Diseases with GBM Abnormalities: Alport Syndrome and Thin GBM Disease

Diseases with GBM Abnormalities: Alport Syndrome and Thin GBM Disease Alport Syndrome Alport syndrome is an inherited disorder of basement membranes. In more than half of the patients, the disease results from a mutation in the gene (COL4A5) that codes for the α5 chain of type IV collagen α5(IV). The syndrome is characterized by a progressive nephritis manifested by persistent or intermittent hematuria and is frequently associated with sensorineural hearing loss and ocular abnormalities. Most patients have mild proteinuria, which progresses with age; kidneys become nephrotic in approximately one-third of the patients. The disease is X-linked in at least 80% of the patients, but autosomal recessive and autosomal dominant patterns of inheritance have been described. In virtually all male patients, the syndrome progresses to ESRD, often by age 16 to 35. The disease is usually mild in heterozygous females, but some develop ESRD, usually after age 50. The rate of progression to ESRD is fairly constant among affected males within individual families, but it varies markedly from family to family. On light microscopy, the glomerular changes are nonspecific. Diagnostic features are usually seen on electron microscopy. At an early stage, thinning of the GBM may be the only visible abnormality and may suggest thin basement membrane disease. With time, the GBM thickens and the lamina densa splits into several irregular layers that may branch and rejoin, producing a characteristic “basket weave” appearance. Immunohistochemical studies of type IV collagen show the absence of α3(IV), α4(IV), and α5(IV) chains from the GBM and distal tubular basement membrane. This abnormality occurs only in patients with Alport syndrome and is diagnostic. In families with a previously defined mutation, molecular diagnosis of affected males or gene-carrying females is possible. For families in which mutations have not been defined, genetic linkage analysis can determine whether an at-risk person carries the mutant gene, provided that at least two other affected members are available for testing. No specific treatment is available for Alport syndrome. Tight control of blood pressure and moderate protein restriction are recommended to retard the progression of renal disease, but the benefit is unproven. Peritoneal dialysis, hemodialysis, and renal transplant are used successfully. Transplant recipients have a 5% to 10% risk of Goodpasture disease developing (because of the presence of Goodpasture antigen in the transplanted kidney).