Cerebellar ataxia in patients with mitochondrial DNA disease: a molecular clinicopathological study

J Neuropathol Exp Neurol. 2012 Feb;71(2):148-61. doi: 10.1097/NEN.0b013e318244477d.


Cerebellar ataxia is a prominent clinical symptom in patients with mitochondrial DNA (mtDNA) disease. This is often progressive with onset in young adulthood. We performed a detailed neuropathologic investigation of the olivary-cerebellum in 14 genetically and clinically well-defined patients with mtDNA disease. Quantitative neuropathologic investigation showed varying levels of loss of Purkinje cells and neurons of the dentate nucleus and inferior olivary nuclei. Typically, focal Purkinje cell loss was present in patients with the m.3243A>G mutation caused by the presence of microinfarcts, with relative preservation of neuronal cell populations in the olivary and dentate nuclei. In contrast, patients with the m.8344A>G mutation or recessive POLG mutations showed extensive and global neuronal cell loss in all 3 olivary-cerebellum areas examined. Molecular analysis of mutated mtDNA heteroplasmy levels revealed that neuronal cell loss occurred independently of the level of mutated mtDNA present within surviving neurons. High levels of neuronal respiratory chain deficiency, particularly of complex I, were detected in surviving cells; levels of deficiency were greater in regions with extensive cell loss. We found a relationship between respiratory deficiency and neuronal cell density, indicating that neuronal cell death correlates with respiratory deficiency. These findings highlight the vulnerability of the olivary-cerebellum to mtDNA defects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Count
  • Cell Death / genetics
  • Cerebellar Ataxia / complications
  • Cerebellar Ataxia / genetics*
  • Cerebellar Ataxia / pathology*
  • Cerebellum / pathology
  • DNA Polymerase gamma
  • DNA, Mitochondrial / genetics
  • DNA-Directed DNA Polymerase / genetics*
  • Disability Evaluation
  • Electron Transport Complex IV / metabolism
  • Female
  • Gliosis / etiology
  • Gliosis / pathology
  • Humans
  • Laser Capture Microdissection
  • Male
  • Middle Aged
  • Mitochondrial Diseases / complications
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / pathology*
  • Mutation / genetics*
  • Neurons / pathology
  • Olivary Nucleus / pathology
  • Succinate Dehydrogenase / metabolism
  • Young Adult


  • DNA, Mitochondrial
  • Succinate Dehydrogenase
  • Electron Transport Complex IV
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human