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Original Investigation
February 13, 2017

Clinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion

Author Affiliations
  • 1Center for Molecular Neurology, VIB, Antwerp, Belgium
  • 2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
  • 3Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium
  • 4Department of Neurology, Antwerp University Hospital, Edegem, Belgium
  • 5Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium
  • 6Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium
  • 7Department of Neurology, University Hospitals Leuven, Leuven, Belgium
  • 8Department of Neurology, General Hospital Sint-Jan Brugge-Oostende, Brugge, Belgium
  • 9Department of Neurology, Saint-Luc University Hospital and Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium
  • 10Department of Neurology, Jessa Hospital, Hasselt, Belgium
JAMA Neurol. Published online February 13, 2017. doi:10.1001/jamaneurol.2016.4847
Key Points

Question  Is there clinical evidence for the occurrence of disease anticipation in families carrying a C9orf72 repeat expansion?

Findings  In this cohort study within 36 C9orf72 pedigrees, a significant decrease in age at onset was seen across successive generations, but no generational effect was seen on disease duration or age at death.

Meaning  These data provide supportive evidence for the occurrence of disease anticipation in families carrying a C9orf72 repeat expansion and may help clinicians decide from which age onward it may be relevant to clinically follow presymptomatic individuals who carry a C9orf72 repeat expansion.

Abstract

Importance  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.

Objective  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.

Design, Setting, and Participants  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).

Main Outcomes and Measures  Generational effect on age at onset, disease duration, and age at death.

Results  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.

Conclusions and Relevance  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.

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