alport syndrome a review

ELS EVI E R Clinical Eye and Vision Care 12 (2000) 139-150 www.elsevier.com/locate/clineyeviscare

Clinical review

Alport syndrome: a review

Patricia A. McCarthy, Dominick M. Maino"

Illinois College of Optometry, 3241 S. Michigan Ave., Chicago, IL 60616, USA

Accepted 28 January 2000

Abstract

Alport syndrome, a hereditary nephritis accompanied by high-tone sensorineural deafness and distinctive ocular signs was first noted in the literature during the early 1900s. This disease is caused by a genetic defect in Type IV collagen which makes up basement membranes in many body systems. The patient will usually have bilateral anterior lenticonus causing varied refractive errors. You may also note yellow-white to silver flecks within the macular and midperipheral regions of the retina. The treatment of the visual problems is an important but secondary concern due to the seriousness of the systemic disease. Dual sensory loss, however, creates an urgent need for appropriate vision care. Due to the high risk for developmental delay and decreased social integration, early intervention should be considered in the treatment plan. Coping strategies for the patient (and the family) need to be addressed because of the chronicity of this syndrome. The primary care optometrist will be challenged by the individual with Alport syndrome since a balance between oculo-visual, developmental/psycho-educational and systemic care is required. A multi-disciplinary approach by the healthcare management team will enhance the quality of life and positive outcomes for these patients. 0 2000 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: intervention programs

Hereditary nephritis; Lenticonus; Alport syndrome; Deafness; Cataracts; Flecked retinopathy; Developmental delay; Early

1. Introduction

Alport syndrome, a hereditary nephritis accompanied by high tone sensorineural deafness and distinctive ocular signs [1-3] was first reported in the early 1900s. Guthrie described several cases of familial idiopathic hematuria and suggested maternal genetic transmittance 141. Alport linked the hematuria with the auditory defects and noted that the severity of the disease corresponded to gender [5]. The ocular signs were initially discussed by Sohar in 1954 with 50% of the cases studied demonstrating spherophakia [6]. Flecked retinopathy involving the macular and

* Corresponding author. Tel.: + 1-312-949-7282; fax: + 1-312- 949-7358.

midperipheral areas may be seen upon fundus exami- nation as well. This syndrome should be included in the differential diagnosis of any flecked retinopathy

Alport syndrome (AS) is caused by a genetic defect within one of the alpha chains of the Type IV collagen molecule. Type IV collagen is a major constituent of basement membranes throughout the body. The anomalous basement membranes of the ocular, auditory and renal systems cause the characteristic triad of abnormalities in these patients (i.e. hereditary nephritis, sensorineural deafness and ocular signs) [1,16-211. Previous authors have attempted to classify the characteristics used to diagnose Alport syndrome and its numerous variants. However, legitimate objec- tions to the current diagnostic parameters exist

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140 P.A. McCavthy, D.M. Main0 /Clinical Eye and Vuion Cave 12 (2000) 139-150

A patient presenting with signs of AS will challenge the optometrists assessment skills due to the variable nature of the refractive error [12]. One of the primary concerns, however, must be the diagnosis and management of the systemic disease. A missed diagnosis of AS in a young male can eventually be fatal due to end stage renal disease 171. Secondary management goals should consider developmental and perceptual delays, management of any psychosocial anomalies, and the creation of coping strategies for the patient and his family. Early intervention programs (EIP) need to be incorporated into the treatment plan on an individual basis. Appropriate healthcare should involve the skills of the optometrist, physician, psy- chologist and early intervention staff. A multi-disciplinary approach by the health-care management team for AS patients is necessary to maximize their quality of life and to ensure desired outcomes [25-281.

2. Etiology

2.1. Basement membrane lesion

The signs and symptoms of AS are due to defective basement membranes in specific organ systems (i.e. renal, auditory, and ocular systems). Basement membranes (BM) are the subcellular foundations in tissues and are composed of Type IV collagen. These microscopic platforms are key to the appropriate separation, maintenance and regeneration of the juxtaposing tissues [ 1,18-211. The glomerular basement membrane (GBM) is defective in the patients renal system. The affected kidney loses its ability to filter blood effec- tively [19]. The stria vascularis of the cochlea and the lens capsule are also affected [7,29].

2.1.1. Renal system The GBM is the location of the hallmark non-

ocular lesion in AS [3,30]. The histological description of this lesion varies within the literature. Thickening of the basement membrane was initially described during the 1970s [3]. Recent research has described the defective membrane as a thinned area with associated regions of additional membrane layers due to splitting of this tissue [l-31. The splitting of the membranes coincides with proteinuria that may signify severe renal disease 121.

An interesting contradiction exists between the articles written by Churg and Rumpelt. According to Rumpelt et al., a combination of thinning and splitting of the GBM in the same glomerulus is the distinctive renal defect in AS. Thinning of the membrane occurs with subsequent duplication, ultimately giving a faux layered appearance to the BM. This

lesion, seen upon electron microscopy, was noted to be diffuse with a range of severity. Eventually, the split tissues involved a greater area than the thinning membrane. Neither of these basement membrane en- tities alone are specific for AS with thickening of the GBM being a late stage finding [31].

In contrast, Churg et al. described the GBM abnormality as splitting with subsequent thickening of affected areas. The appearance of the renal tissue re- sembled kidneys previously assessed with deficits in lipid filtration. This inference supports the hypothesis of a GBM lesion along with the clinical signs of hematuria and proteinuria [32].

The onset of the thickening of the GBM appears to be the primary conflict between the definitions pro- posed by Rumpelt and Churg. Both studies report areas of splitting or layering of these membranes. The number of subjects must be considered when compar- ing the two studies. Rumpelt studied biopsies from 70 subjects while Churg analyzed specimens from 17 patients [31,32].

2.1.2. Auditory system The auditory basement membrane lesions have

been difficult to discern due to problems procuring specimens from AS patients. The stria vascularis of the cochlea seems to show similar basement changes to the GBM. Tissue atrophy with cellular loss and edema may be present as well. The hair cells of the organ of Corti are affected by this lesion with a resultant loss of hearing at the higher frequencies [1,2,71.

2.1.3. Visual system The best known basement membrane within the

eye, the lens capsule, is also the thickest BM within the human body [l l] . Streeten et al. [29] identified three specific histological structures that are affected in the crystalline lens capsule. First, large fractures lined with abnormal filaments are distributed in a honeycomb pattern throughout the central area of the capsule. Coincident vacuoles containing osmophilic spheres and membranes have also been identified with cellular debris found adjacent to these breaks. Second, the capsules epithelial cells contained dis- tended mitochondria with cells missing from several layers of the capsule. Third, the lens fibers next to the thinner, affected capsule also had mitochondria1 swelling with amorphous clumping of the cytoplasm. Although thinning of the lens capsule does occur with age, this pathological thinning combined with abnormal epithelial cells and fibers may lead to capsule fragility. Streeten implied the appearance of the lens capsule lesion was similar to the Bowmans capsule BM defect in the renal system of AS patients.

The exact etiology of the defect in these basement

P A . McCavthy, D.M. Main0 /Clinical Eye and Vuion Cave 12 (2000) 139-150 141

membranes was not initially known. Alport 151 suggested the toxins from Streptococcus were responsible for this renal disease. Later questions about possible biochemical abnormalities and problems with tissue perfusion were considered [31]. The collagenous structure of the basement membranes became the key to unraveling some of the uncertainty with this syndrome.

2.2. Type W collagen

The flexibility and stability of basement membranes are largely due to Type IV collagen which comprises 50% (dry wt.) of these structures [3].

Type IV collagen is a non-fibrillar, triple helical macromolecule composed of three chains. These chains may be any one of six alpha chains that are distributed within basement membranes (Table 1 outlines the systemic distribution of these alpha chains [16,17,19]). Each chain is secreted by a cell and be- comes part of the extracellular matrix. The distin- guishing features of Type IV collagen include specific non-collagenous areas (NC1) within the final product and frequent interruptions within the primary structure of the alpha chains [3-9,16-19,301.

Study of the BM finally gave definitive clues to the etiology of AS. Two important points were noted about the alpha 5 chain of Type IV collagen: first, this chain gives structural stability to the final collagen molecule. Second, deficiencies within the alpha 5 chain often cause dysfunction of all three chains of the collagen product [30,33]. The manufacturing process of the Type IV collagen molecule may be compromised [19]. Although alpha 5 is present in many tissues, only some of them are affected in AS [34]. This mystery has yet to be explained.

2.3. COL4A5 gene

Gene COL4A5 has been identified as the cause of the alpha 5 chain anomalies in AS. Genetic loci for the alpha 1 through 4 chains have been previously identified on autosomal chromosomes. Hybridization studies localized COLAAS to the long arm of the X chromosome, q22-23. Confirmatory in situ studies were also performed to further localize the gene to

Thirty to 40 mutations [20,22] have been described in the COL4A5 gene, including deletions, insertions, rearrangements and point mutations. Several small mutations are worth noting here because of their catastrophic effect on the final structure of the collagen molecule. Cysteine to serine point mutations [22] and glycine substitutions [19] disrupt the fabrication of the collagen product. Also, any mutations within the NC1 domains can disturb the alignment of the

Xq22 [16-181.

Table 1 Localization of Type IV collagen alpha chains [16,17,19]

Alpha 1 and 2 Renal glomerular basement

membrane (GBM)

Skin Nerve

Muscle Vascular

Alpha 3 and 4 Renal GBM

Muscle Vascular

Ocular

Alpha 5 Renal GBM Skin Ocularb

Alpha 6 Gastrointestinal Pulmonary

Mesangial matrix Vascular BM" Tubular BM Bowman's capsule Epidermal BM Endoneurium Perineurium Extrasynaptic muscle fibers Blood vessels, specifically arterial

Distal tubule BM Bowman's capsule Synaptic muscle fiber BM Aorta (low levels only with

Lens capsule BM (low levels with alpha 1 & 2)

alpha 1 & 2)

Epidermal BM Cornea epithelial BM Descemet's membrane Vascular BM of choroid

Eesophagus Lung

"BM, basement membrane bWithin rabbit eyes.

chains of the collagen molecule and disrupt many intermolecular interactions [ 191. The clinical presentation of AS may parallel the severity of the mutation. In one study, the severity of the hearing loss did correspond with the mutation while another study identified that no obvious correlation between geno- type and phenotype existed 122,331.

3. Inheritance

Within the United States, the genetic frequency ranges from 1/5000 to 1/10000. The higher end of this range has been documented in the Western states with Utah having twice the incidence of this syndrome when compared to the rest of the US. Spontaneous mutations have been noted in 15518% of the cases with mutations occurring in 1/100000 gametes. Fi- nally, AS is not biased toward any particular race or geographic area [1,21.

3.1. X-linked inheritance

COLAAS has been definitively implicated through X-linkage to AS [2,16-181. Currently, 85% of these


patients have an X-linked dominant inheritance pattern [3,21]. This particular type of transmission causes severe disease in the male patient and a varied presentation of the syndrome in females [2]. The broad range of phenotypes for women is caused by random inactivation of one X chromosome causing two populations of cells within organ systems (lyonization) 12,351.

3.2. Autosomal inheritance

Approximately 15% of all cases of AS are due to autosomal inheritance [3,19,21]. Autosomal recessive (AR) inheritance has been cited as a rare occurrence with the lesion involving the long arm of chromosome 2. This would involve the genes of the alpha 3 and 4 chains of Type IV collagen [36]. Autosomal dominant (AD) transmission of this syndrome is questionable [22]. (This will be discussed later in the paper.) Atkin et al. also has questions about AD inheritance in AS due to a reduction in individuals advancing to severe renal disease. Reduced penetrance with AD inheritance should result in an increased amount of end stage renal disease (ESRD) in some AS patients as they age. Autosomal dominance should be considered if male-to-male inheritance is discovered within a pedigree 111.

4. Diagnosis of Alport syndrome and variants

The diagnosis of Alport syndrome seems to offer additional hurdles to the healthcare provider. Alport- like variants have been described [1,23,37,38]. Recog- nition of these variants is important for appropriate management of the patient and their family members. Atkin et al. 111 categorized this syndrome based on the different phenotypic expressions, as well as the knowledge that the severity of AS depends primarily on the gender and the age of the patient. The princi- pal divisions of the syndrome depend on the onset of the renal disease (as illustrated in Table 2). (Table 3 further outlines the six types of Alport syndrome and variants that were described by Atkin accounting for non-renal signs and symptoms.) As can be seen (Table

Table 2 Juvenile- vs. adult-onset Alport syndrome [l]"

Characteristic Juvenile Adult

Inheritance XD, AD XD End stage < 31 years old > 31 years old

Auditory deficit 100% 50% Ocular anomalies Present Absent

renal disease

"XD, X-linked dominant; AD, autosomal dominant.

Table 3 Types of Alport syndrome and variants [1Ia

Characteristics Types

I I1 I11 IV v VI

Inheritance XD,AD XD XD XD AD AD Adult vs. juvenile J J A A A/J J

Ocular anomalies + + -

AS variant

Auditory deficit + + - + +

Subtypes + - + - - + - - - - +* -

- + -

"XD, X - linked dominant; AD, autosomal dominant; J, juvenile; A, adult; +, present; -, absent; +*, Epstein syndrome.

31, types I and VI appear quite similar. However, the type I male patient does not produce offspring secondary to morbidity while the type VI group can include normal male carriers. Although this system of classification seemed to simplify the diagnostic process, Atkin et al. acknowledged the discordance between the adult versus juvenile criteria [l].

Flinter et al. 1221 has a more specific standard for definitive diagnosis of classic Alport syndrome. Sev- enty-five percent of these specifications listed below must be fulfilled to make the diagnosis. A complete case history of the disease process in family members must be obtained before using this criterion. The rules for the appropriate diagnosis include the following:

1. Hematuria in other family members with or without chronic renal failure (CRF).

2. A kidney biopsy with the characteristic histological lesions (i.e. thickening and splitting of the GBM).

3. Ocular involvement, specifically, anterior lenticonus and macular flecked retinopathy.

4. Auditory involvement (high-tone sensorineural deafness) which is progressive.

Amari claims several Alport-like variants may present without ocular involvement and must be kept in mind when making a differential diagnosis. Heredi- tary nephritis without deafness or ocular involvement is one possible variation. Second, Epstein syndrome, also described as Type V AS, has hematological deficits, (thrombocytfopathology), in addition to the renal and auditory lesions. Flechtner syndrome is the third variant worth considering which presents with proteinuria and deafness, as well as leukocyte and platelet abnormalities [ 1,231. Finally, an AS-like glomerulonephritis with multiple benign tumors of smooth muscle tissue (leiomyomatosis) has been reported by several authors. The gene associated with diffuse leiomyomatosis (DL), COL4A6, has also been mapped to the long arm of the X chromosome. Dele-


tions of areas of COLAAS and COLAA6 have been found in patients with this AS variant [19,23,37,38].

Leiomyomatosis, when associated with AS, presents with cataracts in addition to hematuria and hearing loss. This AS variant is important to the optometrist because it is associated with cataracts. These cataracts may have an early onset and unilateral presentation. Twenty-five percent of these patients will have congenital lens opacifications as well. This ocular presentation is not common in patients with AS or es- ophageal leiomyomatosis alone [ 19,37,38].

Surprisingly, Govan [ 111 suggests that only one of three ocular features is needed to diagnose Alport syndrome:

1. Anterior lenticonus. 2. Flecked retinopathy of the macula. 3. Flecked retinopathy of the periphery.

This article appears to disregard the seriousness of renal disease in this syndrome. The presence of one of the ocular triad warrants additional systemic investigation before a firm diagnosis of AS is made.

Current variations of the definition of AS may cause a misdiagnosis by the physician. Exclusion of X-linked inheritance secondary to male-to-male transmission is the only definitive determination in the current diagnostic process [24].

5. Patient presentation

Table 4 Clinical Course of X-linked AS [22Ia

Males 5 years old

10 years old 15 years old 20 years old 25 years old

Cam'ev females 20 years old 25 years old MA LTR

Microscopic hematuria High-tone sensorineural deafness Hypertension Renal function deterioration Chronic renal failure

Microscopic hematuria Renal function deterioration (3% of carriers) Hypertension (1/3 of carriers) Chronic renal failure (5510% of carriers)

"MA, middle age; LTR, life-time risk.

ultrastructural changes within the GBM. This indicates the severity of the kidney dysfunction [2,30].

To definitively diagnose renal disease, electron microscopy of a kidney biopsy should be performed for all suspected male and female patients followed by immunofluorescent evaluation of the tissue [29]. Monoclonal antibody studies of the defective collagen chains are able to positively identify 75580% of the affected males and will provide a mosaic pattern in carrier females 1301. A specific monoclonal antibody, H51, to the NC1 region of the alpha 5 chain has been developed. The strong positive feature of this particular antibody is the capability to use it on skin tissue biopsies, especially if renal biopsies are unattainable [16]. Future diagnostic assessment techniques will probably make extensive use of molecular genetics 1301.

5.1. Renal system 5.2. Auditory system

What is the typical presentation of a patient with AS? The most significant organs affected are in the renal system 171. Hematuria is the earliest clinical sign [4]. This may be the primary presentation of the syndrome in children [l]. Guthrie described the hematuria as a constant finding with variable severity [4]. AS males have the hematuria from birth with approximately 80590% of the women showing this important clinical sign [1,21. The frequency and amount of hematuria may vary considerably from one carrier female to another and usually will not result in ESRD [2,21]. Lyonization probably plays a significant role in this phenotypic presentation [2,35]. Females who are carriers (but otherwise healthy) tend to have intermittent microscopic hematuria 1241.

Systemic hypertension will result with continued deterioration of the renal system (Table 4 lists a time-line of renal events for affected individuals [22]). The onset of auditory anomalies may start at this time as well [22]. Focal sclerosis of the glomeruli has been identified as a signal of advancing renal disease with subsequent proteinuria being a manifestation of the

The auditory presentation of bilateral, symmetrical hearing loss with AS is quite significant [2,7]. Most of the AS individuals have hearing loss by age 10 [9,14,20,35,39]. Auditory manifestations appear to parallel the severity of renal involvement and may be coincident with the ocular signs [1,5,20]. Females with AS are less severely affected and the deficit is usually non-progressive [2,9]. Carrier identification is en- hanced via audiology studies since the defect is not normally manifest in carrier females [39].

The actual defect of the auditory system has been narrowed down over the years. Anatomically, the middle ear is intact and unaffected 111. The brainstem also has not shown any significant lesions and cranial nerve VIII has been ruled out as an etiology [1,12]. A vestibular component has been identified with this defect. The patient may present with tinnitis and vertigo before the detection of the auditory lesion [1,21. The cochlea is also affected with a loss of neurons within the organ [7].

The auditory lesion is detected using audiometry.


Recently, audioscans 6.e. sweep frequency audiometry using a pulse tone from 250 Hz to 8 kHz at a 30-s/octave rate) have been conducted on these patients. Detections of very small deficiencies in middle frequency areas have been noted even in carrier females. Audioscans along with confirmatory linkage studies may help identify these carriers 1351.

5.3. Ksual system

Ocular anomalies have been noted in 1 1 ~ 4 3 % of the AS patients studied [7,39,40]. Males have equal or greater ocular involvement compared to females [1,9,39,40]. These ocular abnormalities occur in both the anterior and posterior segments of the globe with the most common finding being uncorrectable refractive error due to lenticular involvement [l]. Behav- ioral changes may signify the onset of decreased visual acuity in younger patients. Sudden difficulties with school, changes in social behavior and increased mobility problems may be part of the patients presentation [41]. Ocular anomalies (primarily lens changes) can coincide with poor kidney function which can progress to renal failure. Lack of ocular signs in family members is helpful in ruling out AS 1391. (Table 5 contains a complete list of the ocular findings associated with AS [1,7-15,23,29,33,39,40,42-441.) The most common of these signs are discussed below.

5.3.1. Cornea Two prominent corneal findings frequently encoun-

tered in AS individuals are posterior polymorphous dystrophy (PPMD) and arcus. PPMD is due to the thickening of Descemets layer with subsequent endothelial cell changes [39]. This basement membrane appears immature with several layers of Descemets identified in association with the defective endothelial cells [ 131. Obviously, compromised endothelial cells can lead to corneal edema. Iridocorneal adhesions and transparent membranes due to PPMD cause an increase risk for glaucoma in these patients [41]. Arcus, although a non-specific finding, has an increased incidence associated with AS 1111. Usually, the arcus will appear bilaterally with interpalpebral sparing and tends to be coincident with foam cells noted on renal biopsy [7,11].

It should be noted that certain corneal abnormalities may be observed in all renal failure patients regardless of etiology 1451. These findings include white limbal girdle of Vogt and band keratopathy. Care must be taken to insure a complete differential diagnosis of the etiology of the patients renal disease.

5.3.2. Crystalline lens 5.3.2.1. Lenticonus. Bilateral anterior lenticonus has

been noted in Alport syndrome since 1966. Lenti-

Table 5 Ocular findings in Alport syndrome

Cornea [1,7,12,39,40,43] Posterior polymorphous dystrophya Arcus Anterior layer thickening Lattice dystrophy Recurrent epithelial corneal erosions White limbal girdle of Vogt Band keratopathy Posterior polymorphous opacities Pigment dispersion syndrome

Crystalline lens [7,9-11,23,29,33,421 Anterior lenticonusa Posterior lenticonus Lens coloboma Cataracts

Anterior pole subcapsular Anterior axial cortical Internal lenticonus Posterior axial Posterior cortical Posterior subcapsular (secondary to steroids) Subcapsular vacuolization Blue dot opacities

Pundus [1,7-15,44] Flecked retinopathya

Macular Midperipheral Combination

Foveal reflex ~ decreased to absent Epiretinal membrane Optic disc drusen Retinal telangiectasia

Major clinical presentation.

conus appears in men more than women during the second to third decade of life [1,2,9,10,13,29,33]. Patients will present with variable vision depending on the surrounding illumination. In photopic condi- tions, the patient will show myopia. Hyperopia and monocular diplopia may be manifest in mesopic con- ditions [12].

When using a parallelepiped or optic section during biomicroscopy, the lenticonus is seen as an axial pro- trusion, often conical or nipple-like, within the pupillary zone of the lens. It may also appear as an oil drop on retroillumination of the pupillary area [1,2,11,12,29]. This lenticular anomaly may produce up to 30 diopters of measurable myopia [7].

The primary defect for lenticonus lies within the lens capsule. The paucity of other anterior chamber defects rules out anomalies during embryogenesis. The alpha 3-5 chains of Type IV collagen may be absent or abnormally arranged causing fragility of the capsule. Normally, the capsule is the thinnest at the anterior pole and 3 mm radially in the periphery. The decreased number of epithelial cells and increased


capsular thinning allows bulging of the anterior cor- tex. Besides the anatomical problems with the capsule, manipulation of the lens due to accommodation and normal growth causes additional stress on an already weakened structure. This weakness can cause the capsule to rupture with consecutive formation of an anterior pole subcapsular cataract [1,11,26,30,42].

Anterior lenticonus is an important indicator of poor systemic prognosis due to renal disease [7,13,39]. It has been reported that no isolated cases of ocular changes without renal dysfunction had been noted 1241. At this point, the conscientious optometrist will consult with a nephrologist since visual changes may be identified before an actual AS diagnosis is de- termined [13,15].

5.3.2.2. Spherophakia. Spherophakia is a sudden developmental arrest of the lens with aplastic zonules and is due to the lack of normal zonules in these patients. Other authors, however, have suggested that spherophakia is another name for marked lenticonus [6,111.

5.3.2.3. Cataracts. Although cataracts are not a specific finding for AS, certain lens opacities are significant for these patients. First, anterior subcapsular formations can occur secondarily to lens capsule rupture. Second, posterior subcapsular cataracts may appear due to steroid use with post-renal transplant

Table 6 Differential diagnosis of inherited flecked retinopathies [1,46,47]"

therapy. Third, internal lenticonus may be seen as a posterior lamellar opacity with a posterior projection along the visual axis [7,11,421.

5.3.2.4. Lens coloboma. Only one case of lens coloboma has been reported. Amari et al. stated this anomaly was not noticeable without dilation. This defect was presented as a zonular lesion in addition to the lens malformation. Since zonules are not made of collagen, a questionable relationship exists between this particular coloboma and traditional Alport syndrome. However, a correlation between lens colobo- mas and AS variants has not been ruled out 1231.

5.3.3. Fundus Alport syndrome must be considered in the differ-

ential diagnosis of flecked retinopathy [ 1,7-151 (see Tables 6 and 7 [1,46-48]). In addition, polycystic kidney disease and medullary cystic disease may cause a similar fundus appearance [49]. (The characteristics of these renal diseases are listed in Table 8.) The flecked retinopathy of AS does not affect visual function of the patient and is often noted by the clinician only if fundus photographs are taken [1,11]. The flecks may be seen in the macular region, midperiphery or both with sparing of the fovea [1,7-151.

5.3.3.1. Macula. The macula is frequently affected in AS [11,15]. Men are usually affected more than

Alport syndrome Fundus Stargardt syndrome Retinitis punctata Fundus flavimaculatus albescens albipunctatus

XD, AD, AR Bilateral Flecks ~ macular to

midperiphery, yellow to white with ( - ) foveal reflex, pigment changes, all retinal levels

EOG ~ normal

ERG ~ normal

FA ~ normal to hyperfluorescent

No significant VA loss

AR Bilateral, symmetric Flecks ~ fish-tail yellow-white, posterior pole at RPE level

EOG ~ abnormal

ERG ~ normal to mild

FA ~ hyper 2nd to atrophy

Complications ~ red/green defects, central scotomas, retinal neovasc., cystoid mac. edema No significant VA loss

AR Bilateral, symmetric Flecks ~ fish-tail, beaten bronze, central or peripheral fundus

EOG ~ normal to abnormal ERG ~ normal to abnormal

FA ~ transmission defects, occ. bull's eye pattern Complications ~ red/green defects, central scotomas

VA worse than 20/200

Flecks ~ white or Flecks ~ discrete yellow, scattered spots, no atrophy

EOG ~ normal with time

ERG ~ severely ERG ~ reduced abnormal photopic, normal

scotopic FA ~ questionable pattern

Complications - contracted fields worse with time

aAbbveuiations: XD, X-linked dominant; EOG, electrooculogram; AD, autosomal dominant; FA, fluorescein angiography; AR, autosomal recessive; ERG, electroretinogram; VA, visual acuity.


women during their second to third decade of life. The flecks are yellowish white to silver, round or oval and up to 50 p m in diameter. They are usually in a scattered arrangement but may become confluent. They lie within the superficial layers of the retina following the nerve fiber layer (NFL) [1,7-9,11,12]. Retinal pigment epithelium (RPE) changes are also noted [1,9,13].

There are four important components of the macular flecks: first, an abnormal form of the alpha 5 collagen chain seems likely due to the various retinal membranes involved [i.e. internal limiting membrane (ILM), external limiting membrane (ELM), Bruch's and glia limitans of the vessels]. Second, an opaque substance appears to be deposited without evidence of a retinal biochemical abnormality. These deposits may be collagen with defective alpha 5 chains. Slow accumulation of these deposits with increasing age is noted. Third, the deposits tend to be extracellular (if the flecks were located intracellularly, they would interfere with normal retinal function). This location also coincides with other basement membrane lesions elsewhere in the body. Finally, more than one retinal layer may be involved with some flecks appearing to lie deep to the ILM, following the NFL and involving the retinal vessels [15].

It has been suggested that the macular flecks are a product of the Miiller cells. Miiller cells are present in all retinal layers and produce basement membranes. They also compartmentalize the NFL and form the glia limitans of the vasculature. Normal retinal function of AS patients indicates a purely structural defect of the Miiller cells and macular flecks are not evident within the fovea [15].

5.3.3.2. Midperipheral area. These flecks are similar to those found in the macular area with a few excep- tions. They can be small and round but tend to coalesce into areas covering up to one-third of a disc

Table 7 Differential diagnosis of drug-induced flecked retinopathies [1,48]"

diameter [ll]. Deeper retinal layers are involved with the flecks being located at the level of the RPE or Bruch's membrane [9,13,15]. Occasionally, flecks may be seen in the macular and midperipheral areas of the same fundus with a bull's eye appearance [ll].

Three major areas of contention regarding flecked retinopathy due to AS include the amount of vessel involvement, the appearance on fluorescein angiography (FA) and the results of electrophysiology testing. The vessel involvement may range from no involvement to encrusting of the vessels with the flecks in a honey-combed pattern [11,151. FA will show variable results as well. Some studies detected hyperfluores- cence secondary to RPE disruption. Yet, no corre- spondence seems to exist between the window defects and the flecks [7,11]. Particular fluorescent patterns without evidence of leakage may become evident with disease progression [8,91. Electrophysiology showed the greatest inconsistencies. Different articles noted results ranging from the electrooculogram (EOG) and electroretinogram (ERG) being normal to both showing subnormal results [1,8-11,141. Visually evoked potential (VEP) latencies were increased secondary to lens changes in one article reviewed 1141.

The optometrist should realize that, as with the cornea, electrophysiology results may be abnormally affected by renal disease [8,11,14]. Decreased b wave amplitudes on ERG can occur with non-AS renal failure, dialysis and renal transplantation. Steroid use and systemic hypertension may also change these results. Decreased EOG findings can be due to dialysis treatment while increased VEP latencies tend to correlate with kidney dysfunction [11,14].

5.4. Psychosocial presentation

Children with severe systemic illnesses may face disruption of normal developmental milestones [28].

Aport syndrome Tamoxifen retinopathy Talc retinopathy Canthaxanthin retinopathy

Flecks ~ macula or midperipheral, yellow to white with ( - ) foveal reflex, pigment changes, all retinal levels

Cornea ~ PPMD, arcus

Flecks ~ tiny, white, refractile at retinal pigment epithelial level

Cornea ~ white, superficial opacities

EOG ~ normal ERG ~ normal

Complications ~ cystoid mac. edema

No significant VA loss VA ~ mild to moderate defect

Flecks ~ small, crystal, within vessels inner retina layers

Flecks ~ gold-dust spots in

circumventing macula

EOG ~ normal ERG ~ small b wave

Complications ~ disc neovasc., ischemia, retinal detachment, vitreal heme VA ~ normal

"Abbreviations: PPMD, posterior polymorphous corneal dystrophy; EOG, electrooculogram; ERG, electroretinogram; VA, visual acuity.


Table 8 Diffuse familial nephropathies [49]

Polyqstic hidney disease Adult type

Autosomal dominant Symptoms/signs:

Abdominal pain Palpable masses Hematuria Proteinuria Urinary tract infection Anemia Cardiovascular involvement Hypertension Organ cysts

Retinal dystrophy

Autosomal recessive Symptoms/signs:

Ocular:

Infantile

Like adult Urogenital defects

Fatal at an early age

Medullary cystic disease Inheritance unknown Symptoms/signs:

Polydipsia Polyuria Renal salt wasting Anemia Hypertension

Ocular: Congenital cataracts

Fatal by 40 years of age

Decreased vision and hearing are also high-risk factors for developmental disabilities [50]. Optometrists need to consider additional multidisciplinary evaluation if the patient presents with signs of developmental delays 6.e. problems with general development, motor skills, and knowledge). A careful investigation of socialization skills in young patients should be considered since bimodal sensory loss in AS patients can further complicate the socialization process [27].

Children with chronic diseases suffer great psychological stress due to the disease and treatment process. Adequate coping mechanisms are necessary to master these added demands with strategies matching the severity of the illness and age of onset 1281. Unfortu- nately, emotional regression including apathy can also occur in young patients with chronic illnesses [51].

Families may be angry and anxious about the situa- tion and blame the medical community for having to deal with all the different aspects of the disease. They may become overprotective of the ill individual as a coping mechanism. This can prevent appropriate development of the patient both academically and so- cially. The stress of a chronically ill family member

can also cause a significant strain and a deterioration of relationships within the family may be evident [51].

Optometrists and other members of the healthcare team must be aware of the effect of chronic illness on a patient and his family. The ability of the child and his family to cope with the psychological stress of a chronic illness should be considered when deciding on appropriate management options [ 5 11.

6. Management of the AS patient

The management of a patient who presents with possible ocular signs and symptoms of Alport syndrome requires a team effort from medical, behav- ioral, psychosocial and educational specialists. The primary concern for the optometrist should be to attain appropriate care for the patient and his family. When the systemic health of the patient has been stabilized, the patients sensory, developmental and emotional anomalies can be appropriately addressed [7] and several treatment goals should be established by the healthcare management team [1-3].

Unfortunately no cure is available at this time, systemic complications secondary to the renal disease are minimized by controlling hypertension and pro- tein intake [1,2]. Current treatment of ESRD requires dialysis and/or renal transplantation. Future management of renal disease may include pharmacologic therapy (i.e. cyclosporin A) [1,3,52]. Treatment of the hearing deficiency will include management of the possible ototoxicity side effects when medications for renal problems are used [1,2]. Reduced vision secondary to lenticular changes are treated with topical mydriatics or cataract extraction and the application of lenses [1,11]. Intervention programs may be needed if significant developmental delays are identified [26,50]. Appropriate coping strategies for the patient and his family should be considered in the treatment plan as well [25,28].

6.1. Genetic counseling

Appropriate genetic counseling is essential for the management for Alport syndrome [3]. Carrier identification is important for the probands family especially if the urinalysis findings are inconsistent [21]. Molecular genetics can be used to determine the amino acid sequence of the genetic lesion. This is important since greater than 80% of X-linked disease is due to a point mutation [21,30]. Linkage studies will frequently confirm the genetic etiology [ll]. Further renal examinations, including ultrasound and biopsy, should be conducted 1301.


6.2. Renal system treatment

6.2.1. Cyclosporin A The use of cyclosporin A is being studied for man-

agement of the kidney disease in these patients. This drug appears to reduce the proteinuria and may in- fluence systemic regulation of renal function. How- ever, progression to renal failure can still occur. Un- fortunately, cyclosporin A has toxic side effects in renal tissues. Therefore, it is currently not recommended for the treatment of AS until further studies have been completed [52].

6.2.2. Renal transplantation Careful screening of potential renal donors must be

implemented both for the health of the donor and the recipient. Monoclonal antibody studies are used to screen for genetic patency of the donor [16]. Identi- fied male carriers should be denied as a renal donor because of possible renal disease progression and the reduced life-span of these organs. Fortunately, female carriers may donate a kidney to the patients because severe renal disease usually will not occur [30,53].

Glomerular basement membrane nephritis, a post- transplant complication, occurs in 3 ~ 4 % of AS individuals. The typical composite of these patients is a male with sensorineural deafness and ESRD before 30 years of age. Approximately 75% of these cases occur during the first year and 3/4 of the grafts are lost. Recurrence of this problem with another transplant is a possibility 1301.

6.3. Auditory management

Significant renal disease accompanied by hearing loss may be prematurely assessed as Alport syndrome. Anatomic anomalies, congenital etiologies and middle ear disease must be ruled out. Therefore, appropriate referral for audiology testing is indicated. If an AS diagnosis can be made, the results of the audiology consult will not only be of prognostic value but will aid in identification of carriers within the other family members [1,2,391.

Treatment of the sensorineural hearing loss should be implemented as warranted [2]. Unfortunately, previous attempts with hearing aids in these patients have been unsatisfactory. Improved audition after renal transplantation have been cited in the literature but this does not appear to be the norm. Vision deficits should be addressed as soon as possible to enhance communication skills for those with hearing deficiencies [l].

6.4. Ocular management

The AS patient presenting with posterior polymor-

phous dystrophy may be at risk for glaucoma (GLC) due to iridocorneal adhesions. GLC medications that reduce aqueous production are typically used. Filter- ing surgery is also an option for these patients. Laser trabeculoplasty, however, is contraindicated due to the growing membranes in the anterior chamber. Penetrating keratoplasty (PKP) can be considered a treatment option in severe cases of reduced vision due to corneal edema. Unfortunately, preexisting glaucoma and/or iridocorneal adhesions are poor prognostic factors for PKP 1541.

The lenticonus and other lens changes need to be addressed as well. Topical phenylephrine can be administered if the patient has axial opacities. Care must be taken if the patient has systemic hypertension by using a dilute concentration. Although the efficacy of extracapsular cataract extraction (ECCE) has been questioned, three cases of ECCE were noted in this review without evidence of a fragile capsule. If the patient also has posterior lenticonus, the capsular bag may be stretched during the ECCE procedure to reduce its magnitude. Steroids used after the transplant can cause a posterior subcapsular cataract (PSC). Cataract extraction for the lenticonus and PSC is the treatment of choice [11,55,56].

6.5. Management of psychosocial issues

An optometrist should recommend a developmental evaluation for the patient when decreased vision and/or hearing is suspect as an etiology for developmental delay. Formal social assessments, such as the Meadow-Kendall Social-Emotional Assessment In- ventory for Deaf and Hearing Impaired Students should also be administered. This particular inventory has preschool- and school-aged items to determine social and emotional adjustment for a child with hearing loss 1271. Placement in an intervention program is recommended if developmental or social deficiencies are present. Federal mandates require care for children beginning at 3 years of age when high-risk factors are present. These educational and rehabilitative programs can assist in the development of intellec- tual, social and language skills needed in school. Good communication between optometrists and the EIP staff can facilitate the incorporation of visual, perceptual and developmental therapy into daily ac- tivities [26,50].

The health management team should work within a holistic approach to enhance the patients quality of life. Treatment regimens must be considered for their effect on the patients life along with their ability to control symptoms or disease progression. The patients perception of the disease process can affect his self- esteem and the emotional adjustment to AS [25]. Additional factors affecting the patients coping abili-

P A . McCavthy, D.M. Maino /Clinical Eye and Vuion Cave 12 (2000) 139-150 149

ties include parental coping, family cohesiveness and intrafamilial communication [28]. Psychological intervention may be needed to assist the patient with coping strategies for AS. Frequent emotional adjust- ments by the patient (and the family) to the stages of the illness and treatment regimens are necessary to maintain as normal a lifestyle as possible 1251.

7. Conclusion

Alport syndrome offers many challenges to the optometrist. Patients will present with the characteristic triad of hereditary nephritis, hearing loss and ocular manifestations. A thorough investigation of the hereditary nature of this syndrome within a family is essential for appropriate classification [ 1-31. In addition, a careful investigation of the full cause of the flecked retinopathy must not be neglected [1,7-151 Conscientious management of the ocular anomalies should be emphasized to avoid dual sensory disability [l]. A multi-disciplinary approach in the management of these patients, including assistance for developmental and social deficiencies, as well as coping mechanisms, is necessary to minimize detrimental effects on their quality of life and to improve management outcomes.

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alport syndrome a review

Documents

abstract alport syndrome

introduction alport

distinctive ocular signs

hereditary nephritis

systemic care

early intervention

systemic disease

anomalous basement membranes