title: Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate.
abstract: A patient with severe pyruvate carboxylase deficiency presented at age 11 weeks with metabolic decompensation after routine immunization. She was comatose, had severe lactic acidemia (22 mM) and ketosis, low aspartate and glutamate, elevated citrulline and proline, and mild hyperammonemia. Head magnetic resonance imaging showed subdural hematomas and mild generalized brain atrophy. Biotin-unresponsive pyruvate carboxylase deficiency was diagnosed. To provide oxaloacetate, she was treated with high-dose citrate (7.5 mol/kg(-1)/day(-1)), aspartate (10 mmol/kg(-1)/day(-1)), and continuous drip feeding. Lactate and ketones diminished dramatically, and plasma amino acids normalized, except for arginine, which required supplementation. In the cerebrospinal fluid (CSF), glutamine remained low and lysine elevated, showing the treatment had not normalized brain chemistry. Metabolic decompensations, triggered by infections or fasting, diminished after the first year. They were characterized by severe lactic and ketoacidosis, hypernatremia, and a tendency to hypoglycemia. At age 3(1/2) years she has profound mental retardation, spasticity, and grand mal and myoclonic seizures only partially controlled by anticonvulsants. The new treatment regimen has helped maintain metabolic control, but the neurological outcome is still poor.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ahmad
authors.forename: S G
authors.initials: SG
authors.lastname: Kahler
authors.forename: P S
authors.initials: PS
authors.lastname: Kishnani
authors.forename: M
authors.initials: M
authors.lastname: Artigas-Lopez
authors.forename: A S
authors.initials: AS
authors.lastname: Pappu
authors.forename: R
authors.initials: R
authors.lastname: Steiner
authors.forename: D S
authors.initials: DS
authors.lastname: Millington
authors.forename: J L
authors.initials: JL
authors.lastname: Van Hove
mesh_terms: D000596:Amino Acids / Q000097:blood / Q000187:drug effects; D001224:Aspartic Acid / Q000627:therapeutic use*; D002675:Child, Preschool; D019343:Citric Acid / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000473:pathology; D007662:Ketosis / Q000097:blood / Q000188:drug therapy; D019344:Lactic Acid / Q000097:blood; D015324:Pyruvate Carboxylase Deficiency Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000596:Amino Acids; D019343:Citric Acid; D001224:Aspartic Acid; D019344:Lactic Acid