2. Academic Validation
  3. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood

Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood

  • Am J Hum Genet. 2014 Mar 6;94(3):453-61. doi: 10.1016/j.ajhg.2014.01.006.
Clara D van Karnebeek 1,  William S Sly 2,  Colin J Ross 3,  Ramona Salvarinova 4,  Joy Yaplito-Lee 5,  Saikat Santra 6,  Casper Shyr 7,  Gabriella A Horvath 4,  Patrice Eydoux 8,  Anna M Lehman 9,  Virginie Bernard 7,  Theresa Newlove 10,  Henry Ukpeh 11,  Anupam Chakrapani 6,  Mary Anne Preece 12,  Sarah Ball 12,  James Pitt 13,  Hilary D Vallance 14,  Marion Coulter-Mackie 15,  Hien Nguyen 2,  Lin-Hua Zhang 3,  Amit P Bhavsar 7,  Graham Sinclair 14,  Abdul Waheed 2,  Wyeth W Wasserman 7,  Sylvia Stockler-Ipsiroglu 4
Affiliations

Affiliations

  • 1 Division of Biochemical Diseases, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3V4, Canada; Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3V4, Canada; Treatable Intellectual Disability Endeavour in British Columbia, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada. Electronic address: cvankarnebeek@cw.bc.ca.
  • 2 Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
  • 3 Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3V4, Canada; Treatable Intellectual Disability Endeavour in British Columbia, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
  • 4 Division of Biochemical Diseases, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3V4, Canada; Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3V4, Canada; Treatable Intellectual Disability Endeavour in British Columbia, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
  • 5 Metabolic Genetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
  • 6 Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
  • 7 Treatable Intellectual Disability Endeavour in British Columbia, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 8 Treatable Intellectual Disability Endeavour in British Columbia, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3N1, Canada; Department of Pathology & Laboratory Medicine, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 9 Treatable Intellectual Disability Endeavour in British Columbia, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 10 Treatable Intellectual Disability Endeavour in British Columbia, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Department of Psychology, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 11 Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3V4, Canada.
  • 12 Department of Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
  • 13 Metabolic Genetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia.
  • 14 Treatable Intellectual Disability Endeavour in British Columbia, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Biochemical Genetics Laboratory, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3N1, Canada; Department of Pathology & Laboratory Medicine, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 15 Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3V4, Canada; Treatable Intellectual Disability Endeavour in British Columbia, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
PMID: 24530203 DOI: 10.1016/j.ajhg.2014.01.006
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.

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