Introduction
Pyruvate Dehydrogenase Deficiency frequently causes a complex biochemical and metabolic processes that lead to the appearance of a group of neurons having a low excitation threshold in the brain (Quintana et al., 2010). A group of such neurons forms an epileptic focus. A nerve impulse is generated in the epileptic focus, which spreads to surrounding cells and by excitation captures more and more new neurons (Waldbaum & Patel, 2010). Women, who carry a gene mutation of E1-alpha subunit pyruvate dehydrogenase, can develop Pyruvate Dehydrogenase Deficiency more frequently than men can. National Organization for Rare Disorders states that Women with Pyruvate Dehydrogenase Deficiency have a 50% chance with each pregnancy having an infant affected with the disease, and 50% chance to have a non-carrier (Quintana et al., 2010). This fact proves that female carriers of PDH deficiency have a high risk of affecting the child with epilepsy as one of the consequences of the disease. Epileptogenesis in PDH deficiency is linked to energy failure, development of structural brain anomalies and abnormal neurotransmitter metabolism (Waldbaum & Patel, 2010). It is evident that epilepsy on numerous occasions is associated with PDH deficiency (Quintana et al., 2010). Epileptogenesis in PDH differs from other disorders of energy metabolism according to the presence or absence of structural and functional brain abnormalities. There is a vast body of in vivo and in vitro literature linking mitochondrial dysfunction with the epileptic state (Waldbaum & Patel, 2010).
There is substantial evidence of metabolic coupling that exists between energy metabolism and neurotransmitter synthesis and turnover cycles within neurons and the supporting cells of the glial network. A biologically plausible hypothesis would be to suggest that PDH deficiency could destabilize the neurotransmitter balance in the glial-neuronal unit and broader neuronal systems through effects on glutamate and GABA, as these compounds are sourced from the TCA cycle through alpha-ketoglutarate (Quintana et al., 2010). Published clinical data would suggest that energy failure could target different regional networks and other neurotransmitter systems (dopaminergic) producing the variable neurological phenotypes paroxysmal dystonia from basal ganglia injury and cerebellar ataxia in late-onset PDH deficiency (Quintana et al., 2010).
Mechanisms
Clinical evidence suggests a strong relationship of defects in mitochondrial energy metabolism as a cause of epileptic seizures. Nevertheless, evidence from an experiment, on the other hand, indicates mitochondrial energy metabolism is affected as a consequence of epileptic seizures resulting in both neuronal death, as well as altered neuronal function leading to epileptogenesis (Lissens et al., 2000). There is some evidence that tonic seizures themselves can trigger mitochondrial dysfunction implicating a vicious spiral in the etiology of mitochondrial epilepsy (Lissens et al., 2000). For example, a man showed to have an acute encephalopathy and pathogenic POLG mutations, and through a histological examination of his brain biopsy evidence of acute disseminated encephalomyelitis has been identified. Finally, in individuals with the rare mitochondrial disease, seizures may be secondary to electrolyte disturbances arising from severe renal tubulopathy (Lissens et al., 2000).
Numerous correlates of the electrophysiological measures of epilepsy link energy metabolism with enhanced excitability of the brain, and the generation of conditions that are capable of sustaining abnormal neuronal firing, leading eventually to epileptogenesis (Lissens et al., 2000). Evidence suggests that the neurotransmitter pools of GABA, as well as glutamate and aspartate, are synthesized from glucose via pyruvate (Quintana et al., 2010). Incorporation of glucose into these amino acids is sensitive to changes in physiological function, whereas incorporation from other precursors is not. For example, anesthetic doses of sodium pentobarbitone lead to decreased incorporation of 14C-glucose into amino acids but do not affect incorporation of 14C-butyrate or 14C-acetate (Quintana et al., 2010). Therefore, impairment of cerebral glucose metabolism results in the reduction of GABA, glutamate, and aspartate in the brain (Quintana et al., 2010). Another mechanism by which PDH deficiency may affect cerebral function is by alteration of calcium homeostasis. There are significant pieces of evidence available to suggest that mitochondrial metabolism can influence neurotransmitter release by regulation of calcium accumulation. Brain mitochondria appear to be tightly linked to PDH activity by the phosphorylation state of the enzyme complex. Dichloroacetate, the PDH kinase inhibitor, stimulates pyruvate-supported calcium accumulation at concentrations at which it stimulates cerebral PDH activity (Quintana et al., 2010).
The Pathogenesis of epilepsy prominent pathological neocortical involvement due to PDH deficiency probably accounts for the epileptogenic susceptibility associated with defects of pyruvate metabolism (Waldbaum & Patel, 2010). In a study of epilepsy related to infantile-onset mitochondrial encephalopathies, PDH deficiency accounted for 41% of patients with epilepsy (Waldbaum & Patel, 2010). Besides, early onset presentations include infantile spasms and subsequent evolution into one of the intractable epilepsy syndromes associated with developmental lesions, while generalized seizures presenting in later life tend to be pharmacy sensitive or at least partially responsive to the introduction of the ketogenic diet and thiamine supplementation (Quintana et al., 2010). In situations with later onset and milder epilepsy phenotypes, the epileptogenic process may be similar to the situation encountered in other disorders of energy failure that are associated with epilepsy like GLUT1 transporter defect and mitochondrial encephalopathies such as MELAS and MERRF (Waldbaum & Patel, 2010). Another mechanism by which PDH deficiency may affect cerebral function is by alteration of calcium homeostasis. There is considerable evidence available to suggest that mitochondrial metabolism can influence neurotransmitter release by regulation of calcium accumulation. Brain mitochondria appear to be tightly linked to PDH activity by the phosphorylation state of the enzyme complex Dichloroacetate, the PDH kinase inhibitor, stimulates pyruvate-supported calcium accumulation at concentrations at which it stimulates cerebral PDH activity (Lissens et al., 2000).
The Pathophysiology of Mitochondrial Epilepsy
The pathogenesis of mitochondrial epilepsy remains poorly understood, contributing to the immense difficulties in treating this condition. The exact prevalence of mitochondrial epilepsy is not known, but seizures have been reported to occur in 35% to 60% of individuals with biochemically confirmed mitochondrial disease (Lissens et al., 2000). In another study, one-third of individuals with refractory seizures were found to have biochemical evidence of mitochondrial dysfunction (Lissens et al., 2000). Few reports have systematically examined epilepsy phenotypes in the context of mitochondrial disease (Lissens et al., 2000). Epilepsy has been identified as a poor prognostic sign in mitochondrial disease, and this has brought more emphasis on the urgent need for formal clinical trials of patients’ treatments, including the ketogenic diet and novel therapeutic agents (Lissens et al., 2000). De Meirleir highlighted on female patients with epileptogenic encephalopathy, including infantile spasms in two individuals in whom neuropathology revealed heterotopias (Quintana et al., 2010). Therefore, these very early, unmanageable, and probably contusion epilepsies related with infantile spasms should be differentiated from the epilepsies that might occur later in life, in which generalized seizures frequently are partially pharmacy sensitive and better controlled by the ketogenic diet, which often permits the tapering of antiepileptic drugs. Thus, late-onset epileptic seizures in these participants could be purely functional and result from brain energy failure, as experienced in Creatine and Glut-1 deficiency syndrome. Strikingly, atypical absences and myoclonic seizures beginning in childhood, combined with dystonic movements, is a standard feature of these disorders (Quintana et al., 2010)
References
- Lissens, W., De Meirleir, L., Seneca, S., Liebaers, I., Brown, G. K., Brown, R. M., … & Wexler, I. D. (2000). Mutations in the X‐linked pyruvate dehydrogenase (E1) α subunit gene (PDHA1) in patients with a Pyruvate Dehydrogenase complex deficiency. Human mutation, 15(3), 209-219.
- Quintana, E., Gort, L., Busquets, C., Navarro‐Sastre, A., Lissens, W., Moliner, S., … & Briones, P. (2010). A mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency. Clinical Genetics, 77(5), 474-482.
- Waldbaum, S., & Patel, M. (2010). Mitochondria, oxidative stress, and temporal lobe epilepsy. Epilepsy research, 88(1), 23-45.
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