Figure 31

Alport's syndrome. Alport's syndrome (hereditary nephritis) is a hereditary disorder in which glomerular and other basement membrane collagen is abnormal. This disorder is characterized clinically by hematuria with progressive renal insufficiency and proteinuria. Many patients have neurosensory hearing loss and abnormalities of the eyes. The disease is inherited as an X-linked trait; in some families, however, autosomal recessive and perhaps autosomal dominant forms exist. Clinically, the disease is more severe in males than in females. End-stage renal disease develops in persons 20 to 40 years of age. In some families, ocular manifestations, thrombocytopenia with giant platelets, esophageal leiomyomata, or all of these also occur. In the X-linked form of Alport's syndrome, mutations occur in genes encoding the a-5 chain of type IV collagen (COL4A5). In the autosomal recessive form of this syndrome, mutations of either a-3 or a-4 chain genes have been described. On light microscopy, in the early stages of the disease the glomeruli appear normal. With progression of the disease, however, an increase in the mesangial matrix and segmental sclerosis develop. Interstitial foam cells are common but are not used to make a diagnosis. Results of immunofluorescence typically are negative, except in glomeruli with segmental sclerosis in which segmental immunoglobulin M and complement (C3) are in the sclerotic lesions. Ultrastructural findings are diagnostic and consist of profound abnormalities of glomerular basement membranes. These abnormalities range from extremely thin and attenuated to considerably thickened membranes. The thickened glomerular basement membranes have multiple layers of alternating medium and pale staining strata of basement membrane material, often with incorporated dense granules. The subepithelial contour of the basement membrane typically is scalloped.

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