Boxer AL, Mackenzie IR, Boeve BF, et al. Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

UCSF Memory and Aging Center, University of California-San Francisco, CA 94143, USA.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 02/2011; 82(2):196-203. DOI: 10.1136/jnnp.2009.204081
Source: PubMed


Frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.
The authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.
Ten members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.
Family VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.

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    • "Examination of foci formed of sense or antisense transcripts of the expanded C9ORF72 repeat revealed that, in addition to the frontal cortex and spinal cord, RNA foci accumulate in the cerebellum. Together with other studies, it is now evident that numerous pathological features are present in the cerebellum of c9FTD/ALS patients, including nuclear RNA foci, c9RAN protein inclusions, as well as p62-positive inclusions [1, 3, 6, 25, 26]. Furthermore, FTD cases caused by the C9ORF72 repeat expansion show atrophy of the parietal lobe and cerebellum, in addition to frontal and temporal lobe atrophy [37]. "
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    ABSTRACT: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders with clinical, genetic, and neuropathological overlap. A hexanucleotide (GGGGCC) repeat expansion in a non-coding region of C9ORF72 is the major genetic cause of both diseases. The mechanisms by which this repeat expansion causes “c9FTD/ALS” are not definitively known, but RNA-mediated toxicity is a likely culprit. RNA transcripts of the expanded GGGGCC repeat form nuclear foci in c9FTD/ALS, and also undergo repeat-associated non-ATG (RAN) translation resulting in the production of three aggregation-prone proteins. The goal of this study was to examine whether antisense transcripts resulting from bidirectional transcription of the expanded repeat behave in a similar manner. We show that ectopic expression of (CCCCGG)66 in cultured cells results in foci formation. Using novel polyclonal antibodies for the detection of possible (CCCCGG)exp RAN proteins [poly(PR), poly(GP) and poly(PA)], we validated that (CCCCGG)66 is also subject to RAN translation in transfected cells. Of importance, foci composed of antisense transcripts are observed in the frontal cortex, spinal cord and cerebellum of c9FTD/ALS cases, and neuronal inclusions of poly(PR), poly(GP) and poly(PA) are present in various brain tissues in c9FTD/ALS, but not in other neurodegenerative diseases, including CAG repeat disorders. Of note, RNA foci and poly(GP) inclusions infrequently co-occur in the same cell, suggesting these events represent two distinct ways in which the C9ORF72 repeat expansion may evoke neurotoxic effects. These findings provide mechanistic insight into the pathogenesis of c9FTD/ALS, and have significant implications for therapeutic strategies. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1192-8) contains supplementary material, which is available to authorized users.
    Acta Neuropathologica 10/2013; 126(6). DOI:10.1007/s00401-013-1192-8 · 10.76 Impact Factor
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    • "All of the 12 p62 positive cases where frozen brain tissues were available for analysis showed an expansion in C9ORF72 by Southern blotting, and are therefore consistent with the suggestion [17,18] that this type of p62 pathology is pathognomic for cases of FTLD and/or MND associated with C9ORF72 mutation. Thus, it can be presumed that an expansion was also present in the other four FTLD cases with relevant p62 pathology where no southern blotting (or repeat primed PCR) was possible due to lack of fresh frozen brain tissue. "
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    ABSTRACT: Background Cases of Frontotemporal Lobar Degeneration (FTLD) and Motor Neurone Disease (MND) associated with expansions in C9ORF72 gene are characterised pathologically by the presence of TDP-43 negative, but p62 positive, inclusions in granule cells of the cerebellum and in cells of dentate gyrus and area CA4 of the hippocampus. Results We screened 84 cases of pathologically confirmed FTLD and 23 cases of MND for the presence of p62 positive inclusions in these three brain regions, and identified 13 positive cases of FTLD and 3 of MND. All cases demonstrated expansions in C9ORF72 by Southern blotting where frozen tissues were available. The p62 positive inclusions in both cerebellum and hippocampus were immunostained by antibodies to dipeptide repeat proteins (DPR), poly Gly-Ala (poly-GA), poly Gly-Pro (poly-GP) and poly Gly-Arg (poly-GR), these arising from a putative non-ATG initiated (RAN) sense translation of the GGGGCC expansion. There was also some slight, but variable, immunostaining with poly-AP antibody implying some antisense translation might also occur, though the relative paucity of immunostaining could reflect poor antigen avidity on the part of the antisense antibodies. Of the FTLD cases with DPR, 6 showed TDP-43 type A and 6 had TDP-43 type B histology; one had FTLD-tau with the pathology of corticobasal degeneration. There were no qualitative or quantitative differences in the pattern of immunostaining with antibodies to DPR, or p62, proteins between TDP-43 type A and type B cases. Ratings for frequency of inclusions immunostained by these poly-GA, poly-GP and poly-GR antibodies broadly correlated with those for immunolabelled by p62 antibody in all three regions. Conclusion We conclude that DPR are a major component of p62 positive inclusions in FTLD and MND.
    10/2013; 1(1). DOI:10.1186/2051-5960-1-68
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    • "Forty five (22.5%) of the 200 cases of AD showed TDP-43 pathology mostly resembling FTLD-TDP type A histology [13], within the dentate gyrus granule cells and entorhinal cortex/fusiform gyrus, and within layer II pyramidal cells of inferior and middle temporal gyri (as described previously by us [22] and others [21,23,24]). However, no p62 immunoreactive NCI were seen within pyramidal cells of areas CA2/3/4, or within dentate gyrus granule cells, of the hippocampus [9], or within granule cells of the cerebellum [10], in any of these 45 cases, or in any of those cases of AD not showing TDP-43 pathology. Hence, we conclude that, even in the absence of formal genetic analysis, none of the 200 cases of AD examined here would likely be carriers of C9ORF72 expansion. "
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    ABSTRACT: We have sought histological evidence, using TDP-43 and p62 immunohistochemistry, for the presence of expansions in C9ORF72 among 200 patients with pathologically confirmed AD. We noted TDP-43 pathological changes in hippocampus and temporal cortex in 45 (22.5%) of these patients, but did not detect any cases where p62 positive changes in hippocampus and cerebellum, considered pathognomic for C9ORF72 expansions, were present. We conclude that expansions in C9ORF72 associated with AD are a rare occurrence, and in those instances in the literature where these have been reported, the presence of AD may in fact be coincidental and unrelated to the expansion.
    08/2013; 1(1):50. DOI:10.1186/2051-5960-1-50
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