Alport syndrome

Alport syndrome is suspected based on a family history or clinical signs of the condition. A doctor may order a kidney biopsy to look for signs of the condition such as abnormalities of the cells of the glomeruli. A kidney biopsy can also allow to test specifically for type IV collagen protein, as this protein would be absent in a person with Alport syndrome. Doctors may also order a test to measure the amount of blood and protein in the urine. An ophthalmologic exam may be used to look for signs characteristic of the condition such as anterior lenticonus. When Alport syndrome is suspected, genetic testing can be used to confirm the diagnosis and determine the pattern of inheritance. This can provide information about the chance that other family members are affected.

Alport syndrome was previously thought to not occur more often in different ethnicities. But in 2014 an article reported a Ashkenazi Jewish "founder mutation" in the COL4A3 gene. The mutation involves a deletion of genetic material and is called c.40_63del. The researchers in this study initially identified the mutation in three sisters with Alport syndrome of Ashkenazi Jewish (AJ) ancestry. The researchers then completed mutation testing on about 1,000 healthy volunteers of AJ ancestry. They identified the COL4A3 c.40_63del mutation in 6 of the volunteers. The carrier frequency was determined to be 1 in 183 or 0.55%. Although this mutation has been reported in other ethnic populations, the carrier frequency remains unknown. Of note, this mutation was not identified in the 1000 genomes project, which included genomic testing of individuals of European, East Asian, West African, and American ancestry.

Alport syndrome damages the tiny blood vessels in the glomeruli of the kidneys. The glomeruli filter blood to make urine and remove waste products from the blood. In the early stages of disease, there are often no symptoms. However, the destruction of the glomeruli over time can lead to blood in the urine and may decrease the effectiveness of the kidney's filtering system. Often kidney function is lost over time and waste products and fluids build up in the body.

If the mutation has been identified in an affected male, the mother of the affected male can have a urinalysis and/or molecular genetic testing. The presence of hematuria (blood in the urine) generally indicates that she is likely to be a carrier of XLAS; molecular genetic testing can confirm whether she is a carrier. If the family history indicates risk to other family members, urinalysis and/or molecular genetic testing may be informative for them as well.

Individuals interested in determining the genetic risk and status for themselves or family members should speak with a genetics professional to determine whether they are at risk and/or the type of testing that is indicated.

Males with a disease-causing mutation in a gene on the X chromosome will typically be affected with the associated condition if it is known to have 100% penetrance. In males (who have only one X chromosome), a disease-causing mutation in their one copy of the COL4A5 gene in each cell is sufficient to cause the signs and symptoms of X-linked Alport syndrome. This means that an unaffected male with a family history of X-linked Alport syndrome is assumed to not be a carrier of the condition. Males who are not carriers are not at risk to pass the condition on to their children.

Whether the maternal female cousins of a male with X-linked Alport syndrome (XLAS) are at risk to be carriers of the condition depends on whether the mother of the affected individual is a carrier. In a family with more than one affected male, the mother of an affected individual is an obligate carrier. If only one male in a family is affected, the likelihood that that individual's mother is a carrier is estimated to be 85%-90%. Approximately 10%-15% of affected males have XLAS as the result of a de novo mutation (a new mutation occurring for the first time in that individual). A de novo mutation is not usually inherited from a parent; therefore, in these cases, cousins are typically not at increased risk.

The mother of a male with XLAS should have a urinalysis and/or molecular genetic testing if the mutation has been identified in her son. The presence of hematuria generally indicates that she is likely to be a carrier of XLAS. If the mother of an affected male is indeed a carrier of XLAS, the maternal female cousins are also at risk to be carriers of XLAS. Whether their children are at risk would likewise depend on whether they are carriers.

Individuals interested in learning about specific genetic risks to themselves or family members should speak with a genetics professional.

No. If a woman is not a carrier for X-linked Alport syndrome (XLAS), she does not have the disease-causing mutation; therefore, her sons are not at risk for being affected and her daughters are not at risk to be carriers. This means that her grandchildren are also not at risk to be affected or to be carriers for XLAS.

Although there is no one specific treatment for Alport syndrome, the goals of treatment include monitoring and controlling progression of the disease and treating the symptoms. Strict control of blood pressure is very important in order to keep the kidneys as healthy as possible. Research suggests that ACE inhibitors, angiotensins, and statins can help reduce proteinuria and the progression of kidney disease. However, treatment of chronic kidney failure often becomes necessary. This can include dietary modifications and fluid restriction. Ultimately, chronic kidney failure progresses to end-stage kidney disease, requiring dialysis or transplantation. Kidney transplantation in people with Alport syndrome is usually successful, but some studies have reported that about 10% of transplanted patients develop inflammation of the kidneys (nephritis).

Treatment for other aspects of the condition are addressed as needed. For instance, surgical repairs of the eye manifestations may be recommended. Loss of hearing is likely to be permanent, but affected individuals can be assisted with hearing aids. Counseling and education to increase coping skills can be helpful. Learning new skills such as lip reading or sign language may be of some benefit. Young men with Alport syndrome should use hearing protection in noisy environments. Genetic counseling may be recommended to explain the inherited pattern of the disorder.

Additional information related to the treatment of Alport syndrome can be accessed through GeneReviews and eMedicine.