Dementia with Lewy bodies is a neurodegenerative disease, sharing features with Parkinson’s and Alzheimer’s diseases. We report a case of a patient dementia with Lewy bodies carrying combined PSEN1 and ATP7B mutations. A man developed dementia with Lewy bodies starting at the age of 60 years. CSF biomarkers were of Alzheimer’s disease and DaTSCAN was abnormal. Whole-exome sequencing revealed a heterozygous p.Ile408Thr PSEN1 variant and a homozygous p.Arg616Trp ATP7B variant. This case reinstates the need of considering ATP7B mutations when evaluating a patient with parkinsonism and supports p.Ile408Thr as a pathogenic PSEN1 variant.
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Walker L, McAleese KE, Thomas AJ et al (2015) Neuropathologically mixed Alzheimer’s and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes. Acta Neuropathol 129(5):729–748
McKeith IG, Boeve BF, Dickson DW et al (2017) Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology 89(1):88–100
Berg D, Postuma RB, Bloem B et al (2014) Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Disord: Off J Mov Disord Soc 29(4):454–462
Orme T, Guerreiro R, Bras J (2018) The genetics of dementia with Lewy bodies: current understanding and future directions. Curr Neurol Neurosci Rep 18(10):67
Guerreiro R, Ross OA, Kun-Rodrigues C et al (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17(1):64–74
Geiger JT, Ding J, Crain B et al (2016) Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. Neurobiol Dis 94:55–62
Guerreiro R, Escott-Price V, Hernandez DG et al (2019) Heritability and genetic variance of dementia with Lewy bodies. Neurobiol Dis 127:492–501
McKenna A, Hanna M, Banks E et al (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303
Van der Auwera GA, Carneiro MO, Hartl C et al (2013) From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinforma 43:11.10.1-11.10.33
Cingolani P, Platts A, le Wang L et al (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 6(2):80–92
Liu X, Jian X, Boerwinkle E (2013) dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations. Hum Mutat 34(9):E2393-2402
Patel ZH, Kottyan LC, Lazaro S et al (2014) The struggle to find reliable results in exome sequencing data: filtering out Mendelian errors. Front Genet 5:16
Robinson PN, Kohler S, Oellrich A et al (2014) Improved exome prioritization of disease genes through cross-species phenotype comparison. Genome Res 24(2):340–348
Kohler S, Carmody L, Vasilevsky N et al (2019) Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. Nucleic Acids Res 47(D1):D1018–D1027
Mattsson N, Andreasson U, Persson S et al (2011) The Alzheimer’s Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement: J Alzheimers Assoc 7(4):386-395.e386
Baldeiras IE, Ribeiro MH, Pacheco P et al (2009) Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients. J Neurol 256(9):1540–1550
Kapaki E, Kilidireas K, Paraskevas GP, Michalopoulou M, Patsouris E (2001) Highly increased CSF tau protein and decreased beta-amyloid (1–42) in sporadic CJD: a discrimination from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 71(3):401–403
Jack CR Jr, Bennett DA, Blennow K et al (2018) NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14(4):535–562
Tedde A, Bartoli A, Piaceri I et al (2016) Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late-onset Alzheimer’s disease. Neurosci Lett 610:150–153
Caca K, Ferenci P, Kuhn HJ et al (2001) High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis. J Hepatol 35(5):575–581
Savica R, Grossardt BR, Bower JH, Boeve BF, Ahlskog JE, Rocca WA (2013) Incidence of dementia with Lewy bodies and Parkinson disease dementia. JAMA Neurol 70(11):1396–1402
Wenisch E, De Tassigny A, Trocello JM, Beretti J, Girardot-Tinant N, Woimant F (2013) Cognitive profile in Wilson’s disease: a case series of 31 patients. Rev Neurol 169(12):944–949
Iwanski S, Seniow J, Lesniak M, Litwin T, Czlonkowska A (2015) Diverse attention deficits in patients with neurologically symptomatic and asymptomatic Wilson’s disease. Neuropsychology 29(1):25–30
Shanmugavel KP, Kumar R, Li Y, Wittung-Stafshede P (2019) Wilson disease missense mutations in ATP7B affect metal-binding domain structural dynamics. Biometals: Int J Role Metal Ions Biol Biochem Med 32(6):875–885
Huster D, Kuhne A, Bhattacharjee A et al (2012) Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology 142(4):947-956.e945
Gourdon P, Sitsel O, Lykkegaard Karlsen J, Birk Moller L, Nissen P (2012) Structural models of the human copper P-type ATPases ATP7A and ATP7B. Biol Chem 393(4):205–216
Curtis D, Durkie M, Balac P et al (1999) A study of Wilson disease mutations in Britain. Hum Mutat 14(4):304–311
Guerreiro R, Sassi C, Gibbs JR, Edsall C, Hernandez D, Brown K, Lupton MK, Parkinnen L, Ansorge O, Hodges A, Ryten M, for the UK Brain Expression Consortium, Tienari PJ, Van Deerlin VM, Trojanowski JQ, MorganK, Powell J, Singleton A, Hardy J, Bras J (2018) A comprehensive assessment of benign genetic variability for neurodegenerative disorders. bioRxiv 270686. https://doi.org/10.1101/270686
Jozwiak K, Zekanowski C, Filipek S (2006) Linear patterns of Alzheimer’s disease mutations along alpha-helices of presenilins as a tool for PS-1 model construction. J Neurochem 98(5):1560–1572
Laudon H, Hansson EM, Melen K et al (2005) A nine-transmembrane domain topology for presenilin 1. J Biol Chem 280(42):35352–35360
Aldudo J, Bullido MJ, Valdivieso F (1999) DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer’s disease presenilin-1 gene: two novel mutations. Hum Mutat 14(5):433–439
Sherrington R, Rogaev EI, Liang Y et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375(6534):754–760
Southon A, Greenough MA, Ganio G, Bush AI, Burke R, Camakaris J (2013) Presenilin promotes dietary copper uptake. PLoS One 8(5):e62811
Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G (2019) Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 15(9):501–518
Tsuang D, Leverenz JB, Lopez OL et al (2013) APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70(2):223–228
Sando SB, Melquist S, Cannon A et al (2008) APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from central Norway. BMC Neurol 8:9
Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG067426. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Tábuas-Pereira, M., Guerreiro, R., Kun-Rodrigues, C. et al. Whole-exome sequencing reveals PSEN1 and ATP7B combined variants as a possible cause of early-onset Lewy body dementia: a case study of genotype–phenotype correlation. Neurogenetics 23, 279–283 (2022). https://doi.org/10.1007/s10048-022-00699-0
- Lewy body dementia
- Wilson’s disease