Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis

TY - JOUR

T1 - Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis

AU - Diez-Fernandez, Carmen

AU - Rüfenacht, Véronique

AU - Santra, Saikat

AU - Lund, Allan M

AU - Santer, René

AU - Lindner, Martin

AU - Tangeraas, Trine

AU - Unsinn, Caroline

AU - de Lonlay, Pascale

AU - Burlina, Alberto

AU - van Karnebeek, Clara D M

AU - Häberle, Johannes

PY - 2016/10

Y1 - 2016/10

N2 - PURPOSE: Four mitochondrial metabolic liver enzymes require bicarbonate, which is provided by the carbonic anhydrase isoforms VA (CAVA) and VB (CAVB). Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates. This study aimed to test for CAVA or CAVB deficiencies in a group of 96 patients with early-onset hyperammonemia and to prove the disease-causing role of the CAVA variants found.METHODS: We performed CA5A and CA5B sequencing in the described cohort and developed an expression system using insect cells, which enabled the characterization of wild-type CAVA, clinical mutations, and three variants that affect functional residues.RESULTS: In 10 of 96 patients, mutations in CA5A were identified on both alleles but none in CA5B. Exhibiting decreased enzyme activity or thermal stability, all CAVA mutations were proven to cause disease, whereas the three variants showed no relevant effect.CONCLUSION: CAVA deficiency is a differential diagnosis of early-onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs. It seems to be more common than other rare metabolic diseases, and early identification may allow specific treatment of hyperammonemia and ultimately prevent neurologic sequelae.Genet Med advance online publication 25 February 2016Genetics in Medicine (2016); doi:10.1038/gim.2015.201.

AB - PURPOSE: Four mitochondrial metabolic liver enzymes require bicarbonate, which is provided by the carbonic anhydrase isoforms VA (CAVA) and VB (CAVB). Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates. This study aimed to test for CAVA or CAVB deficiencies in a group of 96 patients with early-onset hyperammonemia and to prove the disease-causing role of the CAVA variants found.METHODS: We performed CA5A and CA5B sequencing in the described cohort and developed an expression system using insect cells, which enabled the characterization of wild-type CAVA, clinical mutations, and three variants that affect functional residues.RESULTS: In 10 of 96 patients, mutations in CA5A were identified on both alleles but none in CA5B. Exhibiting decreased enzyme activity or thermal stability, all CAVA mutations were proven to cause disease, whereas the three variants showed no relevant effect.CONCLUSION: CAVA deficiency is a differential diagnosis of early-onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs. It seems to be more common than other rare metabolic diseases, and early identification may allow specific treatment of hyperammonemia and ultimately prevent neurologic sequelae.Genet Med advance online publication 25 February 2016Genetics in Medicine (2016); doi:10.1038/gim.2015.201.

U2 - 10.1038/gim.2015.201

DO - 10.1038/gim.2015.201

M3 - SCORING: Journal article

C2 - 26913920

VL - 18

SP - 991

EP - 1000

JO - GENET MED

JF - GENET MED

SN - 1098-3600

IS - 10

ER -