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

Boxer, Adam L.; Mackenzie, Ian R.; Boeve, Bradley F.; Baker, Matthew; Seeley, William W.; Crook, Richard; Feldman, Howard; Hsiung, Ging-Yuek Robin; Rutherford, Nicola J.; Laluz, Victor; Whitwell, Jennifer; Foti, Dean; McDade, Eric; Molano, Jennifer Rose V.; Karydas, Anna; Wojtas, Aleksandra; Goldman, Jill; Mirsky, Jacob B.; Sengdy, Pheth; DeArmond, Stephen J.; Miller, Bruce L.; Rademakers, Rosa

doi:10.1136/jnnp.2009.204081

Cited by 172 publications

(197 citation statements)

References 28 publications

(33 reference statements)

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“…Sections of cerebellar cortex immunostained for DPR with poly‐GA antibody showed small rounded or oat‐shaped NCI within granule cells, though occasionally larger, more rounded and solid NCI (as described in reference [8]) were seen (Figure 1 d ). A few, thin and short neuritic profiles (DN) were seen, and neuronal intranuclear inclusions (NII) were occasionally observed.…”

Section: Resultsmentioning

confidence: 74%

“…Positive cases were defined where p62‐positive, TDP‐43‐negative NCI within either the cerebellum (see [8]) or hippocampus (see [7]) could be clearly seen under low power objective (×20) and the majority of high power fields (×40) contained at least two NCI. Either negative cases were completely devoid of p62 immunostaining, or small amounts of apparently extracellular and ‘extraneous’ p62‐positive particulate material was observed in occasional high power fields.…”

Section: Methodsmentioning

confidence: 99%

“…Most of the early pathological descriptions following the discovery of the C9ORF72 mutation indicated that the associated TDP‐43 pathology was usually type B, characterized by NCI in all cortical layers but with relatively few dystrophic neurites or neuronal intranuclear inclusions [7, 8, 9, 15]. However, more recent studies have frequently reported a significant proportion of C9ORF72 mutation cases to have other patterns of FTLD‐TDP, most often type A [9, 11, 15], and rarely type C [16].…”

Section: Introductionmentioning

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: 74%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…6 A total of 5 mg of DNA was fragmented with a Bioruptor (Wolf Laboratories Ltd, York, UK) at 30 s on/off bursts for 45 mins to sizes of 200-300 bp. End repair was followed by addition of adenine ends and ligation of adaptors (Illumina, Little Chesterford, Essex, UK) and peak sizes checked using a Bioanlayzer (Agilent Technologies, Wokingham, UK).…”

Section: P212 Locus-capture and Sequencingmentioning

confidence: 99%

“…3,4 Linkage was subsequently confirmed in eight other dominant kindreds defining a minimal overlapping region of B3.6 Mb. 5,6 Genome-wide association studies in sporadic and familial ALS demonstrated highly significant association with single-nucleotide polymorphisms (SNPs) across a 170-Kb region at 9p21.2. [7][8][9][10][11] A massive GGGGCC hexanucleotide repeat expansion mutation (HREM) has recently been identified within intron 1 of C9ORF72 as the pathogenic mutation responsible for familial and sporadic ALS and FTD in these cases.…”

Section: Introductionmentioning

confidence: 99%

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

et al. 2012

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A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS þ / ÀFTD from five European cohorts (total n ¼ 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n ¼ 434) and controls (n ¼ 856). Haplotypes were analysed using PLINK and aged using DMLE þ . In a London clinic cohort, the HREM was the most common mutation in familial ALS þ / ÀFTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS þ / ÀFTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, Po10 À8 ). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

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Investigation of C9orf72 in 4 Neurodegenerative Disorders

et al. 2012

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To estimate the allele frequency of C9orf72 (G 4 C 2 ) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD).Design: The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes.Setting: Hospitals specializing in neurodegenerative disorders. Subjects:We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation.Main Outcome Measure: The expansion frequency.Results: Based on a prior cutoff (Ͼ30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly Author Affil the end of th Author Affiliations are listed at the end of this article.

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

Cited by 172 publications

References 28 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

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

Investigation of C9orf72 in 4 Neurodegenerative Disorders

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