Co-incidental C9orf72 expansion mutation-related frontotemporal lobar degeneration pathology and sporadic Creutzfeldt-Jakob disease

Eur J Neurol. 2021 Mar;28(3):1009-1015. doi: 10.1111/ene.14621. Epub 2020 Dec 1.

Abstract

Background: The C9orf72 hexanucleotide expansion mutation is the most common cause of genetic frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and combined FTD-ALS. Its underlying neuropathology combines TDP-43 pathology and dipeptide repeat protein (DPR) deposits and may also associate with other neurodegeneration-associated protein aggregates. Herein we present a unique combination of C9orf72 mutation with sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old patient with rapidly progressive dementia.

Methods: Detailed neuropathological examination including immunohistochemistry for several proteinopathies. Genetic analysis was conducted by repeat primed polymerase chain reaction (PCR). Furthermore, we analyzed additional C9orf72 mutation carriers for prion-protein (PrP) deposits in brain tissue and screened the cerebellar cortex of other CJD cases for p62/DPR neuronal inclusions to assess the frequency of combined pathologies.

Results: Postmortem brain examination of a patient with a rapidly progressive neurological deterioration of 8 months' duration confirmed the diagnosis of CJD. She harbored valine homozygosity at PRNP codon 129. In addition, a frontotemporal lobar degeneration (FTLD)-pattern with TDP-43 protein aggregates and p62+/C9RANT+ positive inclusions along with a high degree of Alzheimer-related pathology (A3B3C3) were identified. The suspected C9orf72 expansion mutation was confirmed by repeat-primed PCR. Screening of 13 C9orf72 cases showed no pathological PrP aggregates and screening of 100 CJD cases revealed no other C9orf72 expansion mutation carriers.

Conclusion: A combination of a C9orf72 expansion mutation-related FTLD with sporadic CJD in the same patient is rare. While the rarity of both diseases makes this concurrence most likely to be coincidental, questions regarding a potential link between these two neurodegenerative pathologies deserve further studies.

Keywords: C9orf72; CJD; FTLD; TDP-43; prion.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis* / genetics
  • C9orf72 Protein / genetics
  • Creutzfeldt-Jakob Syndrome* / genetics
  • DNA Repeat Expansion / genetics
  • DNA-Binding Proteins / genetics
  • Female
  • Frontotemporal Dementia* / genetics
  • Frontotemporal Lobar Degeneration* / genetics
  • Humans
  • Mutation

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins