Analysis of C9orf72 Repeat Expansions in a Large International Cohort of Dementia with Lewy Bodies

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

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References

Geiger J, Arthur K, Dawson T, Rosenthal L, Pantelyat A, Albert M . C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies. Neurodegener Dis. 2016; 16(5-6):370-2. PMC: 5011449. DOI: 10.1159/000445872. View

Boeve B, Boylan K, Graff-Radford N, DeJesus-Hernandez M, Knopman D, Pedraza O . Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain. 2012; 135(Pt 3):765-83. PMC: 3286335. DOI: 10.1093/brain/aws004. View

Weisman D, McKeith I . Dementia with Lewy bodies. Semin Neurol. 2007; 27(1):42-7. DOI: 10.1055/s-2006-956754. View

Majounie E, Abramzon Y, Renton A, Perry R, Bassett S, Pletnikova O . Repeat expansion in C9ORF72 in Alzheimer's disease. N Engl J Med. 2012; 366(3):283-4. PMC: 3513272. DOI: 10.1056/NEJMc1113592. View

Bras J, Guerreiro R, Darwent L, Parkkinen L, Ansorge O, Escott-Price V . Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet. 2014; 23(23):6139-46. PMC: 4222357. DOI: 10.1093/hmg/ddu334. View

Xi Z, Zhang M, Bruni A, Maletta R, Colao R, Fratta P . The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients. Acta Neuropathol. 2015; 129(5):715-27. DOI: 10.1007/s00401-015-1401-8. View

Hensman Moss D, Poulter M, Beck J, Hehir J, Polke J, Campbell T . C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology. 2013; 82(4):292-9. PMC: 3929197. DOI: 10.1212/WNL.0000000000000061. View

Heidebrink J . Is dementia with Lewy bodies the second most common cause of dementia?. J Geriatr Psychiatry Neurol. 2002; 15(4):182-7. DOI: 10.1177/089198870201500402. View

Lesage S, Le Ber I, Condroyer C, Broussolle E, Gabelle A, Thobois S . C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain. 2013; 136(Pt 2):385-91. PMC: 3984141. DOI: 10.1093/brain/aws357. View

10.

DeJesus-Hernandez M, Mackenzie I, Boeve B, Boxer A, Baker M, Rutherford N . Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011; 72(2):245-56. PMC: 3202986. DOI: 10.1016/j.neuron.2011.09.011. View

11.

Robinson A, Davidson Y, Snowden J, Mann D . C9ORF72 in dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2014; 85(12):1435-6. DOI: 10.1136/jnnp-2014-307622. View

12.

Guerreiro R, Escott-Price V, Darwent L, Parkkinen L, Ansorge O, Hernandez D . Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiol Aging. 2015; 38:214.e7-214.e10. PMC: 4759606. DOI: 10.1016/j.neurobiolaging.2015.10.028. View

13.

Claassen D, Parisi J, Giannini C, Boeve B, Dickson D, Josephs K . Frontotemporal dementia mimicking dementia with Lewy bodies. Cogn Behav Neurol. 2008; 21(3):157-63. DOI: 10.1097/WNN.0b013e3181864a09. View

14.

Sieben A, Danek A, Martin J, Vandenberghe R, De Deyn P, Corsmit E . A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat. 2012; 34(2):363-73. PMC: 3638346. DOI: 10.1002/humu.22244. View

15.

Majounie E, Renton A, Mok K, Dopper E, Waite A, Rollinson S . Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012; 11(4):323-30. PMC: 3322422. DOI: 10.1016/S1474-4422(12)70043-1. View

16.

Keogh M, Kurzawa-Akanbi M, Griffin H, Douroudis K, Ayers K, Hussein R . Exome sequencing in dementia with Lewy bodies. Transl Psychiatry. 2016; 6:e728. PMC: 4872424. DOI: 10.1038/tp.2015.220. View

17.

Rollinson S, Halliwell N, Young K, Callister J, Toulson G, Gibbons L . Analysis of the hexanucleotide repeat in C9ORF72 in Alzheimer's disease. Neurobiol Aging. 2012; 33(8):1846.e5-6. DOI: 10.1016/j.neurobiolaging.2012.01.109. View

18.

Meeus B, Verstraeten A, Crosiers D, Engelborghs S, Van den Broeck M, Mattheijssens M . DLB and PDD: a role for mutations in dementia and Parkinson disease genes?. Neurobiol Aging. 2011; 33(3):629.e5-629.e18. DOI: 10.1016/j.neurobiolaging.2011.10.014. View

19.

Yeh T, Lai S, Weng Y, Kuo H, Wu-Chou Y, Huang C . Screening for C9orf72 repeat expansions in parkinsonian syndromes. Neurobiol Aging. 2012; 34(4):1311.e3-4. PMC: 4022748. DOI: 10.1016/j.neurobiolaging.2012.09.002. View

20.

Xi Z, Zinman L, Grinberg Y, Moreno D, Sato C, Bilbao J . Investigation of c9orf72 in 4 neurodegenerative disorders. Arch Neurol. 2012; 69(12):1583-90. PMC: 4005900. DOI: 10.1001/archneurol.2012.2016. View