Why hypothesized to be due to the reliance of the brain on glucose as the principal energy source during both the prenatal and postnatal periods. Fetal rodent brain has low level of PDC activity and it increases rapidly during the suckling period reaching the adult level soon after weaning to support increased energetic and biosynthetic needs of the developing brain.. Therefore, prenatal and immediate postnatal periods may represent the most vulnerable periods for PDC deficiency. The brain is comprised of several heterogeneous cell types with variable capacities for glucose metabolism. The glycolytic and oxidative capacities for glucose metabolism are differentially compartmentalized between astroglia and neurons which represent two major cell populations in the brain. Astroglia metabolize glucose to lactate via the glycolytic pathway far in excess of its rate of oxidation in the mitochondria resulting in lactate Mepiroxol release in the extracellular space. The PDC, in part, appears to be rate limiting step in the oxidation of pyruvate in astroglia. Neurons, on the other hand, readily oxidize both glucose and lactate to CO2 with the preference to oxidize external lactate over intracellular pyruvate and lactate generated from glucose via glycolysis. PDC deficiency 3,4,5-Trimethoxyphenylacetic acid should affect both types of cells by reducing their overall capacity to generate energy from glucose and lactate. This prediction is supported by a significant reduction in glucose oxidation to CO2 by brain slices of PDC-deficient females on P15 and P35. Since glucose is the primary fuel for energy production in the brain, the reduction in glucose oxidation in PDC-deficient brains during development would cause deficits in energy production, possibly resulting in impaired cell proliferation and differentiation, as observed in this study. Furthermore, developing brain synthesizes largely its lipids de novo from acetylCoA derived from glucose metabolism via the PDC reaction. Our results on lipogenesis demonstrated that the biosynthesis of fatty acids from glucose-carbons by brains of P15 PDC-deficient mice was significantly reduced compared to control females. This finding also supports the observed reduction in the brain weight of P35 PDC-deficient females. Interestingly, we did not find increased levels of blood lactate in PDC-deficient female mice. The reason for such an outcome is not clear. It is possible that the mild degree of PDC-deficiency in the mouse model as compared to much severe PDC deficiency in affected subjects may account for such an outcome for the blood lactate levels. It should be noted that the reduction in PDC activity in all tissues from PDC-deficient female mice is due to mosaic expression of PDC activity. In the majority of reported cases of PDC deficiency, histopathological evaluation of the brain was not present. In selected cases of early neonatal morbidity, a common set of malformations has been identified. The most frequent observation is dilation of the cerebral ventricles, consistent with atrophy of cortex, and most pronounced laterally. Underdevelopment of large white matter structures such as the corpus callosum, pons and pyramids have also been well described. Atrophy or neuronal loss combined with gliosis has been often found in the cortex and less often in basal ganglia, thalamus, hypothalamus and cerebellum. A decrease in Purkinje neuron number was observed in cerebellar cortex. Heterotopias have been found in all brain regions. Magnetic resonance imaging and post-mortem human studies have also shown profound decreases in the size of corpus callossum. Based on clinical findings and brain imaging data derived from 22 PDC-deficient subjects, Barnerias et al. identified four different neurological presentations, namely malformations, acute brainstem dysfunction, congenital motor disorders, and relapsing ataxia.