Inside the Mitochondria: The Biology of CA-VA Deficiency

To understand Carbonic Anhydrase VA (CA-VA) deficiency, it helps to think of the mitochondria (the energy-producing parts of your child’s cells) as a complex factory. For this factory to run, it needs raw materials. One of the most important materials is bicarbonate ^[1].

The CA5A gene provides the instructions for making the CA-VA enzyme, which lives inside the mitochondria ^[2]. Its job is to rapidly create bicarbonate from carbon dioxide and water ^[1]. When this enzyme is missing, several major “assembly lines” in the factory slow down or stop, leading to the metabolic crises seen in this condition.

The Missing Ingredient

The lack of bicarbonate affects several critical enzymes that depend on it to function. These include:

• CPS1 (Carbamoyl-phosphate synthetase I): This is the first step in the urea cycle, the system that clears toxic ammonia from the body ^[2]. With reduced bicarbonate, CPS1 reduces activity, and ammonia levels rise (hyperammonemia) ^[3].
• Pyruvate Carboxylase: This enzyme helps the body make glucose (blood sugar) and manage energy. When its activity is impaired, the body may experience low blood sugar (hypoglycemia) and a buildup of lactate (lactic acid) ^[4][2].
• Other Carboxylases: Enzymes like propionyl-CoA carboxylase are also affected, which can further disrupt how the body processes fats and proteins ^[2].

The Suggestive Metabolic Pattern

Because CA-VA deficiency affects multiple pathways at once, it creates a suggestive metabolic pattern during a crisis. While other metabolic disorders might only show one or two of these signs, children with CA-VA deficiency may show some or all of them simultaneously ^[3]:

1. Hyperammonemia: High levels of ammonia in the blood.
2. Lactic Acidosis: High levels of lactate, making the blood too acidic ^[5].
3. Ketonuria: The presence of ketones (byproducts of fat breakdown) in the urine ^[6].
4. Metabolic Acidosis: An overall “acidic” state in the body’s chemistry.
5. Hypoglycemia: Occasionally, low blood sugar levels are also present ^[3].

It is important to note that these findings overlap with urea-cycle disorders, organic acidemias, and fatty-acid disorders; absence of one finding does not exclude CA-VA deficiency.

Why Diagnosis is a Challenge

Diagnosing CA-VA deficiency is tricky because its initial pattern looks very much like other, more common metabolic disorders. For example, the high ammonia and certain amino acid patterns can closely mimic OTC deficiency (Ornithine Transcarbamylase deficiency), a more well-known urea cycle disorder ^[5].

Routine tests like plasma amino acids (which may show high glutamine) or urine organic acids (which may show high orotic acid) are essential first steps, but they often cannot provide a “smoking gun” that points only to CA-VA ^[5][3]. This is why children with this condition were often misdiagnosed in the past before genetic testing became widely available.

The Role of Genetic Testing

A definitive diagnosis requires genetic testing to find “biallelic” variants in the CA5A gene—meaning the child inherited one mutated copy from each parent ^[7][8].

Common ways this is diagnosed include:

• Whole Exome Sequencing (WES): A broad test that looks at all the genes in the body. This is often how rare conditions like CA-VA are discovered when other tests are inconclusive ^[9].
• Targeted Panels: A test specifically looking at genes related to hyperammonemia or metabolic disorders.
• Deletion/Duplication Analysis: Because some CA5A mutations involve large “missing” chunks of DNA, specialized testing is sometimes needed to find them ^[7].

Confirming the diagnosis through genetics is vital because it changes how the child is treated. A variant of uncertain significance does not establish the diagnosis, and a negative test may require specialist review for structural or hard-to-detect variants (like CA5A “pseudogenes”).