Original Investigations
A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport's syndrome

https://doi.org/10.1053/ajkd.2001.29217Get rights and content

Abstract

Previous series that described phenotypes in carriers of Alport's syndrome did not distinguish genetically between carriers of X-linked and autosomal recessive disease. In this study, modes of inheritance in unselected families with Alport's syndrome associated with two city and two provincial hospitals were determined using microsatellite markers, and carriers of disease haplotypes were identified within these families. All 47 carriers (100%) from 18 families with X-linked Alport's syndrome had dysmorphic hematuria on phase-contrast microscopy, but few developed renal failure (3 of 40 carriers; 8%), clinical hearing loss (2 of 45 carriers; 4%), retinopathy (1 of 30 carriers; 3%), or lenticonus (0 of 30 carriers; 0%). Eleven of the 14 carriers (79%) from 2 families with autosomal recessive disease had dysmorphic hematuria, but none had renal failure, clinical hearing loss, retinopathy, or lenticonus. Urinary red blood cell counts in carriers of X-linked Alport's syndrome were greater than those in carriers of autosomal recessive disease (P < 0.0001), but the frequency of proteinuria and hypertension and levels of proteinuria were not different. There was more tubulointerstitial damage in carriers of X-linked disease (P = 0.012); however, carriers of autosomal recessive disease had more widespread and more uniform thinning of the glomerular basement membrane (P < 0.0001) and less lamellation (P < 0.04). © 2001 by the National Kidney Foundation, Inc.

Section snippets

Patients and methods

We identified all patients with typical clinical features of Alport's syndrome or a lamellated GBM known to our two city and two provincial hospitals. Two authors (J.S. and D.C.) examined all index cases and their family members. The study also included a family referred from elsewhere with presumed autosomal recessive disease.

In addition, we examined individuals with TBMD diagnosed when their average GBM width was less than 250 nm, as well as their families, if hematuria segregated with the

Results

Twenty-three families with the presumptive diagnosis of Alport's syndrome were studied. Families were of northern and southern European, Chinese, and Indochinese origins. All hematuria shown in any individual was dysmorphic (or glomerular) in nature.

Only one person invited to take part, a child, refused to participate fully and was examined, but would not provide a buccal brushing. Nevertheless, she was presumed to be a carrier of X-linked Alport's syndrome because her father was affected and

Discussion

This study compared clinical, histopathologic, and ultrastructural characteristics of an unselected series of carriers of X-linked and autosomal recessive Alport's syndrome who had been identified by haplotype analysis. Most previously published descriptions of carrier phenotypes did not distinguish between X-linked and autosomal recessive disease12, 13, 14, 15, 16 and probably consisted of both forms of inheritance, as well as some individuals who did not have Alport's syndrome. Even series in

References (35)

  • CL Atkin et al.

    Mapping of Alport syndrome to the long arm of the X chromosome

    Am J Hum Genet

    (1988)
  • N Hinglais et al.

    Characteristic ultrastructural lesion of the glomerular basement membrane in progressive nephritis (Alport's syndrome)

    Lab Invest

    (1972)
  • JC Myers et al.

    Molecular cloning of the α5(IV) collagen and assignment of the gene to the region of the X chromosome containing the Alport syndrome locus

    Am J Hum Genet

    (1990)
  • DF Barker et al.

    Identification of mutations in the COL4A5 collagen gene in Alport syndrome

    Science

    (1990)
  • T Mochizuki et al.

    Identification of mutations in the α3(IV) and α4(IV) collagen genes in autosomal recessive Alport syndrome

    Nat Genet

    (1994)
  • MM Kleppel et al.

    Distribution of familial nephritis antigen in normal tissue and renal basement membranes of patients with homozygous and heterozygous Alport familial nephritis

    Lab Invest

    (1989)
  • K Yoshioka et al.

    Type IV collagen α5 chain; Normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody

    Am J Pathol

    (1994)
  • Cited by (0)

    Supported in part by the National Health and Medical Research Council of Australia and the Australian Kidney Foundation.

    Address reprint requests to Judy Savige, PhD, MD, University Department of Medicine, Austin and Repatriation Medical Centre, Heidelberg, Vic 3084, Australia. E-mail: [email protected]

    0272-6386/01/3806-0009$35.00/0

    View full text