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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


  • 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


  • 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

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