Alport Syndrome is a genetic disease, meaning it is passed on through genes in families. Often, many generations in a family are affected. Frequently, the disease does go undiagnosed or misdiagnosed. Accurate diagnosis is important to allow for intervention with medications to slow progression of the disease. At this time, gene therapy and/or gene editing is not available.
There are multiple genetic types of Alport Syndrome.
The three most commonly studied include:
- XLAS (X-linked Alport syndrome)
- ARAS (autosomal recessive Alport syndrome)
- ADAS (autosomal dominant Alport syndrome)
ASF Medical Advisory Committee member, Dr. Clifford Kashtan, outlines the varying types of Alport syndrome in this summary article. Additionally, Dr. Kashtan summarizes specific gene mutations at this link.
(X-linked Alport syndrome)
(autosomal recessive Alport syndrome)
(autosomal dominant Alport syndrome)
Autosomal Recessive Alport Syndrome (ARAS)
Autosomal recessive disorders result when both copies of a gene are defective. Typically, each parent of a child with a recessive condition passes a mutant gene to the affected child.
The genes COL4A3 and COL4A4 are located on chromosome 2. Each person has two copies of this chromosome, and two copies of both the COL4A3 and COL4A4 genes. The parents only have one mutation in one of the chromosomes and so they can have no symptoms or have some hematuria (blood in the urine). However, they will not have progression of the disease.
When each parent carries a mutation in COL4A3 or COL4A4, there is a 25% chance with every pregnancy that the child will have ARAS. Unlike X-linked Alport syndrome, the autosomal recessive type affects females just as severely as males.
Autosomal Dominant Alport Syndrome (ADAS)
ADAS was long believed to account for roughly 5% of cases. Next Generation Sequencing has resulted in estimates ranging from approximately 4-6 times that percentage.
These people have one mutant copy of the COL4A3 or COL4A4 gene. Mutation in one copy of COL4A3 or COL4A4 can cause progressive kidney disease and hearing loss. People with ADAS resemble people with XLAS, with some differences: kidney failure occurs relatively late in life (after age 40), changes in the eyes are very unusual and there is no difference in severity of disease in males and females. People with ADAS usually have a family history that is positive for progressive kidney disease and hearing loss. Mutation in one copy of COL4A3 or COL4A4 can also cause thin basement membrane nephropathy (TBMN), which differs from ADAS in that progressive kidney disease and hearing loss are very unusual. People with TBMN usually have a family history that is negative for progressive kidney disease and hearing loss. Researchers are still trying to understand why some people with these mutations have ADAS and others have TBMN.
Each child of an affected parent has a 50% chance of inheriting the mutation.
Clinicians in many parts of the world now have access to genetic testing for diagnosis of Alport syndrome through commercial laboratories or laboratories associated with medical institutions. Such testing offers high rates of diagnostic accuracy, particularly for X-linked Alport syndrome, although testing is available for autosomal recessive and autosomal dominant forms of the disease, too. Insurance coverage for genetic testing varies widely so patients are encouraged to seek the help of certified genetic counselors to determine their eligibility.
Why have genetic testing?
In most cases, genetic testing can confirm a diagnosis of Alport syndrome. Genetic testing is the only way to diagnose a female with no symptoms yet a family history of X-Linked Alport syndrome. It may also be useful when results of a skin, saliva or kidney biopsy are not conclusive. Genetic testing is also used to clarify inheritance patterns of the disease. This is important for not only assessing the current and future health of others in the family, but can clarify potential living kidney donors within an immediate family, if the need arises.
Genetic Counseling for Patients
Couples are strongly urged to meet with a licensed genetic counselor to discuss their individual situation and options in greater detail. The National Society of Genetic Counselors has a “Find a Genetic Counselor” tool on their website that allows people to search for local providers. It shows each genetic counselor’s specialty, which could be useful as some people have never met with a genetic counselor, while others may have met with a clinical/pediatric genetic counselor but now wish to discuss or pursue one of the above options and therefore should meet with a prenatal genetic counselor.