Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features
Colin J. Mahoney,Jon Beck,Jonathan D. Rohrer,Tammaryn Lashley,Kin Y. Mok,Timothy J. Shakespeare,Tom Yeatman,Elizabeth K. Warrington,Jonathan M. Schott,Nick C. Fox,Martin N. Rossor,John Hardy,John Collinge,Tamas Revesz,Simon Mead,Jason D. Warren +15 more
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TLDR
Findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.Abstract:
An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43-68 years) and duration (1.7-22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration-TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.read more
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Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.
TL;DR: It is presented the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.
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The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
Kohji Mori,Shih-Ming Weng,Thomas Arzberger,Stephanie May,Kristin Rentzsch,Elisabeth Kremmer,Bettina Schmid,Bettina Schmid,Hans A. Kretzschmar,Marc Cruts,Christine Van Broeckhoven,Christian Haass,Christian Haass,Dieter Edbauer,Dieter Edbauer +14 more
TL;DR: It is found that characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown, and a new class of proteins links a common genetic mutation to the predominant pathology in certain neurodegenerative diseases.
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Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis
Jonathan D. Rohrer,Jennifer M. Nicholas,Jennifer M. Nicholas,David M. Cash,John C. van Swieten,Elise G.P. Dopper,Lize C. Jiskoot,Rick van Minkelen,Serge A.R.B. Rombouts,M. Jorge Cardoso,Shona Clegg,Miklos Espak,Simon Mead,David L. Thomas,Enrico De Vita,Mario Masellis,Sandra E. Black,Morris Freedman,Ron Keren,Bradley J. MacIntosh,Ekaterina Rogaeva,David F. Tang-Wai,Maria Carmela Tartaglia,Robert Laforce,Fabrizio Tagliavini,Pietro Tiraboschi,Veronica Redaelli,Sara Prioni,Marina Grisoli,Barbara Borroni,Alessandro Padovani,Daniela Galimberti,Elio Scarpini,Andrea Arighi,Giorgio G. Fumagalli,James B. Rowe,Ian Coyle-Gilchrist,Caroline Graff,Caroline Graff,Marie Fallström,Vesna Jelic,Vesna Jelic,Anne Kinhult Ståhlbom,Anne Kinhult Ståhlbom,Christin Andersson,Christin Andersson,Håkan Thonberg,Håkan Thonberg,Lena Lilius,Giovanni B. Frisoni,Giuliano Binetti,Michela Pievani,Martina Bocchetta,Luisa Benussi,Roberta Ghidoni,Elizabeth Finger,Sandro Sorbi,Benedetta Nacmias,Gemma Lombardi,Cristina Polito,Jason D. Warren,Sebastien Ourselin,Nick C. Fox,Martin N. Rossor +63 more
TL;DR: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia, which could help to define biomarkers that can stage presymPTomatic disease and track disease progression.
Journal ArticleDOI
Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins
Kohji Mori,Thomas Arzberger,Thomas Arzberger,Friedrich A. Grässer,Ilse Gijselinck,Stephanie May,Kristin Rentzsch,Shih Ming Weng,Martin H. Schludi,Julie van der Zee,Marc Cruts,Christine Van Broeckhoven,Elisabeth Kremmer,Hans A. Kretzschmar,Christian Haass,Christian Haass,Dieter Edbauer,Dieter Edbauer +17 more
TL;DR: The data show that the GGGGCC repeat is bidirectionally translated into five distinct DPR proteins that co-aggregate in the characteristic p62-positive TDP-43 negative inclusions found in FTLD/ALS cases with C9orf72 repeat expansion.
Journal ArticleDOI
C9orf72 -mediated ALS and FTD: multiple pathways to disease
Rubika Balendra,Adrian M. Isaacs +1 more
TL;DR: It is suggested that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-aut autonomous and non-cell-autonomous effects contributes to disease progression.
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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
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TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
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