Alport syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Genetics
Alport syndrome is caused by mutations in the COL4A3, COL4A4, and COL4A5 collagen biosynthesis genes. Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structural component of the glomerular basement membranes in the kidney, inner ear, and eye.
This syndrome can have different inheritance patterns depending on the type of genetic mutation. In most people with the disorder, the condition is inherited in an X-linked pattern due to mutations in the COL4A5 gene. A condition is considered X-linked if the gene involved in the disorder is located on the X chromosome.
Alport syndrome can also be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2, have been mutated. Most often, the parents of a child with an autosomal recessive disorder are not affected but are only carriers of one copy of the altered genes.
In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome. This single X chromosome explains why most affected males eventually develop chronic kidney failure. In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in blood in the urine, but most affected females do not develop kidney failure.
Associated Conditions
Some associated conditions that occur with Alport syndrome are chronic kidney failure, and proteinuria.
Microscopic Pathology
Basement membranes are thin, sheet-like structures that separate and support cells in many tissues. When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine properly, which allows blood and protein to enter into the urine.
The abnormalities of type IV collagen in the glomerular basement membrane cause gradual scarring of the kidneys, eventually leading to chronic renal failure in many people with the disease.