Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes

Alport syndrome (AS) is a genetically heterogeneous disease arising from mutations in genes coding for basement membrane type IV collagen. About 80% of AS is X-linked, due to mutations in COL4A5, the gene encoding the alpha 5 chain of type IV collagen (alpha 5[IV]). A subtype of X-linked Alport syndrome (XLAS) in which diffuse leiomyomatosis is an associated feature reflects deletion mutations involving the adjacent COL4A5 and COL4A6 genes. Most other patients have autosomal recessive Alport syndrome (ARAS) due to mutations in COL4A3 or COL4A4, which encode the alpha 3(IV) and alpha 4(IV) chains, respectively. Autosomal dominant AS has been mapped to chromosome 2 in the region of COL4A3 and COL4A4. The features of AS reflect derangements of basement membrane structure and function resulting from changes in type IV collagen expression. The primary pathologic event appears to be the loss from basement membranes of a type IV collagen network composed of alpha 3, alpha 4, and alpha 5(IV) chains. While this network is not critical for normal glomerulogenesis, its absence appears to provoke the overexpression of other extracellular matrix proteins, such as the alpha 1 and alpha 2(IV) chains, in glomerular basement membranes, leading to glomerulosclerosis. The diagnosis of AS still relies heavily on histologic studies, although routine application of molecular genetic diagnosis will probably be available in the future. Absence of epidermal basement membrane expression of alpha 5(IV) is diagnostic of XLAS, so in some cases kidney biopsy may not be necessary for diagnosis. Analysis of renal expression of alpha 3(IV)-alpha 5(IV) chains may be a useful adjunct to routine renal biopsy studies, especially when ultrastructural changes in the GBM are ambiguous. There are no specific therapies for AS. Spontaneous and engineered animal models are being used to study genetic and pharmacologic therapies. Renal transplantation for AS is usually very successful. Occasional patients develop anti-GBM nephritis of the allograft, almost always resulting in graft loss.