TY - JOUR
T1 - Mitochondrial Carbonic Anhydrase VA Deficiency Resulting from CA5A Alterations Presents with Hyperammonemia in Early Childhood
AU - van Karnebeek, Clara D.
AU - Sly, William S.
AU - Ross, Colin J.
AU - Salvarinova, Ramona
AU - Yaplito-Lee, Joy
AU - Santra, Saikat
AU - Shyr, Casper
AU - Horvath, Gabriella A.
AU - Eydoux, Patrice
AU - Lehman, Anna M.
AU - Bernard, Virginie
AU - Newlove, Theresa
AU - Ukpeh, Henry
AU - Chakrapani, Anupam
AU - Preece, Mary Anne
AU - Ball, Sarah
AU - Pitt, James
AU - Vallance, Hilary D.
AU - Coulter-Mackie, Marion
AU - Nguyen, Hien
AU - Zhang, Lin-Hua
AU - Bhavsar, Amit P.
AU - Sinclair, Graham
AU - Waheed, Abdul
AU - Wasserman, Wyeth W.
AU - Stockler-Ipsiroglu, Sylvia
PY - 2014
Y1 - 2014
N2 - 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
AB - 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
U2 - https://doi.org/10.1016/j.ajhg.2014.01.006
DO - https://doi.org/10.1016/j.ajhg.2014.01.006
M3 - Article
C2 - 24530203
SN - 0002-9297
VL - 94
SP - 453
EP - 461
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -