Energy Metabolism Disorders

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