Carbonic anhydrase VA deficiency is an inherited disorder characterized by episodes during which the balance of certain substances in the body is disrupted (known as metabolic crisis) and brain function is abnormal (known as acute encephalopathy). These potentially life-threatening episodes can cause poor feeding, vomiting, weight loss, tiredness (lethargy), rapid breathing (tachypnea), seizures, or coma.

During an episode, people with carbonic anhydrase VA deficiency have excess ammonia in the blood (hyperammonemia), problems with acid-base balance in the blood (metabolic acidosis and respiratory alkalosis), low glucose in the blood (hypoglycemia), and reduced production of a substance called bicarbonate in the liver. These imbalances lead to the signs and symptoms that occur during the episodes.

People with carbonic anhydrase VA deficiency typically first experience episodes of the disorder by age 2. These episodes may be triggered by going without food (fasting) for longer than usual between meals or when energy demands are increased, such as during illness. Between episodes, children with carbonic anhydrase VA deficiency are generally healthy, and more than half have no further episodes after the first one. Some affected children have mildly delayed development or learning disabilities, while others develop normally for their age.

The risk of metabolic crisis and acute encephalopathy is thought to decrease after childhood. Because of the small number of people with carbonic anhydrase VA deficiency who have come to medical attention, the effects of this disorder in adults are not well understood.

Carbonic anhydrase VA deficiency is caused by mutations in the CA5A gene. This gene provides instructions for making the carbonic anhydrase VA enzyme, which helps convert carbon dioxide to a substance called bicarbonate. Bicarbonate is necessary to maintain the proper acid-base balance in the body, which is necessary for most biological reactions to proceed properly. The carbonic anhydrase VA enzyme is particularly important in the liver, where it provides bicarbonate needed by four enzymes in the energy-producing centers of cells (mitochondria). These enzymes help control the amount of various other substances in the body.

Mutations in the CA5A gene result in absent or impaired carbonic anhydrase VA enzyme function, leading to reduced bicarbonate production. Insufficient bicarbonate results in impaired control of acid-base balance and reduces the activity of the four affected mitochondrial enzymes, resulting in the various biochemical abnormalities associated with carbonic anhydrase VA deficiency. These imbalances cause acute encephalopathy and the other signs and symptoms associated with this disorder. Studies suggest that a related enzyme produced from the CA5B gene may increasingly compensate for the lack of carbonic anhydrase VA as affected individuals mature, which may result in a reduced risk of metabolic crisis and acute encephalopathy after childhood.

Normal Function

The CA5A gene provides instructions for making an enzyme called carbonic anhydrase VA. This enzyme helps convert carbon dioxide to a substance called bicarbonate. Bicarbonate is necessary to maintain the proper acid-base balance in the body, which is necessary for most biological reactions to proceed properly.

The carbonic anhydrase VA enzyme is particularly important in the liver, where it provides bicarbonate needed by four enzymes in the energy-producing centers of cells (mitochondria): carbomoyl phosphate synthetase-1, pyruvate carboxylase, propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase. These enzymes help control the amount of certain other substances in the body. Carbomoyl phosphate synthetase-1 is involved in the urea cycle, which processes excess nitrogen and prevents it from accumulating as ammonia, a substance that is toxic to the brain. Pyruvate carboxylase is involved in the production of the simple sugar glucose (gluconeogenesis) in the liver. Propionyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase help break down certain protein building blocks (amino acids).

Health Conditions Related to Genetic Changes

Carbonic anhydrase VA deficiency

At least three CA5A gene mutations have been identified in people with carbonic anhydrase VA deficiency. This inherited disorder is characterized by potentially life-threatening episodes of poor feeding, vomiting, weight loss, tiredness (lethargy), rapid breathing (tachypnea), seizures, or coma. The risk of these episodes is thought to decline after childhood.

Mutations in the CA5A gene result in absent or impaired carbonic anhydrase VA enzyme function, leading to reduced bicarbonate production. Insufficient bicarbonate results in impaired control of acid-base balance and reduces the activity of the four affected mitochondrial enzymes, leading to various biochemical abnormalities that are associated with carbonic anhydrase VA deficiency and that cause the episodes that occur in this disorder. Studies suggest that a related enzyme produced from the CA5B gene may increasingly compensate for the lack of carbonic anhydrase VA as affected individuals mature, which may result in a reduced risk of disease episodes after childhood.

Other Names for This Gene

• CA-VA
• CA5
• CA5AD
• carbonate dehydratase VA
• carbonic anhydrase 5A, mitochondrial precursor
• carbonic anhydrase V, mitochondrial
• carbonic anhydrase VA, mitochondrial
• carbonic dehydratase
• CAV
• CAVA
• GS1-21A4.1

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Some people who have two copies of the altered gene never develop the condition, a situation known as reduced penetrance. Researchers suggest that if people with these mutations get through the vulnerable period of childhood without having an episode of encephalopathy, they may never show signs or symptoms of the disorder.

The prevalence of carbonic anhydrase VA deficiency is unknown. Only a small number of affected individuals have been described in the medical literature. However, the disorder may be underdiagnosed because the metabolic crisis often does not recur after the first episode; researchers suspect that some babies diagnosed with transient hyperammonemia may actually have carbonic anhydrase VA deficiency.