Abstract
A clinical and molecular overlap between Alzheimer’s disease (AD) and frontotemporal dementia (FTD) has been reported. Presenilins have been associated with FTD or with FTD-like phenotype, while mutations in the MAPT gene have been linked to a clinical phenotype of AD. We performed a clinical and genetic examination in two FTD siblings and their family tree has been reconstructed. We identified a novel Val75Ala MAPT mutation in one patient and in the other the Arg62His Presenilin2 mutation. The DNA variations identified, defined mutations by frequency, per se are not causative of the disease. These mutations, possibly in association with other unknown environmental and genetic factors, may contribute to neurodegeneration. In this family, the disease might result from a genetically interconnected spectrum of altered pathways that could link most neurodegenerative disorders. Moreover, the novel mutation identified merits further functional studies that would contribute to the unravelling of such a complex field.
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Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 51:1546–1554
Pickering-Brown SM, Baker M, Gass J, Boeve BF, Loy CT, Brooks WS, Mackenzie IR, Martins RN, Kwok JB, Halliday GM, Kril J, Schofield PR, Mann DM, Hutton M (2006) Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain 129:3124–3126
Foster NL, Wilhelmsen K, Sima AA, Jones MZ, D’Amato CJ, Gilman S (1997) Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 41(6):706–715
Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924
Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, Hummerich H, Nielsen JE, Hodges JR, Spillantini MG, Thusgaard T, Brandner S, Brun A, Rossor MN, Gade A, Johannsen P, Sørensen SA, Gydesen S, Fisher EM, Collinge J (2005) Mutations in the endosomal ESCRTIII-complex sub-unit CHMP2B in frontotemporal dementia. Nat Genet 37:806–808
Watts GDJ, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381
Raux G, Gantier R, Thomas-Anterion C, Boulliat J, Verpillat P, Hannequin D, Brice A, Frebourg T, Campion D (2000) Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation. Neurology 55:1577–1578
Tang-Wai D, Lewis P, Boeve B, Hutton M, Golde T, Baker M, Hardy J, Michels V, Ivnik R, Jack C, Petersen R (2002) Familial frontotemporal dementia associated with a novel presenilin-1 mutation. Dement Geriatr Cogn Disord 14:13–21
Dermaut B, Kumar-Singh S, Engelborghs S, Theuns J, Rademakers R, Saerens J, Pickut BA, Peeters K, van den Broeck M, Vennekens K, Claes S, Cruts M, Cras P, Martin JJ, Van Broeckhoven C, De Deyn PP (2004) A novel presenilin 1 mutation associated with Pick’s disease but not beta-amyloid plaque. Ann Neurol 55:617–626
Zekanowski C, Golan MP, Krzyśko KA, Lipczyńska-Łojkowska W, Filipek S, Kowalska A, Rossa G, Pepłońska B, Styczyńska M, Maruszak A, Religa D, Wender M, Kulczycki J, Barcikowska M, Kuźnicki J (2006) Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol 200:82–88
Bernardi L, Tomaino C, Anfossi M, Gallo M, Geracitano S, Costanzo A, Colao R, Puccio G, Frangipane F, Curcio SA, Mirabelli M, Smirne N, Iapaolo D, Maletta RG, Bruni AC (2008) Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiol Aging (Epub ahead of print)
Lindquist SG, Holm IE, Schwartz M, Law I, Stokholm J, Batbayli M, Waldemar G, Nielsen JE (2008) Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation. Eur J Neurol 15:377–385
Nitrini R, Teixeira da Silva LS, Rosemberg S, Caramelli P, Carrilho PE, Iughetti P, Passos-Bueno MR, Zatz M, Albrecht S, LeBlanc A (2001) Prion disease resembling frontotemporal dementia and parkinsonism linked to chromosome 17. Arq Neuropsiquiatr 59:161–164
Carlesimo GA, Caltagirone C, Gainotti G (1996) The Mental Deterioration Battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment. The Group for the Standardization of the Mental Deterioration Battery. Eur Neurol 36:378–384
Brun A, Englund B, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS (1994) Consensus statement: clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 57:416–418
Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825
Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C (1998) Estimation of the genetic contribution of presenilin 1 and 2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet 7:43–51
Huang N, Marie SK, Kok F, Nitrini R (2001) Familial Creutzfeldt–Jakob disease associated with a point mutation at codon 210 of the prion protein gene. Arq Neuropsiquiatr 59:932–935
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706
Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31:545–548
Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, Hardy J, Lynch T, Bigio E, Hutton M (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8:711–715
Rahman S, Robbins TW, Sahakian BJ (1999) Comparative cognitive neuropsychological studies of frontal lobe function: implications for therapeutic strategies in frontal variant frontotemporal dementia. Dement Geriatr Cogn Disord 10:15–28
Bozeat S, Gregory CA, Ralph MA, Hodges JR (2000) Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 69:178–186
Curcio SA, Kawarai T, Paterson AD, Maletta RG, Puccio G, Perri M, Di Natale M, Palermo S, Foncin JF, Hyslop PH, Bruni AC (2002) A large Calabrian kindred segregating frontotemporal dementia. J Neurol 249:911–922
Bruni AC, Momeni P, Bernardi L, Tomaino C, Frangipane F, Elder J, Kawarai T, Sato C, Pradella S, Wakutani Y, Anfossi M, Gallo M, Geracitano S, Costanzo A, Smirne N, Curcio SA, Mirabelli M, Puccio G, Colao R, Maletta RG, Kertesz A, St George-Hyslop P, Hardy J, Rogaeva E (2007) Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation. Neurology 69:140–147
Hayashi S, Toyoshima Y, Hasegawa M, Umeda Y, Wakabayashi K, Tokiguchi S, Iwatsubo T, Takahashi H (2002) Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol 51:525–530
Poorkaj P, Muma NA, Zhukareva V, Cochran EJ, Shannon KM, Hurtig H, Koller WC, Bird TD, Trojanowski JQ, Lee VM, Schellenberg GD (2002) An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol 52:511–516
Kanai Y, Chen J, Hirokawa N (1992) Microtubule bundling by tau proteins in vivo: analysis of functional domains. EMBO J 11:3953–3961
Rosenberg KJ, Ross JL, Feinstein HE, Feinstein SC, Israelachvili J (2008) Complementary dimerization of microtubule-associated tau protein: implications for microtubule bundling and tau-mediated pathogenesis. Proc Natl Acad Sci USA 105:7445–7450
Jeganathan S, von Bergen M, Brutlach H, Steinhoff HJ, Mandelkow E (2006) Global hairpin folding of tau in solution. Biochemistry 45:2283–2293
Brandt R, Léger J, Lee GJ (1995) Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J Cell Biol 131:1327–1340
Walker ES, Martinez M, Brunkan AL, Goate A (2005) Presenilin 2 familial Alzheimer’s disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem 92:294–301
Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J (2008) Genetic screening of Alzheimer’s disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging (Epub ahead of print)
To MD, Gokgoz N, Doyle TG, Donoviel DB, Knight JA, Hyslop PS, Bernstein A, Andrulis IL (2006) Functional characterization of novel presenilin-2 variants identified in human breast cancers. Oncogene 25:3557–3564
Hughes A, Mann D, Pickering-Brown S (2003) Tau haplotype frequency in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Exp Neurol 181:12–16
Bernardi L, Maletta RG, Tomaino C, Smirne N, Di Natale M, Perri M, Longo T, Colao R, Curcio SA, Puccio G, Mirabelli M, Kawarai T, Rogaeva E, St George Hyslop PH, Passarino G, De Benedictis G, Bruni AC (2006) The effects of APOE and tau gene variability on risk of frontotemporal dementia. Neurobiol Aging 27:702–709
Hardy J (2001) The genetic causes of neurodegenerative diseases. J Alzheimers Dis 3:109–116
Acknowledgments
We thank all subjects participating to the study; the Associazione per la Ricerca Neurogenetica-ONLUS Lamezia Terme for invaluable help in assisting persons and families. This study was partially supported by finalized projects of the Italian Health Ministery: (1) DGRST no. 4/2760-P/I.9.ab, 2007; (2) RFPS-2006-7-334858, 2006.
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M. Gallo and C. Tomaino contributed equally to this work.
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Gallo, M., Tomaino, C., Puccio, G. et al. Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia. Neurol Sci 31, 65–70 (2010). https://doi.org/10.1007/s10072-009-0132-9
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DOI: https://doi.org/10.1007/s10072-009-0132-9