Ophthalmology Unit, 1 University Department of Medicine, and 2 Renal Unit, Austin and Repatriation Medical Centre, Heidelberg, Australia
Correspondence and offprint requests to: A/Prof Judy Savige, University Department of Medicine, Austin and Repatriation Medical Centre, Heidelberg, VIC 3084, Australia.
Keywords: Alport syndrome; dot-and-fleck retinopathy; lenticonus
Case report
Mr AA was a 51-year-old Italian-born factory worker with kidney failure of unknown cause who now complained of deteriorating vision.
He had first presented to another hospital at the age of 26 with macroscopic haematuria and an elevated serum creatinine. No cause for the renal impairment was found. He had had no urinary tract infections, sore throat, haemoptysis, arthralgia or skin rash, and was normotensive and on no medication. Furthermore, there was no family history of kidney disease or deafness. A renal biopsy was performed, and light microscopic examination showed only glomerular scarring, with chronic interstitial and tubular damage and no distinguishing features. Immunofluorescent and ultrastructural examinations were not performed.
Three years later Mr AA began haemodialysis, and had his first renal transplant at the age of 34 years. This failed after 2 months and a biopsy showed vascular rejection, with negative immunofluorescence for IgG and C3. A second transplant was performed when the patient was 42-years-old, and failed 7 years later. Again the biopsy showed only vascular rejection, and no IgG or C3 deposits.
After the failure of the second transplant, the patient recommenced haemodialysis for 5 h three times a week, and his only other significant medical problem was ischaemic heart disease. He lived with his wife in their own home, and they had no children.
He became a patient of our renal unit when he moved house. Since the initial presentation, he had developed hearing loss, and now used two hearing aides. He complained to us of 5 years of deteriorating vision, for which he had required a change of spectacles each year. He had used spectacles for more than 20 years, but was able to read a newspaper and drive a car.
Mr AA was referred to an ophthalmologist who found that he had no eye pain, deterioration of night vision or redness of the eyes. On examination he had 6/6 vision in each eye with spectacles, normal visual fields to confrontation, and normal colour vision on testing with Ishihara colour charts. His pupils were dilated and on slit lamp biomicroscopy, there was no evidence of a corneal dystrophy. Hand-held retinoscopy demonstrated the `oil droplet' sign of anterior lenticonus, and on indirect ophthalmoscopy of the retina with a 20D lens there were many small perimacular dots. These were confirmed with retinal photographs (Figure 1).
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Each 10 µl reaction mix contained about 100 ng of dialysed genomic DNA, 50 ng of the primers, with the 3' primer end-labelled with [-32P]ATP using T4 polynucleotide kinase (Geneworks), 2 mM dNTP (Amersham Pharmacia Biotech) 1 µl of 10x Taq reaction buffer, 2.5 mM MgCl2 and 1 µ Taq polymerase (Geneworks). This was overlaid with a drop of mineral oil and amplified using appropriate conditions in a Perkin Elmer/Cetus DNA thermal cycler. After amplification 2 µl of formamide stop solution (95% formamide, 20 mM EDTA, 0.05% bromophenol blue, 0.05% xylene cyanol) was added to each reaction tube which was incubated at 95°C for 15 min and then chilled immediately. Six µl of the amplification product was electrophoresed in a denaturing polyacrylamide gel at 50°C/80 W for 23 h. Allele sizes were determined after exposing the gel to X-ray film (Biomax Kodak) for 13 h. Linkage to the COL4A4 locus was further examined using an intragenic HaeIII restriction fragment length polymorphism, where the digestion products were examined on a 1% agarose gel.
Lod scores were calculated using the LINKAGE program (V 5.1). Penetrance was assumed to be 70% at the autosomal recessive locus, and 90% at the X-linked locus. The results were more consistent with linkage to the locus for autosomal recessive Alport syndrome than for the X-linked locus (Table 2a,b), although the family was too small for the Lod scores to be conclusive. All family members, except III-2, were carriers of the disease haplotype, and five of these (5/7, 71%) had haematuria but none were deaf or had the eye abnormalities seen in Alport syndrome.
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In this patient, the cause of renal failure was unrecognised for 25 years, until ocular examination demonstrated features typical of Alport syndrome.
The diagnosis of Alport syndrome usually depends on the presence of other affected family members, the characteristic clinical features, and a lamellated ultrastructural appearance of the glomerular basement membrane (GBM) [3]. Sometimes the diagnosis is made when the Goodpasture antigen cannot be demonstrated in affected GBM [4], or with gene linkage studies.
In the family described here there were no other members with Alport syndrome. This occurs with about 15% of patients who have X-linked disease, where mutations occur de novo [5]. However it is more typical of autosomal recessive disease where parents and offspring who are carriers may have haematuria as their only clinical manifestation, and renal failure is not seen in previous or subsequent generations. The consanguinity of Mr AA's parents and the presence of haematuria but not renal failure in other family members suggested autosomal recessive disease, which was consistent with the Lod scores at the corresponding gene locus.
The clinical features of Alport syndrome have been best described in patients with the juvenile-onset form of X-linked disease, where affected males have renal failure, and often a high tone sensorineural deafness, dot-and-fleck retinopathy and lenticonus [69]. The dot-and-fleck retinopathy is rare in conditions other than Alport syndrome, and anterior lenticonus is pathognomonic for this disease [9]. Less common ocular manifestations include recurrent corneal erosions and corneal dystrophies [10,11]. These clinical features are probably identical in autosomal recessive disease, but while males with adult onset X-linked disease have renal failure, the deafness and the eye abnormalities are less common. In the patient described here, the presence of renal failure and deafness at a young age suggested the diagnosis of Alport syndrome, and the subsequent frequent changes of spectacles, which occurs with anterior lenticonus, further supported this. However, the retinopathy was difficult to see on fundoscopy, and was more readily demonstrated with retinal photography.
In Mr AA, the renal biopsy had no diagnostic features, and ultrastructural examination in an end-stage kidney was unlikely to have added further useful information. The diagnosis of X-linked or autosomal recessive Alport syndrome can however be made even in end-stage kidneys when the Goodpasture antigen, or the 35 (IV) collagen chains are absent from affected GBM [4,12]. All mutations in X-linked and autosomal recessive Alport syndrome affect the genes encoding type IV collagen chains (COL4A5 and COL4A3/COL4A4, respectively) which are major components of the basement membranes of the glomerulus, cochlea, retina and lens. The absence of these chains from the affected membranes and the consequent loss of structural integrity probably causes the clinical manifestations of Alport syndrome in the kidney, ear and eye [13]. However, studies looking at type IV collagen chains are technically difficult and rarely performed in a routine laboratory.
In Mr AA's family, gene linkage was more consistent with autosomal recessive Alport syndrome than with X-linked disease. While demonstration of the genetic mutation in the COL4A3 or COL4A4 genes would confirm this form of inheritance, mutation detection techniques are laborious, time-consuming and expensive. Interestingly, haematuria was the only clinical manifestation in carriers of the disease haplotype in this family. None were deaf, or had the retinopathy or lens abnormality.
There are many patients with end-stage renal failure in whom the nature of the underlying disease is never determined. However, it may be important to identify the cause if the disease is inherited or if there is a risk it will recur after transplantation. If the disease is inherited, other family members may also develop renal failure, and the onset can be delayed by lowering their blood pressure, and by reducing proteinuria. In families with autosomal recessive disease the risk of subsequent generations being affected is very low because carriers are rare in the community. Alport syndrome does not recur after transplantation but about 5% of patients develop antiGBM disease in the graft, when they `see' immunologically for the first time the Goodpasture and other antigens that are absent from their own kidneys [14]. These antibodies necessitate removal of the graft, and are likely to recur with subsequent transplants. There was no evidence of antiGBM antibodies in the biopsies of either of Mr AA's renal allografts.
Teaching point
Careful ocular examination and fundus photographs may indicate the diagnosis of Alport syndrome in patients with end-stage renal disease, where the cause has been unknown.
Acknowledgments
This study was supported by the National Health and Medical Research Council of Australia.
References