title: Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy.
abstract: A six-day-old girl was referred for severe hepatic failure, dehydratation, axial hypotonia, and both lactic acidosis and ketoacidosis. Biotin-unresponsive pyruvate carboxylase deficiency type B was diagnosed. Triheptanoin, an odd-carbon triglyceride, was administrated as a source for acetyl-CoA and anaplerotic propionyl-CoA. Although this patient succumbed to a severe infection, during the six months interval of her anaplerotic and biochemical management, the following important observations were documented: (1) the immediate reversal (less than 48 h) of major hepatic failure with full correction of all biochemical abnormalities, (2) on citrate supplementation, the enhanced export from the liver of triheptanoin's metabolites, namely 5 carbon ketone bodies, increasing the availability of these anaplerotic substrates for peripheral organs, (3) the demonstration of the transport of C5 ketone bodies-representing alternative energetic fuel for the brain-across the blood-brain barrier, associated to increased levels of glutamine and free gamma-aminobutyric acid (f-GABA) in the cerebrospinal fluid. Considering that pyruvate carboxylase is a key enzyme for anaplerosis, besides the new perspectives brought by anaplerotic therapies in those rare pyruvate carboxylase deficiencies, this therapeutic trial also emphasizes the possible extended indications of triheptanoin in various diseases where the citric acid cycle is impaired.
authors.affiliation: Metabolic Unit, Departments of Pediatrics and Biochemistry, Hospital Necker-Enfants Malades, Paris, France. fanny.mochel@freesbee.fr
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
authors.forename: Pascale
authors.initials: P
authors.lastname: DeLonlay
authors.forename: Guy
authors.initials: G
authors.lastname: Touati
authors.forename: Henri
authors.initials: H
authors.lastname: Brunengraber
authors.forename: Renee P
authors.initials: RP
authors.lastname: Kinman
authors.forename: Daniel
authors.initials: D
authors.lastname: Rabier
authors.forename: Charles R
authors.initials: CR
authors.lastname: Roe
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saudubray
mesh_terms: D001344:Autopsy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002951:Citrates / Q000627:therapeutic use; D002952:Citric Acid Cycle; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006537:Heptanoates / Q000627:therapeutic use*; D006801:Humans; D006843:Hydrocarbons, Chlorinated; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011422:Propionates / Q000627:therapeutic use; D015324:Pyruvate Carboxylase Deficiency Disease / Q000178:diet therapy* / Q000378:metabolism*; D014280:Triglycerides / Q000627:therapeutic use*; D005680:gamma-Aminobutyric Acid / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D002951:Citrates; D006537:Heptanoates; D006843:Hydrocarbons, Chlorinated; D011422:Propionates; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C021974:2-chloropropionic acid