Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Ferrari, Raffaele; Grassi, Mario; Graziano, Francesca; Palluzzi, Fernando; Archetti, Silvana; Bonomi, Elisa; Bruni, Amalia C.; Maletta, Raffaele; Bernardi, Livia; Cupidi, Chiara; Colao, Rosanna; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Galimberti, Daniela; Scarpini, Elio; Serpente, María; Nacmias, Benedetta; Piaceri, Irene; Bagnoli, Silvia; Rossi, Giacomina; Giaccone, Giorgio; Tagliavini, Fabrizio; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Singleton, Andrew B.; Hardy, John; Momeni, Parastoo; Padovani, Alessandro; Borroni, Barbara

doi:10.3233/jad-160949

Cited by 4 publications

(2 citation statements)

References 34 publications

(42 reference statements)

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“…Although much has been learned over the past decade about the clinical features of these genetic forms of frontotemporal demen tia, most studies explor ing age at symptom onset and disease duration have been small and geographic ally restricted. [4][5][6] In particular, although indivi dual case series have suggested that such phenotypic characteristics can be quite variable, no studies have syste matically investi gated these factors across all the differ ent genetic groups and the different mutations found within these groups.…”

Section: Implications Of All the Available Evidencementioning

confidence: 99%

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Moore

Nicholas

Grossman

et al. 2020

The Lancet Neurology

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Background Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49•5 years (SD 10•0; onset) and 58•5 years (11•3; death) in the MAPT group, 58•2 years (9•8; onset) and 65•3 years (10•9; death) in the C9orf72 group, and 61•3 years (8•8; onset) and 68•8 years (9•7; death) in the GRN group. Mean disease duration was 6•4 years (SD 4•9) in the C9orf72 group, 7•1 years (3•9) in the GRN group, and 9•3 years (6•4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0•45 between individual and parental age at onset, r=0•63 between individual and mean family age at onset, r=0•58 between individual and parental age at death, and r=0•69 between individual and mean family age at death) than in either the C9orf72 group (r=0•32 individual and parental age at onset, r=0•36 individual and mean family age at onset, r=0•38 individual and parental age at death, and r=0•40 individual and mean family age at death) or the GRN group (r=0•22 individual and parental age at onset, r=0•18 individual and mean family age at onset, r=0•22 individual and parental age at death, and r=0•32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even mor...

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Section: Implications Of All the Available Evidencementioning

confidence: 99%

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Moore

Nicholas

Grossman

et al. 2020

The Lancet Neurology

Self Cite

213

230

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“…In FTLD, one of the most heterogeneous clinical features is the age of onset, even in the same family pedigree [ 26 ]. Due to the high hereditability of this group of disorders [ 5 ], some genetic studies have been performed in this field, showing the presence of genes potentially affecting the age of onset [ 27 , 28 , 29 , 34 , 35 ]. However, this issue is still far from being fully addressed.…”

Section: Discussionmentioning

confidence: 99%

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration

Rossi

Benussi

Mehmeti

et al. 2022

IJMS

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Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10–12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (−5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease.

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Modifiers of GRN -Associated Frontotemporal Lobar Degeneration

Wauters

Mossevelde

Zee

et al. 2017

Trends in Molecular Medicine

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Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials. Multiple studies have demonstrated the heterogeneity in clinical presentation and wide variability in age of onset in patients carrying a GRN LOF mutation. Recently, this heterogeneity became an opportunity to identify disease modifiers, considering that these might constitute suitable targets for developing disease-modifying or disease-delaying therapies.

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Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Cited by 4 publications

References 34 publications

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration

Modifiers of GRN -Associated Frontotemporal Lobar Degeneration

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