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

Ber, Isabelle Le; Camuzat, Agnès; Guillot‐Noël, Léna; Hannequin, Didier; Lacomblez, Lucette; Golfier, Véronique; Puel, Michèle; Martinaud, Olivier; Deramecourt, Vincent; Rivaud-Péchoux, Sophie; Millecamps, Stéphanie; Vercelletto, Martine; Couratier, Philippe; Sellal, François; Pasquier, Florence; Salachas, François; Thomas‐Antérion, Catherine; Didic, Mira; Pariente, Jérémie; Seilhean, Danielle; Ruberg, Merle; Wargon, I.; Blanc, F.; Camu, William; Michel, Bernard‐François; Berger, Ėric; Sauvée, Mathilde; Thauvin‐Robinet, Christel; Mondon, Karl; Tournier‐Lasserve, Elisabeth; Goizet, Cyril; Fleury, Marie; Viennet, G.; Verpillat, Patrice; Meininger, Vincent; Duyckaerts, Charles; Dubois, Bruno; Brice, Alexis

doi:10.3233/jad-121456

Cited by 93 publications

(61 citation statements)

References 44 publications

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“…The frequency of GRN mutations in this cohort is within the range reported by North American and European studies (3-15%), 3,6,8,17-20 , but higher than reported by Asian groups (0-1.6%). 7,21,22 Among familial FTD cases, the frequency of GRN mutations is higher than reported by other groups, such as studies conducted in Northern Italy (24.8%), United Kingdom (20%) or France (14%).…”

Section: Discussionsupporting

confidence: 78%

“…1,2 Mutations in more than ten genes are currently known to be causative of monogenic forms of FTD, but the most commonly reported worldwide are found in GRN (progranulin), MAPT (microtubule-associated protein tau) and C9orf72 (chromosome 9 open reading frame 72). 3 GRN mutations cause disease through haploinsufficiency, and progranulin levels are low in plasma and cerebrospinal fluid of mutation carriers. 4,5 …”

Section: Introductionmentioning

confidence: 99%

“…6,7 The frequencies of MAPT mutations in FTD cohorts were 17.9% in a British study, and 4.7% in a French study. 3,8 World regions such as Latin America and Africa, however, have been largely understudied and data is still scarce on monogenic FTD in those regions.…”

Section: Introductionmentioning

confidence: 99%

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GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil

Takada

Bahia

Guimarães

et al. 2016

Alzheimer Disease &Amp; Associated Disorders

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Background Mutations in GRN (progranulin) and MAPT (microtubule-associated protein tau) are among the most frequent causes of monogenic Frontotemporal Dementia (FTD), but data on the frequency of those mutations in regions such as Latin America is still lacking. Objective We aimed to investigate the frequencies of GRN and MAPT mutations in FTD cohorts from two Brazilian dementia research centers, from University of Sao Paulo (USP) and Federal University of Minas Gerais (UFMG) medical schools. Methods We included 76 probands diagnosed with behavioral variant FTD (n=55), semantic variant Primary Progressive Aphasia (PPA) (n=11), or nonfluent variant PPA (n=10). Twenty-five percent of the cohort had at least one relative affected with FTD. Results Mutations in GRN were identified in seven probands, and in MAPT, in two probands. We identified three novel GRN mutations (p.Q130X, p.317Afs*12, and p.K259Afs*23), in patients diagnosed with nfvPPA or bvFTD. Plasma progranulin levels were measured and a cutoff value of 70ng/ml was found with 100% sensitivity and specificity to detect null GRN mutations. Conclusions The frequency of GRN mutations was 9.6% and of MAPT mutations, was 7.1%. Among familial cases of FTD, the frequency of GRN mutations was 31.5%, and of MAPT mutations was 10.5%.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

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GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil

Takada

Bahia

Guimarães

et al. 2016

Alzheimer Disease &Amp; Associated Disorders

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“…Despite the small size of the cohort, the percentage of positive cases was in good concordance with those presented by the different epidemiologic studies performed in Europe [5]. In the same way, no difference concerning sex ratio was observed between C9ORF72 expansion carriers and noncarriers [14]. …”

Section: Discussionsupporting

confidence: 72%

C9orf72 Protein Plasmatic Concentrations Are Similar between <b><i>C9ORF72</i></b> Expansion Carriers and Noncarriers in Frontotemporal Dementia

Fourier

Formaglio

Sauvée

et al. 2018

Dement Geriatr Cogn Disord

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Background/Aims: The aim of the study was to assess the theory of haploinsufficiency in C9ORF72 expansion carriers, the most frequent causative gene of frontotemporal dementia. Methods: Plasmatic concentrations of C9orf72 protein were measured in 33 patients suspected of familial frontotemporal dementia using an enzyme-linked immunosorbent assay. Results: No difference was observed between C9ORF72 expansion carriers (21.2% of patients) and noncarriers (78.8% of patients). C9orf72 protein determination is not a suitable biomarker for screening C9ORF72 expansion carriers. Conclusion: Our results provide new evidence against the hypothesis of haploinsufficiency leading to frontotemporal dementia in C9ORF72 expansion carriers.

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“…Indeed, there are now more than 900 families in the world with mutations associated with FTD. A flow chart for FTD genetic testing was recently published [81].…”

Section: Genetics Of Ftdmentioning

confidence: 99%

FDG PET and the genetics of dementia

Nacmias

Berti

Piaceri

et al. 2013

Clin Transl Imaging

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Dementias are the most common neurodegenerative diseases and they are increasingly becoming a major public health problem. The most common form of dementia, affecting over 20 million people worldwide, is Alzheimer's disease (AD). AD is a neurodegenerative disease of the central nervous system mainly found in older adults, with an incidence that increases with age. With the development of newer technologies, including genetic screening technologies and PET/MRI scanning, the role of genetic studies and neuroimaging is being redefined; indeed, these approaches are able to provide support not only in the clinical diagnosis of dementia, but also in its presymptomatic evaluation. Many researchers agree that early identification of AD, before abnormal accumulation of amyloid and tau proteins, could provide an opportunity to hinder the progression of the disease. [18 F]2-fluoro-2-deoxy-D-glucose (FDG) PET studies have shown that decreased glucose metabolism in AD precedes clinical diagnosis and that the degree of clinical disability in AD correlates closely with the magnitude of the reduction in brain glucose metabolism. Data on presymptomatic mutation carriers from families with known early-onset autosomal dominant AD (familial AD) show reductions in the cerebral metabolic rate of glucose (CMRglc), consistent with the expected AD PET pattern, in the absence of severe atrophy on MRI. These results suggest that PET CMRglc measures have the potential to serve as preclinical biomarkers of dementia, useful also for tracking disease progression. This review highlights the role of genetics and FDG PET in understanding the pathogenesis of dementia.

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

Cited by 93 publications

References 44 publications

GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil

GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil

C9orf72 Protein Plasmatic Concentrations Are Similar between <b><i>C9ORF72</i></b> Expansion Carriers and Noncarriers in Frontotemporal Dementia

FDG PET and the genetics of dementia

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