Primary Distal Renal Tubular Acidosis

Primary distal renal tubular acidosis (primary dRTA) is caused by changes (also called a loss-of-function variants or mutations) in one of three genes (ATP6V0A4, ATP6V1B1, and SLC4A1). These genes are involved in processes that manage the pH levels of blood and body.

The ATP6V1B1 and ATP6V0A4 genes carry the instructions for making a big set of proteins called "vacuolar H+-ATPase" (V-ATPase) which are important for controlling the pH of the blood and the fluid in the inner ear. We normally have two working copies of the ATP6V1B1 and ATP6V0A4 genes in our cells and we inherit one copy from our biological mother and the other from our biological father. In order to develop symptoms of primary dRTA, both copies of ATP6V1B1 or ATP6V0A4 genes are not working properly. This is also called autosomal recessive inheritance, which means that both parents of someone with primary dRTA disease are carriers of one working and one non-working copy of either the ATP6V1B1 and ATP6V0A4 genes. Since each parent has one working copy, they don't have symptoms of primary dRTA themselves. However, when they have children, they each have a 1 in 2 or 50% chance of passing on the non-working copy to their child. When both parents are carriers, there is a 1 in 4 or 25% chance of both of them passing on the non-working copy and having a child with primary dRTA. Even if a couple already has one child with primary dRTA, it is important to know that they can have another affected child because the chances are 1 in 4 for each pregnancy.

The SLC4A1 gene provides the instructions to create a special protein known as anion exchanger 1 (AE1). This protein transports negatively charged atoms (anions) across cell membranes and is important in managing pH levels in the blood. We normally have two working copies of the SLC4A1 gene in our cells and we inherit one copy from our biological mother and the other from our biological father. Distal renal tubular acidosis (primary dRTA) caused by loss-of-function variants in SLC4A1 usually occurs when a baby inherits one nonworking copy of the SLC4A1 gene from one parent. Missing a single working copy of the SLC4A1 gene decreases the body's ability to control the pH of the blood, resulting in the medical issues of primary dRTA. This is also called autosomal dominant inheritance, which means that one parent of a person with primary dRTA disease probably has a non-working copy of the SLC4A1 gene and accordingly has symptoms of primary dRTA themselves. When they have children there is a 1 in 2 or 50% chance of passing on the non-working copy to their child and having a child with primary dRTA. Even if a couple already has one child with primary dRTA, it is important to know that they can have another affected child because the chances are 1 in 2 for each pregnancy. However, in Thailand, Malaysia, the Philippines and Papua New Guinea there is a common form of primary dRTA with anemia caused when a baby inherits two nonworking copies of the SLC4A1 gene, one from each parent. In this situation, when both parents are carriers of one nonworking copy of the SLC4A1 gene, there is a 1 in 4 or 25% chance of both of them passing on the non-working copy and having a child with primary dRTA.

A genetic counselor can help with understanding the pattern that primary dRTA runs in a specific family, who may be at increased risk to have primary dRTA, and discuss genetic testing options as appropriate. To find a genetic counselor in your area, you can use the National Society of Genetic Counselor's "Find a Genetic Counselor" https://www.nsgc.org/findageneticcounselor).