Improved redox status after liver transplantation in a patient with MMA mut0 subtype; functional evidence for EPI-743 therapy

We have followed 8 patients (4 males) with biochemically and/or molecular genetically proven deficiencies of the E1α subunit of the pyruvate dehydrogenase complex (PDC; 3 patients) or complexes I (1 patient), IV (3 patients) or I+IV (1 patient) for 10.9 to 16.5 years. All subjects originally participated in randomized controlled trials for dichloroacetate (DCA) and were continued on an open-label chronic safety study. Patients (1 adult) ranged in age from 3.5 to 40.2 years at the start of DCA administration and are currently aged 16.9 to 49.9 years (mean±SD: 23.5±10.9 years). Subjects were either normal or below normal body weight for age and gender. They have been evaluated at least twice annually for routine tests of hematopoietic, renal, hepatic, lipid and lipoprotein metabolism, peripheral nerve conduction and plasma trough DCA concentrations. The 3 PDC deficient patients consumed a modestly increased fat diet (~2 fat:1 carbohydrate+protein). Oral DCA was administered at a dose of 12.5 mg/kg every 12 h. Potentially relevant concomitant medications included carbamazepine and clonazepam (1 patient) and progesterone (1 patient). DCA was well-tolerated and maintained normal blood lactate concentrations, even in PDC deficient children on essentially unrestricted diets. Hematological, renal and electrolyte status remained stable. Mean serum alanine transaminase (ALT) levels were modestly higher on DCA (1.609-fold above baseline; p=0.008), but serum aspartate transaminase and lipid and lipoprotein levels were not significantly altered while on the drug. Nerve conduction either did not change or decreased modestly and led to reduction or temporary discontinuation of DCA in 2 patients. We conclude that chronic DCA administration is effective in maintaining normal blood lactate levels and is generally well-tolerated, particularly in pediatric patients with PDC deficiency and other congenital causes of lactic acidosis.