Biochemical and structural brain alterations in female mice with cerebral pyruvate dehydrogenase deficiency.

[pyruvate dehydrogenase deficiency]

Pyruvate dehydrogenase complex (PDC ) deficiency is an inborn metabolic disorder associated with a variety of neurologic abnormalities . This report describes the development and initial characterization of a novel murine model system in which PDC deficiency has been introduced specifically into the developing nervous system . The absence of liveborn male and a roughly 50 % reduction in female offspring following induction of the X-linked mutation indicate that extensive deficiency of PDC in the nervous system leads to pre-natal lethality . Brain tissue from surviving females at post-natal days 15 and 35 was shown to have approximately 75 % of wild-type PDC activity , suggesting that a threshold of enzyme activity exists for post-natal survival . Detailed histological analyses of brain tissue revealed structural defects such as disordered neuronal cytoarchitecture and neuropil fibers in grey matter , and reduced size of bundles and disorganization of fibers in white matter . Many of the histologic abnormalities resemble those found in human female patients who carry mutations in the X-linked ortholog . These findings demonstrate a requirement for PDC activity within the nervous system for survival in utero and suggest that impaired pyruvate metabolism in the developing brain can affect neuronal migration , axonal growth and cell-cell interactions .