Elsevier

Neurobiology of Aging

Volume 34, Issue 6, June 2013, Pages 1710.e7-1710.e9
Neurobiology of Aging

Genetic reports abstract
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Investigation of C9orf72 repeat expansions in Parkinson's disease

https://doi.org/10.1016/j.neurobiolaging.2012.11.025Get rights and content

Abstract

Large repeat expansions in the C9orf72 gene were recently reported to be a major cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Given some of the clinical and pathologic overlap between these 2 diseases and Parkinson's disease, we sought to evaluate the presence of these expansions in a cohort of French-Canadian patients with Parkinson's disease. No pathologic expansion was found in our cohort of patients suggesting that C9orf72 repeat expansions do not play a major role in the pathogenesis of Parkinson's disease.

Introduction

A large hexanucleotide repeat expansion (GGGGCC) in the first intron of the C9orf72 gene has recently been identified as the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). This discovery ended the search for the genetic cause of chromosome 9p21-linked ALS/FTD (c9ALS/FTD) families and further strengthened the suspected link between these 2 diseases, initially considered as 2 largely separate clinical conditions. It is now believed that ALS and FTD may belong to a single disease spectrum and one of the key shared pathologic features is the presence of ubiquitinated TDP-43 positive inclusion bodies in the central nervous system (Neumann et al., 2006). TDP-43 positive inclusions were also reported in other neurodegenerative disorders, called TDP-43 proteinopathies, including Alzheimer's disease and Parkinson's disease (PD) (Nakashima-Yasuda et al., 2007).

PD is a neurodegenerative disorder characterized by the degeneration of dopamine-producing neurons in the substantia nigra, which results in bradykinesia, truncal and limb muscle rigidity, resting tremor, and postural instability (Dauer and Przedborski, 2003). Lewy bodies (LB) containing α-synuclein found in surviving dopaminergic neurons of the substantia nigra are deemed to be the major pathologic hallmark of this disease.

Given the clinical and pathologic link between ALS/FTD and PD, we investigated whether the hexanucleotide repeat expansion in the C9orf72 gene could be observed in a cohort of patients with PD and consequently be a contributing factor to PD pathogenesis.

Section snippets

Methods

A total of 285 French-Canadian patients with PD were enrolled in this study. A detailed standardized clinical assessment form was completed for each patient. Patients with PD were recruited through movement disorder clinics in Montréal and Québec City (Québec, Canada). Every index case was seen by a neurologist specialized in movement disorders and met the Ward and Gibb criteria for PD. The control cohort comprised 190 unrelated neurologically healthy individuals matched for age and ethnicity.

Results

The clinical description of the cohort of patients with PD is summarized in Table 1. The C9orf72 hexanucleotide repeat was amplified by repeat-primed PCR in 285 patients with PD and 190 controls. Only 1 patient with PD had an atypical sawtooth-like electrophoresis pattern with a 6 bp periodicity, similar to the patterns observed in patients with C9orf72-expanded ALS (Fig. 1A). To further assess the exact size of the repeat expansion in this patient, Southern blot hybridization analysis was

Discussion

The identification of C9orf72 hexanucleotide repeat expansions as a common cause of familial ALS and familial FTD greatly contributed to the merging of these 2 diseases into a common disease spectrum; thus supporting the idea that this expansion may be involved in other neurodegenerative disorders and trigger a broad range of clinical manifestations. This hypothesis has recently been tested as the C9orf72 repeat expansion has been investigated in other neurodegenerative disorders (Majounie

Disclosure statement

The authors declare that they have no conflicts of interest.

References (11)

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    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.

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    The family assessed in our study expands this list with the clinical picture of mild cognitive impairment and slowly progressive dementia over a time frame of >30 years. Of interest is that, according to preliminary studies, the C9ORF72 expansion does not seem to be a major cause of typical schizophrenia [24] and it is rare in idiopathic Parkinson's disease [25,26]. In any case, the frequency of C9ORF72 repeat expansions exceeds that of any other neurodegenerative disease–causing mutation, and is particularly high in Caucasian populations of northern European countries and in North America, where it has already been associated with around 30% of the familial and 7% of sporadic FTLD/ALS cases [27].

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    The mutation was shown to be more frequent in northern Europe with a possible common founder arising several thousand years ago (Majounie et al., 2012b; Smith et al., 2013) and is a much rarer cause for the disease among the Asian population (Alavi et al., 2014; Ishiura et al., 2012; Jang et al., 2013; Jiao et al., 2014; Kim et al., 2014; Konno et al., 2013; Liu et al., 2013; Ogaki et al., 2012). The C9ORF72 repeat expansions were also investigated in other neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, and other motor neuron diseases, however, they were rare and not the main cause of these neurodegenerative disorders (Cacace et al., 2013; Cooper-Knock et al., 2013; Daoud et al., 2013; Fahey et al., 2014; Fenoglio et al., 2014; Galimberti et al., 2014; Harms et al., 2013; Hubers et al., 2014; Huey et al., 2013; Jiao et al., 2013; Lesage et al., 2013; Majounie et al., 2012a; Nuytemans et al., 2013; Rollinson et al., 2012; van Doormaal et al., 2013; Yeh et al., 2013). The C9ORF72 gene is comprised of 12 exons that can be alternatively spliced to produce 3 transcript variants (V1, V2, and V3).

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    Among C9ORF72 RE-bearing subjects of the Mayo Clinic diagnosed with behavioral variant FTD or FTD/ALS, more than 40% had Parkinsonism although none were diagnosed with PD (Boeve et al., 2012). At least 5 studies have screened C9ORF72 REs in typical PD patients (Daoud et al., 2013; Dejesus-Hernandez et al., 2013; Harms et al., 2012; Lesage et al., 2013; Majounie et al., 2012a). Among the 3445 PD patients studied, the repeats were observed in only 3 patients (Lesage et al., 2013).

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