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Browsing by Author "Holton, J"

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  • A comprehensive screening of copy number variability in dementia with Lewy bodies
    Publication . Kun-Rodrigues, C; Orme, T; Carmona, S; Hernandez, DG; Ross, OA; Eicher, JD; Shepherd, C; Parkkinen, L; Darwent, L; Heckman, MG; Scholz, SW; Troncoso, JC; Pletnikova, O; Dawson, T; Rosenthal, L; Ansorge, O; Clarimon, J; Lleo, A; Morenas-Rodriguez, E; Clark, L; Honig, LS; Marder, K; Lemstra, A; Rogaeva, E; St George-Hyslop, P; Londos, E; Zetterberg, H; Barber, I; Braae, A; Brown, K; Morgan, K; Troakes, C; Al-Sarraj, S; Lashley, T; Holton, J; Compta, Y; Van Deerlin, V; Serrano, GE; Beach, TG; Lesage, S; Galasko, D; Masliah, E; Santana, I; Pastor, P; Diez-Fairen, M; Aguilar, M; Tienari, PJ; Myllykangas, L; Oinas, M; Revesz, T; Lees, A; Boeve, BF; Petersen, RC; Ferman, TJ; Escott-Price, V; Graff-Radford, N; Cairns, NJ; Morris, JC; Pickering-Brown, S; Mann, D; Halliday, GM; Hardy, J; Trojanowski, JQ; Dickson, DW; Singleton, A; Stone, DJ; Guerreiro, R; Bras, J
    The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
    2019Journal article Open access Show more
  • Sporadic inclusion body myositis: an unsolved mystery
    Publication . Machado, P; Miller, A; Holton, J; Hanna, M
    Sporadic inclusion body myositis (sIBM) is considered to be the most common acquired muscle disease associated with aging. It is a disabling disorder still without effective treatment. sIBM causes weakness and atrophy of the distal and proximal muscles. Involvement of quadriceps and deep finger flexors are clues to early diagnosis. Dysphagia in the course of the disease is common. Muscle biopsy shows chronic myopathic features, lymphocytic infiltration invading non-necrotic fibbers, rimmed vacuoles and accumulation of amyloid-related proteins. It remains uncertain whether sIBM is primarily an immune-mediated inflammatory myopathy or a degenerative myopathy with an associated inflammatory component. This review describes the epidemiology and clinical features of the disease as well as the current genetic and pathogenic concepts and therapeutic approaches. Despite recent clues, in many respects sIBM remains an unsolved mystery.
    2009Journal article Open access Show more