The severity of symptomatology in females can vary tremendously, even when individuals carry the same mutation. The inter-individual variability has been attributed to differences in patterns of X chromosome inactivation between individuals. Despite identification of a large number of mutations in the PDHA1 gene, impairment at the cellular level in affected PDCdeficient patients remains largely uncharacterized. Previous studies investigating this metabolic disorder have been limited due to the lack of availability of a suitable animal model. We have developed a murine model that carries a Folinic acid calcium salt pentahydrate mutation in the X-linked Pdha1 gene, the orthologue of the human PDHA1 gene. Earlier we developed a murine model of PDC deficiency that expressed PDC deficiency in the brain only. These PDC-deficient female mice developed brain structural LOUREIRIN-B abnormalities somewhat similar to those observed in female patients with this disorder, including underdevelopment of white matter structures and gross reduction of white matter. The ‘systemic’ PDC deficiency model reported here also develops similar brain structural abnormalities to that observed in the ‘cerebral’ PDC-deficient murine model, and more importantly it resembles closely to PDC deficiency observed in female patients developing PDC deficiency during early embryogenesis and expressing in all tissues. Additionally, in the present study we have addressed the question of the developmental origin of brain defects characteristic for systemic PDC deficiency by monitoring proliferation, migration and differentiation of neuronal cells during development. Although PDC deficiency results in malformation of brain structures and often severe neurological symptoms in PDCdeficient patients, the mechanisms responsible for aberrant brain development in affected patients remains largely uncharacterized. This is due primarily to the lack of availability of an animal model to investigate the effects of PDC deficiency on brain development and to test treatment options. A zebrafish model of PDC deficiency was developed to evaluate its effect on growth and efficacy of a ketogenic dietary treatment. The findings of this study were interesting but were of limited applicability to human PDC deficiency due to a non-mammalian species origin of this model. The present study reports an additional mouse model of ‘systemic’ PDC deficiency presenting its central nervous system structural pathology that confirms what has already been reported for a mouse model with ‘cerebral’ PDCdeficiency and also extends the previous study by demonstrating abnormal cellular proliferation and migration especially in the cerebellum. As shown in a previous study and in the present study, no males with PDC deficiency were born under our breeding scheme indicating that null mutation in the Pdha1 gene is lethal for male embryos. Indeed all reported male patients with PDC deficiency have a variable level of residual enzymatic activity ranging from 5�C40% in cultured skin fibroblasts. As expected, heterozygous female mice with ‘systemic’ PDC deficiency were born under our breeding protocol. Surprisingly, compared to the previously reported model of ‘cerebral’ PDC deficiency, where about one half of all female embryos did not survive in utero, there is no indication of embryonic lethality for female embryos in the present study even though the deletion of exon 8 was initiated earlier on embryonic day 1 in the ‘systemic’ PDC deficiency model and despite having a similar degree of PDC deficiency in the brains from both the murine models. The reason for this unexpected difference between two models remains unexplained at present. Although the deletion of Pdha1 exon 8 was initiated in the ‘systemic’ murine model at an early embryonic stage, the percentages of reduction in PDC activity differed in different tissues.