title: Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis.
abstract: Four mitochondrial metabolic liver enzymes require bicarbonate, which is provided by the carbonic anhydrase isoforms VA (CAVA) and VB (CAVB). Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates. This study aimed to test for CAVA or CAVB deficiencies in a group of 96 patients with early-onset hyperammonemia and to prove the disease-causing role of the CAVA variants found.
  
  
  
  We performed CA5A and CA5B sequencing in the described cohort and developed an expression system using insect cells, which enabled the characterization of wild-type CAVA, clinical mutations, and three variants that affect functional residues.
  
  
  
  In 10 of 96 patients, mutations in CA5A were identified on both alleles but none in CA5B. Exhibiting decreased enzyme activity or thermal stability, all CAVA mutations were proven to cause disease, whereas the three variants showed no relevant effect.
  
  
  
  CAVA deficiency is a differential diagnosis of early-onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs. It seems to be more common than other rare metabolic diseases, and early identification may allow specific treatment of hyperammonemia and ultimately prevent neurologic sequelae.Genet Med 18 10, 991-1000.
authors.affiliation: Division of Metabolism, University Children's Hospital and Children's Research Center, Zurich, Switzerland.
authors.forename: Carmen
authors.initials: C
authors.lastname: Diez-Fernandez
authors.affiliation: Division of Metabolism, University Children's Hospital and Children's Research Center, Zurich, Switzerland.
authors.forename: Véronique
authors.initials: V
authors.lastname: Rüfenacht
authors.affiliation: Birmingham Children's Hospital, Birmingham, England.
authors.forename: Saikat
authors.initials: S
authors.lastname: Santra
authors.affiliation: Center for Inherited Metabolic Diseases, Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Lund
authors.affiliation: Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.affiliation: Universitäts Kinderklinik Frankfurt, Frankfurt, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Department of Paediatric Medicine, Oslo University Hospital, Oslo, Norway.
authors.forename: Trine
authors.identifier: 0000-0003-3137-2117
authors.initials: T
authors.lastname: Tangeraas
authors.affiliation: Division of Metabolism, University Children's Hospital and Children's Research Center, Zurich, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Unsinn
authors.affiliation: Center for Inherited Metabolic Diseases, Hopital Necker Enfants Malades, Institut Imagine, APHP, University Paris Descartes, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.affiliation: Division of Inherited Metabolic Diseases, Department of Pediatrics, University Hospital Padova, Padova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Burlina
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital and Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
authors.affiliation: Division of Metabolism, University Children's Hospital and Children's Research Center, Zurich, Switzerland.
authors.forename: Johannes
authors.identifier: 0000-0003-0635-091X
authors.initials: J
authors.lastname: Häberle
mesh_terms: D000138:Acidosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D001639:Bicarbonates / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D020033:Protein Isoforms
chemical_list: D001639:Bicarbonates; D020033:Protein Isoforms; D019344:Lactic Acid; D002256:Carbonic Anhydrases