Abstract
Presenilin 1 (PSEN1) mutations are the major cause of autosomal dominant Alzheimer’s disease (ADAD). Here we report three novel PSEN1 mutations: Ile238_Lys239insIle, Ala246Pro and Ala164Val from patients who manifested in their twenties, forties and seventies, respectively, with variant clinical presentations of dementia. These cases exemplify the tremendous heterogeneity of clinical phenotypes and age of onset associated with PSEN1 mutations. The possibility of ADAD—not previously suspected in two of our patients—should always be considered in neurodegenerative conditions albeit they might neither exhibit the typical clinical picture of Alzheimer’s disease nor early onset dementia, which is regarded the primary clinical sign of hereditary neurodegeneration.
References
Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Poyhonen M, Kucera S, Haltia M (1998) A variant of Alzheimer’s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med 4:452–455
De Jonghe C, Cruts M, Rogaeva EA et al (1999) Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer’s disease by increased Abeta42 secretion. Hum Mol Genet 8:1529–1540
Dumanchin C, Tournier I, Martin C et al (2006) Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat 27:1063
Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, De Jonghe P, Vandenberghe R, Santens P, De Bleecker J, Maes G, Bäumer V, Dillen L, Joris G, Cuijt I, Corsmit E, Elinck E, Van Dongen J, Vermeulen S, Van den Broeck M, Vaerenberg C, Mattheijssens M, Peeters K, Robberecht W, Cras P, Martin JJ, De Deyn PP, Cruts M, Van Broeckhoven C (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11(1):54–65. Erratum in: Lancet Neurol (2012) 11(2):125
Kowalska A, Wender M, Florczak J, Pruchnik-Wolinska D, Modestowicz R, Szczech J, Rossa G, Kozubski W (2003) Molecular genetics of Alzheimer’s disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet 44:231–234
Lladó A, Fortea J, Ojea T, Bosch B, Sanz P, Valls-Solé J, Clarimon J, Molinuevo JL, Sánchez-Valle R (2010) A novel PSEN1 mutation (K239N) associated with Alzheimer’s disease with wide range age of onset and slow progression. Eur J Neurol 17(7):994–996
Loy CT, Schofield PR, Turner AM, Kwok JB (2014) Genetics of dementia. Lancet 383(9919):828–840
Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T (2001) Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer’s disease. Am J Pathol 158:2165–2175
Menendez M (2004) Pathological and clinical heterogeneity of presenilin 1 gene mutations. J Alzheimers Dis 6(5):475–482
Ringman JM, Gylys KH, Medina LD, Fox M, Kepe V, Flores DL, Apostolova LG, Barrio JR, Small G, Silverman DH, Siu E, Cederbaum S, Hecimovic S, Malnar M, Chakraverty S, Goate AM, Bird TD, Leverenz JB (2011) Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer’s disease due to a novel PSEN1 mutation. Neurosci Lett 487(3):287–292
Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P (2001) Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology 57:621–625
Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P, Ghetti B, Langbaum JB, Lopera F, Martins R, Masters CL, Mayeux RP, McDade E, Moreno S, Reiman EM, Ringman JM, Salloway S, Schofield PR, Sperling R, Tariot PN, Xiong C, Morris JC, Bateman RJ, Dominantly Inherited Alzheimer Network (2014) Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83(3):253–260
Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375(6534):754–760
Acknowledgments
This study was supported by Grants from the German Ministry of Health (Bundesgesundheitsministerium) for the German Brain Bank (BrainNet, BMG 01GI0505), the European Commission (TSELAB QLK 2-CT-2002-81523) and the German Centre for Neurodegenerative Diseases (DZNE) e.V. We thank B. Vanmassenhove, D. Ringleb-Wieden, I. Pigur and K. Rentzsch for expert technical assistance in genetic analysis and histological processing. We thank Dr. Meyer and Dr. Katzinski for providing information about the clinical history. Drs. N. Ackl and F. Sürer assisted in the clinical assessment.
Author information
Authors and Affiliations
Corresponding author
Additional information
S. Roeber and F. Müller-Sarnowski contributed equally.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Roeber, S., Müller-Sarnowski, F., Kress, J. et al. Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer’s disease. J Neural Transm 122, 1715–1719 (2015). https://doi.org/10.1007/s00702-015-1450-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-015-1450-0