Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content +++ Key Features ++ Most common disorders of central mitochondrial energy metabolism are pyruvate dehydrogenase deficiency and deficiencies of respiratory chain components In pyruvate dehydrogenase deficiency, the lactate-pyruvate ratio is normal In respiratory chain disorders the lactate-pyruvate ratio is often increased Respiratory chain disorders Common (1:5000) Involve a heterogenous group of genetic defects that produce a variety of clinical syndromes (now > 50) of varying severity and presentation Common causes of static, progressive, or self-limited neurodevelopmental problems in children +++ Clinical Findings ++ Pyruvate dehydrogenase complex Agenesis of the corpus callosum or Leigh syndrome (lesions in the globus pallidus, dentate nucleus, and periaqueductal gray matter) Mild facial dysmorphism Recurrent altered mental status, recurrent ataxia, and recurrent acidosis Most common genetic defect is in the X-linked E1α component, with males carrying milder mutations and females carrying severe mutations leading to periventricular cystic brain lesions Respiratory chain disorders can be indicated by following set of symptoms (not intended as a comprehensive listing) Failure to thrive Progressive neurodegeneration, Leigh syndrome, myoclonic seizures, brain atrophy, movement disorders, cerebellar atrophy, and subcortical leukodystrophy Optic neuropathy, retinitis pigmentosa, progressive external ophthalmoplegia, and cataracts Nerve deafness Myopathy with decreased endurance or rhabdomyolysis Renal Fanconi syndrome, proteinuria (in CoQ deficiency) Diabetes mellitus and hypoparathyroidism Pancreatic or liver insufficiency or pseudoobstruction Cardiomyopathy, conduction defects, and arrhythmias +++ Diagnosis ++ Pyruvate dehydrogenase deficiency Enzyme assay in leukocytes or fibroblasts is diagnostic Molecular analysis confirms diagnosis Diagnosis of respiratory chain disorders is based on a convergence of clinical, biochemical, morphologic, enzymatic, and molecular data Classic pathologic features of mitochondrial disorders Accumulation of mitochondria, which produces ragged red fibers in skeletal muscle biopsy Abnormal mitochondrial shapes and inclusions inside mitochondria on electron microscopy However, these findings are only present in 5% of children Blue native polyacrylamide gel electrophoresis (PAGE) analyzes the assembly of the respiratory chain enzyme complexes Defects in mtDNA maintenance (such as mtDNA polymerase γ, POLG1 gene) Often presents with liver disease and neurodegeneration Sequencing the causative nuclear genes is diagnostic +++ Treatment ++ Pyruvate dehydrogenase deficiency A ketogenic diet is useful Dichloroacetic acid has limited clinical response and has adverse effects Thiamine and lipoic acid have been tried Respiratory chain defects Coenzyme Q and riboflavin have been helpful in some patients Avoidance of catabolism and of medications that impair mitochondrial function is important Transcriptional upregulation in partial deficiencies of nuclear origin and new antioxidants such as EPI-743 offer hope In patients with primary coenzyme Q deficiency, coenzyme Q treatment is very effective Your Access profile is currently affiliated with '[InstitutionA]' and is in the process of switching affiliations to '[InstitutionB]'. Please click ‘Continue’ to continue the affiliation switch, otherwise click ‘Cancel’ to cancel signing in. Get Free Access Through Your Institution Learn how to see if your library subscribes to McGraw Hill Medical products. Subscribe: Institutional or Individual Sign In Username Error: Please enter User Name Password Error: Please enter Password Forgot Password? Forgot Username? Sign in via OpenAthens Sign in via Shibboleth