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Clinical evidence of disease anticipation in families segregating a C9orf72 repeat expansion

(2017) JAMA NEUROLOGY. 74(4). p.445-452
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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 studywas 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.
Keywords
AMYOTROPHIC-LATERAL-SCLEROSIS, GGGGCC HEXANUCLEOTIDE REPEAT, FRONTOTEMPORAL DEMENTIA, HUNTINGTON DISEASE, ALZHEIMERS-DISEASE, DIAGNOSIS, SIZE, ALS, SPECTRUM, CRITERIA

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Citation

Please use this url to cite or link to this publication:

Chicago
Van Mossevelde, Sara, Julie van der Zee, Ilse Gijselinck, Kristel Sleegers, Jan De Bleecker, Anne Sieben, Rik Vandenberghe, et al. 2017. “Clinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion.” Jama Neurology 74 (4): 445–452.
APA
Van Mossevelde, S., van der Zee, J., Gijselinck, I., Sleegers, K., De Bleecker, J., Sieben, A., Vandenberghe, R., et al. (2017). Clinical evidence of disease anticipation in families segregating a C9orf72 repeat expansion. JAMA NEUROLOGY, 74(4), 445–452.
Vancouver
1.
Van Mossevelde S, van der Zee J, Gijselinck I, Sleegers K, De Bleecker J, Sieben A, et al. Clinical evidence of disease anticipation in families segregating a C9orf72 repeat expansion. JAMA NEUROLOGY. 2017;74(4):445–52.
MLA
Van Mossevelde, Sara, Julie van der Zee, Ilse Gijselinck, et al. “Clinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion.” JAMA NEUROLOGY 74.4 (2017): 445–452. Print.
@article{8512640,
  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 studywas 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 {\textlangle} .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.},
  author       = {Van Mossevelde, Sara and van der Zee, Julie and Gijselinck, Ilse and Sleegers, Kristel and De Bleecker, Jan and Sieben, Anne and Vandenberghe, Rik and Van Langenhove, Tim and Baets, Jonathan and Deryck, Olivier and Santens, Patrick and Ivanoiu, Adrian and Willems, Christiana and B{\"a}umer, Veerle and Van den Broeck, Marleen and Peeters, Karin and Mattheijssens, Maria and De Jonghe, Peter and Cras, Patrick and Martin, Jean-Jacques and Cruts, Marc and De Deyn, Peter P and Engelborghs, Sebastiaan and Van Broeckhoven, Christine},
  issn         = {2168-6149},
  journal      = {JAMA NEUROLOGY},
  language     = {eng},
  number       = {4},
  pages        = {445--452},
  title        = {Clinical evidence of disease anticipation in families segregating a C9orf72 repeat expansion},
  url          = {http://dx.doi.org/10.1001/jamaneurol.2016.4847},
  volume       = {74},
  year         = {2017},
}

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