Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study (original) (raw)
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, 2AP-HP, Hôpital de la Salpêtrière, F-75013, 3AP-HP, Pitié-Salpêtrière Hospital, Centre des Maladies Cognitives et Comportementales, Paris, 4INSERM U614 and Department of Neurology, Rouen University Hospital, 5Department of Neurology and EA2691, University Hospital, Lille, 6Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, 7Centre d’Exploration Métabolique par Résonance Magnétique, UMR 6612 CNRS, Université de la Méditerranée, Marseille, France, 8Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, 9University of Antwerp, Antwerpen, Belgium, 10Service de Neurologie, CHU Maison Blanche, Reims, 11Service de Neurologie, CHU Purpan, Toulouse, 12UPMC Univ Paris 06, UMR_S679, F-75005, 13AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, F- 75013, 14Service d’ Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, 15Service de Neurologie, Centre Hospitalier Départemental, La Roche sur Yon, 16Service de Neurologie, CHU Cote de nacre, Caen, 17Service de Neurologie, CHU, Rennes, 18Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, 19Service de Neurologie, Centre Hospitalier Intercommunal, Creteil, 20INSERM U744, Institut Pasteur, Lille, 21Department of Nuclear Medicine, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013 and 22INSERM U610, Paris, France
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, 2AP-HP, Hôpital de la Salpêtrière, F-75013, 3AP-HP, Pitié-Salpêtrière Hospital, Centre des Maladies Cognitives et Comportementales, Paris, 4INSERM U614 and Department of Neurology, Rouen University Hospital, 5Department of Neurology and EA2691, University Hospital, Lille, 6Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, 7Centre d’Exploration Métabolique par Résonance Magnétique, UMR 6612 CNRS, Université de la Méditerranée, Marseille, France, 8Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, 9University of Antwerp, Antwerpen, Belgium, 10Service de Neurologie, CHU Maison Blanche, Reims, 11Service de Neurologie, CHU Purpan, Toulouse, 12UPMC Univ Paris 06, UMR_S679, F-75005, 13AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, F- 75013, 14Service d’ Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, 15Service de Neurologie, Centre Hospitalier Départemental, La Roche sur Yon, 16Service de Neurologie, CHU Cote de nacre, Caen, 17Service de Neurologie, CHU, Rennes, 18Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, 19Service de Neurologie, Centre Hospitalier Intercommunal, Creteil, 20INSERM U744, Institut Pasteur, Lille, 21Department of Nuclear Medicine, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013 and 22INSERM U610, Paris, France
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, 2AP-HP, Hôpital de la Salpêtrière, F-75013, 3AP-HP, Pitié-Salpêtrière Hospital, Centre des Maladies Cognitives et Comportementales, Paris, 4INSERM U614 and Department of Neurology, Rouen University Hospital, 5Department of Neurology and EA2691, University Hospital, Lille, 6Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, 7Centre d’Exploration Métabolique par Résonance Magnétique, UMR 6612 CNRS, Université de la Méditerranée, Marseille, France, 8Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, 9University of Antwerp, Antwerpen, Belgium, 10Service de Neurologie, CHU Maison Blanche, Reims, 11Service de Neurologie, CHU Purpan, Toulouse, 12UPMC Univ Paris 06, UMR_S679, F-75005, 13AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, F- 75013, 14Service d’ Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, 15Service de Neurologie, Centre Hospitalier Départemental, La Roche sur Yon, 16Service de Neurologie, CHU Cote de nacre, Caen, 17Service de Neurologie, CHU, Rennes, 18Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, 19Service de Neurologie, Centre Hospitalier Intercommunal, Creteil, 20INSERM U744, Institut Pasteur, Lille, 21Department of Nuclear Medicine, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013 and 22INSERM U610, Paris, France
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, 2AP-HP, Hôpital de la Salpêtrière, F-75013, 3AP-HP, Pitié-Salpêtrière Hospital, Centre des Maladies Cognitives et Comportementales, Paris, 4INSERM U614 and Department of Neurology, Rouen University Hospital, 5Department of Neurology and EA2691, University Hospital, Lille, 6Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, 7Centre d’Exploration Métabolique par Résonance Magnétique, UMR 6612 CNRS, Université de la Méditerranée, Marseille, France, 8Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, 9University of Antwerp, Antwerpen, Belgium, 10Service de Neurologie, CHU Maison Blanche, Reims, 11Service de Neurologie, CHU Purpan, Toulouse, 12UPMC Univ Paris 06, UMR_S679, F-75005, 13AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, F- 75013, 14Service d’ Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, 15Service de Neurologie, Centre Hospitalier Départemental, La Roche sur Yon, 16Service de Neurologie, CHU Cote de nacre, Caen, 17Service de Neurologie, CHU, Rennes, 18Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, 19Service de Neurologie, Centre Hospitalier Intercommunal, Creteil, 20INSERM U744, Institut Pasteur, Lille, 21Department of Nuclear Medicine, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013 and 22INSERM U610, Paris, France
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, 2AP-HP, Hôpital de la Salpêtrière, F-75013, 3AP-HP, Pitié-Salpêtrière Hospital, Centre des Maladies Cognitives et Comportementales, Paris, 4INSERM U614 and Department of Neurology, Rouen University Hospital, 5Department of Neurology and EA2691, University Hospital, Lille, 6Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, 7Centre d’Exploration Métabolique par Résonance Magnétique, UMR 6612 CNRS, Université de la Méditerranée, Marseille, France, 8Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, 9University of Antwerp, Antwerpen, Belgium, 10Service de Neurologie, CHU Maison Blanche, Reims, 11Service de Neurologie, CHU Purpan, Toulouse, 12UPMC Univ Paris 06, UMR_S679, F-75005, 13AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, F- 75013, 14Service d’ Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, 15Service de Neurologie, Centre Hospitalier Départemental, La Roche sur Yon, 16Service de Neurologie, CHU Cote de nacre, Caen, 17Service de Neurologie, CHU, Rennes, 18Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, 19Service de Neurologie, Centre Hospitalier Intercommunal, Creteil, 20INSERM U744, Institut Pasteur, Lille, 21Department of Nuclear Medicine, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013 and 22INSERM U610, Paris, France
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, 2AP-HP, Hôpital de la Salpêtrière, F-75013, 3AP-HP, Pitié-Salpêtrière Hospital, Centre des Maladies Cognitives et Comportementales, Paris, 4INSERM U614 and Department of Neurology, Rouen University Hospital, 5Department of Neurology and EA2691, University Hospital, Lille, 6Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, 7Centre d’Exploration Métabolique par Résonance Magnétique, UMR 6612 CNRS, Université de la Méditerranée, Marseille, France, 8Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, 9University of Antwerp, Antwerpen, Belgium, 10Service de Neurologie, CHU Maison Blanche, Reims, 11Service de Neurologie, CHU Purpan, Toulouse, 12UPMC Univ Paris 06, UMR_S679, F-75005, 13AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, F- 75013, 14Service d’ Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, 15Service de Neurologie, Centre Hospitalier Départemental, La Roche sur Yon, 16Service de Neurologie, CHU Cote de nacre, Caen, 17Service de Neurologie, CHU, Rennes, 18Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, 19Service de Neurologie, Centre Hospitalier Intercommunal, Creteil, 20INSERM U744, Institut Pasteur, Lille, 21Department of Nuclear Medicine, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013 and 22INSERM U610, Paris, France
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, 2AP-HP, Hôpital de la Salpêtrière, F-75013, 3AP-HP, Pitié-Salpêtrière Hospital, Centre des Maladies Cognitives et Comportementales, Paris, 4INSERM U614 and Department of Neurology, Rouen University Hospital, 5Department of Neurology and EA2691, University Hospital, Lille, 6Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, 7Centre d’Exploration Métabolique par Résonance Magnétique, UMR 6612 CNRS, Université de la Méditerranée, Marseille, France, 8Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, 9University of Antwerp, Antwerpen, Belgium, 10Service de Neurologie, CHU Maison Blanche, Reims, 11Service de Neurologie, CHU Purpan, Toulouse, 12UPMC Univ Paris 06, UMR_S679, F-75005, 13AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, F- 75013, 14Service d’ Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, 15Service de Neurologie, Centre Hospitalier Départemental, La Roche sur Yon, 16Service de Neurologie, CHU Cote de nacre, Caen, 17Service de Neurologie, CHU, Rennes, 18Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, 19Service de Neurologie, Centre Hospitalier Intercommunal, Creteil, 20INSERM U744, Institut Pasteur, Lille, 21Department of Nuclear Medicine, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013 and 22INSERM U610, Paris, France
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, 2AP-HP, Hôpital de la Salpêtrière, F-75013, 3AP-HP, Pitié-Salpêtrière Hospital, Centre des Maladies Cognitives et Comportementales, Paris, 4INSERM U614 and Department of Neurology, Rouen University Hospital, 5Department of Neurology and EA2691, University Hospital, Lille, 6Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, 7Centre d’Exploration Métabolique par Résonance Magnétique, UMR 6612 CNRS, Université de la Méditerranée, Marseille, France, 8Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, 9University of Antwerp, Antwerpen, Belgium, 10Service de Neurologie, CHU Maison Blanche, Reims, 11Service de Neurologie, CHU Purpan, Toulouse, 12UPMC Univ Paris 06, UMR_S679, F-75005, 13AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, F- 75013, 14Service d’ Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, 15Service de Neurologie, Centre Hospitalier Départemental, La Roche sur Yon, 16Service de Neurologie, CHU Cote de nacre, Caen, 17Service de Neurologie, CHU, Rennes, 18Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, 19Service de Neurologie, Centre Hospitalier Intercommunal, Creteil, 20INSERM U744, Institut Pasteur, Lille, 21Department of Nuclear Medicine, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013 and 22INSERM U610, Paris, France
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1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, 2AP-HP, Hôpital de la Salpêtrière, F-75013, 3AP-HP, Pitié-Salpêtrière Hospital, Centre des Maladies Cognitives et Comportementales, Paris, 4INSERM U614 and Department of Neurology, Rouen University Hospital, 5Department of Neurology and EA2691, University Hospital, Lille, 6Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, 7Centre d’Exploration Métabolique par Résonance Magnétique, UMR 6612 CNRS, Université de la Méditerranée, Marseille, France, 8Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, 9University of Antwerp, Antwerpen, Belgium, 10Service de Neurologie, CHU Maison Blanche, Reims, 11Service de Neurologie, CHU Purpan, Toulouse, 12UPMC Univ Paris 06, UMR_S679, F-75005, 13AP-HP, Hôpital de la Salpêtrière, Service de pharmacologie, Paris, F- 75013, 14Service d’ Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, 15Service de Neurologie, Centre Hospitalier Départemental, La Roche sur Yon, 16Service de Neurologie, CHU Cote de nacre, Caen, 17Service de Neurologie, CHU, Rennes, 18Service de Neurologie, CHU Guillaume et René Laënnec, Nantes, 19Service de Neurologie, Centre Hospitalier Intercommunal, Creteil, 20INSERM U744, Institut Pasteur, Lille, 21Department of Nuclear Medicine, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, INSERM U678, Paris, F-75013 and 22INSERM U610, Paris, France
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Received:
05 October 2007
Revision received:
08 January 2008
Accepted:
10 January 2008
Published:
02 February 2008
Cite
Isabelle Le Ber, Agnès Camuzat, Didier Hannequin, Florence Pasquier, Eric Guedj, Anne Rovelet-Lecrux, Valérie Hahn-Barma, Julie van der Zee, Fabienne Clot, Serge Bakchine, Michèle Puel, Mustapha Ghanim, Lucette Lacomblez, Jacqueline Mikol, Vincent Deramecourt, Pascal Lejeune, Vincent de la Sayette, Serge Belliard, Martine Vercelletto, Christian Meyrignac, Christine Van Broeckhoven, Jean-Charles Lambert, Patrice Verpillat, Dominique Campion, Marie-Odile Habert, Bruno Dubois, Alexis Brice, the French research network on FTD/FTD-MND, Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study, Brain, Volume 131, Issue 3, March 2008, Pages 732–746, https://doi.org/10.1093/brain/awn012
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Abstract
Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.
© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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