Brain MR Imaging and Proton MR Spectroscopy in Female Mice with Pyruvate Dehydrogenase Complex Deficiency

Abstract

Pyruvate dehydrogenase complex (PDC) deficiency is an inborn metabolic disorder that causes neurological abnormalities. In this report, a murine model of PDC deficiency was analyzed using histology, magnetic resonance (MR) imaging and MR spectroscopy (MRS) and the results compared to PDC-deficient female patients. Histological analysis of brains from PDC-deficient mice revealed defects in neuronal cytoarchitecture in grey matter and reduced size of white matter structures. MR results were comparable to previously published clinical MR findings obtained from PDC-deficient female patients. Specifically, a 15.4% increase in relative lactate concentration, 64.4% loss of N-acetylaspartate concentration and a near complete loss of discernable glutamine plus glutamate concentration were observed in a PDC deficient mouse compared to wild-type control. Lower apparent diffusion coefficients (ADCs) were observed within the brain consistent with atrophy. These results demonstrate the usefulness of this murine model to systematically evaluate the beneficial effects of dietary and pharmacological interventions.

Cortical metabolism in pyruvate dehydrogenase deficiency revealed by ex vivo multiplet 13C NMR of the adult mouse brain

“…All institutional regulations for animal acquisition and care by UT Southwestern were followed. The generation and neuropathological characteristics of the mice deficient in brain PDC used here were previously described (Pliss et al, 2007; Pliss et al, 2004). Animal breeding for the generation of PDC-deficient and control female mice and their genotype identification were also performed as described (Pliss et al, 2004).…”

“…In the brain, PDC is expressed by neurons and, to a lesser degree, by glia, but uncertainty exists about the extent and magnitude of metabolic impact of PDC deficiency in vivo . Nevertheless, reductions in PDC activity, as typically observed in tissues obtained from PDC-deficient patients, can be presumed to limit acetyl-CoA production from glucose in both major brain cell types (neurons and glia) (Pliss et al, 2007), which may then secondarily impact closely related and regulated metabolic activities, such as the TCA cycle and anaplerosis. This hypothesis, however, has not been evaluated in PDC-deficient neural tissue in situ .…”

“…Human PDC deficiency encompasses a broad clinical spectrum that preferentially impacts the nervous system, ranging from minimal neurological impairment (such as mild intermittent movement incoordination or ataxia) to severe neurobehavioral disability or even neonatal or infantile death (Robinson, 2006; Robinson et al, 1996). Brain structural abnormalities are prominent, affecting neurons in the gray matter (manifested as neuronal migration defects in the cerebral cortex) and myelin structure in the white matter (ranging from hypoplasia to absence of myelinated tracts such as the corpus callosum of the cerebral hemispheres) (Brown et al, 1994; Chow et al, 1987; Michotte et al, 1993; Pliss et al, 2007; Pliss et al, 2004). Therapies have focused on metabolic interventions intended to enhance acetyl-CoA synthesis, such as the induction of hepatic ketone body production using high-fat ketogenic diets (Pithukpakorn, 2005).…”

“…A reduction of this magnitude can cause clinical manifestations typical of PDC deficiency in man when assayed in fibroblasts or skeletal muscle samples (Quintana et al, 2010; Robinson et al, 1996; Shevell et al, 1994), and manifest cerebral malformations similar to those harbored by PDC-deficient patients (Johnson et al, 2001; Pliss et al, 2007; Pliss et al, 2004). More severe reductions in PDC activity are almost invariably lethal.…”

Pyruvate dehydrogenase complex: mRNA and protein expression patterns of E1α subunit genes in human spermatogenesis

“…PDC deficiency is one of the most common neurodegenerative disorders associated with altered mitochondrial metabolism leading to energy deprivation, especially in the central nervous system (Brown and Brown, 1994;Pliss et al, 2007). The most frequent form of genetically determined PDC deficiency is caused by mutations in E1α subunit (OMIM #312170) (Lissens et al, 2000).…”