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Unravelling the Clinical Spectrum and the Role of Repeat Length in C9ORF72 Repeat Expansions Emma L

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Unravelling the Clinical Spectrum and the Role of Repeat Length in C9ORF72 Repeat Expansions Emma L J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325377 on 15 January 2021. Downloaded from Neurodegeneration Review Unravelling the clinical spectrum and the role of repeat length in C9ORF72 repeat expansions Emma L. van der Ende ,1 Jazmyne L. Jackson,2 Adrianna White,2,3 Harro Seelaar ,1 Marka van Blitterswijk ,2,3 John C. Van Swieten 1 ► Additional material is ABSTRACT repeat expansion disorders, including Hunting- published online only. To view, Since the discovery of the C9orf72 repeat expansion ton’s disease (HD), several spinocerebellar ataxias please visit the journal online 5 (http:// dx. doi. org/ 10. 1136/ as the most common genetic cause of frontotemporal and myotonic dystrophy, an explanation for this jnnp- 2020- 325377). dementia (FTD) and amyotrophic lateral sclerosis, it has heterogeneity has primarily been sought in repeat increasingly been associated with a wider spectrum length. Studies relating C9orf72 repeat length to 1 Department of Neurology and of phenotypes, including other types of dementia, clinical features have produced inconsistent results, Alzheimer Center, Erasmus movement disorders, psychiatric symptoms and slowly but they have been hampered by technical difficul- University Medical Center, 6–8 Rotterdam, Netherlands progressive FTD. Prompt recognition of patients with ties in detecting and sizing expansions. 2Department of Neuroscience, C9orf72- associated diseases is essential in light of In this review, we present an overview of the Mayo Clinic, Jacksonville, upcoming clinical trials. The striking clinical heterogeneity clinical spectrum associated with C9orf72 repeat Florida, USA associated with C9orf72 repeat expansions remains expansions. We then discuss the role of repeat 3Department of Biology, University of North Florida, largely unexplained. In contrast to other repeat length in relation to the C9orf72 phenotype. Jacksonville, Florida, USA expansion disorders, evidence for an effect of repeat Finally, we provide an in-depth examination of length on phenotype is inconclusive. Patients with the advantages and limitations of current and Correspondence to C9orf72- associated diseases typically have very long novel methods to identify and measure repeat Dr John C. Van Swieten, repeat expansions, containing hundreds to thousands expansions. Neurology, Erasmus Medical of GGGGCC-repeats , but smaller expansions might Center, Rotterdam 3015 GD, Zuid- Holland, The Netherlands; also have clinical significance. The exact threshold at j. c. vanswieten@ erasmusmc. nl which repeat expansions lead to neurodegeneration is GENETICS AND PATHOPHYSIOLOGY OF unknown, and discordant cut- offs between laboratories C9ORF72 REPEAT EXPANSIONS ELvdE and JLJ contributed pose a challenge for genetic counselling. Accurate and equally. The C9orf72 repeat expansion is located in a large- scale measurement of repeat expansions has been MvB and JCVS contributed non- coding region and consists of an expanded equally. severely hindered by technical difficulties in sizing long GGGGCC- repeat. Healthy individuals commonly expansions and by variable repeat lengths across and carry less than 30 repeats, whereas those with Received 14 October 2020 within tissues. Novel long- read sequencing approaches C9orf72- associated diseases usually have several Revised 16 December 2020 have produced promising results and open up avenues 1 2 9 Accepted 23 December 2020 hundreds to thousands of repeats. The exact to further investigate this enthralling repeat expansion, function of the C9orf72 protein is unknown, but it is elucidating whether its length, purity, and methylation thought to play a role in autophagy and endosomal pattern might modulate clinical features of C9orf72- trafficking. Three possibly coexisting disease mech- http://jnnp.bmj.com/ related diseases. anisms have been proposed: (1) haploinsufficiency due to reduced expression of C9orf72 from the expanded allele, (2) formation of repeat-containing INTRODUCTION RNA foci through bidirectional transcription of A repeat expansion in C9orf72 is the most common the expansion and (3) production of aggregation- prone dipeptide repeat (DPR) proteins via repeat- genetic cause of frontotemporal dementia (FTD) on October 1, 2021 by guest. Protected copyright. and amyotrophic lateral sclerosis (ALS) world- associated non- ATG translation. These mechanisms wide.1 2 Besides typical features of FTD and ALS, the have in turn been associated with a wide range of expansion is increasingly associated with a broader downstream cellular defects, such as alterations in range of symptoms, including psychiatric manifes- stress granules, proteostasis, nucleocytoplasmic tations and parkinsonism, and has also been iden- and vesicular transport, mitochondrial function and immunity.10 11 Each disease mechanism alone © Author(s) (or their tified in patients with no known family history for employer(s)) 2021. Re- use neurodegenerative disease.3 4 Early recognition of might not be sufficient to cause neurodegeneration, permitted under CC BY- NC. No C9orf72- related illnesses is becoming increasingly and a synergistic model in which C9orf72 loss- of- commercial re- use. See rights important with the advent of disease-modifying function exacerbates gain- of- function mechanisms and permissions. Published has been proposed. A better understanding of their by BMJ. therapeutic trials. The substantial clinical heterogeneity observed in relative contributions across various disease stages To cite: van der Ende EL, C9orf72 expansion carriers, in terms of phenotype, is essential in order to determine viable treatment Jackson JL, White A, et al. J age at symptom onset and rate of disease progres- targets. Promising therapeutic strategies currently Neurol Neurosurg Psychiatry Epub ahead of print: [please sion, suggests that there are underlying disease being researched include small molecules and include Day Month Year]. modifiers which may serve as prognostic factors gene- silencing tools that inhibit C9orf72 transcrip- doi:10.1136/jnnp-2020- as well as targets for therapeutic interventions. tion, antisense oligonucleotides that bind to and 325377 Drawing on evidence from other neurodegenerative inactivate repeat- containing RNA, antibody- based van der Ende EL, et al. J Neurol Neurosurg Psychiatry 2021;0:1–8. doi:10.1136/jnnp-2020-325377 1 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325377 on 15 January 2021. Downloaded from Neurodegeneration approaches to inhibit accumulation of DPR proteins, and targeting downstream cellular defects.10 11 Box 1 Representative case histories of notable C9orf72 Pathologically, C9orf72- related diseases are characterised by expansion carriers, highlighting the variability in clinical cytoplasmic aggregates of transactive response DNA- binding presentation, age at symptom onset and disease course. protein 43 (TDP-43) and p62- positive neuronal cytoplasmic inclusions containing DPR proteins.1 2 While TDP-43 pathology Case 1 coincides neuroanatomically with affected regions of the central A middle-aged woman was admitted to the psychiatric ward nervous system (CNS) in ALS and FTD, DPR proteins gener- due to severe vital depression and attempted suicide. She had ally do not. Sense and antisense C9orf72 RNA foci are widely experienced a similar episode of depression with psychosis distributed throughout the CNS in affected expansion carriers.10 2 years previously which was unresponsive to antidepressants and eventually treated with electroconvulsive therapy (ECT). Before that time, she had no history of psychiatric disease. Her EPIDEMIOLOGY OF C9ORF72 REPEAT EXPANSIONS mother had exhibited strange social behaviour from her late A C9orf72 expansion is identified in approximately 5%–10% sixties; her maternal grandfather had been diagnosed with of all patients with FTD or ALS, and in up to 30% of patients 4 12 Alzheimer’s disease. Extensive laboratory testing and brain MR with both diseases. Collectively, these diseases are referred to imaging were normal; a fluorodeoxyglucose positron emission as c9FTD/ALS. The prevalence varies strongly between ethnic tomography (FDG-PET) scan revealed bilateral temporal groups: the highest rates are found in Caucasians and the lowest 12 and mesiofrontal hypometabolism compatible with FTD. Her in Asians. The expansion is highly penetrant, with cumulative depression was treated successfully with ECT again, but she percentages of 90.9%–99.5% by the age of 83. The first symp- subsequently suffered progressive cognitive decline and was toms usually manifest themselves in the fifth decade, but age at admitted to a nursing home 5 years after her first episode of onset is highly variable, even within families, and can range from depression. 20 to 90 years.9 13 14 The initial presentation and disease course also vary widely (box 1, table 1); survival after symptom onset Cases 2 and 3 ranges from 2 months in rapidly progressive ALS to over 30 A man in his thirties presented with a 2- year history of word years in slowly progressive behavioural variant FTD (bvFTD).14 finding difficulties and memory complaints. Family members also reported mild behavioural changes. His father had been diagnosed with frontotemporal dementia in his seventies and CLINICAL MANIFESTATIONS OF C9ORF72 REPEAT several paternal relatives had suffered from amyotrophic lateral EXPANSIONS sclerosis (ALS). MRI of the brain demonstrated mild bilateral Cognitive disorders frontotemporal atrophy, and neuropsychological assessment Frontotemporal
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