Atypical parkinsonism in C9orf72 expansions: a case report and systematic review of 45 cases from the literature

J Neurol. 2016 Mar;263(3):558-74. doi: 10.1007/s00415-016-8021-7. Epub 2016 Jan 25.


While C9orf72 repeat expansions usually present with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS), an increasing number of reports suggests that the primary phenotype of C9orf72 patients may also include movement disorders. We here provide the first systematic clinical characterisation of C9orf72-associated parkinsonism. We report a C9orf72 expansion carrier presenting with a clinical syndrome of progressive supranuclear palsy (PSP), pronounced mesencephalic atrophy on MRI and PSP-characteristic electrooculography findings. Moreover, we systematically review all previous reports on C9orf72 patients with parkinsonian features. Review of 28 reports revealed 45 C9orf72-positive patients with hypokinesia, rigidity and/or resting tremor. C9orf72-associated parkinsonism predominantly consisted in a hypokinetic-rigid syndrome without resting tremor (61%), with both asymmetric (59%) and symmetric (41%) distributions. Additional features included upper motor neuron signs (60%), lower motor neuron signs (36%), cognitive dysfunction (85%), behaviour and/or personality change (55%) and psychiatric symptoms (29%). Vertical supranuclear gaze palsy was reported in three further cases and cerebellar dysfunction in four cases. Family history frequently yielded evidence of ALS (31%) and FTD (21%). Atypical parkinsonism is a recurrent phenotypic manifestation of C9orf72 expansions. It occurs as part of a broad spectrum of C9orf72-related multi-system neurodegeneration, which can include basal ganglia, mesencephalic and cerebellar dysfunction. C9orf72 genotyping should be considered in those patients with atypical parkinsonism who present with a family history of ALS or FTD, upper or lower motor neuron signs and/or cognitive dysfunction with pronounced frontotemporal impairment.

Keywords: C9orf72 repeat expansion; Electrooculography; Mesencephalic atrophy; Parkinsonism; Parkinson’s disease; Progressive supranuclear palsy.

Publication types

  • Case Reports
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / diagnostic imaging
  • Amyotrophic Lateral Sclerosis / genetics
  • Brain / diagnostic imaging
  • C9orf72 Protein
  • DNA Repeat Expansion / genetics*
  • Electrooculography
  • Family Health
  • Female
  • Fluorodeoxyglucose F18
  • Humans
  • Male
  • Middle Aged
  • Parkinsonian Disorders / diagnostic imaging
  • Parkinsonian Disorders / genetics*
  • Positron-Emission Tomography
  • Proteins / genetics*
  • PubMed / statistics & numerical data
  • Young Adult


  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins
  • Fluorodeoxyglucose F18