C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flow-chart for Genetic Testing

Isabelle Le Ber, Agnès Camuzat, Lena Guillot-Noel, Didier Hannequin, Lucette Lacomblez, Véronique Golfier, Michèle Puel, Olivier Martinaud, Vincent Deramecourt, Sophie Rivaud-Pechoux, Stéphanie Millecamps, Martine Vercelletto, Philippe Couratier, François Sellal, Florence Pasquier, François Salachas, Catherine Thomas-Antérion, Mira Didic, Jérémie Pariente, Danielle Seilhean, Merle Ruberg, Isabelle Wargon, Frédéric Blanc, William Camu, Bernard-François Michel, Eric Berger, Mathilde Sauvée, Christel Thauvin-Robinet, Karl Mondon, Elisabeth Tournier-Lasserve, Cyril Goizet, Marie Fleury, Gabriel Viennet, Patrice Verpillat, Vincent Meininger, Charles Duyckaerts, Bruno Dubois, Alexis Brice,
JAD. 2013-06-20; 34(2): 485-499
DOI: 10.3233/JAD-121456

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1. J Alzheimers Dis. 2013;34(2):485-99. doi: 10.3233/JAD-121456.

C9ORF72 repeat expansions in the frontotemporal dementias spectrum of diseases: a
flow-chart for genetic testing.

Le Ber I(1), Camuzat A, Guillot-Noel L, Hannequin D, Lacomblez L, Golfier V, Puel
M, Martinaud O, Deramecourt V, Rivaud-Pechoux S, Millecamps S, Vercelletto M,
Couratier P, Sellal F, Pasquier F, Salachas F, Thomas-Antérion C, Didic M,
Pariente J, Seilhean D, Ruberg M, Wargon I, Blanc F, Camu W, Michel BF, Berger E,
Sauvée M, Thauvin-Robinet C, Mondon K, Tournier-Lasserve E, Goizet C, Fleury M,
Viennet G, Verpillat P, Meininger V, Duyckaerts C, Dubois B, Brice A.

Author information:
(1)CRicm-UMRS975, Paris, France AP-HP, Hôpital de la Pitié-Salpêtrière, Centre de
Référence des Démences Rares, Paris, France.

Frontotemporal dementia (FTD) refers to a disease spectrum including the
behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive
supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with
amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major
cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and
PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72
expansions were much more frequent in the large subgroup of patients with
familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more
frequent than in familial pure ALS, according to estimated frequencies in the
literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%)
indicates that C9ORF72 should be analyzed even when family history is negative.
Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a
clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72.
Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients
(46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6
years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT
and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT
mutations, whereas hallucinations were indicative of PGRN mutations;
prioritization of genetic testing is thus possible. Penetrance was age- and
gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52%
of females. This can also guide genetic testing and counseling. A flowchart for
genetic testing is thus proposed.

DOI: 10.3233/JAD-121456
PMID: 23254636 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus