Causative mutations and genetic risk factors ...
Type de document :
Article dans une revue scientifique: Article original
DOI :
PMID :
URL permanente :
Titre :
Causative mutations and genetic risk factors in sporadic early onset alzheimer''s disease before 51 years
Auteur(s) :
Lacour, Morgane [Auteur]
Quenez, Olivier [Auteur]
Rovelet-Lecrux, Anne [Auteur]
Salomon, Bruno [Auteur]
Rousseau, Stéphane [Auteur]
Richard, Anne-Claire [Auteur]
Quillard-Muraine, Muriel [Auteur]
Pasquier, Florence [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U1171
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Rollin-Sillaire, Adeline [Auteur]
Martinaud, Olivier [Auteur]
Zarea, Aline [Auteur]
De La Sayette, Vincent [Auteur]
Boutoleau-Bretonniere, Claire [Auteur]
Etcharry-Bouyx, Frederique [Auteur]
Chauvire, Valerie [Auteur]
Sarazin, Marie [Auteur]
Le Ber, Isabelle [Auteur]
Epelbaum, Stéphane [Auteur]
Jonveaux, Therese [Auteur]
Rouaud, Olivier [Auteur]
Ceccaldi, Mathieu [Auteur]
Godefroy, Olivier [Auteur]
Formaglio, Maite [Auteur]
Croisile, Bernard [Auteur]
Auriacombe, Sophie [Auteur]
Magnin, Eloi [Auteur]
Sauvee, Mathilde [Auteur]
Marelli-Tosi, Cecilia [Auteur]
Gabelle, Audrey [Auteur]
Pariente, Jeremie [Auteur]
Paquet, Claire [Auteur]
Boland, Anne [Auteur]
Deleuze, Jean-François [Auteur]
Campion, Dominique [Auteur]
Hannequin, Didier [Auteur]
Nicolas, Gael [Auteur]
Wallon, David [Auteur]
Quenez, Olivier [Auteur]
Rovelet-Lecrux, Anne [Auteur]
Salomon, Bruno [Auteur]
Rousseau, Stéphane [Auteur]
Richard, Anne-Claire [Auteur]
Quillard-Muraine, Muriel [Auteur]
Pasquier, Florence [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U1171
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Rollin-Sillaire, Adeline [Auteur]
Martinaud, Olivier [Auteur]
Zarea, Aline [Auteur]
De La Sayette, Vincent [Auteur]
Boutoleau-Bretonniere, Claire [Auteur]
Etcharry-Bouyx, Frederique [Auteur]
Chauvire, Valerie [Auteur]
Sarazin, Marie [Auteur]
Le Ber, Isabelle [Auteur]
Epelbaum, Stéphane [Auteur]
Jonveaux, Therese [Auteur]
Rouaud, Olivier [Auteur]
Ceccaldi, Mathieu [Auteur]
Godefroy, Olivier [Auteur]
Formaglio, Maite [Auteur]
Croisile, Bernard [Auteur]
Auriacombe, Sophie [Auteur]
Magnin, Eloi [Auteur]
Sauvee, Mathilde [Auteur]
Marelli-Tosi, Cecilia [Auteur]
Gabelle, Audrey [Auteur]
Pariente, Jeremie [Auteur]
Paquet, Claire [Auteur]
Boland, Anne [Auteur]
Deleuze, Jean-François [Auteur]
Campion, Dominique [Auteur]
Hannequin, Didier [Auteur]
Nicolas, Gael [Auteur]
Wallon, David [Auteur]
Titre de la revue :
Journal of Alzheimer's disease . JAD
Nom court de la revue :
J. Alzheimers Dis.
Date de publication :
2019-07-25
ISSN :
1875-8908
Mot(s)-clé(s) en anglais :
PSEN1
APP
cerebrospinal fluid biomarkers (APOE)
early onset Alzheimer''s disease
genetics
PSEN2
APP
cerebrospinal fluid biomarkers (APOE)
early onset Alzheimer''s disease
genetics
PSEN2
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
BACKGROUND: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic ...
Lire la suite >BACKGROUND: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. OBJECTIVE: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. METHODS: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. RESULTS: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. CONCLUSIONS: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.Lire moins >
Lire la suite >BACKGROUND: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. OBJECTIVE: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. METHODS: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. RESULTS: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. CONCLUSIONS: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
CHU Lille
CNRS
Inserm
Université de Lille
CNRS
Inserm
Université de Lille
Collections :
Équipe(s) de recherche :
Troubles cognitifs dégénératifs et vasculaires
Date de dépôt :
2019-11-27T14:33:12Z