A lot of clinical descriptions have come forth since the initial discovery of the C9ORF72 mutations last year. It is clear that, like other frontotemporal dementias (FTDs), C9ORF72 is highly heterogeneous in presentation, and it is difficult to distinguish FTD due to C9ORF72 mutations from FTD with other pathology (i.e., tau or other mutations) based on clinical presentation alone. However, there are some features emerging that may alert the clinician to a C9ORF72 mutation. First, the presence of motor neuron disease (ALS) in the patient at any time, or if present in any other family members, should raise a red flag. Also, while some patients can start with a non-fluent aphasia phenotype, over time, most patients develop significant behavioral issues that would fit the behavioral FTD criteria as well, and in a number of cases, psychosis is quite prominent. Rigidity and parkinsonism can also be present. Compared to FTD due to progranulin, FTD due to the C9ORF72 mutation tends to have a slightly older age of onset, while the duration of disease is dictated by the co-development of...  Read more

A lot of clinical descriptions have come forth since the initial discovery of the C9ORF72 mutations last year. It is clear that, like other frontotemporal dementias (FTDs), C9ORF72 is highly heterogeneous in presentation, and it is difficult to distinguish FTD due to C9ORF72 mutations from FTD with other pathology (i.e., tau or other mutations) based on clinical presentation alone. However, there are some features emerging that may alert the clinician to a C9ORF72 mutation. First, the presence of motor neuron disease (ALS) in the patient at any time, or if present in any other family members, should raise a red flag. Also, while some patients can start with a non-fluent aphasia phenotype, over time, most patients develop significant behavioral issues that would fit the behavioral FTD criteria as well, and in a number of cases, psychosis is quite prominent. Rigidity and parkinsonism can also be present. Compared to FTD due to progranulin, FTD due to the C9ORF72 mutation tends to have a slightly older age of onset, while the duration of disease is dictated by the co-development of ALS. Patients who developed ALS have a much shorter survival compared to those without.

Neuroimaging studies also reveal that C9 cases have a pattern of involvement that is wider than expected. I think moving forward, while clinical presentation may help us differentiate these different pathological forms of FTD to a certain degree, say, to prioritize for genetic screening, ultimately, biomarkers will be needed to be able to definitively identify each of the pathological FTDs, especially when specific treatments aimed for each pathology are being developed.

View all comments by Ging-Yuek Robin Hsiung

In our lab, we simply call it "the expansion"!

View all comments by Bryan Traynor