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

Clémence Fournier; Mathieu Barbier; Agnès Camuzat; Vincent Anquetil; Serena Lattante; Fabienne Clot; Cécile Cazeneuve; Daisy Rinaldi; Philippe Couratier; Vincent Deramecourt; Mario Sabatelli; Serge Belliard; Martine Vercelletto; Sylvie Forlani; Ludmila Jornea; Alexis Brice; Sophie Auriacombe; Frédéric Blanc; Claire Bouteleau-Bretonnière; Mathieu Ceccaldi; Mira Didic; Bruno Dubois; Charles Duyckaerts; Frédérique Etcharry-Bouix; Véronique Golfier; Didier Hannequin; Lucette Lacomblez; Isabelle Le Ber; Richard Levy; Bernard François Michel; Florence Pasquier; Catherine Thomas-Anterion; Jérémie Pariente; François Sellal; Eve Benchetrit; Hugo Bertin; Anne Bertrand; Anne Bissery; Stéphanie Bombois; Marie Paule Boncoeur; Pascaline Cassagnaud; Mathieu Chastan; Yaohua Chen; Marie Chupin; Olivier Colliot; Xavier Delbeucq; Christine Delmaire; Emmanuel Gerardin; Claude Hossein-Foucher; Pierre François Pradat; French Clinical and Genetic Research Network on FTLD/FTLD-ALS; PREVDEMALS and FTLD-Exome Study Groups

doi:10.1016/j.neurobiolaging.2018.09.010

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

Clémence Fournier
, Mathieu Barbier
, Agnès Camuzat
, Vincent Anquetil
, Serena Lattante
, Fabienne Clot
, Cécile Cazeneuve
, Daisy Rinaldi
, Philippe Couratier
, Vincent Deramecourt
, Mario Sabatelli
, Serge Belliard
, Martine Vercelletto
, Sylvie Forlani
, Ludmila Jornea
, Alexis Brice
, Sophie Auriacombe
, Frédéric Blanc
, Claire Bouteleau-Bretonnière
, Mathieu Ceccaldi

Mira Didic, Bruno Dubois, Charles Duyckaerts, Frédérique Etcharry-Bouix, Véronique Golfier, Didier Hannequin, Lucette Lacomblez, Isabelle Le Ber, Richard Levy, Bernard François Michel, Florence Pasquier, Catherine Thomas-Anterion, Jérémie Pariente, François Sellal, Eve Benchetrit, Hugo Bertin, Anne Bertrand, Anne Bissery, Stéphanie Bombois, Marie Paule Boncoeur, Pascaline Cassagnaud, Mathieu Chastan, Yaohua Chen, Marie Chupin, Olivier Colliot, Xavier Delbeucq, Christine Delmaire, Emmanuel Gerardin, Claude Hossein-Foucher, Pierre François Pradat, French Clinical and Genetic Research Network on FTLD/FTLD-ALS, PREVDEMALS and FTLD-Exome Study Groups

School of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

42 Citations (Scopus)

Abstract

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 < 10^e−4) but our results suggested that the association was mainly driven by age at collection (p < 10^e−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.

Original language	English
Pages (from-to)	234.e1-234.e8
Journal	Neurobiology of Aging
Volume	74
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.09.010
Publication status	Published (in print/issue) - 1 Feb 2019

Funding

The authors thank the DNA and cell bank of the ICM, Hopital Pitié-Salpêtrière, Paris. The authors are very grateful to the Adrian Isaac's team (UCL, London) for their technical advices. Funding sources: The research leading to these results has received funding from the program “Investissements d'avenir” ANR-10-IAIHU-06. This work was partially funded by the Program Hospitalier de Recherche Clinique FTLD-exome (to ILB., promotion Assistance Publique–Hôpitaux de Paris) and by the ANR-PRTS PREV-DEMALS project (to ILB, promotion by Assistance Publique–Hôpitaux de Paris). The French Clinical and Genetic Research Network on FTLD/FTLD-ALS includes: Alexis Brice (Hôpital de la Salpêtrière, Paris), Sophie Auriacombe (CHU Pellegrin, Bordeaux), Serge Belliard (CHU Rennes), Frédéric Blanc (Hôpitaux Civils, Strasbourg), Claire Bouteleau-Bretonnière (CHU Laennec, Nantes), Mathieu Ceccaldi (CHU La Timone, Marseille), Philippe Couratier (CHU Limoges), Mira Didic (CHU La Timone, Marseille), Bruno Dubois (Hôpital de la Salpêtrière, Paris), Charles Duyckaerts (Hôpital de la Salpêtrière, Paris), Frédérique Etcharry-Bouix (CHU Angers), Véronique Golfier (CHU Rennes), Didier Hannequin (CHU Charles Nicolle, Rouen), Lucette Lacomblez (Hôpital de la Salpêtrière, Paris), Isabelle Le Ber (Hôpital de la Salpêtrière, Paris), Richard Levy (Hôpital de la Salpêtrière, Paris), Bernard-François Michel (CH Sainte-Marguerite, Marseille), Florence Pasquier (CHU Roger Salengro, Lille), Catherine Thomas-Anterion (Plein-Ciel, Lyon), Jérémie Pariente (CHU Rangueil, Toulouse), François Sellal (CH Colmar), Martine Vercelletto (CHU Laennec, Nantes). PREVDEMALS & FTLD-Exome Study Groups include: Eve Benchetrit (Hôpital Pitié-Salpêtrière, Paris), Hugo Bertin (Hôpital de la Salpêtrière, Paris), Anne Bertrand (Hôpital Pitié-Salpêtrière, Paris), Anne Bissery (Hôpital Pitié-Salpêtrière, Paris), Stéphanie Bombois (CHU Roger Salengro, Lille), Marie-Paule Boncoeur (CHU Limoges), Pascaline Cassagnaud (CHU Roger Salengro, Lille), Mathieu Chastan (CHU Charles Nicolle, Rouen), Yaohua Chen (CHU Roger Salengro, Lille), Marie Chupin (CATI, ICM, Paris), Olivier Colliot (ICM, Paris), Philippe Couratier (CHU Limoges), Xavier Delbeucq (CHU Roger Salengro, Lille), Vincent Deramecourt (CHU Roger Salengro, Lille), Christine Delmaire (CHU Roger Salengro, Lille), Emmanuel Gerardin (CHU Charles Nicolle, Rouen), Claude Hossein-Foucher (CHU Roger Salengro, Lille), Bruno Dubois (Hôpital Pitié-Salpêtrière, Paris), Marie-Odile Habert (Hôpital Pitié-Salpêtrière, Paris), Didier Hannequin (CHU Charles Nicolle, Rouen), Géraldine Lautrette (CHU Limoges), Thibaud Lebouvier (CHU Roger Salengro, Lille), Isabelle Le Ber (Hôpital Pitié-Salpêtrière Salpêtrière, Paris), Stéphane Lehéricy (Hôpital Pitié-Salpêtrière Salpêtrière, Paris), Benjamin Le Toullec (ICM, Paris), Richard Levy (Hôpital Pitié-Salpêtrière, Paris), Kelly Martineau (CATI, ICM, Paris), Marie-Anne Mackowiak (CHU Roger Salengro, Lille), Jacques Monteil (CHU Limoges), Florence Pasquier (CHU Roger Salengro, Lille), Grégory Petyt (CHU Roger Salengro, Lille), Pierre-François Pradat (Hôpital Pitié-Salpêtrière, Paris), Assi-Hervé Oya (Hôpital Pitié-Salpêtrière, Paris), Daisy Rinaldi (Hôpital Pitié-Salpêtrière, Paris), Adeline Rollin-Sillaire (CHU Roger Salengro, Lille), François Salachas (Hôpital Pitié-Salpêtrière, Paris), Sabrina Sayah (Hôpital Pitié-Salpêtrière, Paris), David Wallon (CHU Rouen). Appendix A

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Amyotrophic Lateral sclerosis
Anticipation
C9orf72
Frontotemporal dementia
Frontotemporal lobar degeneration
TDP-43

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10.1016/j.neurobiolaging.2018.09.010

Cite this

Fournier, C., Barbier, M., Camuzat, A., Anquetil, V., Lattante, S., Clot, F., Cazeneuve, C., Rinaldi, D., Couratier, P., Deramecourt, V., Sabatelli, M., Belliard, S., Vercelletto, M., Forlani, S., Jornea, L., Brice, A., Auriacombe, S., Blanc, F., Bouteleau-Bretonnière, C., ... PREVDEMALS and FTLD-Exome Study Groups (2019). Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers. Neurobiology of Aging, 74, 234.e1-234.e8. https://doi.org/10.1016/j.neurobiolaging.2018.09.010

@article{422979f458b74e24a0786eb9f7eb6250,

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

abstract = "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",

author = "Cl{\'e}mence Fournier and Mathieu Barbier and Agn{\`e}s Camuzat and Vincent Anquetil and Serena Lattante and Fabienne Clot and C{\'e}cile Cazeneuve and Daisy Rinaldi and Philippe Couratier and Vincent Deramecourt and Mario Sabatelli and Serge Belliard and Martine Vercelletto and Sylvie Forlani and Ludmila Jornea and Alexis Brice and Sophie Auriacombe and Fr{\'e}d{\'e}ric Blanc and Claire Bouteleau-Bretonni{\`e}re and Mathieu Ceccaldi and Mira Didic and Bruno Dubois and Charles Duyckaerts and Fr{\'e}d{\'e}rique Etcharry-Bouix and V{\'e}ronique Golfier and Didier Hannequin and Lucette Lacomblez and \{Le Ber\}, Isabelle and Richard Levy and Michel, \{Bernard Fran{\c c}ois\} and Florence Pasquier and Catherine Thomas-Anterion and J{\'e}r{\'e}mie Pariente and Fran{\c c}ois Sellal and Eve Benchetrit and Hugo Bertin and Anne Bertrand and Anne Bissery and St{\'e}phanie Bombois and Boncoeur, \{Marie Paule\} and Pascaline Cassagnaud and Mathieu Chastan and Yaohua Chen and Marie Chupin and Olivier Colliot and Xavier Delbeucq and Christine Delmaire and Emmanuel Gerardin and Claude Hossein-Foucher and Pradat, \{Pierre Fran{\c c}ois\} and \{French Clinical and Genetic Research Network on FTLD/FTLD-ALS\} and \{PREVDEMALS and FTLD-Exome Study Groups\}",

year = "2019",

month = feb,

day = "1",

doi = "10.1016/j.neurobiolaging.2018.09.010",

language = "English",

volume = "74",

pages = "234.e1--234.e8",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

}

Fournier, C, Barbier, M, Camuzat, A, Anquetil, V, Lattante, S, Clot, F, Cazeneuve, C, Rinaldi, D, Couratier, P, Deramecourt, V, Sabatelli, M, Belliard, S, Vercelletto, M, Forlani, S, Jornea, L, Brice, A, Auriacombe, S, Blanc, F, Bouteleau-Bretonnière, C, Ceccaldi, M, Didic, M, Dubois, B, Duyckaerts, C, Etcharry-Bouix, F, Golfier, V, Hannequin, D, Lacomblez, L, Le Ber, I, Levy, R, Michel, BF, Pasquier, F, Thomas-Anterion, C, Pariente, J, Sellal, F, Benchetrit, E, Bertin, H, Bertrand, A, Bissery, A, Bombois, S, Boncoeur, MP, Cassagnaud, P, Chastan, M, Chen, Y, Chupin, M, Colliot, O, Delbeucq, X, Delmaire, C, Gerardin, E, Hossein-Foucher, C, Pradat, PF, French Clinical and Genetic Research Network on FTLD/FTLD-ALS & PREVDEMALS and FTLD-Exome Study Groups 2019, 'Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers', Neurobiology of Aging, vol. 74, pp. 234.e1-234.e8. https://doi.org/10.1016/j.neurobiolaging.2018.09.010

TY - JOUR

T1 - Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers

AU - Fournier, Clémence

AU - Barbier, Mathieu

AU - Camuzat, Agnès

AU - Anquetil, Vincent

AU - Lattante, Serena

AU - Clot, Fabienne

AU - Cazeneuve, Cécile

AU - Rinaldi, Daisy

AU - Couratier, Philippe

AU - Deramecourt, Vincent

AU - Sabatelli, Mario

AU - Belliard, Serge

AU - Vercelletto, Martine

AU - Forlani, Sylvie

AU - Jornea, Ludmila

AU - Brice, Alexis

AU - Auriacombe, Sophie

AU - Blanc, Frédéric

AU - Bouteleau-Bretonnière, Claire

AU - Ceccaldi, Mathieu

AU - Didic, Mira

AU - Dubois, Bruno

AU - Duyckaerts, Charles

AU - Etcharry-Bouix, Frédérique

AU - Golfier, Véronique

AU - Hannequin, Didier

AU - Lacomblez, Lucette

AU - Le Ber, Isabelle

AU - Levy, Richard

AU - Michel, Bernard François

AU - Pasquier, Florence

AU - Thomas-Anterion, Catherine

AU - Pariente, Jérémie

AU - Sellal, François

AU - Benchetrit, Eve

AU - Bertin, Hugo

AU - Bertrand, Anne

AU - Bissery, Anne

AU - Bombois, Stéphanie

AU - Boncoeur, Marie Paule

AU - Cassagnaud, Pascaline

AU - Chastan, Mathieu

AU - Chen, Yaohua

AU - Chupin, Marie

AU - Colliot, Olivier

AU - Delbeucq, Xavier

AU - Delmaire, Christine

AU - Gerardin, Emmanuel

AU - Hossein-Foucher, Claude

AU - Pradat, Pierre François

AU - French Clinical and Genetic Research Network on FTLD/FTLD-ALS

AU - PREVDEMALS and FTLD-Exome Study Groups

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - Amyotrophic Lateral sclerosis

KW - Anticipation

KW - C9orf72

KW - Frontotemporal dementia

KW - Frontotemporal lobar degeneration

KW - TDP-43

UR - https://www.scopus.com/pages/publications/85055094662

U2 - 10.1016/j.neurobiolaging.2018.09.010

DO - 10.1016/j.neurobiolaging.2018.09.010

M3 - Article

C2 - 30337192

AN - SCOPUS:85055094662

SN - 0197-4580

VL - 74

SP - 234.e1-234.e8

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

Abstract

Funding

UN SDGs

Keywords

Access to Document

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