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Alport syndrome is a condition that develops due to mutations in three different genes – COL4A3, COL4A4 and COL4A5. The reason that the syndrome has a significant impact on the kidneys is because all of these genes provide instructions that affect the type IV collagen in a protein present in the kidneys.
This protein impacts the function of the glomeruli blood vessels in the kidneys which help with the filtering process. These capillaries remove water and waste from the blood to produce urine.
When there are mutations in these genes, the kidneys do not carry out the filtering process as well as they should. This can result in chronic kidney disease (CKD) in the patient.
This same collagen is also found in the inner ear structures. Abnormalities can result in sensorineural hearing loss due to how they affect the function of the organ.
This same collagen is also present in the eyes where its role is keeping the shape of the lens. Mutations in the genes can result in a misshapen, conical eye lens and flecks of discoloration in the retina.
In Alport syndrome, 80% of the cases are due to mutation in COL4A5, the X-linked pattern. For a male, this means that they have a mutation on their X chromosome but they do not have another X chromosome to compensate for this. The other chromosome is Y and is not affected.
Females have two X chromosomes, which means that even if they have the Alport Syndrome mutation on one chromosome, the other X chromosome can compensate. This can limit the development of symptoms for females in comparison to males.
For males, this means that they can experience chronic kidney disease leading up to kidney failure and other more dramatic symptoms of the disease. In contrast, the impact on the females will be milder. Women tend to have hematuria (blood in the urine) but kidney problems are not as marked.
Additionally, males cannot pass on the X-chromosome to male offspring as male children receive the Y chromosome from their father. They can however pass their X chromosome to female offspring who will be a carrier for the syndrome.
If a woman’s mother has the mutation, she has a 1 in 2 chance of being a carrier. Tests will help to confirm whether she has the mutation or not, as symptoms can be mild. The chance of a male descendant receiving the mutation is also 50% but the symptoms will be much stronger and he is likely to develop the full syndrome.
The rarer forms of the syndrome make up about 20% of cases in total. About 15% of these cases will have the autosomal recessive inheritance pattern. Patients will have mutations in the COL4A3 and COL4A4 genes.
In autosomal recessive Alport syndrome, men and women are both affected in similar ways. They will have symptoms such as renal failure, eye issues and reduced hearing.
A person with the condition would have to receive two mutations in the same genes from both parents. The carriers may show signs of blood in their urine (hematuria). Offspring of both sexes have a 1 in 4 chance of inheriting the condition.
Another rare condition is autosomal dominant Alport syndrome, which also causes a mutation in the COL4A3 or COL4A4 genes. This affects about 5% of the cases of Alport syndrome. Patients with this type can develop kidney failure much later, after the age of 40. They also have hearing loss and their eyes are affected. Their children have a 50% chance of inheriting the mutation.