Abstract
In 2011, a pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was discovered to be the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Before this, the C9ORF72 gene and its protein were unknown. The repeat expansion was found to cause both haploinsufficiency and gain of toxicity through aggregating RNA products and dipeptide repeat proteins. A worldwide effort was then initiated to define C9ORF72 ALS/FTD and unravel the pathogenic mechanism for the development of therapeutic options. A decade later, C9ORF72 genetic testing is readily available. There is now an increasing appreciation that C9ORF72 not only is the leading genetic cause of ALS/FTD but may contribute to a spectrum of disorders. This article reviews what is currently known about the C9ORF72 expansion and how C9ORF72 expansion manifests in ALS, FTD, psychiatric disorders, and movement disorders. With therapeutic strategies fast approaching the clinic, earlier recognition of possible C9ORF72 expansion related disorders is even more paramount to improve patient care.
Glossary
- ALS=
- amyotrophic lateral sclerosis;
- ASD=
- autism spectrum disorder;
- ASO=
- antisense oligonucleotide;
- CE=
- capillary electrophoresis;
- DM1=
- myotonic dystrophy;
- DPR=
- dipeptide repeat protein;
- FTD=
- frontotemporal dementia;
- FTDbv=
- behavioral variant FTD;
- FTLD=
- frontotemporal lobar degeneration;
- FTSD=
- frontotemporal lobe spectrum disorder;
- HD=
- Huntington disease;
- HRE=
- hexanucleotide repeat;
- NPC=
- nuclear pore complex;
- PD=
- Parkinson disease;
- RAN=
- repeat-associated non-ATG;
- rp-PCR=
- repeat-primed PCR;
- TDP-43=
- TAR DNA-binding protein 43
Footnotes
Go to Neurology.org/NG for full disclosures. Full information is provided at the end of the article.
The Article Processing Charge was funded by NG.
Solicited and externally peer reviewed. The handling editor was Raymond P. Roos, MD, FAAN.
- Received January 26, 2022.
- Accepted in final form March 18, 2022.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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