Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies

doi:10.1016/j.neurobiolaging.2016.08.023

Neurobiology of Aging

Volume 49, January 2017, Pages 214.e13-214.e15

https://doi.org/10.1016/j.neurobiolaging.2016.08.023 Get rights and content

Abstract

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.

Introduction

Hexanucleotide repeat expansions (HREs) in a noncoding region of C9orf72 are recognized as the most common genetic cause of familial and sporadic amyotrophic lateral sclerosis, frontotemporal dementia (FTD), amyotrophic lateral sclerosis-FTD, and Huntington disease phenocopies (Beck et al., 2013; Boeve et al., 2012; Hensman Moss et al., 2014; Majounie et al., 2012c; Simon-Sanchez et al., 2012; van der Zee et al., 2013).

A normal repeat expansion shows 1 to 23 GGGGCC repeats located between exons 1a and 1b of C9orf72 (DeJesus-Hernandez et al., 2011; Renton et al., 2011). HREs identified in several neurodegenerative syndromes were found to range from 500 to 4400 repeats, but on a repeat-primed polymerase chain reaction (PCR), more than 32 repeats are often considered a pathogenic genotype (Beck et al., 2013).

C9orf72 HREs have been identified in nonmotor neurodegenerative phenotypes including Alzheimer's disease (AD) at frequencies of ∼1% (Beck et al., 2013; Harms et al., 2013; Kohli et al., 2013; Majounie et al., 2012b), although conflicting reports exist in the literature (Rollinson et al., 2012; Xi et al., 2012).

Dementia with Lewy bodies (DLB) accounts for 15%–25% of all dementia cases (Heidebrink, 2002). Its core features encompass cognitive impairment, fluctuating attention, parkinsonism, and recurrent visual hallucinations (Weisman and McKeith, 2007). Neuropathological diagnosis of DLB is achieved when the presence of Lewy bodies is confirmed in the cortex and the brainstem (McKeith et al., 2005). Little is known about the genetics of DLB, although molecular studies seem to point toward genetic overlaps with other neurodegenerative diseases, mainly with AD and Parkinson's disease (PD) (Bras et al., 2014; Guerreiro et al., 2016; Keogh et al., 2016; Meeus et al., 2012).

So far, the C9orf72 repeat expansion has only been genotyped in small cohorts of ∼100 DLB cases or less (Geiger et al., 2016; Lesage et al., 2013; Robinson et al., 2014; Snowden et al., 2012; Yeh et al., 2013). We have recently shown in a large cohort that C9orf72 repeat expansions are not a common cause of DLB in pathologically diagnosed cases (Guerreiro et al., 2015). Here, we expand on these findings using a cohort of 1524 DLB cases.

Section snippets

Material and methods

Samples consisted of an international cohort of 1398 neuropathologically diagnosed DLB cases and 126 clinically diagnosed DLB cases (Supplementary Table 1). DNA was extracted from brain tissue for the neuropathologically diagnosed samples and from blood for the clinical diagnosed samples using standard procedures. We performed repeat-primed PCR according to Renton et al. (2011). Genotypes were assessed using Peak Scanner v2.0 (Applied Biosystems) with repeat expansions displaying a

Results

Repeat mean number was 5.17 (±4.30 standard deviation) ranging from 1 to 58. All except 5 samples presented less than 23 repeats in the repeat-primed PCR (Supplementary Fig. 1). Two neuropathologically diagnosed DLB samples showed 32 repeats and 1 showed 33 repeats; and 2 clinically diagnosed samples exhibited 33 and 58 repeats. These last 2 samples had been previously analyzed as part of the cohort published by Snowden et al. (2012).

Discussion

This is the first study genotyping the C9orf72 HREs in a large cohort of mainly neuropathologically diagnosed DLB samples. Within the neuropathologically defined DLB cases, we did not find any HREs above the typical threshold for pathogenicity (∼32 repeats). This is concordant with previous studies that found no repeat expansions in 34 clinically diagnosed cases of a Taiwanese cohort or in 111 pathological DLB cases (Geiger et al., 2016; Yeh et al., 2013). Snowden et al. (2012) found 2 cases

Disclosure statement

Ronald C. Petersen reports consultancies with Roche, Inc, Merck, Inc, Genentech, Inc, Biogen, Inc, and Eli Lilly. Brad F. Boeve reports GE Healthcare, FORUM Pharmaceuticals, and C2N Diagnostics as research support and advisory board member of the Tau Consortium. The remaining authors report no competing interests.

Acknowledgements

This work was supported in part by the National Institutes of Neurological Disease and Stroke . Jose Bras and Rita Guerreiro are supported by fellowships from the Alzheimer's Society. Tatiana Orme is supported by a scholarship from the Lewy Body Society. For the neuropathologically confirmed samples from Australia, tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales. This study was also partially funded by

References (0)

Cited by (15)

Elucidating distinct molecular signatures of Lewy body dementias
2023, Neurobiology of Disease
Dementia with Lewy bodies and Parkinson's disease dementia are common neurodegenerative diseases that share similar neuropathological profiles and spectra of clinical symptoms but are primarily differentiated by the order in which symptoms manifest. The question of whether a distinct molecular pathological profile could distinguish these disorders is yet to be answered. However, in recent years, studies have begun to investigate genomic, epigenomic, transcriptomic and proteomic differences that may differentiate these disorders, providing novel insights in to disease etiology. In this review, we present an overview of the clinical and pathological hallmarks of Lewy body dementias before summarizing relevant research into genetic, epigenetic, transcriptional and protein signatures in these diseases, with a particular interest in those resolving “omic” level changes. We conclude by suggesting future research directions to address current gaps and questions present within the field.
Epigenetic regulation in the pathophysiology of Lewy body dementia
2020, Progress in Neurobiology
Citation Excerpt :
Several other case control studies with small sample sizes, or family studies, have looked at rare gene variants and their association with DLB and PDD. Studies found associations between MAPT variants and DLB while have failed to show associations between ADORA1, LRRK2 mutations or C9orf72 expansions and DLB (Blauwendraat et al., 2017; Geiger et al., 2016a; Heckman et al., 2016, p. 2; Kun-Rodrigues et al., 2017; Snowden et al., 2012). On the other hand a case report identified mutations in ADORA1 in a family with early onset parkinsonism and cognitive dysfunction, however it appears that the cognitive difficulties of the affected family members were related to neurodevelopmental deficits and not dementia (Jaberi et al., 2016)
Lewy body dementia encompasses both dementia with Lewy bodies and Parkinson’s disease dementia. Although both are common causes of dementia, they remain relatively understudied. The review summarises the clinico-pathologic characteristics of Lewy Body dementia and discusses the genetic and environmental evidence contributing to the risk of developing the condition. Considering that the pathophysiology of Lewy body dementia is not yet fully understood, here we focus on the role of epigenetic mechanisms as potential key mediators of gene–environment interactions in the development of the disease. We examine available important data on genomics, epigenomics, gene expression and proteomic studies in Lewy body dementia on human post-mortem brain and peripheral tissues. Genetic variation and epigenetic modifications in key genes involved in the disorder, such as apolipoprotein E (APOE), α-synuclein (SNCA) and glucocerobrosidase (GBA), suggest a central involvement of epigenetics in DLB but conclusive evidence is scarce. This is due to limitations of existing literature, such as small sample sizes, lack of replication and lack of studies interrogating cell-type specific epigenetic modifications in the brain. Future research in the field can improve the understanding of this common but complex and rapidly progressing type of dementia and potentially open early diagnostic and effective therapeutic targets.
Parkinsonism in frontotemporal dementias
2019, International Review of Neurobiology
Citation Excerpt :
But, the third patient developed left hemi-parkinsonism at age 29 with rest tremor, akinesia, rigidity and dystonia and dopamine agonists were only partially effective. Based on screening of large research or clinical cohorts of patients with clinically diagnosed Parkinson's disease, most groups have suggested that C9orf72 is not a cause of Parkinson's disease: none of 781 US Caucasians with IPD (Majounie et al., 2012); 135 Swedish patients (Akimoto et al., 2013); 676 US Caucasians (Dejesus-Hernandez et al., 2013); none of 478 US patients (Harms et al., 2013) (although 3/662 controls did); none of 285 French-Canadian IPD patients (Daoud et al., 2013); in Italy, none of 190 cases (Ticozzi et al., 2014); none of 619 patients with PD in China (Chen et al., 2016); and none of 1398 neuropathologically diagnosed DLB (Kun-Rodrigues et al., 2017) and none of 488 autopsy-confirmed IPD cases (Nuytemans et al., 2014). Collating IPD cases, just 4 of 7232 cases had >50 G4C2 repeats (Theuns et al., 2014), each with a positive family history of dementia, amyotrophic lateral sclerosis, or atypical parkinsonism.
Frontotemporal dementia is a clinically and pathologically heterogeneous group of neurodegenerative disorders, with progressive impairment of behavior and language. They can be closely related to amyotrophic lateral sclerosis, clinically and through shared genetics and similar pathology. Approximately 40% of people with frontotemporal dementia report a family history of dementia, motor neuron disease or parkinsonism, and half of these familial cases are attributed to mutations in three genes (C9orf72, MAPT and PGRN). Akinetic-rigidity is a common feature in several types of frontotemporal dementia, particularly the behavioral variant and the non-fluent agrammatic variant of primary progressive aphasia, and the familial dementias. The majority of patients develop a degree of parkinsonism during the course of the illness, and signs may be present at the time of initial diagnosis. However, the parkinsonism of frontotemporal dementia is very different from that observed in idiopathic Parkinson's disease: it may be symmetric, axial, and poorly responsive to levodopa. Tremor is uncommon, and may be postural, action or occasionally rest tremor. The emergence of parkinsonism is often part of an evolving phenotype, in which frontotemporal dementia comes to resemble corticobasal syndrome or progressive supranuclear palsy. This chapter describes the prevalence and phenomenology of parkinsonism in each of the major syndromes, and according to the common genetic forms of frontotemporal dementia. We discuss the changing nosology and terminology surrounding the diagnoses, and the significance of parkinsonism as a core feature of frontotemporal dementia, relevant to clinical management and the design of future clinical trials.
Are dementia with lewy bodies and parkinson's disease dementia the same disease?
2023, Advances in Surgical and Medical Specialties
Mechanisms of neurodegeneration in various forms of parkinsonism—similarities and differences
2021, Cells
C9orf72-associated frontotemporal dementia in the Russian population
2020, Zhurnal Nevrologii i Psihiatrii imeni S.S. Korsakova

View all citing articles on Scopus

View full text

Genetic report abstractNegative resultsAnalysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies