A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4% of pedigrees had high family history, 6.5% medium, 15.4% low; 39% were apparent sporadic cases and 26.6% had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74%) and decreased in other categories (medium: 15.4%; low: 9.7%; sporadic: 1.3%). Mutation carriers with unknown family history (5.6%) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7%), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4%) in our cohort. An elevated proportion of FTLD patients belonging to “high risk” pedigrees asked for genetic counseling (42%); requests decreased according to the estimated family risk (medium: 26.9%; low: 17.7%; sporadic: 5.1%). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.
Lomen-HoerthC, AndersonT, MillerB (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology59, 1077–1079.
6.
JosephsKA, PetersenRC, KnopmanDS, BoeveBF, WhitwellJL, DuffyJR, ParisiJE, DicksonDW (2006) Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology66, 41–48.
7.
BurrellJR, KiernanMC, VucicS, HodgesJR (2011) Motor neuron dysfunction in frontotemporal dementia. Brain134, 2582–2594.
8.
RohrerJD, GuerreiroR, VandrovcovaJ, UphillJ, ReimanD, BeckJ, IsaacsAM, AuthierA, FerrariR, FoxNC, MackenzieIR, WarrenJD, de SilvaR, HoltonJ, ReveszT, HardyJ, MeadS, RossorMN (2009) The heritability and genetics of frontotemporal lobar degeneration. Neurology73, 1451–1456.
9.
PoorkajP, BirdTD, WijsmanE, NemensE, GarrutoRM, AndersonL, AndreadisA, WiederholtWC, RaskindM, SchellenbergGD (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol43, 815–825.
10.
HuttonM, LendonCL, RizzuP, BakerM, FroelichS, HouldenH, Pickering-BrownS, ChakravertyS, IsaacsA, GroverA, HackettJ, AdamsonJ, LincolnS, DicksonD, DaviesP, PetersenRC, StevensM, de GraaffE, WautersE, van BarenJ, HillebrandM, JoosseM, KwonJM, NowotnyP, CheLK, NortonJ, MorrisJC, ReedLA, TrojanowskiJ, BasunH, LannfeltL, NeystatM, FahnS, DarkF, TannenbergT, DoddPR, HaywardN, KwokJB, SchofieldPR, AndreadisA, SnowdenJ, CraufurdD, NearyD, OwenF, OostraBA, HardyJ, GoateA, van SwietenJ, MannD, LynchT, HeutinkP (1998) Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature393, 702–705.
CrutsM, GijselinckI, van der ZeeJ, EngelborghsS, WilsH, PiriciD, RademakersR, VandenbergheR, DermautB, MartinJJ, van DuijnC, PeetersK, SciotR, SantensP, De PooterT, MattheijssensM, Van den BroeckM, CuijtI, VennekensK, De DeynPP, Kumar-SinghS, Van BroeckhovenC (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature442, 920–924.
BocchettaM, MegaA, BernardiL, Di MariaE, BenussiL, BinettiG, BorroniB, ColaoR, Di FedeG, FostinelliS, GalimbertiD, GennarelliM, GhidoniR, PiaceriI, PievaniM, PorteriC, RedaelliV, RossiG, SuardiS, BabiloniC, ScarpiniE, TagliaviniF, PadovaniA, NacmiasB, SorbiS, FrisoniGB, BruniAC, SINdem Collaborators (2016) Genetic counseling and testing for Alzheimer’s disease and frontotemporal lobar degeneration: An Italian consensus protocol. J Alzheimers Dis51, 277–291.
16.
StevensM, van DuijnCM, KamphorstW, de KnijffP, HeutinkP, van GoolWA, ScheltensP, RavidR, OostraBA, NiermeijerMF, van SwietenJC (1998) Familial aggregation in frontotemporal dementia. Neurology50, 1541–1545.
GoldmanJS, FarmerJM, WoodEM, JohnsonJK, BoxerA, NeuhausJ, Lomen-HoerthC, WilhelmsenKC, LeeVM, GrossmanM, MillerBL (2005) Comparison of family histories in FTLD subtypes and related tauopathies. Neurology65, 1817–1819.
19.
WoodEM, FalconeD, SuhE, IrwinDJ, Chen-PlotkinAS, LeeEB, XieSX, Van DeerlinVM, GrossmanM (2013) Development and validation of pedigree classification criteria for frontotemporal lobar degeneration. JAMA Neurol70, 1411–1417.
20.
LoyCT, SchofieldPR, TurnerAM, KwokJB (2014) Genetics of dementia. Lancet383, 828–840.
FarrerLA, MyersRH, ConnorL, CupplesLA, GrowdonJH (1991) Segregation analysis reveals evidence of a major gene for Alzheimer disease. Am J Hum Genet48, 1026–1033.
23.
GhidoniR, StoppaniE, RossiG, PiccoliE, AlbertiniV, PaterliniA, GlionnaM, PegoianiE, AgnatiLF, FenoglioC, ScarpiniE, GalimbertiD, MorbinM, TagliaviniF, BinettiG, BenussiL (2012) Optimal plasma progranulin cutoff value for predicting null progranulin mutations in neurodegenerative diseases: A multicenter Italian study. Neurodegener Dis9, 121–127.
24.
BenussiL, GhidoniR, PegoianiE, MorettiDV, ZanettiO, BinettiG (2009) Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide. Neurobiol Dis33, 379–385.
BinettiG, NicosiaF, BenussiL, GhidoniR, FeudatariE, BarbieroL, SignoriniS, VillaA, MattioliF, ZanettiO, AlbericiA (2003) Prevalence of TAU mutations in an Italian clinical series of familial frontotemporal patients. Neurosci Lett338, 85–87.
28.
van der ZeeJ, GijselinckI, DillenL, Van LangenhoveT, TheunsJ, EngelborghsS, PhiltjensS, VandenbulckeM, SleegersK, SiebenA, BaumerV, MaesG, CorsmitE, BorroniB, PadovaniA, ArchettiS, PerneczkyR, Diehl-SchmidJ, de MendoncaA, Miltenberger-MiltenyiG, PereiraS, PimentelJ, NacmiasB, BagnoliS, SorbiS, GraffC, ChiangHH, WesterlundM, Sanchez-ValleR, LladoA, GelpiE, SantanaI, AlmeidaMR, SantiagoB, FrisoniG, ZanettiO, BonviciniC, SynofzikM, MaetzlerW, Vom HagenJM, ScholsL, HenekaMT, JessenF, MatejR, ParobkovaE, KovacsGG, StrobelT, SarafovS, TournevI, JordanovaA, DanekA, ArzbergerT, FabriziGM, TestiS, SalmonE, SantensP, MartinJJ, CrasP, VandenbergheR, De DeynPP, CrutsM, Van BroeckhovenC, van der ZeeJ, GijselinckI, DillenL, Van LangenhoveT, TheunsJ, PhiltjensS, SleegersK, BaumerV, MaesG, CorsmitE, CrutsM, Van BroeckhovenC, van der ZeeJ, GijselinckI, DillenL, Van LangenhoveT, PhiltjensS, TheunsJ, SleegersK, BaumerV, MaesG, CrutsM, Van BroeckhovenC, EngelborghsS, De DeynPP, CrasP, EngelborghsS, De DeynPP, VandenbulckeM, VandenbulckeM, BorroniB, PadovaniA, ArchettiS, PerneczkyR, Diehl-SchmidJ, SynofzikM, MaetzlerW, Muller Vom HagenJ, ScholsL, SynofzikM, MaetzlerW, Muller Vom HagenJ, ScholsL, HenekaMT, JessenF, RamirezA, KurzwellyD, SachtlebenC, MairerW, de MendoncaA, Miltenberger-MiltenyiG, PereiraS, FirmoC, PimentelJ, Sanchez-ValleR, LladoA, AntonellA, MolinuevoJ, GelpiE, GraffC, ChiangHH, WesterlundM, GraffC, Kinhult StahlbomA, ThonbergH, NennesmoI, Borjesson-HansonA, NacmiasB, BagnoliS, SorbiS, BessiV, PiaceriI, SantanaI, SantiagoB, SantanaI, Helena RibeiroM, Rosario AlmeidaM, OliveiraC, MassanoJ, GarretC, PiresP, FrisoniG, ZanettiO, BonviciniC, SarafovS, TournevI, JordanovaA, TournevI, KovacsGG, StrobelT, HenekaMT, JessenF, RamirezA, KurzwellyD, SachtlebenC, MairerW, JessenF, MatejR, ParobkovaE, DanelA, ArzbergerT, Maria FabriziG, TestiS, FerrariS, CavallaroT, SalmonE, SantensP, CrasP, European Early-Onset Dementia Consortium (2013) A pan-European study of the C9orf72 repeat associated with FTLD: Geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat34, 363–373.
29.
Pickering-BrownS, BakerM, BirdT, TrojanowskiJ, LeeV, MorrisH, RossorM, JanssenJC, NearyD, CraufurdD, RichardsonA, SnowdenJ, HardyJ, MannD, HuttonM (2004) Evidence of a founder effect in families with frontotemporal dementia that harbor the tau +16 splice mutation. Am J Med Genet B Neuropsychiatr Genet125B, 79–82.
30.
RademakersR, BakerM, GassJ, AdamsonJ, HueyED, MomeniP, SpinaS, CoppolaG, KarydasAM, StewartH, JohnsonN, HsiungGY, KelleyB, KuntzK, SteinbartE, WoodEM, YuCE, JosephsK, SorensonE, WomackKB, WeintraubS, Pickering-BrownSM, SchofieldPR, BrooksWS, Van DeerlinVM, SnowdenJ, ClarkCM, KerteszA, BoylanK, GhettiB, NearyD, SchellenbergGD, BeachTG, MesulamM, MannD, GrafmanJ, MackenzieIR, FeldmanH, BirdT, PetersenR, KnopmanD, BoeveB, GeschwindDH, MillerB, WszolekZ, LippaC, BigioEH, DicksonD, Graff-RadfordN, HuttonM (2007) Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C⟶ T (Arg493X) mutation: An international initiative. . Lancet Neurol6, 857–868.
31.
van der ZeeJ, RademakersR, EngelborghsS, GijselinckI, BogaertsV, VandenbergheR, SantensP, CaekebekeJ, De PooterT, PeetersK, LubkeU, Van den BroeckM, MartinJJ, CrutsM, De DeynPP, Van BroeckhovenC, DermautB (2006) A Belgian ancestral haplotypes harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain129, 841–852.
32.
BenussiL, RademakersR, RutherfordNJ, WojtasA, GlionnaM, PaterliniA, AlbertiniV, BetteckenT, BinettiG, GhidoniR (2013) Estimating the age of the most common Italian GRN mutation: Walking back to Canossa times. J Alzheimers Dis33, 69–76.
33.
BenussiL, GhidoniR, BinettiG (2010) Progranulin mutations are a common cause of FTLD in Northern Italy. Alzheimer Dis Assoc Disord24, 308–309.
34.
GalimbertiD, ArosioB, FenoglioC, SerpenteM, CioffiSM, BonsiR, RossiP, AbbateC, MariD, ScarpiniE (2014) Incomplete penetrance of the C9ORF72 hexanucleotide repeat expansions: Frequency in a cohort of geriatric non-demented subjects. J Alzheimers Dis39, 19–22.
35.
GassJ, CannonA, MackenzieIR, BoeveB, BakerM, AdamsonJ, CrookR, MelquistS, KuntzK, PetersenR, JosephsK, Pickering-BrownSM, Graff-RadfordN, UittiR, DicksonD, WszolekZ, GonzalezJ, BeachTG, BigioE, JohnsonN, WeintraubS, MesulamM, WhiteCL3rd, WoodruffB, CaselliR, HsiungGY, FeldmanH, KnopmanD, HuttonM, RademakersR (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet15, 2988–3001.
BinettiG, BenussiL, RobertsS, VillaA, PasqualettiP, SheuCF, GigolaL, LussignoliG, Dal FornoG, BarbieroL, CorbelliniG, GreenRC, RossiniPM, GhidoniR (2006) Areas of intervention for genetic counselling of dementia: Cross-cultural comparison between Italians and Americans. Patient Educ Couns64, 285–293.
38.
PievaniM, PaternicoD, BenussiL, BinettiG, OrlandiniA, CobelliM, MagnaldiS, GhidoniR, FrisoniGB (2014) Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers. Alzheimers Dement10, S354–S363.e1.
