Format

Send to

Choose Destination
Am J Hum Genet. 2014 Mar 6;94(3):453-61. doi: 10.1016/j.ajhg.2014.01.006. Epub 2014 Feb 13.

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

Author information

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.

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.

PMID:
24530203
PMCID:
PMC3951944
DOI:
10.1016/j.ajhg.2014.01.006
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center