The C9ORF72 syndrome: implications for clinical practice

Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a clinical spectrum associated with specific pathological findings and kindreds which variably express ALS, FTD, or overlapping features of both these disorders. Until recently, only two groups of mutations had been described associated with these kindreds; firstly mutations in the microtubule-associated protein tau gene (MAPT) in FTD with tauopathy in 1998, and secondly progranulin (PGRN) mutations in FTD in 2006. However, even together, these mutations accounted for only a minority of familial cases. The continuing work to explore the relationship between MND and FTD has eventually borne further fruits. Building on initial reports of linkage to 9p21 in 2006, as the area of genetic interest gradually narrowed, a race between two research groups developed. Eventually, the relevant mutation was recently identified as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). Since the original back-to-back publications in October 2011 in Neuron, the neurological communities have raced to understand the implications for patients and those in clinical practice managing these complex disorders. Initial reports suggest that these findings, and the novel genetic mechanisms described, may have significant implications for understanding disease, not only in ALS and FTD, but also for other neuropsychiatric disorders including Alzheimer’s and psychosis as the clinical spectrum encompassing this genetic syndrome starts to enlarge. In this month’s Journal Club, we review three papers exploring these issues and which collectively underline the importance of effective archiving of clinical and biological data. Together with the availability and transferability of technologies between research groups, this now allows an impressively rapid response to the identification of an important new genetic syndrome. It has been suggested that the appropriate terminology for this disorder should be C9FTD/ALS, but it seems unlikely this catchy name will survive first clinical contact.