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

2009; Lippincott Williams & Wilkins; Volume: 72; Issue: 19 Linguagem: Inglês

10.1212/wnl.0b013e3181a55f1c

1526-632X

Isabelle Le Ber, A. Camuzat, E. Berger, Didier Hannequin, A. Laquérrière, Véronique Golfier, Danielle Seilhean, G. Viennet, Philippe Couratier, Patrice Verpillat, Simon Heath, William Camu, Olivier Martinaud, L. Lacomblez, Martine Vercelletto, François Salachas, François Sellal, Mira Didic, C. Thomas-Antérion, Michèle Puel, B. -F. Michel, Céline Besse, Charles Duyckaerts, Vincent Meininger, Dominique Campion, Bruno Dubois, Alexis Brice,

Prion Diseases and Protein Misfolding

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).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.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.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.