X-Linked Alport Syndrome

Abstract

Abstract. Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of heterozygous girls and women belonging to the 195 families with proven COL4A5 mutation are compared with those of hemizygous boys and men. Hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively. The probability of developing end-stage renal disease or deafness before the age of 40 yr was 12% and 10%, respectively, in girls and women versus 90 and 80%, respectively, in boys and men. The risk of progression to end-stage renal disease appears to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified: the occurrence and progressive increase in proteinuria, and the development of a hearing defect.

Prognostic Value of Glomerular Collagen IV Immunofluorescence Studies in Male Patients with X-Linked Alport Syndrome

“…Finally, correlation between the severity of renal involvement and extrarenal symptoms is well established in X-AS (3,4,20,27). Likewise, we also observed that patients with early-onset CKD developed deafness earlier.…”

Thin Basement Membrane Nephropathy

“…Thus, individuals with autosomal TBMN are carriers for autosomal Alport syndrome. Heterozygosity for mutations in COL4A5 in female carriers for X-linked Alport syndrome can also mimic a TBMN condition, although some of those individuals will later develop progressive hematuria (94). It is not clear whether the individuals with TBMN and female carriers who simulate TBMN and develop progressive disease could have a second mutation in some other of the six alleles that encode the ␣3: ␣4:␣5 collagen form.…”

“…Practically all female carriers for X-linked Alport syndrome who have a mutation in one COL4A5 allele exhibit hematuria. In a study of 288 heterozygous female individuals from 329 families with X-linked Alport syndrome, 96% had hematuria, and a relatively large proportion (30%) had progressive disease that led to chronic renal failure and ESRD (94). This type of progression is not considered typical for TBMN (1).…”

Mammalian collagen IV

“…However, it was not until 1990 that the genetic basis for what came to be known as X-linked Alport's syndrome was described (Barker et al, 1990;Hostikka et al, 1990;Myers et al, 1990;Pihlajaniemi et al, 1990). Since then, a large number of different mutations in the COL4A5 gene as well as in the COL4A3 and COL4A4 genes have been reported (Jais et al, 2000(Jais et al, , 2003Longo et al, 2002). These mutations not only include nonsense and missense mutations, but also mutations that affect splicing, stability of triple-helical structure, posttranslational modifications, and the assembly of chains into heterotrimeric molecules.…”