Dichloroacetate is a Novel Safe Treatment for Beta-ketothiolase Deficiency: Towards Better Therapeutic Outcomes (An Original Article)

Beta-ketothiolase deficiency (BKTD) is an inborn error of ketone bodies and isoleucine metabolism. Patients with BKTD manifest during late infancy and early childhood with recurrent episodes of ketoacidosis (accumulated acetoacetate and β-hydroxybutyrate) that may be refractory to treatment and life-threatening. BKTD is exaggerated by fasting, starvation and catabolic conditions. Dichloroacetate (DCA) is a safe effective treatment for both lactic acidosis and non-Hodgkin’s lymphoma. DCA is non-toxic and non-carcinogenic at therapeutic doses. DCA toxic doses are hundred times (12- gram/l) more than the therapeutic doses. In experimental models of ketosis, DCA reduces ketonemia and ketonuria while significantly lowering blood glucose. Importantly, DCA was reported to divert pyruvate (amino group acceptor to form alanine in transamination reactions to regenerate α-ketoglutarate from glutamate) to oxidative pathways to form acetyl CoA that is oxidized in Krebs cycle. That inhibits first step of isoleucine catabolism (transamination step) and consequently blocks formation of acetoacetate and β-hydroxybutyrate. That alleviates ketone bodies-induced refractory metabolic acidosis. On biochemical and pharmacological bases, we suggest DCA as a novel evidence-based adjuvant and life-saving treatment for BKTD. Moreover, DCA-induced inhibition of ketone bodies uptake will be alleviated by insulin effects. Causes of refractory metabolic acidosis in BKTD are increased levels of ketone bodies (due to increased isoleucine catabolism, increased ketone bodies formation and decreased ketone bodies utilization). DCA relieves most of these. Biochemically, DCA and ketone bodies (acetoacetate and β-hydroxybutyrate) are structural analogs derived from acetic acid. In neonatology, DCA improved neonatal septicaemia-induced refractory metabolic acidosis that did not respond to conventional sodium bicarbonate. In conclusion, DCA is strongly suggested to treat BKTD.