Expanding Clinical Spectrum of <i>C9ORF72</i> -Related Disorders and Promising Therapeutic Strategies
Sarah R. Breevoort, Summer Gibson, Karla P. Figueroa, Mark B. Bromberg, Stefan M. Pulst
Abstract
In 2011, a pathogenic hexanucleotide repeat expansion in the <i>C9ORF72</i> gene was discovered to be the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Before this, the <i>C9ORF72</i> 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, <i>C9ORF72</i> genetic testing is readily available. There is now an increasing appreciation that <i>C9ORF72</i> 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 <i>C9ORF72</i> expansion and how <i>C9ORF72</i> expansion manifests in ALS, FTD, psychiatric disorders, and movement disorders. With therapeutic strategies fast approaching the clinic, earlier recognition of possible <i>C9ORF72</i> expansion related disorders is even more paramount to improve patient care.