Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
CA5A encodes mitochondrial carbonic anhydrase VA (CA-VA), which provides bicarbonate to key hepatic enzymes. Pathogenic variants in CA5A have been identified in children presenting with early‐onset hyperammonemia and lethargy, consistent with urea cycle and anaplerotic dysfunction. The association between CA5A and hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency is supported by multiple unrelated probands, segregation data, and concordant functional studies.
Four children from three unrelated families (including one consanguineous family) presented with neonatal or early‐childhood hyperammonemia and lethargy due to biallelic CA5A variants (PMID:24530203). Segregation of homozygous mutations in two affected siblings provided additional support (PMID:24530203). Functional assays and therapeutic rescue further confirm causality. Overall, this constitutes a Strong gene–disease association.
Inheritance is autosomal recessive. Case-level data include 4 probands with homozygous or compound heterozygous CA5A variants across 3 families (PMID:24530203). Segregation analysis demonstrated two affected siblings in one consanguineous pedigree. Variant classes encompass missense, splice site, nonsense, and multi‐exon deletions. Recurrent alleles include c.697T>C (p.Ser233Pro) in two siblings and c.619-3421_774+502del of exon 6.
Variants uniformly reduce CA‐VA enzymatic activity, increase thermal sensitivity, and abolish protein expression in liver tissue (PMID:24530203). Insect cell expression assays of clinical missense and nonsense variants confirmed loss of function and decreased stability (PMID:26913920). Administration of carglumic acid resolved hyperammonemia in patients, demonstrating therapeutic rescue and mechanistic relevance.
Biallelic CA5A deficiency impairs hepatic bicarbonate provision to carbamoylphosphate synthetase 1, pyruvate carboxylase, propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase, leading to combined urea cycle and organic acid metabolic crisis. Early genetic diagnosis allows prompt initiation of carglumic acid therapy, preventing neurologic sequelae. CA5A deficiency should be considered in the differential diagnosis of neonatal and early childhood hyperammonemia.
Key Take-home: CA5A pathogenic variants cause autosomal recessive hyperammonemic encephalopathy; early detection enables targeted carglumic acid treatment.
Gene–Disease AssociationStrong4 probands in 3 families (including consanguineous siblings) and concordant functional data Genetic EvidenceModerate4 probands from 3 families with segregation in a consanguineous pedigree Functional EvidenceModerateEnzyme activity assays, protein stability testing, and carglumic acid rescue confirm loss of CA‐VA function |