Abstract: An 11-year-old girl was referred 10 years ago to the Cliniques Universitaires St. Luc for renal transplantation. At age 7, dipstick proteinuria and microscopic hematuria had been discovered at a school examination. Workup performed at that time at another hospital revealed a serum creatinine of 0.5 mg/dl, marked proteinuria (3.3 g/liter), and 100 red blood cells/high-power field on microscopy of the urine sediment; intravenous pyelography was normal. The patient's parents declined a renal biopsy. The patient was lost to follow-up for four years. She then presented at age 11 with end-stage renal failure (creatinine clearance, 2.6 ml/min /1.73 m2). Ultrasonographic examination disclosed symmetrically reduced kidneys. Proteinuria and microscopic hematuria were again detected. Serologic tests, including complement studies, were unremarkable. There was no family history of renal disease. The patient's mother proposed donating a kidney to her daughter. The mother's assessment did not reveal any abnormality, and transplantation was performed two months after initiation of hemodialysis. Post-transplantation immunosuppression included antilymphocyte globulin, cyclosporine, azathioprine, and prednisolone. The patient was discharged 13 days after surgery with a serum creatinine of 0.6 mg/dl. No rejection episode occurred. Histologic examination of the kidney removed at the time of transplantation showed on light microscopy mostly sclerotic, but also some normal-looking, glomeruli as well as diffuse interstitial scarring with a few inflammatory cells and foci of foam cells. Immunofluorescence studies disclosed only faint, focal staining for IgM, fibrinogen, and C3 along some vessel walls. No specific diagnosis was made. Twenty months after transplantation, a hearing defect was detected at school. An audiogram revealed a symmetric loss of about 50 dB in the 1000 to 8000 Hz range, a loss typical of sensorineural deafness Figure 1. A diagnosis of Alport's syndrome (AS) was suspected. Ophthalmologic evaluation failed to show lenticonus and macular flecks. Electron microscopic examination of the nephrectomy specimen revealed a grossly abnormal appearance of the glomerular basement membrane (GBM) typical of Alport's syndrome, including irregular contours, areas of thinning, and marked thickening and splitting with inclusion of electron-dense granules in electron-lucent areas Figure 2.Figure 2Electron photomicrograph of glomerular basement membrane, showing segments of thickening and thinning with irregular contours (left panel). Magnification of a thickened segment showing lamellation, electron-lucent areas and electron-dense granules (right panel).Courtesy of Dr. J.P. Cosyns.View Large Image Figure ViewerDownload (PPT) Despite the absence of renal disease in this family, a clinical and genetic screening of the first relatives was proposed. The parents told us for the first time that they were first cousins; this information raised the suspicion of a recessive form of Alport's syndrome. Both parents and the patient's three siblings had normal urinalyses and normal serum creatinine levels. The father was mildly hypertensive and had a bilateral, symmetric hearing loss in the 3000 to 6000 Hz range, attributed to his work in a noisy environment. The mother and the three siblings had normal blood pressure and normal audiograms, except for a slight unilateral hearing loss in one sister. Linkage analysis using six genetic markers near and within the COL4A5 gene, the gene responsible for the X-linked form of Alport's syndrome, showed that one unaffected brother had received from his mother a copy of the same haplotype as the proband. Thus the COL4A5 gene was not responsible for the disease in this family. In fact, both the consanguinity and the development of renal failure in a very young female strongly suggested a recessive form of Alport's syndrome involving the COL4A3 or COL4A4 gene. Direct sequencing of PCR products from the first five exons of COL4A3 (counted from the 3′ end of the gene) disclosed a homozygous single-base substitution of T to C in exon 5 of COL4A3; this mutation replaces an arginine codon with a stop codon, shortening the α3(IV) chain by 190 amino acids1.Mochizuki T. Lemmink H.H. Mariyama M. Antignac C. Gubler M.C. Pirson Y. Verellen-Dumoulin C. Chan B. Schröder C.H. Smeets H.J. Reeders S.T. Identification of mutations in the α3 (IV) and α4 (IV) collagen genes in autosomal recessive Alport syndrome.Nat Genet. 1994; 8: 77-82Crossref PubMed Scopus (401) Google Scholar. Further immunohistochemical study of the preserved glomeruli and tubules from the nephrectomy specimen revealed no fixation of anti-α3, -α4, and -α5(IV) antibodies in the GBM, whereas isolated staining of anti-α5(IV) was observed in the basement membranes of Bowman's capsules and collecting ducts Figure 3, a pattern consistent with the autosomal-recessive form of Alport's syndrome2.Gubler M.C. Knebelmann B. Beziau A. Broyer M. Pirson Y. Haddoum F. Kleppel M.M. Antignac C. Autosomal recessive Alport syndrome: Immunohistochemical study of type IV collagen chain distribution.Kidney Int. 1995; 47: 1142-1147Abstract Full Text PDF PubMed Scopus (159) Google Scholar. The patient was given information on the recessive nature of her disease. She subsequently became pregnant and gave birth one year ago to a normal girl. She is currently doing well 10 years after transplantation and has normal graft function. Her maintenance daily immunosuppressive regimen includes cyclosporine, 2 mg/kg; azathioprine, 1 mg/kg; and prednisolone, 0.1 mg/kg. dr. yves pirson (Clinical Professor, Service de Néphrologie, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium): As the case presentation illustrates, the diagnosis of Alport's syndrome can escape a physician's attention in the absence of a family history of the disease. Furthermore, even after the recognition of both sensorineural deafness and GBM abnormalities, this case would not have met the strict diagnostic criteria proposed 10 years ago for "classic" AS3.Flinter F.A. Cameron J.S. Chantler C. Houston I. Bobrow M. Genetics of classic Alport's syndrome.Lancet. 1988; 2: 1005-1007Abstract PubMed Scopus (175) Google Scholar, because both a family history and ophthalmic signs were absent. Since identification of the genes responsible for AS, first the "classic" X-linked in 19904.Hostikka S.L. Eddy R.L. Byers M.C. Höyhtyä M. Shows T.B. Tryggvason K. Identification of a distinct type IV collagen α chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome.Proc Natl Acad Sci USA. 1990; 87: 1606-1610Crossref PubMed Scopus (308) Google Scholar and in 1994 the autosomal-recessive forms1.Mochizuki T. Lemmink H.H. Mariyama M. Antignac C. Gubler M.C. Pirson Y. Verellen-Dumoulin C. Chan B. Schröder C.H. Smeets H.J. Reeders S.T. Identification of mutations in the α3 (IV) and α4 (IV) collagen genes in autosomal recessive Alport syndrome.Nat Genet. 1994; 8: 77-82Crossref PubMed Scopus (401) Google Scholar, genetic mutation detection has become the ultimate and sufficient diagnostic criterion. However, mutation analysis of the AS genes remains a tedious and sometimes unsuccessful task because the incriminated genes contain more than 50 exons and there is no "hot spot." The development of new DNA analyses such as the chip technology could improve the yield of mutation screening in the near future5.Ramsay G. DNA chips: State-of-the-art.Nat Biotechnol. 1998; 16: 40-44Crossref PubMed Scopus (736) Google Scholar. In the meantime, the diagnosis of AS rests in the majority of cases on a careful stepwise approach exemplified by the case presentation: careful collection and analysis of family history and clinical features, electron microscopic and immunohistologic examination of basement membranes, and genetic linkage analysis. After a brief review of the pathogenesis of the disease, I will critically review the diagnostic value of each clinical and pathologic feature and propose a diagnostic strategy. Alport's syndrome is characterized by a progressive glomerulonephritis erratically associated with various extrarenal features, mainly auditory and ocular defects6.Grünfeld J.P. Nephrology Forum: The clinical spectrum of hereditary nephritis.Kidney Int. 1985; 27: 83-92Abstract Full Text PDF PubMed Scopus (83) Google Scholar,7.Kashtan C.E. Michael A.F. Alport syndrome.Kidney Int. 1996; 50: 1445-1463Abstract Full Text PDF PubMed Scopus (155) Google Scholar. Estimated gene frequency is 1:5000 to 1:10000; AS accounts for 1% to 2% of cases of end-stage renal failure (ESRF) in Western countries8.Grünfeld J.P. Knebelmann B. Alport's syndrome.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2427-2437Google Scholar. Alport's syndrome is caused by defects in type-IV collagen, a major component of basement membranes. Type-IV collagen is composed of three α-chains that form a triple helical molecule. Each α-chain consists of a central domain (the collagenous domain), an amino terminal end (the 7S domain), and a globular carboxy terminal end (the non-collagenous domain or NC1 domain)9.Reeders S.T. Nephrology Forum: Molecular genetics of hereditary nephritis.Kidney Int. 1992; 42: 783-792Abstract Full Text PDF PubMed Scopus (27) Google Scholar. Six genetically distinct type-IV collagen α-chains, α1(IV) through α6(IV), have been identified. They are encoded by genes (called COL4A1 to A6) arranged pairwise on three different chromosomes: COL4A1 and COL4A2 on chromosome 13, COL4A3 and COL4A4 on chromosome 2, and COL4A5 and COL4A6 on chromosome X10.Zhou J. Reeders S.T. The α chains of type IV collagen.Molecular Pathology and Genetics of Alport Syndrome. edited by Tryggvason K. Karger, Basel1996: 80-104Google Scholar. The α1(IV) and α2(IV) chains are present in all basement membranes; mutations in their genes are likely to be lethal in the embryo10.Zhou J. Reeders S.T. The α chains of type IV collagen.Molecular Pathology and Genetics of Alport Syndrome. edited by Tryggvason K. Karger, Basel1996: 80-104Google Scholar. By contrast, the α3, α4, α5, and α6(IV) chains are expressed selectively in the basement membranes of some tissues, including those potentially involved in AS, that is, kidney, cochlea, and eye11.Kashtan C.E. Kleppel M.M. Gubler M.C. Immunohistologic findings in Alport syndrome.Molecular Pathology and Genetics of Alport Syndrome. edited by Tryggvason K. Karger, Basel1996: 142-153Crossref Google Scholar. In approximately 85% of AS pedigrees, the disease is X-linked and mutations identified so far are in the COL4A5 gene. Of 176 mutations in the COL4A5 gene recorded by Lemmink and coworkers, 38 are large- and medium-sized deletions (ranging from a single exon to the complete gene) and 138 are small mutations of all types (mis-sense: 62; frameshift group including small deletion, insertion, splice site and non-sense: 69; inframe group including deletion and duplication: 7)12.Lemmink H.H. Schröder C.H. Monnens L.A.H. Smeets H.J.M. The clinical spectrum of type IV collagen mutations.Hum Mutat. 1997; 9: 477-499Crossref PubMed Scopus (145) Google Scholar. The mutations are interspersed along the gene. New mutations comprise 10% to 15%, a proportion comparable with that found in other X-linked disorders12.Lemmink H.H. Schröder C.H. Monnens L.A.H. Smeets H.J.M. The clinical spectrum of type IV collagen mutations.Hum Mutat. 1997; 9: 477-499Crossref PubMed Scopus (145) Google Scholar. In the few X-linked families with associated leiomyomatosis, Antignac and Heidet have identified contiguous deletions involving both the COL4A5 and the COL4A6 genes13.Antignac C. Heidet L. Mutations in Alport syndrome associated with diffuse esophageal leiomyomatosis.Molecular Pathology and Genetics of Alport Syndrome. edited by Tryggvason K. Karger, Basel1996: 172-182Crossref Google Scholar. So far, no mutation solely within the COL4A6 gene has been reported in patients with AS. In the majority of the non-X-linked families, the transmission appears to be autosomal recessive, with mutations detected in either the COL4A3 or the COL4A4 gene; Lemmink et al have recorded nine different mutations (six in COL4A3, three in COL4A4)12.Lemmink H.H. Schröder C.H. Monnens L.A.H. Smeets H.J.M. The clinical spectrum of type IV collagen mutations.Hum Mutat. 1997; 9: 477-499Crossref PubMed Scopus (145) Google Scholar. Of interest, mutations in the COL4A3/A4 genes appear to be involved in a subset of patients with so-called benign familial hematuria14.Lemmink H.H. Nillesen W.N. Mochizuki T. Schröder C.H. Brunner H.G. van Oost B.A. Monnens L.A.H. Smeets H.J.M. Benign familial hematuria due to mutation of the type IV collagen α4 gene.J Clin Invest. 1996; 98: 1114-1118Crossref PubMed Scopus (170) Google Scholar and perhaps also in a rare, autosomal-dominant, form of AS15.Jefferson J.A. Lemmink H.H. Hughes A.E. Hill C.M. Smeets H.J.M. Doherty C.C. Maxwell A.P. Autosomal dominant Alport syndrome linked to the type IV collagen α3 and α4 genes (COL4A3 and COL4A4).Nephrol Dial Transplant. 1997; 12: 1595-1599Crossref PubMed Scopus (120) Google Scholar. I will discuss these preliminary data briefly in a moment. In the X-linked form of AS, the disease is consistently severe in affected males (hemizygotes) and usually much less symptomatic in affected females (referred to as XL heterozygotes); the wide range of severity observed in females is ascribed to the well-known random inactivation of one of the X chromosomes16.Puck J.M. Willard H.F. X inactivation in females with X-linked disease.N Engl J Med. 1998; 338: 325-327Crossref PubMed Scopus (153) Google Scholar. In the autosomal-recessive form, the disease is, as expected, as severe in male as in female homozygotes or in the rare compound heterozygotes, referred to collectively as AR homozygotes for the sake of simplicity; mild clinical manifestations are occasionally observed in carriers of the autosomal recessive form (referred to as AR heterozygotes). Hematuria is the key clinical feature in AS. Just as in other glomerular diseases, examination of the urine frequently reveals red blood cell casts and, in phase-contrast microscopy, acanthocyturia6.Grünfeld J.P. Nephrology Forum: The clinical spectrum of hereditary nephritis.Kidney Int. 1985; 27: 83-92Abstract Full Text PDF PubMed Scopus (83) Google Scholar. In the X-linked form, microscopic hematuria is observed in all males and in 95% of females17.Flinter F.A. Disorders of the basement membrane: Hereditary nephritis.Inherited Disorders of the Kidney. edited by Morgan SH, Grünfeld JP. Oxford University Press, Oxford1998: 192-214Google Scholar. In hemizygotes, microscopic hematuria is constant from infancy, whereas it can be intermittent in XL heterozygotes. Episodes of gross hematuria occur in 60% to 70% of hemizygotes (sometimes after an upper respiratory tract infection, just as in IgA nephropathy), most often before the age of 158.Grünfeld J.P. Knebelmann B. Alport's syndrome.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2427-2437Google Scholar, and in one-third of XL heterozygotes8.Grünfeld J.P. Knebelmann B. Alport's syndrome.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2427-2437Google Scholar,17.Flinter F.A. Disorders of the basement membrane: Hereditary nephritis.Inherited Disorders of the Kidney. edited by Morgan SH, Grünfeld JP. Oxford University Press, Oxford1998: 192-214Google Scholar. In the autosomal-recessive form, all AR homozygotes have microscopic hematuria and many have episodes of gross hematuria; interestingly, microscopic hematuria is found in about one-half of AR heterozygotes1.Mochizuki T. Lemmink H.H. Mariyama M. Antignac C. Gubler M.C. Pirson Y. Verellen-Dumoulin C. Chan B. Schröder C.H. Smeets H.J. Reeders S.T. Identification of mutations in the α3 (IV) and α4 (IV) collagen genes in autosomal recessive Alport syndrome.Nat Genet. 1994; 8: 77-82Crossref PubMed Scopus (401) Google Scholar,12.Lemmink H.H. Schröder C.H. Monnens L.A.H. Smeets H.J.M. The clinical spectrum of type IV collagen mutations.Hum Mutat. 1997; 9: 477-499Crossref PubMed Scopus (145) Google Scholar. Proteinuria, usually absent in the first years of life, eventually appears in all hemizygotes and AR homozygotes and can lead to the nephrotic syndrome in as many as 30% of patients6.Grünfeld J.P. Nephrology Forum: The clinical spectrum of hereditary nephritis.Kidney Int. 1985; 27: 83-92Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 7.Kashtan C.E. Michael A.F. Alport syndrome.Kidney Int. 1996; 50: 1445-1463Abstract Full Text PDF PubMed Scopus (155) Google Scholar, 8.Grünfeld J.P. Knebelmann B. Alport's syndrome.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2427-2437Google Scholar. Proteinuria is recorded in two-thirds of XL heterozygotes8.Grünfeld J.P. Knebelmann B. Alport's syndrome.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2427-2437Google Scholar. Not unexpectedly, the risk of progression to end-stage renal failure is the highest among hemizygotes and AR homozygotes. In hemizygotes, the probability of developing ESRF is 90% by the age of 40 (abstract, Gubler et al, J Am Soc Nephrol 9:388A, 1998). According to the age at ESRF in hemizygotes, X-linked AS is said to be of either the juvenile or the adult type, the arbitrary cut-off being 31 years18.Gregory M.C. Terreros D.A. Barker D.F. Fain P.N. Denison J.C. Atkin C.L. Alport syndrome: Clinical phenotypes, incidence and pathology.Molecular Pathology and Genetics of Alport Syndrome. edited by Tryggvason K. Karger, Basel1996: 1-28Crossref Google Scholar. The juvenile type is encountered in three-quarters of kindreds. In XL heterozygotes, the probability of developing ESRF is 12% by the age of 40 and 30% by the age of 60 (abstract; Gubler et al, ibid); risk factors for progression are a history of gross hematuria in childhood, nephrotic syndrome, and diffuse GBM thickening19.Grünfeld J.P. Noël L.H. Hafez S. Droz D. Renal prognosis in women with hereditary nephritis.Clin Nephrol. 1985; 23: 267-271PubMed Google Scholar. Renal prognosis also depends on the kind of mutation. Among hemizygotes the probability of ESRF before the age of 30 is significantly higher (90%) in individuals with a large rearrangement of COL4A5 or a small mutation leading to a stop codon than in those with a splice-site (70%) or mis-sense (50%) mutation (abstract; Gubler et al, ibid). As a result, a good concordance usually exists for the age of onset of ESRF among affected relatives8.Grünfeld J.P. Knebelmann B. Alport's syndrome.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2427-2437Google Scholar, especially in the juvenile type. Still, a large intrafamilial variability—as indicated by a more than 20-year difference in the age at ESRF in related hemizygotes—has been reported in the adult type20.Knebelmann B. Deschenes G. Gros F. Hors M.C. Grünfeld J.P. Zhou J. Tryggvason K. Gubler M.C. Antignac C. Substitution of arginine for glycine 325 in the collagen α5 (IV) chain associated with X-linked Alport syndrome: Characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments.Am J Hum Genet. 1992; 51: 135-142PubMed Google Scholar, 21.Renieri A. Meroni M. Sessa A. Battini G. Serbelloni P. Tarelli L.T. Seri M. Galli L. De Marchi M. Variability of clinical phenotype in a large Alport family with gly 1143 ser change of collagen α5 (IV)-chain.Nephron. 1994; 67: 444-449Crossref PubMed Scopus (28) Google Scholar, 22.Barker D.F. Pruchno C.J. Jiang X. Atkin C.L. Stone E.M. Denison J.C. Fain P.R. Gregory M.C. A mutation causing Alport syndrome with tardive hearing loss is common in the Western United States.Am J Hum Genet. 1996; 58: 1157-1165PubMed Google Scholar. A more than 10-year difference in the age at ESRF also has been observed among related AR homozygotes1.Mochizuki T. Lemmink H.H. Mariyama M. Antignac C. Gubler M.C. Pirson Y. Verellen-Dumoulin C. Chan B. Schröder C.H. Smeets H.J. Reeders S.T. Identification of mutations in the α3 (IV) and α4 (IV) collagen genes in autosomal recessive Alport syndrome.Nat Genet. 1994; 8: 77-82Crossref PubMed Scopus (401) Google Scholar,23.Finielz P. Cartault F. Chuet C. Genin R. Alport syndrome in Réunion Island: Phenotypic heterogeneity of the recessive-autosomal form.Nephron. 1998; 79 (letter): 237Crossref PubMed Scopus (6) Google Scholar. Sensorineural deafness used to be a prerequisite for the diagnosis of AS3.Flinter F.A. Cameron J.S. Chantler C. Houston I. Bobrow M. Genetics of classic Alport's syndrome.Lancet. 1988; 2: 1005-1007Abstract PubMed Scopus (175) Google Scholar. It is now clear that hearing is not impaired in some families with X-linked as well as with autosomal-recessive AS1.Mochizuki T. Lemmink H.H. Mariyama M. Antignac C. Gubler M.C. Pirson Y. Verellen-Dumoulin C. Chan B. Schröder C.H. Smeets H.J. Reeders S.T. Identification of mutations in the α3 (IV) and α4 (IV) collagen genes in autosomal recessive Alport syndrome.Nat Genet. 1994; 8: 77-82Crossref PubMed Scopus (401) Google Scholar, 7.Kashtan C.E. Michael A.F. Alport syndrome.Kidney Int. 1996; 50: 1445-1463Abstract Full Text PDF PubMed Scopus (155) Google Scholar, 12.Lemmink H.H. Schröder C.H. Monnens L.A.H. Smeets H.J.M. The clinical spectrum of type IV collagen mutations.Hum Mutat. 1997; 9: 477-499Crossref PubMed Scopus (145) Google Scholar. Hearing loss is never present at birth. Generally (but not always, as exemplified in the case presentation), hearing loss becomes symptomatic before the onset of renal failure. In the early stage, it is detectable only by audiometry, revealing a bilateral high tone loss (defined as -30 dB) most marked in the 2000 to 8000 Hz frequency range7.Kashtan C.E. Michael A.F. Alport syndrome.Kidney Int. 1996; 50: 1445-1463Abstract Full Text PDF PubMed Scopus (155) Google Scholar,24.Gubler M. Levy M. Broyer M. Naizot C. Gonzales G. Perrin D. Habib R. Alport's syndrome: A report of 58 cases and a review of the literature.Am J Med. 1981; 70: 493-505Abstract Full Text PDF PubMed Scopus (187) Google Scholar. Serial studies demonstrate a progressive loss of as much as 50 to 70 dB, as well as loss at lower frequencies7.Kashtan C.E. Michael A.F. Alport syndrome.Kidney Int. 1996; 50: 1445-1463Abstract Full Text PDF PubMed Scopus (155) Google Scholar,24.Gubler M. Levy M. Broyer M. Naizot C. Gonzales G. Perrin D. Habib R. Alport's syndrome: A report of 58 cases and a review of the literature.Am J Med. 1981; 70: 493-505Abstract Full Text PDF PubMed Scopus (187) Google Scholar. Hearing loss can affect conversational speech to the extent that patients require a hearing aid. The risk of developing hearing loss by the age of 40 is about 90% for hemizygotes and 10% for XL heterozygotes (abstract; Gubler et al, ibid). Hearing loss is present in about two-thirds of AR homozygotes, usually before the age of 2012.Lemmink H.H. Schröder C.H. Monnens L.A.H. Smeets H.J.M. The clinical spectrum of type IV collagen mutations.Hum Mutat. 1997; 9: 477-499Crossref PubMed Scopus (145) Google Scholar. Just as for renal prognosis, hearing loss is determined by the kind of mutation: among hemizygotes the probability of developing hearing loss before the age of 30 is significantly lower in those with a mis-sense mutation than in those with other types of mutation (abstract; Gubler et al, ibid). Of note, a specific COL4A5 mis-sense mutation, found in 87 males from nine US families sharing a common ancestry, is associated with a remarkable late-onset hearing loss, reported in only 60% of patients by age 60, 10 years on average after ESRF22.Barker D.F. Pruchno C.J. Jiang X. Atkin C.L. Stone E.M. Denison J.C. Fain P.R. Gregory M.C. A mutation causing Alport syndrome with tardive hearing loss is common in the Western United States.Am J Hum Genet. 1996; 58: 1157-1165PubMed Google Scholar; interestingly, the age at which hearing loss becomes apparent is highly variable in this family (with an interval of as long as 30 years)22.Barker D.F. Pruchno C.J. Jiang X. Atkin C.L. Stone E.M. Denison J.C. Fain P.R. Gregory M.C. A mutation causing Alport syndrome with tardive hearing loss is common in the Western United States.Am J Hum Genet. 1996; 58: 1157-1165PubMed Google Scholar. Limited information is available on the histology of the inner ear in patients with AS. Data point to the stria vascularis of the cochlea as the site of the most striking alterations7.Kashtan C.E. Michael A.F. Alport syndrome.Kidney Int. 1996; 50: 1445-1463Abstract Full Text PDF PubMed Scopus (155) Google Scholar. In a mouse model of AS, a marked thickening of the basement membranes of the strial vessels has been observed25.Cosgrove D. Samuelson G. Meehan D.T. Miller C. McGee J. Walsh E.J. Siegel M. Ultrastructural, physiological, and molecular defects in the inner ear of a gene-knockout mouse model for autosomal Alport syndrome.Hear Res. 1998; 121: 84-98Crossref PubMed Scopus (75) Google Scholar. Sensorineural deafness developing in the presence of nephropathy should suggest several other hereditary disorders (Table 1)9.Reeders S.T. Nephrology Forum: Molecular genetics of hereditary nephritis.Kidney Int. 1992; 42: 783-792Abstract Full Text PDF PubMed Scopus (27) Google Scholar, which are rarer, and therefore less well known, than AS. A specific mitochondrial DNA (mtDNA) mutation (a guanine for adenine substitution at position 3243) is responsible for a syndrome combining diabetes mellitus, sensorineural deafness, and progressive renal failure26.Manouvrier S. Rötig A. Hannebique G. Gheerbrandt J.D. Royer-Legrain G. Munnich A. Parent M. Grünfeld J.P. Largilliere C. Lombes A. Bonnefont J.P. Point mutation of the mitochondrial tRNALeu gene (A 3243 G) in maternally inherited hypertrophic cardiomyopathy, diabetes mellitus, renal failure, and sensorineural deafness.J Med Genet. 1995; 32: 654-656Crossref PubMed Scopus (68) Google Scholar,27.Jansen J.J. Maassen J.A. Van der Woude F.J. Lemmink H.A.J. Van Den Ouweland J.M.W. 't Hart L.M. Smeets H.J.M. Bruijn J.A. Lemkes HHPJ Mutation in mitochondrial tRNALeu(UUR) gene associated with progressive kidney disease.J Am Soc Nephrol. 1997; 8: 1118-1124PubMed Google Scholar; remarkably, several reported patients had been misdiagnosed as having AS27.Jansen J.J. Maassen J.A. Van der Woude F.J. Lemmink H.A.J. Van Den Ouweland J.M.W. 't Hart L.M. Smeets H.J.M. Bruijn J.A. Lemkes HHPJ Mutation in mitochondrial tRNALeu(UUR) gene associated with progressive kidney disease.J Am Soc Nephrol. 1997; 8: 1118-1124PubMed Google Scholar. The manifestations of the other listed diseases are clearly different from AS. Muckle-Wells syndrome is characterized by recurrent bouts of fever with urticaria and limb pain complicated by AA amyloidosis and the eventual development of the nephrotic syndrome28.Benson M.D. Amyloidosis.The Metabolic and Molecular Bases of Inherited Diseases. edited by Scriver CR, Beaudet AL, Sly WS, Valle D. McGraw-Hill, New York1995: 4159-4191Google Scholar. Cockayne syndrome is characterized by a variety of clinical features including glomerulonephritis, photosensitivity, precocious senile appearance, neurologic abnormalities, and retinitis pigmentosa29.Cameron J.S. Some rare inherited syndromes with renal involvement.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2491-2498Google Scholar. Various associations between malformed ears, hearing loss, and renal abnormalities have been described; the most common is the branchio-oto-renal syndrome29.Cameron J.S. Some rare inherited syndromes with renal involvement.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2491-2498Google Scholar. Bardet-Biedl syndrome, as well as its variant, Alström's syndrome (in which hypogenitalism is absent), can include both renal cystic dysplasia and deafness29.Cameron J.S. Some rare inherited syndromes with renal involvement.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2491-2498Google Scholar. A few patients with the Charcot-Marie-Tooth syndrome have focal segmental glomerulosclerosis associated with hearing loss30.Bobrie G. Grünfeld J.P. Nail-patella syndrome and other rare inherited disorders with glomerular involvement.Oxford Textbook of Clinical Nephrology. edited by Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG. Oxford University Press, Oxford1998: 2446-2449Google Scholar. Sensorineural deafness also has been reported in patients with the autosomal-recessive, but not the autosomal-dominant, form of distal tubular acidosis31.Bajaj G. Quan A. Renal tubular acidosis and deafness: Report of a large family.Am J Kidney Dis. 1996; 27: 880-882Abstract Full Text PDF PubMed Scopus (20) Google Scholar. One family with autosomal-dominant hypoparathyroidism, sensorineural deafness, and rena