title: Clinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion.
abstract: Patients carrying a C9orf72 repeat expansion leading to frontotemporal dementia and/or amyotrophic lateral sclerosis have highly variable ages at onset of disease, suggesting the presence of modifying factors.
  
  
  
  To provide clinical-based evidence for disease anticipation in families carrying a C9orf72 repeat expansion by analyzing age at onset, disease duration, and age at death in successive generations.
  
  
  
  This cohort study was performed from June 16, 2000, to June 1, 2016, in 36 extended Belgian families in which a C9orf72 repeat expansion was segregating. The generational effect on age at onset, disease duration, and age at death was estimated using a mixed effects Cox proportional hazards regression model, including random-effects terms for within-family correlation and kinship. Time until disease onset or last examination, time from disease onset until death or last examination, or age at death was collected for for 244 individuals (132 proven or obligate C9orf72 carriers), of whom 147 were clinically affected (89 proven or obligate C9orf72 carriers).
  
  
  
  Generational effect on age at onset, disease duration, and age at death.
  
  
  
  Among the 111 individuals with age at onset available (66 men and 45 women; mean [SD] age, 57.2 [9.1] years), the mean (SD) age at onset per generation (from earliest-born to latest-born generation) was 62.5 (8.3), 57.1 (8.2), 54.6 (10.2), and 49.3 (7.5) years. Censored regression analysis on all affected and unaffected at-risk relatives confirmed a decrease in age at onset in successive generations (P < .001). No generational effect was observed for disease duration or age at death.
  
  
  
  The clinical data provide supportive evidence for the occurrence of disease anticipation in families carrying a C9orf72 repeat expansion by means of a decrease in age at onset across successive generations. This finding may help clinicians decide from which age onward it may be relevant to clinically follow presymptomatic individuals who carry a C9orf72 repeat expansion.
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium3Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium4Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Van Mossevelde
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Gijselinck
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.affiliation: Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: De Bleecker
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium5Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Sieben
authors.affiliation: Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium7Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium4Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Van Langenhove
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium4Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.affiliation: Department of Neurology, General Hospital Sint-Jan Brugge-Oostende, Brugge, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Deryck
authors.affiliation: Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Santens
authors.affiliation: Department of Neurology, Saint-Luc University Hospital and Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ivanoiu
authors.affiliation: Department of Neurology, Jessa Hospital, Hasselt, Belgium.
authors.forename: Christiana
authors.initials: C
authors.lastname: Willems
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bäumer
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Van den Broeck
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium4Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium4Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium3Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium3Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D017668:Age of Onset; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D015331:Cohort Studies; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D016016:Proportional Hazards Models; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins