Carbonic anhydrase VA (CA-VA) deficiency is a rare cause of hyperammonemia caused by biallelic mutations in CA5A. Most patients present with hyperammonemic encephalopathy in early infancy to early childhood, and patients usually have no further recurrence of hyperammonemia with a favorable outcome. This retrospective cohort study reports 18 patients with CA-VA deficiency caused by homozygosity for a founder mutation, c.59G>A p.(Trp20*) in CA5A. The reported patients show significant intrafamilial and interfamilial variability, and display atypical clinical features. Two adult patients were asymptomatic, 7/18 patients had recurrent hyperammonemia, 7/18 patients developed variable degree of developmental delay, 9/11 patients had hyperCKemia, and 7/18 patients had failure to thrive. Microcephaly was seen in three patients and one patient developed a metabolic stroke. The same variant had been reported already in a single South Asian patient presenting with neonatal hyperammonemic encephalopathy and subsequent development of seizures and developmental delay. This report highlights the limitations of current understanding of the pathomechanisms involved in this disorder, and calls for further evaluation of the possible role of genetic modifiers in this condition. 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. 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. 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. 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.

Hyperammonemia and hyperlactatemia in neonates and young children with non-specific biochemical markers poses a diagnostic challenge. An accurate diagnosis is essential for effective management. We present three infants from unrelated families, one with infantile and two with neonatal hyperammonemic encephalopathy, hypoglycaemia, and hyperlactatemia. The underlying cause was confirmed following whole exome sequencing as biochemical markers were not conclusive of a definite diagnosis. The combination of hyperammonemic encephalopathy, hyperlactatemia and hypoglycemia in neonates and infants should prompt physicians to suspect Carbonic anhydrase VA deficiency. Majority of these children can have a favourable long-term outcome with symptomatic treatment.

Objectives Carbonic anhydrase VA (CAVA) deficiency is a rare autosomal recessive inborn error of metabolism that leads to acute metabolic crises, especially in the neonatal or infantile period. It is caused by a deficiency of the enzyme CAVA, which is encoded by the CA5A gene. Case presentation Fifteen patients with homozygous pathogenic CA5A mutations involving 10 different lesions have been reported in the literature up to date. Main clinical and biochemical features of CAVA deficiency include lethargy, hyperammonemic encephalopathy, metabolic acidosis, elevated lactate and hypoglycemia. In most patients reported so far, a single metabolic decompensation attack has been reported, and they have remained stable thereafter with no further crisis. Conclusions We report the 16th case of CAVA deficiency, who was diagnosed by whole-exome sequencing and showed a typical course of the disease with normal development at 18 months.