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

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

doi:10.1212/wnl.0b013e3181a55f1c

Cited by 86 publications

(45 citation statements)

References 27 publications

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“…Consistent with previous reports, all three of our affected family members showed a combination of TDP-43-positive FTLD-U (FTLD-TDP) and classical ALS 10–12 14 15. The pattern of FTLD-TDP in all patients corresponded with FTLD-U type 37 (or type 2 according to the Sampathu, et al .…”

Section: Discussionsupporting

confidence: 91%

“…Whereas the proportion of individuals in this family with each phenotype was similar,15 the mean age of onset (45.7 years) was earlier than in previously reported families 10 14 15. This was particularly apparent in the two pure ALS cases that had a mean onset of 37.5 years as compared with the cases with dementia that had a mean age of onset of 47.3 years.…”

Section: Discussionsupporting

confidence: 38%

“…in 2006,10 11 is likely to contain a gene responsible for a substantial proportion of autosomal dominant FTD-ALS cases. A number of large, independent FTD-ALS kindreds have since been linked to a similar chromosome 9p region,12–14 defining a shared candidate region of 7.7 Mb containing 52 candidate genes 15…”

Section: Introductionmentioning

confidence: 99%

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Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

Boxer

Mackenzie

Boeve

et al. 2010

Journal of Neurology, Neurosurgery & Psychiatry

172

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 38%

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Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

Boxer

Mackenzie

Boeve

et al. 2010

Journal of Neurology, Neurosurgery & Psychiatry

172

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“…At the time of target gene selection, the causative variant within the chromosome 9p linkage region had not been resolved and accordingly MOB3B and IFNK were included as tentative ALS genes 21. Given the large number of study participants and target exons involved, samples were resequenced using a multiplexed targeted high-throughput sequencing strategy 22.…”

Section: Resultsmentioning

confidence: 99%

Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing

et al. 2013

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BackgroundOver 100 genes have been implicated in the aetiology of amyotrophic lateral sclerosis (ALS). A detailed understanding of their independent and cumulative contributions to disease burden may help guide various clinical and research efforts.MethodsUsing targeted high-throughput sequencing, we characterised the variation of 10 Mendelian and 23 low penetrance/tentative ALS genes within a population-based cohort of 444 Irish ALS cases (50 fALS, 394 sALS) and 311 age-matched and geographically matched controls.ResultsKnown or potential high-penetrance ALS variants were identified within 17.1% of patients (38% of fALS, 14.5% of sALS). 12.8% carried variants of Mendelian disease genes (C9orf72 8.78%; SETX 2.48%; ALS2 1.58%; FUS 0.45%; TARDBP 0.45%; OPTN 0.23%; VCP 0.23%. ANG, SOD1, VAPB 0%), 4.7% carried variants of low penetrance/tentative ALS genes and 9.7% (30% of fALS, 7.1% of sALS) carried previously described ALS variants (C9orf72 8.78%; FUS 0.45%; TARDBP 0.45%). 1.6% of patients carried multiple known/potential disease variants, including all identified carriers of an established ALS variant (p<0.01); TARDBP:c.859G>A(p.[G287S]) (n=2/2 sALS). Comparison of our results with those from studies of other European populations revealed significant differences in the spectrum of disease variation (p=1.7×10−4).ConclusionsUp to 17% of Irish ALS cases may carry high-penetrance variants within the investigated genes. However, the precise nature of genetic susceptibility differs significantly from that reported within other European populations. Certain variants may not cause disease in isolation and concomitant analysis of disease genes may prove highly important.

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“…Those with ALS have more dentate gyrus NCIs (Kovari et al 2004). Familial cases may be linked to chromosome 9p or have TARDBP mutations (Cairns et al 2007a, b; Mackenzie et al 2010; Gitcho et al 2009; Luty et al 2008; LeBer et al 2009; Boxer et al 2010; Borroni et al 2009; Borroni et al 2010). FTLD-TDP type 4 is distinctive for cases with VCP mutations and NIIs predominate (Cairns et al 2007a, b; Mackenzie et al 2010; Forman et al 2006; Guinto et al 2007).…”

Section: Ftld-tdp Subtypes Summary Statementsmentioning

confidence: 99%

TDP-43 Variants of Frontotemporal Lobar Degeneration

Bigio

2011

J Mol Neurosci

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It has been only 5 years since the identification of TDP-43 as the major protein component of the ubiquitinated inclusions in FTLD-U. At that time, there were approximately a dozen papers about TDP-43; today, a “TDP-43” search reveals almost 600 papers. It is now clear that the majority of FTLD cases containing tau- and alpha-synuclein-negative, ubiquitin-positive inclusions (FTLD-U) are FTLD-TDP. The spectrum of TDP-43 proteinopathies includes FTLD-TDP with or without ALS, with or without mutations in GRN, VCP, or TARDBP, with or without chromosome 9p linkage, and sporadic and non-SOD1 familial ALS with or without FTLD-TDP. There are four sub-types of FTLD-TDP, and these correlate with specific clinical and genetic profiles. Sub-types are determined by the presence, predominance, and distribution of the various TDP-43 immunopositive insoluble aggregates—neuronal cytoplasmic inclusions, neuronal intranuclear inclusions, and dystrophic neurites. In this paper, FTLD-TDP pathologic sub-types will be described, and examples of each sub-type will be shown, and implications for future research will be discussed.

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

Cited by 86 publications

References 27 publications

Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing

TDP-43 Variants of Frontotemporal Lobar Degeneration

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