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NEUROLOGY 2009;72:1669-1676
© 2009 American Academy of Neurology

Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease

I. Le Ber, MD, PhD, A. Camuzat, BS, E. Berger, MD, D. Hannequin, MD, A. Laquerrière, MD, PhD, V. Golfier, MD, D. Seilhean, MD, G. Viennet, MD, P. Couratier, MD, PhD, P. Verpillat, MD, PhD, S. Heath, PhD, W. Camu, MD, PhD, O. Martinaud, MD, L. Lacomblez, MD, PhD, M. Vercelletto, MD, F. Salachas, MD, F. Sellal, MD, M. Didic, MD, C. Thomas-Anterion, MD, M. Puel, MD, B-F Michel, MD, C. Besse, C. Duyckaerts, MD, PhD, V. Meininger, MD, D. Campion, MD, PhD, B. Dubois, MD, PhD, A. Brice, MD For the French Research Network on FTD/FTD-MND

Authors’ affiliations are listed at the end of the article.
From CRicm-UMRS975 (formerly INSERM, UMR_S679) (I.L.B., A.C., P.V., A.B.), Paris; AP-HP (I.L.B., B.D., A.B.), Hôpital de la Salpêtrière, Centre de Référence "Démences Rares," Paris; AP-HP (I.L.B., L.L., F. Salachas, V.M., B.D., A.B.), Hôpital de la Salpêtrière, Fédération des Maladies du Système Nerveux, Paris; Service de Neurologie (E.B.) and Service de Neuropathologie (G.V.), CHU, Besançon; INSERM U614 and Département de Neurologie (D.H., O.M., D.C.) and Laboratoire de Neuropathologie (A.L.), CHU Charles Nicolle, Rouen; Service de Neurologie (V.G.), CHU, Rennes; Laboratoire de Neuropathologie R Escourolle (D.S., C.D.) and INSERM U610 (B.D.), Hôpital de la Salpêtrière, Paris; Service de Neurologie (P.C.), CHU, Limoges; Centre National de Génotypage (S.H., C.B.), Evry; Service de Neurologie (W.C.), Hôpital Gui de Chauliac, Montpellier; UPMC Univ Paris (L.L., C.D., B.D., A.B.), UMRS975, Paris; Service de Neurologie (M.V.), CHU Guillaume et René Laënnec, Nantes; Service de Neurologie (F. Sellal), Hôpitaux Universitaires et INSERM U-692, Strasbourg; Service de Neurologie & Neuropsychologie (M.D.), Hôpital de la Timone, INSERM U751, Marseille; Service de Neurologie (C.T.-A.), CHU Bellevue, Saint-Etienne; Service de Neurologie (M.P.), CHU Rangueil, Toulouse; Service de Neurogériatrie (B.F.-M.), Hôpital Sainte Marguerite, Marseille; and AP-HP (A.B.), Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France.

Address correspondence and reprint requests to Pr. Alexis Brice, CRicm-UMR675, Hôpital de la Pitié-Salpêtrière, 47, Boulevard de l’Hôpital, 75 651 Paris Cedex 13, France alexis.brice{at}upmc.fr

Background: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3).

Methods: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics.

Results: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 ± 10.3 years (range, 41–84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients.

Conclusions: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.

Abbreviations: BAT = BRLMM Analysis Tool; bvFTD = behavioral variant of frontotemporal dementia; FTD = frontotemporal dementia; MND = motor neuron disease; NCI = neuronal cytoplasmic inclusion; NII = neuronal intranuclear inclusions; SNP = single nucleotide polymorphism.

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Supplemental data at www.neurology.org

*These authors contributed equally.

Members of The French Research Network on FTD/FTD-MND are listed in the appendix.

Supported by France Alzheimer Association and ANR R06363DS (A.B.).

Disclosure: The authors report no disclosures.

Medical Devices: GeneChip mapping 250 K and 500 K assay (Affymetrix Inc., Santa Clara, CA).

Received September 16, 2008. Accepted in final form February 12, 2009.

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