2. Academic Validation
  3. Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis

Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis

  • Genet Med. 2016 Oct;18(10):991-1000. doi: 10.1038/gim.2015.201.
Carmen Diez-Fernandez 1,  Véronique Rüfenacht 1,  Saikat Santra 2,  Allan M Lund 3,  René Santer 4,  Martin Lindner 5,  Trine Tangeraas 6,  Caroline Unsinn 1,  Pascale de Lonlay 7,  Alberto Burlina 8,  Clara D M van Karnebeek 9,  Johannes Häberle 1
Affiliations

Affiliations

  • 1 Division of Metabolism, University Children's Hospital and Children's Research Center, Zurich, Switzerland.
  • 2 Birmingham Children's Hospital, Birmingham, England.
  • 3 Center for Inherited Metabolic Diseases, Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.
  • 4 Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
  • 5 Universitäts Kinderklinik Frankfurt, Frankfurt, Germany.
  • 6 Department of Paediatric Medicine, Oslo University Hospital, Oslo, Norway.
  • 7 Center for Inherited Metabolic Diseases, Hopital Necker Enfants Malades, Institut Imagine, APHP, University Paris Descartes, Paris, France.
  • 8 Division of Inherited Metabolic Diseases, Department of Pediatrics, University Hospital Padova, Padova, Italy.
  • 9 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.
PMID: 26913920 DOI: 10.1038/gim.2015.201
Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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