Mitochondria and peripheral neuropathies

J Neuropathol Exp Neurol. 2012 Dec;71(12):1036-46. doi: 10.1097/NEN.0b013e3182764d47.


There has been considerable progress during the past 24 years in the molecular genetics of mitochondrial DNA and related nuclear DNA mutations, and more than 100 nerve biopsies from hereditary neuropathies related to mitochondrial cytopathy have been accurately examined. Neuropathies were first reported in diseases related to point mutations of mitochondrial DNA, but they proved to be a prominent feature of the phenotype in mitochondrial disorders caused by defects in nuclear DNA, particularly in 3 genes: polymerase gamma 1 (POLG1), mitofusin 2 (MFN2), and ganglioside-induced differentiation-associated protein 1 (GDAP1). Most patients have sensory-motor neuropathy, sometimes associated with ophthalmoplegia, ataxia, seizures, parkinsonism, myopathy, or visceral disorders. Some cases are caused by consanguinity, but most are sporadic with various phenotypes mimicking a wide range of other etiologies. Histochemistry on muscle biopsy, as well as identification of crystalloid inclusions at electron microscopy, may provide a diagnostic clue to mitochondriopathy, but nerve biopsy is often less informative. Nevertheless, enlarged mitochondria containing distorted or amputated cristae are highly suggestive, particularly when located in the Schwann cell cytoplasm. Also noticeable are clusters of regenerating myelinated fibers surrounded by concentric Schwann cell processes, and such onion bulb-like formations are frequently observed in neuropathies caused by GDAP1 mutations.

MeSH terms

  • DNA Polymerase gamma
  • DNA, Mitochondrial / genetics
  • DNA-Directed DNA Polymerase / genetics
  • GTP Phosphohydrolases / genetics
  • Humans
  • Mitochondria / genetics
  • Mitochondria / pathology*
  • Mitochondrial Proteins / genetics
  • Muscles / pathology
  • Muscles / ultrastructure
  • Nerve Tissue Proteins / genetics
  • Peripheral Nervous System Diseases / genetics*
  • Peripheral Nervous System Diseases / pathology*
  • Point Mutation / genetics
  • Schwann Cells / pathology
  • Schwann Cells / ultrastructure


  • DNA, Mitochondrial
  • GDAP protein
  • Mitochondrial Proteins
  • Nerve Tissue Proteins
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human
  • GTP Phosphohydrolases
  • MFN2 protein, human