Erschienen in:
27.03.2019 | Correspondence
An ALS case with 38 (G4C2)-repeats in the C9orf72 gene shows TDP-43 and sparse dipeptide repeat protein pathology
verfasst von:
Lieselot Dedeene, Evelien Van Schoor, Valérie Race, Matthieu Moisse, Rik Vandenberghe, Koen Poesen, Philip Van Damme, Dietmar Rudolf Thal
Erschienen in:
Acta Neuropathologica
|
Ausgabe 5/2019
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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. …
