Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early
Clara D van Karnebeek1, William S Sly2, Colin J Ross3
1Division 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.
Insights
Carbonic anhydrase VA (CA-VA) deficiency, a newly identified metabolic disorder, causes hyperammonemia in children. Prompt diagnosis and treatment with carglumic acid can resolve this condition.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Hyperammonemia in neonates and young children is often of unexplained origin.
- Carbonic anhydrase VA (CA-VA) is crucial for intermediary metabolism.
- Genetic defects in CA5A can lead to severe metabolic disturbances.
Purpose of the Study:
- To identify the genetic cause of unexplained hyperammonemia in affected children.
- To characterize the biochemical consequences of CA-VA deficiency.
- To evaluate the therapeutic efficacy of carglumic acid.
Main Methods:
- Genetic analysis (sequencing, deletion analysis) of the CA5A gene.
- Enzymatic activity assays and temperature sensitivity studies.
- Metabolite profiling and clinical assessment.
Main Results:
- Identified three distinct CA5A mutations (missense, splice site, deletion) in three families.
- Demonstrated reduced enzymatic activity and thermal instability for the missense mutation.
- Observed impaired bicarbonate provision to key metabolic enzymes and successful resolution of hyperammonemia with carglumic acid.
Conclusions:
- CA-VA deficiency is a newly recognized genetic disorder causing hyperammonemia.
- This condition should be considered in the differential diagnosis of neonatal and childhood hyperammonemia.
- Carglumic acid is an effective treatment for CA-VA deficiency.
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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