Alport syndrome is a disease of the filter part of the kidneys. It is caused by large or particularly severe mutations in the genes which code for collagen, a protein that helps build the part of the kidney filters (glomeruli) that is called the basement membrane. The basement membrane is the “wall” part of the filter, and collagen is the cement that holds the wall together. When the basement membrane is weakened, the filters can be damaged and not work well.
The image below shows electron micrographs taken from kidney biopsies to show the difference in the glomerular basement membrane, or GBM, in a normal glomerulus, a glomerulus in thin basement membrane, and a glomerulus in someone with Alport syndrome.
As a result of the weakened glomerular wall and the damaged filters, Alport Syndrome usually shows up first as blood in the urine. This can either be large amounts of blood that are noticed by the person with the disease, or it can be small amounts that are found by a doctor during routine medical exams. With time, abnormal amounts of protein may also be found in the urine. Eventually kidney failure may develop. Collagen also helps build parts of the eye and ear, which also can be affected in Alport Syndrome.
There are three different collagen proteins that can be involved in Alport Syndrome: COL4A3, COL4A4, and COL4A5. Mutations in COL4A3 and COL4A4 cause disease in both men and women with equal severity. Mutations in COL4A5, which is on the X chromosome, usually cause more severe disease in men.
The severity of the disease depends on the particular mutation and how much it affects the building of the basement membrane. Some women, especially with the X-linked form, only have small amounts of blood in their urine and never have any serious kidney damage. Other people, especially men with the X-linked form, may have kidney failure and deafness develop in their early teens.
Thin Basement Membrane Disease (TBMD) is caused by less severe mutations in the same collagen proteins. Most often it is because the person affected has inherited only one copy of the gene with a mutation, and has another normal copy to help balance out mutated gene. TBMD usually shows up as small amounts of blood in the urine found on routine exam. While TBMD does not cause severe kidney problems in most people, it really just represents a very mild form of Alport Syndrome. Since it is difficult early on to distinguish the two, a presumed diagnosis of TBMD should be followed through the years with routine check ups, even when it seems likely that it will take a mild course. If high blood pressure or abnormal urine protein develops in a person with TBMD, further evaluation is needed.
The diagnosis of Alport Syndrome is usually made by examination of the urine, blood tests to check on kidney function, and a kidney biopsy. These tests look for specific signs of Alport Syndrome and help to make sure there are not other causes of the kidney damage.
It may be possible in the next several years to have genetic testing to determine what kind of mutation an affected person caries. This might allow us to have a better idea early on whether the kidney will eventually be damaged, and how rapidly this might occur. Right now those tests are not commonly available, the interpretation of them is difficult, and they give only limited information.