A number sign (#) is used with this entry because hyperammonemia due to carbonic anhydrase VA deficiency (CA5AD) is caused by homozygous mutation in the CA5A gene (114761) on chromosome 16q24.

Carbonic anhydrase VA deficiency is an autosomal recessive inborn error of metabolism characterized clinically by acute onset of encephalopathy in infancy or early childhood. Biochemical evaluation shows multiple metabolic abnormalities, including metabolic acidosis and respiratory alkalosis. Other abnormalities include hypoglycemia, increased serum lactate and alanine, and evidence of impaired provision of bicarbonate to essential mitochondrial enzymes. Apart from episodic acute events in early childhood, the disorder shows a relatively benign course. Treatment with carglumic acid can result in neurologic improvement (summary by van Karnebeek et al., 2014).

Van Karnebeek et al. (2014) reported 3 children from 2 unrelated families who presented on the first days of life with acute lethargy and tachypnea associated with significant metabolic abnormalities. Laboratory findings included metabolic acidosis, respiratory alkalosis, hyperammonemia, hypoglycemia, increased lactate and alanine, and increased levels of metabolites suggesting defects of essential mitochondrial enzymes, including carbamoyl phosphate synthetase-1 (CPS1; 608307), pyruvate carboxylase (PC; 608786), propionyl-CoA carboxylase (PCCA; 232000), and 3-methylcrotonyl-CoA carboxylase (MCCC1; 609010). Treatment with dextrose, bicarbonate, and carglumic acid resulted in clinical stability. The patients later developed episodic acute metabolic decompensation during intercurrent illnesses. In 1 family, an affected girl showed mild axial hypotonia with average development, except for below average motor coordination, at age 4.5 years, whereas her brother showed below average psychomotor development at age 2.3 years. The third child showed normal psychomotor development at age 6 months. An affected child in another unrelated family showed a slightly less severe phenotype. He presented at age 13 months with acute encephalopathy and similar metabolic abnormalities after normal development. He had subsequent similar episodes but showed good developmental progress with mild learning difficulties. His older brother, who carried the same homozygous mutation, was reportedly unaffected at age 17 years.

Diez-Fernandez et al. (2016) performed CA5A and CA5B (300230) sequencing in a cohort of 96 patients with early-onset hyperammonemia. In 10 of 96 patients, mutations in CA5A were identified on both alleles. No mutations were found in CA5B. The age of onset in these 10 patients ranged from 2 days to 20 months. Only 3 had additional crises beyond the newborn period, at 2 years, 4 years, and 23 months of age, respectively. Neurologic outcome was normal for 9 of the 10; 1 patient had learning difficulties and speech delay at age 5 years. Most of these patients came from the Indian subcontinent (India, Pakistan, or Bangladesh), and 1 patient was of Turkish descent. Most families were consanguineous; only 1 family was reported to be nonconsanguineous, and in some cases consanguinity was unknown. Among patients with CA5A mutations, all had hyperammonemia (238-1150 microM/L), elevated lactate (4.8-15 milliM/L), and elevated ketone bodies in urine. Glutamine and glutamate varied from normal to highly elevated, and patients varied between normo- and hypoglycemic. Some patients were treated with N-carbamyl-L-glutamate (NCG) during their initial crisis, either alone or in combination with other measures, and seemed to respond positively, with rapid reduction of ammonia. Diez-Fernandez et al. (2016) stated that carbonic anhydrase VA deficiency is a differential diagnosis of early onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as obligate signs.

The transmission pattern of CA5A deficiency in the families reported by van Karnebeek et al. (2014) was consistent with autosomal recessive inheritance.

In 4 patients from 3 unrelated families with hyperammonemia due to CA5A deficiency, van Karnebeek et al. (2014) identified 3 different homozygous loss-of-function mutations in the CA5A gene (114761.0001-114761.0003). The mutation in the first family was found by whole-exome sequencing.