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JAMA Neurol. 2017 Apr 1;74(4):445-452. doi: 10.1001/jamaneurol.2016.4847.

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

Author information

1
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.
2
Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
3
Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
4
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.
5
Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium7Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
6
Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium4Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
7
Department of Neurology, General Hospital Sint-Jan Brugge-Oostende, Brugge, Belgium.
8
Department of Neurology, Saint-Luc University Hospital and Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.
9
Department of Neurology, Jessa Hospital, Hasselt, Belgium.
10
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium4Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
11
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium3Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium.

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.

PMID:
28192553
DOI:
10.1001/jamaneurol.2016.4847
[Indexed for MEDLINE]

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