Advertisement

Acta Neuropathologica

, Volume 137, Issue 5, pp 855–858 | Cite as

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

  • Lieselot Dedeene
  • Evelien Van Schoor
  • Valérie Race
  • Matthieu Moisse
  • Rik Vandenberghe
  • Koen Poesen
  • Philip Van Damme
  • Dietmar Rudolf ThalEmail author
Correspondence
First Online:

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...

Keywords

Amyotrophic lateral sclerosis C9orf72 repeat expansion Dipeptide repeat proteins Transactive response DNA-binding protein 43 kDa 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

LD is funded by a PhD Fellowship of the Research Foundation–Flanders (FWO-Vlaanderen) (1165119N). EVS is funded by an SB PhD Fellowship of FWO-Vlaanderen (1S46219N). PVD holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the ALS Liga Belgium and the KU Leuven ALS funds ‘Een hart voor ALS’ and ‘Laeversfonds voor ALS onderzoek’. PVD and DRT received C1-internal funds from KU Leuven (C14-17–107). DRT and RV received funding from FWO-Odysseus Grant no. G0F8516N and Vlaamse Impulsfinanciering voor Netwerken voor Dementie Onderzoek (VIND, IWT 135043). We thank Bruno Van Keirsbilck, Alicja Ronisz, Simona Ospitalieri, Petra Weckx and Marta Koper for technical support.

Supplementary material

401_2019_1996_MOESM1_ESM.docx (3 mb)
Supplementary material 1 (DOCX 3055 KB)

References

  1. 1.
    Baborie A, Griffiths TD, Jaros E, Perry R, McKeith IG, Burn DJ, Masuda-Suzukake M, Hasegawa M, Rollinson S, Pickering-Brown S, Robinson AC, Davidson YS, Mann DMA (2015) Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene. Neuropathol Appl Neurobiol 41:601–612.  https://doi.org/10.1111/nan.12178 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Debray S, Race V, Crabbé V, Herdewyn S, Matthijs G, Goris A, Dubois B, Thijs V, Robberecht W, Van Damme P (2013) Frequency Of C9Orf72 repeat expansions in amyotrophic lateral sclerosis: a belgian cohort study. Neurobiol Aging 34:2890.e7–2890.e12.  https://doi.org/10.1016/j.neurobiolaging.2013.06.009 CrossRefGoogle Scholar
  3. 3.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NCA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GYR, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes Chromosome 9p-linked FTD and ALS. Neuron 72:245–256.  https://doi.org/10.1016/j.neuron.2011.09.011 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Dobson-Stone C, Hallupp M, Loy CT, Thompson EM, Haan E, Sue CM, Panegyres PK, Razquin C, Seijo-Martínez M, Rene R, Gascon J, Campdelacreu J, Schmoll B, Volk AE, Brooks WS, Schofield PR, Pastor P, Kwok JBJ (2013) C9ORF72 repeat expansion in australian and spanish frontotemporal dementia patients. PLoS ONE 8:e56899.  https://doi.org/10.1371/journal.pone.0056899 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Fratta P, Polke JM, Newcombe J, Mizielinska S, Lashley T, Poulter M, Beck J, Preza E, Devoy A, Sidle K, Howard R, Malaspina A, Orrell RW, Clarke J, Lu CH, Mok K, Collins T, Shoaii M, Nanji T, Wray S, Adamson G, Pittman A, Renton AE, Traynor BJ, Sweeney MG, Revesz T, Houlden H, Mead S, Isaacs AM, Fisher EMC (2015) Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion. Neurobiol Aging 36:546.e1–546.e7.  https://doi.org/10.1016/j.neurobiolaging.2014.07.037 CrossRefGoogle Scholar
  6. 6.
    Gami P, Murray C, Schottlaender L, Bettencourt C, De Pablo Fernandez E, Mudanohwo E, Mizielinska S, Polke JM, Holton JL, Isaacs AM, Houlden H, Revesz T, Lashley T (2015) A 30-unit hexanucleotide repeat expansion in C9orf72 induces pathological lesions with dipeptide-repeat proteins and RNA foci, but not TDP-43 inclusions and clinical disease. Acta Neuropathol 130:599–601.  https://doi.org/10.1007/s00401-015-1473-5 CrossRefPubMedGoogle Scholar
  7. 7.
    Gijselinck I, Van Mossevelde S, van der Zee J, Sieben A, Engelborghs S, De Bleecker J, Ivanoiu A, Deryck O, Edbauer D, Zhang M, Heeman B, Bäumer V, Van Den Broeck M, Mattheijssens M, Peeters K, Rogaeva E, De Jonghe P, Cras P, Martin JJ, De Deyn PP, Cruts M, Van Broeckhoven C, on behalf of the BELNEU CONSORTIUM (2016) The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter. Mol Psychiatry 21:1112–1124.  https://doi.org/10.1038/mp.2015.159 CrossRefPubMedGoogle Scholar
  8. 8.
    McGoldrick P, Zhang M, van Blitterswijk M, Sato C, Moreno D, Xiao S, Zhang AB, McKeever PM, Weichert A, Schneider R, Keith J, Petrucelli L, Rademakers R, Zinman L, Robertson J, Rogaeva E (2018) Unaffected mosaic C9orf72 case. Neurology 90:e323–e331.  https://doi.org/10.1212/WNL.0000000000004865 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mok K, Traynor BJ, Schymick J, Tienari PJ, Laaksovirta H, Peuralinna T, Myllykangas L, Chiò A, Shatunov A, Boeve BF, Boxer AL, DeJesus-Hernandez M, Mackenzie IR, Waite A, Williams N, Morris HR, Simón-Sánchez J, van Swieten JC, Heutink P, Restagno G, Mora G, Morrison KE, Shaw PJ, Rollinson PS, Al-Chalabi A, Rademakers R, Pickering-Brown S, Orrell RW, Nalls MA, Hardy J (2012) The chromosome 9 ALS and FTD locus is probably derived from a single founder. Neurobiol Aging 33:209.e3–209.e9.  https://doi.org/10.1016/j.neurobiolaging.2011.08.005 CrossRefGoogle Scholar
  10. 10.
    Mori K, Weng S-M, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, Haass C, Edbauer D (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–1338.  https://doi.org/10.1126/science.1232927 CrossRefPubMedGoogle Scholar
  11. 11.
    Nordin A, Akimoto C, Wuolikainen A, Alstermark H, Jonsson P, Birve A, Marklund SL, Graffmo KS, Forsberg K, Brännström T, Andersen PM (2015) Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. Hum Mol Genet 24:3133–3142.  https://doi.org/10.1093/hmg/ddv064 CrossRefPubMedGoogle Scholar
  12. 12.
    Renton AE, Chiò A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17–23.  https://doi.org/10.1038/nn.3584 CrossRefPubMedGoogle Scholar
  13. 13.
    Schönecker S, Neuhofer C, Otto M, Ludolph A, Kassubek J, Landwehrmeyer B, Anderl-Straub S, Semler E, Diehl-Schmid J, Prix C, Vollmar C, Fortea J, Deutsches FTLD-Konsortium, Huppertz H-J, Arzberger T, Edbauer D, Feddersen B, Dieterich M, Schroeter ML, Volk AE, Fließbach K, Schneider A, Kornhuber J, Maler M, Prudlo J, Jahn H, Boeckh-Behrens T, Danek A, Klopstock T, Levin J (2018) Atrophy in the thalamus but not cerebellum is specific for C9orf72 FTD and ALS patients—an atlas-based volumetric MRI study. Front Aging Neurosci 10:45.  https://doi.org/10.3389/fnagi.2018.00045 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Xi Z, van Blitterswijk M, Zhang M, McGoldrick P, McLean JR, Yunusova Y, Knock E, Moreno D, Sato C, McKeever PM, Schneider R, Keith J, Petrescu N, Fraser P, Tartaglia MC, Baker MC, Graff-Radford NR, Boylan KB, Dickson DW, Mackenzie IR, Rademakers R, Robertson J, Zinman L, Rogaeva E (2015) Jump from pre-mutation to pathologic expansion in C9orf72. Am J Hum Genet 96:962–970.  https://doi.org/10.1016/j.ajhg.2015.04.016 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurosciences, Laboratory for Molecular Neurobiomarker ResearchKU Leuven, Leuven Brain Institute (LBI)LeuvenBelgium
  2. 2.Department of Neurosciences, Laboratory for NeuropathologyKU Leuven, Leuven Brain Institute (LBI)LeuvenBelgium
  3. 3.Laboratory MedicineUniversity Hospitals LeuvenLeuvenBelgium
  4. 4.Department of Neurosciences, Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease ResearchVIB, Leuven Brain Institute (LBI)LeuvenBelgium
  5. 5.Laboratory for Molecular Diagnostics, Center for Human GeneticsKU LeuvenLeuvenBelgium
  6. 6.Department of Neurosciences, Laboratory for Cognitive NeurologyKU Leuven, Leuven Brain Institute (LBI)LeuvenBelgium
  7. 7.Department of NeurologyUniversity Hospitals LeuvenLeuvenBelgium
  8. 8.Department of PathologyUniversity Hospitals LeuvenLeuvenBelgium

Personalised recommendations

Cite article

Buy options