Sodium dichloroacetate treatment of children with mitochondrial encephalomyopathies

摘要

Mitochondrial encephalomyopathies due to disorders of the respiratory chain enzymes ATP-synthase and the pyruvate dehydrogenase (PDH) complex represent a group of serious pediatric diseases. Their clinical manifestation is rather heterogeneous and often includes failure to thrive, encephalopathy, myopathy, hepatopathy, hypertrophic cardiomyopathy and lactic acidosis. During the period 1993-1996 mitochondrial encephalomyopathy was diagnosed in 34 children using biochemical and molecular biology approaches. Intrauterine growth retardation and failure to thrive were usually the first clinical symptoms. Developmental delay started in most children during infancy, followed by developmental regress in the second year of life. Eight (8) of the children presented with classical Leigh syndrome, 17 had encephalomyopathy with lactic acidosis, 4 had hypertrophic cardiomyopathy with encephalomyopathy, one girl had encephalomyopathy and sideroblastic anemia, and one newborn died from fatal lactate acidosis; 3 children with their first symptoms during the preschool period had isolated myopathy. Cytochrome c oxidase (COX) deficiency was found in 20 children, a low activity of NADH dehydrogenase was found in 1 child, succinate dehydrogenase defect in 2 children, ATP synthase defect in 4 children, a defect of PDH complex in 5 children and a combined defect of COX and NADH dehydrogenase in 2 children. In 4 children a point mutation of mtDNA was found (1x 8334 MERRF mutation, 3x 8993 NARP mutation); none of the patients had large-scale deletions of mtDNA. Alanine, lactate and the lactate/pyruvate ratio were elevated in blood and CSF from most children. A mild dicarboxylic aciduria, an increased excretion of the Krebs cycle intermediates and an elevated ratio of acylcarnitines to free carnitine in urine were frequently found. The prognosis of children with mitochondrial encephalomyopathy is unfavorable. In an attempt to lower lactic acidosis 7 children were treated with sodium dichloroacetate (12-80 mg/kg/day). As a result the blood lactate levels decreased significantly, but no significant improvement in the clinical course of patients was noticed. The only exception was a slight improvement of physical performance in a boy with myopathy and moderate COX deficiency.