Alport syndrome

Alport syndrome is a genetic condition characterized by the progressive loss of kidney function and hearing. Alport syndrome can also affect the eyes. The presence of blood in the urine (hematuria) is almost always found in this condition. Many people with Alport syndrome also exhibit high levels of protein in their urine (proteinuria). As this condition progresses, the kidneys become less able to function properly and kidney failure results. Hearing loss is a common feature of Alport syndrome, but the abnormalities in the eyes seldom lead to loss of vision.

The prevalence of Alport syndrome is approximately 1 in 50,000 newborns.

Mutations in the COL4A3, COL4A4, and COL4A5 genes cause Alport syndrome.

Mutations in the COL4A3, COL4A4, or COL4A5 genes prevent the proper production or assembly of a specific collagen network composed of alpha3, alpha4, and alpha5 chains of type IV collagen. This network plays an important role in the kidney, specifically in structures called glomeruli. Glomeruli are clusters of specialized blood vessels that remove water and waste products from blood and create urine. When mutations prevent the formation of the type IV collagen network, the kidneys are not able to filter waste products from the blood and create urine normally. This defect allows blood and protein to pass into the urine, and leads to gradual scarring of the kidneys and kidney failure in many people with the disease.

This type IV collagen network is also an important component of inner ear structures, particularly the organ of Corti, that receive sound waves and transform them into nerve impulses. Alterations in type IV collagen often result in inner ear abnormalities that lead to hearing loss. In the eye, this network is important for maintaining the shape of the lens and the normal coloration of the retina (the tissue at the back of the eye that detects light and color). Mutations that disrupt type IV collagen can result in misshapen lenses in the eyes (anterior lenticonus) and abnormal coloration of the retina.

Read more about the COL4A3, COL4A4, and COL4A5 genes.

Alport syndrome can have different inheritance patterns that are dependent on the genetic mutation.

Most cases of Alport syndrome are inherited in an X-linked pattern and involve mutations in the COL4A5 gene. A condition is considered X-linked if the mutated gene involved in the disorder is located on the X chromosome (one of the two sex chromosomes). In males, who have only one X chromosome, one mutated copy of the COL4A5 gene is sufficient to cause kidney failure and other severe symptoms of the disorder. In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in less severe symptoms. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked diseases to their sons.

Alport syndrome can be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2, are 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.

Alport syndrome can also be inherited in an autosomal dominant pattern, which means one copy of the altered gene, either COL4A3 or COL4A4, can be sufficient to cause the disorder.