Neuropediatrics 2004; 35 - P75
DOI: 10.1055/s-2004-819447

Pyruvat carboxylase deficiency – therapeutic concept of a basic defect of neurotransmission

B Gebhardt 1, S Parbel 1, S Dittrich 1, S Vlaho 1, H Böhles 1, M Kieslich 1
  • 1Department of Pediatrics, J.W.Goethe University of Frankfurt/Main, Germany

Introduction: Pyruvat Carboxylase (PC) deficiency is a rare inborn error of metabolism presenting as severe lactate acidosis, multi organ failure and even if treated early and sufficient as massive developmental delay. The impaired anaplerotic function of PC on the tricarbolic acid cycle (TCA) in liver and kidneys effects gluconeogenesis and the synthesis of the glucoplastic amino acids, finally leading into a breakdown of energy metabolism. In contrast in astrocytes the availability of 2-oxoglutaric acid the basic source of central nervous glutamate/glutamine synthesis is essentially connected to PC function. Subsequently the appropriation of the two major neurotransmitters of the CNS GABA and glutamate depends to the glutamine pool. Therefore the morphological presentation of PC deficiency in the brain is a disturbed myelination.

Case report: We report a patient with French-type PC deficiency. Considering the current knowledge of CNS glutamine synthesis we present a therapeutic concept of the neurometabolic disturbance. On the basis of liver transplantation, ensuring metabolic stability, the ability to replace the anaplerotic function in astrocytes with the aim of normalizing CNS glutamine synthesis is described. Clinical data of neurological development as well as morphological (MRI, MRS) and biochemical (CSF amino acids, GABA, NAA, organic acids, Citrate, biogenic amines) parameters are discussed including a one year follow up.

Conclusion: The French-type PC deficiency is, in analogy to atypical phenylketonuria, a prototype of an inborn defect in neurotransmission. Discussing the experiences of this case report on the basis of the current literature reveals an exemplary insight into the biochemical pathology of a developing brain. Furthermore a promising concept for the treatment of a rare neurometabolic disease is presented.

Keywords: pyruvat carboxylase, neurotransmitter, glutamate