Devenney E, Hornberger M, Irish M, Mioshi E, Burrell J, Tan R, Kiernan MC, Hodges JR.
Frontotemporal dementia associated with the C9ORF72 mutation: a unique clinical profile.
JAMA Neurol. 2014 Mar;71(3):331-9.
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Several studies have been published on the clinical characteristics of fronto-temporal lobar degeneration (FTLD) patients carrying a C9orf72 repeat expansion since the discovery of the gene in 2011.
In the March 2014 issue of JAMA Neurology, Devenney et al. aimed further to delineate the unique clinical profile associated with this mutation. The study has the advantage of using data from a prospectively collected, clinically well-characterized FTLD cohort.
Several typical clinical characteristics of the FTLD phenotype associated with C9orf72 repeat expansions emerge in this study that are consistent with previous published results: the co-occurrence of ALS in the patient or in his or her family, the profound behavioral changes (behavioral variant FTD within the spectrum of FTLD phenotypes), and the familial character of the disease.
Interestingly, Devenney et al. find a significantly higher frequency of psychotic features (29 percent) in C9orf72 repeat-expansion carriers, a finding that has also been reported by others. However, several other studies did not find a difference in prevalence of psychotic features between C9orf72 expansion carriers and patients without the expansion. Psychotic features also occur in FTLD patients carrying a GRN or a MAPT mutation. For example, in our Flanders-Belgian study population, the frequency of psychotic features in the C9orf72 expansion carriers, GRN mutation carriers, and sporadic FTLD patients was 12 percent in each group (Van Langenhove et al., 2013).
It is also remarkable from the present study that most C9orf72 repeat-expansion carriers failed to fulfill criteria for probable behavioral-variant FTD, pointing toward limitations of current diagnostic criteria.
It is noteworthy that the phenotype can be very variable. Mutation carriers may develop “pure” FTD or ALS phenotypes, two diseases that until recently were considered separate clinical entities. Some have particular behavioral changes, but others primarily language problems. The age of onset can vary from early in the 30s to 80 years old. Disease progression can be aggressive, with death within a year, or slowly progressive over 20 years. There are clearly other genetic and possibly environmental factors that determine the phenotype of C9orf72 mutation carriers.
Due to the heterogeneity of the phenotype, it is currently not possible to identify a C9orf72 repeat-expansion carrier only on clinical grounds. However, the differences in clinical characteristics between mutation carriers allow prioritization of genetic testing. For example, the FTLD-ALS or behavioral-variant FTD patients should first be tested for C9orf72 expansion, whereas in progressive non-fluent aphasia patients, GRN testing should be prioritized. Following a flow-chart in clinical genetic testing would save time and money (see also Van Langenhove et al., 2013).
Van Langenhove T, van der Zee J, Gijselinck I, Engelborghs S, Vandenberghe R, Vandenbulcke M, De Bleecker J, Sieben A, Versijpt J, Ivanoiu A, Deryck O, Willems C, Dillen L, Philtjens S, Maes G, Bäumer V, Van den Broeck M, Mattheijssens M, Peeters K, Martin JJ, Michotte A, Santens P, De Jonghe P, Cras P, De Deyn PP, Cruts M, Van Broeckhoven C.
Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort.
JAMA Neurol. 2013 Mar 1;70(3):365-73.