Carmen Diez-Fernandez1, Véronique Rüfenacht1, Saikat Santra2, Allan M Lund3, René Santer4, Martin Lindner5, Trine Tangeraas6, Caroline Unsinn1, Pascale de Lonlay7, Alberto Burlina8, Clara D M van Karnebeek9, Johannes Häberle1. 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.
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.
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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