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01-05-2019 | Amyotrophic Lateral Sclerosis | Correspondence

An ALS case with 38 (G4C2)-repeats in the C9orf72 gene shows TDP-43 and sparse dipeptide repeat protein pathology

Authors: Lieselot Dedeene, Evelien Van Schoor, Valérie Race, Matthieu Moisse, Rik Vandenberghe, Koen Poesen, Philip Van Damme, Dietmar Rudolf Thal

Published in: Acta Neuropathologica | Issue 5/2019

Excerpt

The (G4C2)-hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common mutation linked to amyotrophic lateral sclerosis (ALS), as it accounts for 51.6% of the familial ALS cases and 9.6% of the sporadic ALS cases [1, 2]. This repeat expansion also underlies approximately 25% of the familial frontotemporal lobar degeneration (FTLD) cases [12]. The pathogenic (G4C2)-repeat length is estimated to range from hundreds to thousands of repeat units, whereas neurologically healthy controls usually show a repeat length of only 2–30 (G4C2)-repeats [3]. However, the threshold for the repeat length to drive or aggravate ALS pathology is still under debate. Some ALS or FTLD cases show an intermediate (G4C2)-repeat length of 30–90 (G4C2)-repeats in peripheral blood DNA [4, 5, 7, 11], while, in contrast, some 30–70 repeat carriers did not develop symptomatic disease [6, 8]. Several cases with this so-called intermediate repeat length in peripheral blood DNA have been thoroughly investigated, showing somatic instability of the repeat with a mixture of intermediate and long repeat lengths (from hundreds to thousands of repeats) throughout the brain (mosaicism) [5, 7, 8, 11]. Dipeptide repeat proteins (DPRs) resulting from unconventional repeat-associated non-ATG translation of the (G4C2)-hexanucleotide repeat expansion exhibit distinct types of inclusions within neurons [10]. These pathological lesions were investigated for some of these (G4C2)-mosaic carriers, showing full-blown DPR pathology throughout the brain, comparable to non-mosaic carriers with a long repeat length [5, 7, 8]. One intermediate repeat case [30 (G4C2)-repeats] without mosaicism in the examined frontal cortex and cerebellum was previously reported [6]. This 30-repeat case was clinically unaffected and showed only sparse DPR pathology and no transactive response DNA-binding protein 43 kDa (TDP-43) pathology. …

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Title: An ALS case with 38 (G4C2)-repeats in the C9orf72 gene shows TDP-43 and sparse dipeptide repeat protein pathology
Authors: Lieselot Dedeene
Evelien Van Schoor
Valérie Race
Matthieu Moisse
Rik Vandenberghe
Koen Poesen
Philip Van Damme
Dietmar Rudolf Thal
Publication date: 01-05-2019
Publisher: Springer Berlin Heidelberg
Keywords: Amyotrophic Lateral Sclerosis
Pathology
Published in: Acta Neuropathologica / Issue 5/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-01996-z

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An ALS case with 38 (G4C2)-repeats in the C9orf72 gene shows TDP-43 and sparse dipeptide repeat protein pathology

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Keynote webinar | Spotlight on medication adherence

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