Research in context
Evidence before this study
We searched PubMed for articles on genetic frontotemporal dementia with no language restrictions from database inception up to July 1, 2017, using the following terms: “frontotemporal dementia AND genetics”, “progranulin OR GRN”, “tau OR MAPT”, and “chromosome 9 open reading frame 72 OR C9orf72”, focusing on studies that reported age at symptom onset, age at death or disease duration of individuals with symptoms. No studies were found that had systematically investigated age at symptom onset, age at death, or disease duration across all the different genetic groups and the different mutations found within the groups. However, evidence from cohort studies and individual case series suggested that the age at symptom onset, age at death, and disease duration were highly variable across the genes implicated in frontotemporal dementia. Age-related penetrance was described in individuals with GRN and C9orf72 mutations, with MAPT mutations usually being fully penetrant. We found a generational difference in age at symptom onset, with an earlier onset in later generations occurring in individuals with GRN or C9orf72 mutations. Phenotypic differences in age at symptom onset have not been studied in detail yet, but one study showed a shorter disease duration in individuals with a diagnosis of amyotrophic lateral sclerosis in the C9orf72 group compared with those with other diagnoses, and another study showed an earlier age at symptom onset in this group compared with that of other diagnoses.
Added value of this study
To our knowledge, this is the largest international study to date investigating individual age at symptom onset, age at death, and disease duration in patients with genetic frontotemporal dementia, across all the three main genetic groups (C9orf72, GRN, and MAPT), and all known mutations within the GRN and MAPT groups. Our study provides important evidence about the factors underlying age at symptom onset, age at death, and disease duration in the different groups. We showed that only in the MAPT mutation group were age at symptom onset and at death highly correlated with both parental and mean family ages at symptom onset and at death, with variability in these ages explained partly by the specific mutation and more so by family membership. Such correlations were weaker in the other two groups, with the variability in age at symptom onset and age at death for individuals with GRN mutations and C9orf72 expansions not accounted for particularly by family membership or, for individuals with GRN mutations, by the specific mutation. This is the first time that such key differences between genetic frontotemporal dementia groups have been shown.
Implications of all the available evidence
Optimal therapeutic trial design will be important in genetic frontotemporal dementia, and particularly because many trials will aim to include presymptomatic individuals who are expected to be in proximity to symptom onset. Our study suggests that in individuals with MAPT mutations data from other family members will be particularly helpful in estimating time from symptom onset. Further work is needed to understand the variability in the other genetic groups, and other proximity markers, either individually or in combination, are likely to be required to refine the estimation of time to symptom onset in individuals with GRN or C9orf72 mutations. In the meantime, the available data will provide clinicians and family members with a better understanding of the individual risk of probable symptom onset and time to death in each genetic group and within individual mutations.