Abstract
Pyruvate carboxylase (PC) deficiency (OMIM 266150) is an autosomal recessive disorder that usually presents with lactic acidaemia and severe neurological dysfunction, leading to death in infancy. Because the enzyme is involved in gluconeogenesis and anaplerosis of the Krebs cycle, therapeutic strategies have included avoiding fasting and attempts to correct the defect of anaplerosis. Triheptanoin is a triglyceride of C7 fatty acids. The oxidation of odd chain fatty acids leads to the production not only of acetyl-CoA but also of propionyl-CoA, which is an anaplerotic substrate for the Krebs cycle. One infant with PC deficiency has previously been treated with triheptanoin as well as citrate and 2-chloropropionate. We report two further patients with PC deficiency, who were treated with triheptanoin, continuously from 11 and 21 days of age. They were also given citrate, aspartate and dichloroacetate. Triheptanoin did not lead to any clinical or biochemical improvement. The plasma and CSF lactate concentrations remained high with episodes of severe ketoacidosis and lactic acidosis. Both patients had severe hearing loss, roving eye movements, seizures and very limited neurodevelopmental progress; they died at the ages of 7 and 8 months. Conclusion: Though triheptanoin did not alter the clinical course in our patients, it was well tolerated. It remains possible that less severely affected patients might benefit from this form of therapy.
Similar content being viewed by others
Abbreviations
- CSF:
-
Cerebrospinal Fluid
- DNA:
-
Deoxyribonucleic acid
- ERG:
-
Electroretinography
- LCT:
-
Long chain triglycerides
- MRI:
-
Magnetic resonance imaging
- PC:
-
Pyruvate carboxylase
- PDHc:
-
Pyruvate dehydrogenase complex
References
Ahmad A, Kahler SG, Kishnani PS, Artigas-Lopez M, Pappu AS, Steiner R, Millington DS, Van Hove JL (1999) Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate. Am J Med Genet 87:331–338
Brun N, Robitaille Y, Grignon A, Robinson BH, Mitchell GA, Lambert M (1999) Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form. Am J Med Genet 84:94–101
Buist NR (1980) Is pyruvate carboxylase involved in the renal tubular reabsorption of bicarbonate? J Inherit Metab Dis 3:113–116
Garcia-Cazorla A, Rabier D, Touati G, Chadefaux-Vekemans B, Marsac C, de Lonlay P, Saudubray JM (2006) Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann Neurol 59:121–127
Gompertz D, Goodey PA, Thom H, Russell G, Johnston AW, Mellor DH, MacLean MW, Ferguson-Smith ME, Ferguson-Smith MA (1975) Prenatal diagnosis and family studies in a case of propionicacidaemia. Clin Genet 8:244–250
Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, Roe CR, Saudubray JM (2005) Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab 84:305–312
Nyhan WL, Khanna A, Barshop BA, Naviaux RK, Precht AF, Lavine JE, Hart MA, Hainline BE, Wappner RS, Nichols S, Haas RH (2002) Pyruvate carboxylase deficiency—insights from liver transplantation. Mol Genet Metab 77:143–149
Oizumi J, Shaw KN, Giudici TA, Carter M, Donnell GN, Ng WG (1983) Neonatal pyruvate carboxylase deficiency with renal tubular acidosis and cystinuria. J Inherit Metab Dis 6:89–94
Van Coster RN, Fernhoff PM, De Vivo DC (1991) Pyruvate carboxylase deficiency: a benign variant with normal development. Pediatr Res 30:1–4
Acknowledgments
The authors are grateful to Dr Guy Besley for the enzyme assays and helpful discussion.
Conflict of interest
The authors have no conflicts of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Breen, C., White, F.J., Scott, C.A.B. et al. Unsuccessful treatment of severe pyruvate carboxylase deficiency with triheptanoin. Eur J Pediatr 173, 361–366 (2014). https://doi.org/10.1007/s00431-013-2166-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-013-2166-5