The analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism

Lucia V Schottlaender,James M Polke,Helen Ling,Nicola D Macdoanld,Arianna Tucci,Tina Nanji,Alan Pittman,Rohan De Silva,Janice L Holton,Tamas Revesz,Mary G Sweeney,Andy B Singleton,Andrew J Lees,Kailash P Bhatia,Henry Houlden

doi:10.1016/j.neurobiolaging.2014.08.024

Abstract

A GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. There is suggestion that these expansions may be a rare cause of parkinsonian disorders such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). Screening the C9orf72 gene in 37 patients with features of corticobasal syndrome (CBS) detected an expansion in 3 patients, confirmed by Southern blotting. In a series of 22 patients with clinically diagnosed PSP, we found 1 patient with an intermediate repeat length. We also screened for the C9orf72 expansion in a large series of neuropathologically confirmed samples with MSA (n = 96), PSP (n = 177), and CBD (n = 18). Patients were found with no more than 22 GGGGCC repeats. Although these results still need to be confirmed in a larger cohort of CBS and/or CBD patients, these data suggest that in the presence of a family history and/or motor neuron disease features, patients with CBS or clinical PSP should be screened for the C9orf72 repeat expansion. In addition, we confirm that the C9orf72 expansions are not associated with pathologically confirmed MSA, PSP, or CBD in a large series of cases.

Highlights

The identification of a GGGGCC repeat expansion in the C9orf72 gene (OMIM *614260) has been an important breakthrough in the diagnosis and understanding of neurodegenerative disorders
A pathologic expansion in C9orf72 was detected in 3 corticobasal syndrome (CBS) patients, representing a significant association when compared with published British controls (p < 0.001) (Beck et al, 2013) (Fig. 1, Table 1)
The 3 patients that carry a large C9orf72 expansion presented with a CBS phenotype classified as probable corticobasal degeneration (CBD) according to consensus criteria

Summary

Introduction

The identification of a GGGGCC repeat expansion in the C9orf gene (OMIM *614260) has been an important breakthrough in the diagnosis and understanding of neurodegenerative disorders. Expansions in this gene have primarily been identified in familial and sporadic amyotrophic lateral sclerosis (ALS; OMIM #105400) and frontotemporal dementia The authors have no actual or potential conflicts of interest. * Corresponding author at: Department of Molecular Neuroscience, UCL Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK. TAR DNA-binding protein-43 and p62 inclusions are present in samples carrying C9orf expansions but our knowledge of the neuropathology associated with this genetic abnormality is expanding (Bieniek et al, 2013; Neumann, 2013)

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