A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

Renton, Alan E.; Majounie, Elisa; Waite, Adrian James; Simón‐Sánchez, Javier; Rollinson, Sara; Gibbs, J. Raphael; Schymick, Jennifer C.; Laaksovirta, Hannu; Swieten, John C. van; Myllykangas, Liisa; Kalimo, Hannu; Paetau, Anders; Abramzon, Yevgeniya; Remes, Anne M.; Kaganovich, Alice; Scholz, Sonja W.; Duckworth, Jaime; Ding, Jinhui; Harmer, D; Hernandez, Dena G.; Johnson, Janel O.; Mok, Kin Y.; Ryten, Mina; Trabzuni, Danyah; Guerreiro, Rita; Orrell, Richard W.; Neal, James; Murray, Alexandra; Pearson, Justin; Jansen, Iris E.; Sondervan, David; Seelaar, Harro; Blake, Derek J.; Young, Kate; Halliwell, Nicola; Callister, Janis Bennion; Toulson, Greg; Richardson, Anna; Gerhard, Alexander; Snowden, Julie S.; Mann, David; Neary, David; Nalls, Michael A.; Peuralinna, Terhi; Jansson, Lilja; Isoviita, Veli‐Matti; Kaivorinne, Anna-Lotta; Hölttä‐Vuori, Maarit; Ikonen, Elina; Sulkava, Raimo; Benatar, Michael; Wuu, Joanne; Chiò, Adriano; Restagno, Gabriella; Borghero, Giuseppe; Sabatelli, Mario; Heckerman, David; Rogaeva, Ekaterina; Zinman, Lorne; Rothstein, Jeffrey D.; Sendtner, Michael; Drepper, Carsten; Eichler, Evan E.; Alkan, Can; Abdullaev, Ziedulla; Pack, Svetlana D.; Dutra, Amalia; Pak, Evgenia; Hardy, John; Singleton, Andrew B.; Williams, Nigel; Heutink, Peter; Pickering‐Brown, Stuart; Morris, Huw R.; Tienari, Pentti J.; Traynor, Bryan J.

doi:10.1016/j.neuron.2011.09.010

Cited by 3,924 publications

(3,419 citation statements)

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“…Of the 22 Newcastle cases investigated, three (patients 1–3 described below) demonstrated an expansion in C9ORF72 by both repeated primed PCR [6] and by Southern blotting [11]. The 13 Manchester patients with FTLD, known to bear expansions in C9ORF72 , have been reported elsewhere [11, 13].…”

Section: Resultsmentioning

confidence: 99%

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Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Baborie

Griffiths

Jaros

et al. 2015

Neuropathology Appl Neurobio

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AimsFrontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP‐43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non‐ATG RAN translation of the expanded region of the gene.MethodsTwenty‐two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP‐43, p62 and DPR. The extent of TDP‐43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease.ResultsThree Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP‐43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP‐43 pathology was significantly less.ConclusionWidespread accumulation of DPR within nerve cells may occur much earlier than that of TDP‐43 in patients with FTLD bearing expansion in C9ORF72.

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Section: Resultsmentioning

confidence: 99%

“…The presence of expanded hexanucleotide repeats was determined by repeat primed PCR as described previously [6]. Frozen brain tissue (cerebellum) was available for all 35 cases employed in the study, and Southern blotting was performed as described elsewhere [11].…”

Section: Methodsmentioning

confidence: 99%

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Baborie

Griffiths

Jaros

et al. 2015

Neuropathology Appl Neurobio

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“…FTLD patients with an underlying TDP43 pathology (FTLD‐TDP, n = 30) were selected based on autopsy ( n = 8) and C9orf72 /GRN mutations ( n = 15) 13, 14. Diagnostic groups were enriched with CSF from patients with FTLD‐Plus syndromes that reflect high correlation with a specific neuropathology.…”

Section: Methodsmentioning

confidence: 99%

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveFrontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD‐Tau) or TDP43 (FTLD‐TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.Methods YKL40, FABP4, MFG‐E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD‐TDP (n = 30), FTLD‐Tau (n = 20), AD (n = 30), DLB (n = 29), and nondemented controls (n = 29) obtained from two different centers. Models were validated in an independent CSF cohort (n = 188).Results YKL40 and catalase activity were increased in FTLD‐TDP cases compared to controls. YKL40 levels were also higher in FTLD‐TDP compared to FTLD‐Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG‐E8, tTau, and Aβ 42; 78% sensitivity and 83% specificity) and non‐FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD‐TDP from FTLD‐Tau (YKL40, MFGE‐8, βHexA together with βHexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity.InterpretationThis study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.

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“…Up to 15% of patients with FTD concomitantly develop motor neuron disease (MND), and 10–20% of patients with MND develop FTD,3 suggesting that the two disorders lie on a clinical continuum. Pathogenic G 4 C 2 repeat expansions in chromosome 9 open reading frame 72 ( C9orf72) are the most common genetic cause of autosomal‐dominant FTD and amyotrophic lateral sclerosis (ALS) 4, 5. Potential pathomechanisms include the loss of function of normal C9orf72 protein, and/or toxicity resulting from the accumulation of G 4 C 2 transcripts that form RNA foci, interact with RNA‐binding proteins, and impair RNA processing 6.…”

Section: Introductionmentioning

confidence: 99%

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

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A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

Cited by 3,924 publications

References 36 publications

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

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