Alport syndrome is a genetic disorder characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, causing eye abnormalities including cataracts, lenticonus, kerataconus, as well as retinal flecks in the macula and mid-periphery. Visibly bloody urine and protein in the urine are common features of this condition.
- Abnormal urine color
- Ankle, feet, and leg swelling
- Blood in the urine
- Decrease or loss of vision, more common in males
- Loss of hearing, more common in males
- Swelling around the eyes
- Swelling, overall
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, which allows 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. The thickening of the basement membrane (because of the scar tissue) 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 nano-mechanical behavior of mutated molecules. Notably, these lead to a bent molecular shape with kinks in the protein at the site of the mutations.
This uncommon disorder is inherited. Awareness of risk factors, such as a family history of the disorder, may allow the condition to be detected early.
- 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.
- Persistent hematuria without evidence of another possibly inherited nephropathy such as thin glomerular basement membrane disease, polycystic kidney disease or IgA nephropathy.
- Bilateral sensorineural hearing loss in the 2000 to 8000 Hz range. The hearing loss develops gradually, is not present in early infancy, and commonly presents before the age of 30 years.
- A mutation in COL4An (where n = 3, 4 or 5).
- Immunohistochemical evidence of complete or partial lack of the Alport epitope in glomerular, or epidermal basement membranes, or both.
- Widespread glomerular basement membrane ultrastructural abnormalities, in particular thickening, thinning and splitting.
- Eye lesions including anterior lenticonus, kerataconus, posterior subcapsular cataract, posterior polymorphous dystrophy and retinal flecks.
- Gradual progression to end-stage kidney disease in the index case of at least two family members.
- Macrothrombocytopenia or granulocytic inclusions, similar to the May-Hegglin anomaly.
- Diffuse leiomyomatosis of esophagus or female genitalia, or both.
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. Analysis of COL4A3 and COL4A4 should be considered if a COL4A5 mutation is not detected and primarily if autosomal inheritance is suspected.
Clinical utility gene card for: Alport syndrome
Immunohistochemical 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
Women usually have a normal life span with no signs of the disease except for blood in the urine. Rarely, women will have high blood pressure, swelling, and nerve deafness as a complication of pregnancy. In men, deafness, visual difficulties, and kidney failure are likely by age 50.
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.
Gene therapy as a possible treatment option has been discussed.