International view on genetic frontotemporal dementia
Authors: Eline Wauters, Christine Van Broeckhoven
Journal: The Lancet Neurology (2019)

Frontotemporal dementia is a subtype of neurodegenerative dementia, characterised by progressive changes in behaviour and personality or language difficulties. Frontotemporal dementia has a strong genetic component,1Greaves CV Rohrer JD An update on genetic frontotemporal dementia.J Neurol. 2019; 266: 2075-2086Crossref PubMed Scopus (161) Google Scholar and microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) are the most common mutated genes. Patients with this condition show heterogeneity in clinical presentation and a wide variability in age at symptom onset, age at death, and disease duration.2Cruts M Theuns J Van Broeckhoven C Locus-specific mutation databases for neurodegenerative brain diseases.Hum Mutat. 2012; 33: 1340-1344Crossref PubMed Scopus (357) Google Scholar, 3Wauters E Van MS Sleegers K et al.Clinical variability and onset age modifiers in an extended Belgian GRN founder family.Neurobiol Aging. 2018; 67: 84-94Crossref PubMed Scopus (14) Google Scholar, 4Van Mossevelde S van der Zee J Cruts M Van Broeckhoven C Relationship between C9orf72 repeat size and clinical phenotype.Curr Opin Genet Dev. 2017; 44: 117-124Crossref PubMed Scopus (82) Google Scholar This heterogeneity represents a challenge for clinical diagnostics, genetic counselling, and therapy development and evaluation. In The Lancet Neurology, Katrina Moore and colleagues5Moore KM Nicholas J Grossman M et al.Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international cohort study.Lancet Neurol. 2019; (published online Dec 3)https://doi.org/10.1016/S1474-4422(19)30394-1Summary Full Text Full Text PDF PubMed Scopus (110) Google Scholar reported the phenotypic characteristics of patients who have mutations in MAPT, GRN, or C9orf72. An impressive dataset of 3403 patients with genetic frontotemporal dementia, and information on sex, age at symptom onset, age at death, disease duration, and clinical phenotype was gathered by collaborating groups all over the world, combined with data provided by the Alzheimer Disease & Frontotemporal Dementia Mutation Database,2Cruts M Theuns J Van Broeckhoven C Locus-specific mutation databases for neurodegenerative brain diseases.Hum Mutat. 2012; 33: 1340-1344Crossref PubMed Scopus (357) Google Scholar and complemented by a PubMed search. This comprehensive dataset allowed them to identify differences in these parameters between genetic groups, mutations, and generations, as well as by sex and phenotype. The authors found that the GRN group had an overrepresentation of women compared with that of the C9orf72 and MAPT groups, and that patients with MAPT mutations had, on average, a younger age at symptom onset and at death (mean 49·5 years, SD 10·0, for onset; 58·5 years, 11·3, for death) compared with those of the other groups (58·2 years, 9·8 [onset], and 65·3 years, 10·9 [death], in the C9orf72 group; 61·3 years, 8·8 [onset], and 68·8 years, 9·7 [death], in the GRN group). For all genetic groups, second (later) generations were younger at symptom onset than first generations. The mean disease duration was shortest in the C9orf72 group (6·4 years, SD 4·9, compared with 7·1 years, 3·9, in the GRN group and 9·3 years, 6·4, in the MAPT group), and within the C9orf72 group, patients with amyotrophic lateral sclerosis had a significantly shorter disease duration (2·9 years, SD 2·8) than that of patients with other clinical diagnoses. The results also showed a significant correlation between parental and mean familial age at symptom onset and at death and an individual's age at symptom onset and at death in all three genetic groups, with the strongest correlation found in the MAPT group (r=0·45 between individual and parental age at symptom onset, r=0·63 between individual and mean family age at symptom onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death). However, although the findings of this study are significant on a group level, the added value for individual patients is still rather small. The study by Moore and colleagues provides a comprehensive overview of reported ages at symptom onset, ages at death, disease durations, and clinical diagnoses per mutation in the appendix, which could be informative for clinicians. At the same time, this overview highlights again the wide variability that is seen even among patients with the same mutation, reducing the usefulness of the information for individual patients. Furthermore, mutations with more discrete ranges are often only represented by a small number of patients. However, differences between common individual MAPT mutations were found, with patients with the Asn279Lys mutation having a significant earlier mean age of symptom onset compared with those who had the Arg406Trp mutation. Few differences regarding age at symptom onset, age at death, or disease duration were noted for individual GRN mutations, consistent with the common mechanism of haplo-insufficiency.6Cruts M Gijselinck I van der Zee J et al.Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.Nature. 2006; 442: 920-924Crossref PubMed Scopus (1239) Google Scholar, 7Baker M Mackenzie IR Pickering-Brown SM et al.Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.Nature. 2006; 442: 916-919Crossref PubMed Scopus (1608) Google Scholar To provide more information to individual patients, studies of modifiers will be of importance. Currently, only a few genetic or environmental modifiers of age at symptom onset, age at death, and disease duration are known for frontotemporal dementia. When more modifiers are identified, the creation of a score incorporating multiple modifiers might be possible, and this score might be used to predict disease onset, similar to the polygenic risk scores investigated in Alzheimer's disease.8Sleegers K Bettens K De Roeck A et al.A 22-single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ42.Alzheimers Dement. 2015; 11: 1452-1460Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 9Desikan RS Fan CC Wang Y et al.Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.PLoS Med. 2017; 14e1002258Crossref PubMed Scopus (219) Google Scholar For example, a genetic score was computed on the basis of six variables which were suggestively associated with age at symptom onset in an Italian frontotemporal dementia cohort.10Ferrari R Grassi M Graziano F et al.Effects of multiple genetic loci on age at onset in frontotemporal dementia.J Alzheimers Dis. 2017; 56: 1271-1278Crossref PubMed Scopus (4) Google Scholar In families in which a pathogenic mutation segregates with phenotype, such a score might facilitate the clinician's decision on the timing and frequency of follow-ups for individuals who carry the mutation without symptoms. Beyond the advantages for counselling, these scores might be of interest for future clinical trials. For example, estimates of the expected onset age will be informative in trials on presymptomatic individuals with mutations to assess whether the intervention can delay the onset of disease. This is of importance, because Moore and colleagues' study also highlights that the correlation between familial and parental age at symptom onset and at death and individual age at symptom onset and at death is limited, especially for the GRN and C9orf72 groups, despite being significant in all three genetic groups. In the MAPT group, the specific mutation explained 48% (95% CI 35–62) and family membership explained 66% (56–75) of the variability in age at symptom onset, whereas in the GRN group, only 2% (95% CI 0–10) of the variability was explained by the specific mutation and 14% (9–22) by family membership. In the C9orf72 group, family membership explained only 17% (95% CI 11–26) of the variability of age at symptom onset. In this study, the authors included mutations that are likely to be pathogenic. For other MAPT and GRN mutations, the pathogenicity is unclear at this moment. For example, for GRN, some missense mutations result in intermediate granulin levels in blood or CSF. Whether these are likely to be pathogenic or if they are risk factors for disease with lower penetrance is not clear yet. Detailed functional investigations, co-segregation analyses, and clinical and neuropathological investigations are needed to shed light on variants of unknown significance. Altogether, the study by Moore and colleagues provides an overview of phenotypic characteristics of patients with MAPT, GRN, and C9orf72 mutations, and their findings emphasise the importance of future studies into phenotypic modifiers. This online publication has been corrected. The corrected version first appeared at thelancet.com/neurology on January 21, 2020 This online publication has been corrected. The corrected version first appeared at thelancet.com/neurology on January 21, 2020 We declare no competing interests. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort studyOur study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Full-Text PDF Correction to Lancet Neurol 2020; 19: 106–08Wauters E, Van Broeckhoven C. International view on genetic frontotemporal dementia. Lancet Neurol 2020; 19: 106–08—In this Comment, the copyright license was incorrect. This correction has been made to the online version as of Jan 21, 2020, and the printed Comment is correct. Full-Text PDF Open Access