Trait Document

Alport syndrome is a genetic condition where individuals have blood and protein found in urine (hematuria and proteinuria, respectively) due to progressive loss of kidney function. With progression of the condition, individuals can develop end-stage renal disease (ESRD) or permanent kidney failure. Individuals with Alport syndrome often develop sensorineural hearing loss (i.e., loss of hearing caused by abnormalities of the inner ear (cochlea)) in late childhood or adolescence. Alport syndrome can also cause individuals to have changes to the shape of the lenses of the eye called anterior lenticonus and changes to the coloration of the retina (i.e., the light detecting layer at the back of the eye) called dot-and-fleck retinopathy. However, these changes in the eye rarely lead to vision loss.

Establishing a diagnosis of Alport syndrome depends on a person’s signs and symptoms (clinical history), family history, and physical evaluation. Testing often includes kidney function tests and testing of a urine specimen (urinalysis) for the presence of hematuria and proteinuria (blood and protein in urine). Special staining and examination of a kidney biopsy (a procedure where a small piece of tissue from the kidney is removed) may be done to aid in diagnosis. Genetic testing also can be done to establish a diagnosis of Alport syndrome. Individuals with Alport syndrome have genetic changes or mutations in one of three genes: COL4A3, COL4A4, and COL4A5. These three genes provide instructions for a protein called type IV collagen. This protein plays important roles in the kidneys, ears, and eyes. Mutations in any one of these genes do not allow the protein to work properly, leading to the features seen in Alport syndrome.

Management for individuals with Alport syndrome involves care by a kidney doctor (nephrologist), and regular hearing and eye screening. Individuals with Alport syndrome may require certain medications for treatment of high blood pressure (hypertension), and treatment for kidney dysfunction and ESRD (including dialysis or possible transplant). Female carriers of X-linked Alport syndrome (explained below) should also be followed and managed for possible symptoms, and should have blood pressure and kidney function monitored regularly.

Alport syndrome may be inherited in one of three patterns of inheritance: X-linked recessive, autosomal recessive, and autosomal dominant. They are explained below.

Most cases of Alport syndrome (approximately 80%) are caused by mutations in the COL4A5 gene located on the X-chromosome. An X-linked recessive pattern means that in females, both copies of the COL4A5 gene (i.e., one on each X chromosome) must have a change or mutation, whereas in males, only one copy of the COL4A5 gene must have a mutation to be affected. A female with a mutation in one copy of the COL4A5 gene is said to be a “carrier” of Alport syndrome, and often experience hematuria.

Autosomal recessive inheritance accounts for a small proportion (approximately 15%) of Alport syndrome. This inheritance pattern means that an individual has to inherit two mutations (i.e., one from each parent) to be affected. If both parents are carriers of a mutation they have a 1 in 4 (25%) chance with each pregnancy of having a child with the condition.

Autosomal dominant inheritance accounts for a small proportion (approximately 5%) of Alport syndrome. This means inheriting one mutation is enough for an individual to be affected and show signs of Alport syndrome. The mutation can be inherited from an affected parent or it can occur brand new (de novo) in an affected child. Approximately 10%-15% of males with X-linked Alport syndrome have the condition as result of a de novo mutation.

The risk to family members depends on the pattern of inheritance.

If a father is affected with Alport syndrome, his daughters will be carriers of Alport syndrome and his sons will be unaffected. If a mother is a carrier of Alport syndrome, each daughter has a 1 in 2 chance (i.e., 50%) of being a carrier and each son has a 1 in 2 chance (i.e., 50%) of being affected with Alport syndrome.

Parents of a child with Alport syndrome are carriers of Alport syndrome. If a sibling of a child with Alport syndrome is unaffected, he/she has a 2 in 3 (66%) chance of being a carrier of Alport syndrome.

The risk to family members depends on whether or not the individual with Alport syndrome has a parent affected with Alport. If a parent also has the condition, the risk of having a child with Alport syndrome is 50% with each pregnancy. If a parent does not have Alport syndrome, the risk of other siblings being affected is very low.

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