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

作者：Le Ber I; Camuzat A; Berger E; Hannequin D; Laquerriere A; Golfier V; Seilhean D; Viennet G; Couratier P; Verpillat P; Heath S; Camu W; Martinaud O; Lacomblez L; Vercelletto M; Salachas F; Sellal F; Didic M; Thomas Anterion C; Puel M; Michel B F; Besse C; Duyckaerts C; Meininger V; Campion D; Dubois B; Brice A^*

来源：Neurology, 2009, 72(19): 1669-1676.

DOI：10.1212/WNL.0b013e3181a55f1c

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. Neurology (R) 2009;72:1669-1676

• 出版日期2009-5-12