo evidence for a role of UPR in cataract formation in response to accumulation of terminally unfolded proteins in the endoplasmic reticulum.
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For this reason, renal and auditory diseases must be considered in patients in whom PPD is diagnosed. The association of capsule fragility with anterior lenticonus secondary to Alport syndrome is well documented.4,8,11 In our cases, however, we found that the anterior capsule was highly elastic, making the capsulorhexis technically more difficult in almost all cases.
We report the ocular manifestations of Alport syndrome and the surgical results in 4 patients. All 4 patients had anterior lenticonus; 2 also had posterior lenticonus in both eyes, 3 had flecked retina, and 1 had posterior polymorphous dystrophy. In both eyes of the 4 patients, phacoemulsification with intraocular lens (IOL) implantation was performed to treat anterior and posterior lenticonus. The postoperative visual acuity was excellent in all patients. We recommend phacoemulsification with IOL implantation as a safe and effective procedure in patients with lenticonus secondary to Alport syndrome.
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The Ultrastructure of the Lens Capsule Abnormalities in Alport’s Syndrome

Abstract

Introduction

Section snippets

Case Report

Discussion

Ophthalmology

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Struct Biol

Kidney Int

Genomics

Anterior lenticonus in familial hemorrageic nephritisdemonstration of lens pathology

Arch Ophthalmol