C9ORF72 expansion in a family with bipolar disorder
Miriam H. Meisler,Adrienne E. Grant,Julie M. Jones,Guy M. Lenk,Fang He,Peter K. Todd,Masoud Kamali,Roger L. Albin,Andrew P. Lieberman,Scott A. Langenecker,Melvin G. McInnis +10 more
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TLDR
The disease course in the two generations described here demonstrates that expansion of the C9ORF72 may be associated with a form of bipolar disorder that presents clinically with classic phenomenology and progression to neurodegenerative disease.Abstract:
Objective
To investigate the role in bipolar disorder of the C9ORF72 hexanucleotide repeat expansion responsible for frontotemporal lobe dementia and amyotrophic lateral sclerosis
Methods
Eighty-nine subjects from a previously described panel of individuals with bipolar disorder ascertained for genetic studies were screened to detect expansion of the C9ORF72 repeat One two-generation family with bipolar disorder and an expanded repeat was characterized in depth using molecular diagnostics, imaging, histopathology, and neurological and neuropsychological evaluation
Results
One proband, with the typical clinical presentation of bipolar disorder, carried an expanded C9ORF72 allele of heterogeneous length between 14 and 20 kilobases (kb) as assessed by Southern blot The expanded allele was inherited from a parent with atypical, late onset clinical features of bipolar disorder, who subsequently progressed to frontotemporal lobe dementia The expansion in peripheral blood of the parent ranged from 85 to 20 kb Cultured lymphoblastoid cells from this parent exhibited a homogeneous expansion of only 85 kb
Conclusions
The disease course in the two generations described here demonstrates that expansion of the C9ORF72 may be associated with a form of bipolar disorder that presents clinically with classic phenomenology and progression to neurodegenerative disease The frequency in our bipolar disorder cohort was only 1%, indicating that C9ORF72 is not a major contributor to bipolar disorder DNA from cultured cells may be biased towards shorter repeats and nonrepresentative of the endogenous C9ORF72 expansionread more
Citations
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Journal ArticleDOI
C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis
Jonathan D. Rohrer,Adrian M. Isaacs,Sarah Mizielinska,Simon Mead,Tammaryn Lashley,Selina Wray,Katie Sidle,Pietro Fratta,Richard W. Orrell,John Hardy,Janice L. Holton,Tamas Revesz,Martin N. Rossor,Jason D. Warren +13 more
TL;DR: Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation.
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Genetics of FTLD: overview and what else we can expect from genetic studies.
TL;DR: How FTLD specific issues, such as disease heterogeneity, the presence of an unclear family history and the possible role of an oligogenic basis of FTLD, can pose challenges for future FTLD gene identification and risk assessment of specific variants are discussed.
Journal ArticleDOI
The clinical spectrum of sporadic and familial forms of frontotemporal dementia.
TL;DR: This review aims to clarify the often confusing terminology of FTD, and outline the various clinical features and diagnostic criteria of sporadic and familial FTD syndromes.
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The behavioural variant frontotemporal dementia (bvFTD) syndrome in psychiatry
Serggio Lanata,Bruce L. Miller +1 more
TL;DR: It is proposed that largely due to the paucity of biomarkers for primary psychiatric disorders, and the limited use of FTLD-related biomarkers by psychiatrists at present, it is very difficult to separate patients with early bvFTD from those withPrimary psychiatric disorders based on clinical grounds.
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Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms.
Claudia Figueroa-Romero,Junguk Hur,J. Simon Lunn,Ximena Paez-Colasante,Diane E. Bender,Raymond Yung,Stacey A. Sakowski,Eva L. Feldman +7 more
TL;DR: A global reduction of mature microRNAs, alterations in microRNA processing, and support for a role of the nucleotide binding protein, TAR DNA binding protein 43, in regulating sporadic amyotrophic lateral sclerosis-associated micro RNAs are reported, thereby offering a potential underlying mechanism for sporadic ALS.
References
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Journal ArticleDOI
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Mariely DeJesus-Hernandez,Ian R. A. Mackenzie,Bradley F. Boeve,Adam L. Boxer,Matt Baker,Nicola J. Rutherford,Alexandra M. Nicholson,Ni Cole A. Finch,Heather C. Flynn,Jennifer Adamson,Naomi Kouri,Aleksandra Wojtas,Pheth Sengdy,Ging-Yuek Robin Hsiung,Anna Karydas,William W. Seeley,Keith A. Josephs,Giovanni Coppola,Daniel H. Geschwind,Zbigniew K. Wszolek,Howard Feldman,Howard Feldman,David S. Knopman,Ronald C. Petersen,Bruce L. Miller,Dennis W. Dickson,Kevin B. Boylan,Neill R. Graff-Radford,Rosa Rademakers +28 more
TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
Journal ArticleDOI
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease
Bradley T. Hyman,Creighton H. Phelps,Thomas G. Beach,Eileen H. Bigio,Nigel J. Cairns,Maria C. Carrillo,Dennis W. Dickson,Charles Duyckaerts,Matthew P. Frosch,Eliezer Masliah,Suzanne S. Mirra,Peter T. Nelson,Julie A. Schneider,Dietmar Rudolf Thal,Bill Thies,John Q. Trojanowski,Harry V. Vinters,Thomas J. Montine +17 more
TL;DR: The new guidelines recognize the pre‐clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, and establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP‐43 inclusions.
Journal ArticleDOI
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
Elisa Majounie,Alan E. Renton,Kin Y. Mok,Elise G.P. Dopper,Elise G.P. Dopper,Adrian James Waite,Sara Rollinson,Adriano Chiò,Gabriella Restagno,Nayia Nicolaou,Nayia Nicolaou,Javier Simón-Sánchez,Javier Simón-Sánchez,John C. van Swieten,John C. van Swieten,Yevgeniya Abramzon,Janel O. Johnson,Michael Sendtner,Roger Pamphlett,Richard W. Orrell,Simon Mead,Katie C. L. Sidle,Henry Houlden,Jonathan D. Rohrer,Karen E. Morrison,Hardev Pall,Kevin Talbot,Olaf Ansorge,Dena G. Hernandez,Sampath Arepalli,Mario Sabatelli,Gabriele Mora,Massimo Corbo,Fabio Giannini,Andrea Calvo,Elisabet Englund,Giuseppe Borghero,Gian Luca Floris,Anne M. Remes,Hannu Laaksovirta,Leo McCluskey,John Q. Trojanowski,Vivianna M. Van Deerlin,Gerard D. Schellenberg,Mike A. Nalls,Vivian E. Drory,Chin-Song Lu,Chin-Song Lu,Tu-Hsueh Yeh,Tu-Hsueh Yeh,Hiroyuki Ishiura,Yuji Takahashi,Shoji Tsuji,Isabelle Le Ber,Isabelle Le Ber,Isabelle Le Ber,Alexis Brice,Alexis Brice,Alexis Brice,Carsten Drepper,Nigel Williams,Janine Kirby,Pamela J. Shaw,John Hardy,Pentti J. Tienari,Peter Heutink,Huw R. Morris,Huw R. Morris,Huw R. Morris,Stuart Pickering-Brown,Bryan J. Traynor,Bryan J. Traynor +71 more
TL;DR: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD, suggesting a one-off expansion occurring about 1500 years ago.
Journal ArticleDOI
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.
Ilse Gijselinck,Tim Van Langenhove,Julie van der Zee,Kristel Sleegers,Stéphanie Philtjens,Gernot Kleinberger,Jonathan Janssens,Karolien Bettens,Caroline Van Cauwenberghe,Sandra Pereson,Sebastiaan Engelborghs,Anne Sieben,Anne Sieben,Peter De Jonghe,Rik Vandenberghe,Patrick Santens,Jan De Bleecker,Githa Maes,Veerle Bäumer,Lubina Dillen,Geert Joris,Ivy Cuijt,Ellen Corsmit,Ellen Elinck,Jasper Van Dongen,Steven Vermeulen,Marleen Van den Broeck,Carolien Vaerenberg,Maria Mattheijssens,Karin Peeters,Wim Robberecht,Patrick Cras,Jean-Jacques Martin,Peter Paul De Deyn,Marc Cruts,Christine Van Broeckhoven +35 more
TL;DR: The GGGGCC repeat expansion is highly penetrant, explaining all of the contribution of chromosome 9p21 to FTLD and ALS in the Flanders-Belgian cohort and decreased expression of C9orf72 in brain suggests haploinsufficiency as an underlying disease mechanism.
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