Pyruvate dehydrogenase, pyruvate carboxylase, Krebs cycle, and mitochondrial transport disorders

Considered collectively, energy metabolism disorders spare no organ or tissue and therefore can mimic diseases routinely encountered by primary and specialty care clinicians. In addition to the well-established role of many energy metabolism enzymes and transporters in the formation and dissolution of high-energy molecular bonds and in the supply of fuels to cells, some also serve dual or, possibly, multiple or multifaceted roles. For example, some pyruvate metabolism enzyme mutations impair axonal migration or alter craniofacial configuration; many are linked to neuronal necrosis and apoptosis and to edema (spongiosis) of the cerebral white matter and, paradoxically, can manifest in the same individual with both low basal cerebral activity and intermittent hyperexcitation (seizures), which is associated with interneuron synaptic failure and resultant disinhibition. Even Krebs cycle enzyme variants are associated with specific cancers and may confer significant biological aggressivity to glioma, a phenomenon diagnostically exploited via magnetic resonance imaging spectroscopy. These a priori unexpected neurological manifestations probably stem from the fact that flux through energy metabolism reactions sustains the synthesis and recycling of neurotransmitters and other signaling molecules by neural cells and circuits. Consequently, the brain often bears the full burden of these diseases, in conjunction with cardiac and skeletal muscle, liver, and kidney. Metabolic therapies continue to be the mainstay approach to treatment, which assumes that the long-range metabolic and nonmetabolic consequences of enzyme and transport reactions are reversible, although this has not been proven because most such consequences are not well understood.