Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers

Neurobiol Aging. 2019 Feb;74:234.e1-234.e8. doi: 10.1016/j.neurobiolaging.2018.09.010. Epub 2018 Sep 19.


A (GGGGCC)n repeat expansion in C9orf72 gene is the major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The relations between the repeats size and the age at disease onset (AO) or the clinical phenotype (FTD vs. ALS) were investigated in 125 FTD, ALS, and presymptomatic carriers. Positive correlations were found between repeats number and the AO (p < 10e-4) but our results suggested that the association was mainly driven by age at collection (p < 10e-4). A weaker association was observed with clinical presentation (p = 0.02), which became nonsignificant after adjustment for the age at collection in each group. Importantly, repeats number variably expanded or contracted over time in carriers with multiple blood samples, as well as through generations in parent-offspring pairs, conversely to what occurs in several expansion diseases with anticipation at the molecular level. Finally, this study establishes that measure of repeats number in lymphocytes is not a reliable biomarker predictive of the AO or disease outcome in C9orf72 long expansion carriers.

Keywords: Amyotrophic Lateral sclerosis; Anticipation; C9orf72; Frontotemporal dementia; Frontotemporal lobar degeneration; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Age of Onset
  • Aged
  • Amyotrophic Lateral Sclerosis / blood
  • Amyotrophic Lateral Sclerosis / epidemiology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Blood Specimen Collection
  • C9orf72 Protein / blood*
  • C9orf72 Protein / genetics*
  • DNA Repeat Expansion / genetics*
  • Female
  • Frontotemporal Dementia / blood
  • Frontotemporal Dementia / epidemiology
  • Frontotemporal Dementia / genetics*
  • Heterozygote*
  • Humans
  • Male
  • Middle Aged
  • Phenotype


  • C9orf72 Protein
  • C9orf72 protein, human