Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, all genes involved in collagen biosynthesis. 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 basement membranes in the kidney, inner ear, and eye. 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 normally, allowing blood and protein into the urine.
The abnormalities of type IV collagen in kidney basement membranes cause gradual scarring of the kidneys, eventually leading to kidney failure in many people with the disease. Progression of the disease leads to basement membrane thickening and gives a "basket-weave" appearance from splitting of the glomerular basement membrane, specifically the lamina densa layer. Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nanomechanical behavior of mutated molecules. Notably these lead to a bent molecular shape with kinks in the protein at the site of the mutations.
Alport syndrome can have different inheritance patterns that are dependent on the genetic mutation.
In most people with Alport syndrome (about 85%), the condition is inherited in an X-linked dominant 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. In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome, explaining why most affected males eventually develop 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.
Alport syndrome can 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 carriers of one copy of the altered gene.
Past descriptions of an autosomal dominant form are now usually categorized as other conditions, though some uses of the term in reference to the COL4A3 and COL4A4 loci have been published. Autosomal dominant transmission is rare and only accounts for 5% of affected patients.The clinical features of autosomal dominant Alport syndrome are similar to those of X-linked disease. However, deterioration of renal function tends to occur more slowly.
At least four of the following ten criteria must be met to diagnose an individual with Alport syndrome:
Family history of nephritis of unexplained hematuria in a first degree relative of the index case or in a male relative linked through any numbers of females.
The use of eye examinations for screening has been proposed.
A review of pathogenic mutations detected in X-linked Alport syndrome patients in 2011, recommended COL4A5 analysis in any patient meeting at least two clinical diagnostic criteria and that COL4A3 and COL4A4 analysis should be considered if a COL4A5 mutation is not detected and primarily if autosomal inheritance is suspected.
Immunohistochemical (IHC) evidence of the X-linked form Alport syndrome may be obtained from biopsies of either the skin or the renal glomerulus. In this processes, antibodies are used to detect the presence or absence of the alpha3, alpha4, and alpha5 chains of collagen type 4.
All three of these alpha chains are present in the glomerular basement membrane of normal individuals. In individuals expressing the X-linked form of Alport's syndrome, however, the presence of the dysfunctional alpha5 chain causes the assembly of the entire collagen 4 complex to fail, and none of these three chains will be detectable in either the glomerular or the renal tubular basement membrane.
Of these three alpha chains, only alpha5 is normally expressed in the skin, so the hallmark of X-linked Alport syndrome on a skin biopsy is the absence of alpha5 staining.
As there is no known cure for the condition, treatments are symptomatic. Patients are advised on how to manage the complications of kidney failure and the spilling of protein in the urine that develops is often treated with ACE inhibitors.
Once kidney failure has developed, patients are given dialysis or can benefit from a kidney transplant, although this can cause problems. The body may reject the new kidney as it contains normal type IV collagen, which may be recognized as foreign by the immune system.
^Srinivasan M, Uzel SGM, Gautieri A, Keten S, Buehler MJ (2009). "Alport Syndrome mutations in type IV tropocollagen alter molecular structure and nanomechanical properties". J. Structural Biology168 (3): 503–510. doi:10.1016/j.jsb.2009.08.015. PMID19729067.
^Zhang KW, Colville D, Tan R, et al. (August 2008). "The use of ocular abnormalities to diagnose X-linked Alport syndrome in children". Pediatr. Nephrol.23 (8): 1245–50. doi:10.1007/s00467-008-0759-4. PMID18343956.