title: Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.
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.
authors: 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.
authors: Clara D
authors: CD
authors: van Karnebeek
authors: Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
authors: William S
authors: WS
authors: Sly
authors: 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.
authors: Colin J
authors: CJ
authors: Ross
authors: 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.
authors: Ramona
authors: R
authors: Salvarinova
authors: Metabolic Genetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors: Joy
authors: J
authors: Yaplito-Lee
authors: Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
authors: Saikat
authors: S
authors: Santra
authors: 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.
authors: Casper
authors: C
authors: Shyr
authors: 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.
authors: Gabriella A
authors: GA
authors: Horvath
authors: 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.
authors: Patrice
authors: P
authors: Eydoux
authors: 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.
authors: Anna M
authors: AM
authors: Lehman
authors: 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.
authors: Virginie
authors: V
authors: Bernard
authors: 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.
authors: Theresa
authors: T
authors: Newlove
authors: Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC V6H 3V4, Canada.
authors: Henry
authors: H
authors: Ukpeh
authors: Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
authors: Anupam
authors: A
authors: Chakrapani
authors: Department of Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
authors: Mary Anne
authors: MA
authors: Preece
authors: Department of Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
authors: Sarah
authors: S
authors: Ball
authors: Metabolic Genetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia.
authors: James
authors: J
authors: Pitt
authors: 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.
authors: Hilary D
authors: HD
authors: Vallance
authors: 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.
authors: Marion
authors: M
authors: Coulter-Mackie
authors: Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
authors: Hien
authors: H
authors: Nguyen
authors: 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.
authors: Lin-Hua
authors: LH
authors: Zhang
authors: 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.
authors: Amit P
authors: AP
authors: Bhavsar
authors: 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.
authors: Graham
authors: G
authors: Sinclair
authors: Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
authors: Abdul
authors: A
authors: Waheed
authors: 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.
authors: Wyeth W
authors: WW
authors: Wasserman
authors: 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.
authors: Sylvia
authors: S
authors: Stockler-Ipsiroglu
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D024404:Carbonic Anhydrase V / Q000172:deficiency* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics* / Q000628:therapy; D007223:Infant; D008099:Liver / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013696:Temperature
chemical_list: D024404:Carbonic Anhydrase V