Mitochondrial Carbonic Anhydrase VA Deficiency Resulting from CA5A Alterations Presents with Hyperammonemia in Early Childhood

Abstract

Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child.

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

“…Trio whole exome sequencing (WES) was carried out to exclude any novel genetic defects in the biotin pathway, and included analyses for any mutations in the mitochondrial carbonic anhydrase VA (CA5A) gene which presents with MCD phenotype (Karnebeek et al 2014) but all tests were non-contributory.…”

Exome Sequencing and the Management of Neurometabolic Disorders

“…The first discovery was a homozygous missense variant in CA5A (Mendelian Inheritance in Man [MIM] number 114761), encoding mitochondrial carbonic anhydrase VA, which is pivotal to the function of mitochondrial enzymes. 17 Our group reported that a deficiency in this enzyme causes neonatal hyperammonemia, hyperlactatemia, and hypoglycemia. 17 Such a deficiency is amenable to treatment with carglumic acid and an emergency protocol, which can prevent irreversible neurologic sequelae.…”

“…17 Our group reported that a deficiency in this enzyme causes neonatal hyperammonemia, hyperlactatemia, and hypoglycemia. 17 Such a deficiency is amenable to treatment with carglumic acid and an emergency protocol, which can prevent irreversible neurologic sequelae. We added this condition to the two-tiered diagnostic algorithm and interactive tool at Treatable ID.org (freely available as native and Web applications at www.treatable-id.org) to support clinicians in early identification.…”

Expression of Carbonic Anhydrase I in Motor Neurons and Alterations in ALS

“…Patients with a mutation in CA12 exhibit hyponatremia and hyperchlorhydria [34]. Individuals with homozygous mutation in CA5a are reported to have lethargy, hyperlactatemia, and hyperammonemia during the neonatal period and early childhood [35]. CA6 is initially described as a gustatory protein and highly expressed in the salivary and mammary glands.…”