Clinical and molecular diagnosis of Alport syndrome

Alport syndrome is an inherited disorder of collagen that affects the kidney, the eye, and the cochlea. The disease exhibits variability in its clinical and pathological manifestations, and is genetically heterogeneous. The X-linked dominant form of Alport syndrome arises from mutation in the COL4A5 gene, which encodes the alpha 5 chain of type IV collagen. The autosomal recessive form is caused by mutation in the COL4A3 gene, which encodes the alpha 3 chain of type IV collagen, or in the COL4A4 gene, which encodes the alpha 4 chain of type IV collagen. An autosomal dominant variety of Alport syndrome also exists, but mutations in this form of the disease have not yet been described. Cotransmission of X-linked dominant Alport syndrome and diffuse leiomyomatosis in some families results from deletions involving the COL4A5 gene and the contiguous COL4A6 gene. The clinical and pathologic features of Alport syndrome are attributable to abnormalities in the basement membrane collagen network composed of the alpha 3, alpha 4, and alpha 5 chains of type IV collagen, although the mechanism by which mutation in the gene encoding one of these chains effects the other two chains is not yet known. In addition, the processes that lead to progressive glomerular scarring and renal failure are incompletely understood. While diagnosis of Alport syndrome still rests on clinical and pathologic evaluation, immunohistochemical and molecular genetic tools can augment diagnostic precision.