Clinical characteristics: Most children with carbonic anhydrase VA (CA-VA) deficiency reported to date have presented between day 2 of life and early childhood (up to age 20 months) with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma). Given that fewer than 20 affected individuals have been reported to date, the ranges of initial presentations and long-term prognoses are not completely understood. As of 2021 the oldest known affected individual is an adolescent. Almost all affected individuals reported to date have shown normal psychomotor development and no further episodes of metabolic crisis; however, a few have shown mild learning difficulties or delayed motor skills.
Diagnosis/testing: The diagnosis of CA-VA deficiency is established in children with suggestive clinical findings (metabolic hyperammonemic encephalopathy), laboratory findings (complex acid-base status including respiratory alkalosis and metabolic acidosis; elevated plasma glutamine and alanine and low-to-normal citrulline; and urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency), and biallelic pathogenic variants in CA5A identified by molecular genetic testing.
Management: Treatment of manifestations: Acute care: Hospital admission for children with insufficient oral intake and/or signs of metabolic decompensation such as encephalopathy in order to provide IV fluids (maintenance glucose plus extra calories via IV lipids) and to monitor plasma ammonia, serum lactate, serum glucose, blood gases, electrolytes, and liver parameters. If ammonia-lowering medication is needed, consider use of carglumic acid, which (while not yet approved for this indication) has anecdotally shortened the period of hyperammonemia. Although other ammonia-lowering medications such as sodium benzoate could also be reasonable, no conclusive information has been published to date.
To prevent metabolic decompensation during any catabolic state (viral illness or fasting conditions): Use a sick day formula (i.e., with extra calories and lipids, with but limited proteins) and monitor parameters per acute care protocols.
Surveillance: Follow up during infancy and early childhood with a metabolic disease specialist every three to six months for physical and neurologic examinations. If asymptomatic and no further episodes, monitoring can be relaxed during childhood but a sick day regime/emergency plan should be provided and followed.
Agents/circumstances to avoid: Acetazolamide as it inhibits carbonic anhydrase activity. If anti-seizure medications are necessary, avoid topiramate based on its action as carbonic anhydrase inhibitor.
Evaluation of relatives at risk: Neonatal care for:
An affected infant diagnosed prenatally: Delivery in hospital with monitoring for ~3 days (including physical examination and monitoring especially of plasma ammonia, serum lactate, serum glucose, and blood gases)
An infant at risk because of a previous affected sib: Close clinical monitoring for the first week of life by a healthcare professional and immediate action if symptoms (of hyperammonemia or hypoglycemia) occur
Genetic counseling: CA-VA deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CA5A pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two CA5A pathogenic variants and usually being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier. Once the CA5A pathogenic variants in a family are known, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. Note: The results of prenatal testing cannot be used to predict with certainty whether or not an individual will be affected, as asymptomatic individuals with biallelic CA5A pathogenic variants have been identified.
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