Pyruvate dehydrogenase complex deficiency and its relationship with epilepsy frequency--An overview.
The pyruvate dehydrogenase complex (PDHc) is a member of a family of multienzyme complexes that provides the link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the physiologically irreversible decarboxylation of various 2-oxoacid substrates to their corresponding acyl-CoA derivatives, NADH and CO2. PDHc deficiency is a metabolic disorder commonly associated with lactic acidosis, progressive neurological and neuromuscular degeneration that vary with age and gender. In this review, we aim to discuss the relationship between occurrence of epilepsy and PDHc deficiency associated with the pyruvate dehydrogenase complex (E1α subunit (PDHA1) and E1β subunit (PDHB)) and PDH phosphatase (PDP) deficiency. PDHc plays a crucial role in the aerobic carbohydrate metabolism and regulates the use of carbohydrate as the source of oxidative energy. In severe PDHc deficiency, the energy deficit impairs brain development in utero resulting in physiological and structural changes in the brain that contributes to the subsequent onset of epileptogenesis. Epileptogenesis in PDHc deficiency is linked to energy failure and abnormal neurotransmitter metabolism that progressively alters neuronal excitability. This metabolic blockage might be restricted via inclusion of ketogenic diet that is broken up by β-oxidation and directly converting it to acetyl-CoA, and thereby improving the patient's health condition. Genetic counseling is essential as PDHA1 deficiency is X-linked. The demonstration of the X-chromosome localization of PDHA1 resolved a number of questions concerning the variable phenotype displayed by patients with E1 deficiency. Most patients show a broad range of neurological abnormalities, with the severity showing some dependence on the nature of the mutation in the Elα gene, while PDHB and PDH phosphatase (PDP) deficiencies are of autosomal recessive inheritance. However, in females, the disorder is further complicated by the pattern of X-chromosome inactivation, i.e., unfavorable lyonization. Furthermore research should focus on epileptogenic animal models; this might pave a new way toward identification of the pathophysiology of this challenging disorder.
Department of Biotechnology & Bioinformatics, North-Eastern Hill University, Shillong 793 022, India; Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India.
Suman
S
Bhandary
Department of Biotechnology & Bioinformatics, North-Eastern Hill University, Shillong 793 022, India. Electronic address: kmaguan@gmail.com.
Kripamoy
K
Aguan
D000818:Animals; D004827:Epilepsy / Q000209:etiology* / Q000235:genetics; D006801:Humans; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000235:genetics / Q000378:metabolism; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000150:complications* / Q000235:genetics
D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit
Antiepileptic drugs; Epilepsy; Ketogenic diet; Metabolic disorder; PDH complex deficiency; PDHA1; X-linked