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Review
. 2018 Nov 8;5(6):575-585.
doi: 10.1002/mdc3.12677. eCollection 2018 Nov-Dec.

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature

Thomas Bourinaris  1 , Henry Houlden  1
Affiliations
Review

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature

Thomas Bourinaris et al. Mov Disord Clin Pract. .

Abstract

Background: The C9orf72 hexanucleotide expansion is one of the latest discovered repeat expansion disorders related to neurodegeneration. Its association with the FTD/ALS spectrum disorders is well established, and it is considered to be one of the leading related genes. It has also been reported as a possible cause of several other phenotypes, including parkinsonism and other movement disorders. Its significance, though outside the FTD/ALS spectrum, is not well defined.

Methods: A comprehensive search of the literature was performed. All relevant papers, including reviews and case series/reports on movement disorder phenotypes reported with the C9orf72 repeat expansion, were reviewed. Data on frequency, natural history, phenotype, genetics, and possible underlying mechanisms were assessed.

Results and discussion: In a number of studies, C9orf72 accounts for a small fraction of typical PD. Atypical parkinsonian syndromes, including CBS, PSP, and MSA have also been reported. Features that increase the probability of positive testing include early cognitive and/or behavioral symptoms, positive family history of ALS or FTD, and the presence of UMN and LMN signs. Furthermore, several studies conclude that C9orf72 is the most common cause of HD-phenocopies. Interestingly, many cases with the parkinsonian phenotype that bear an intermediate range of repeats are also reported, questioning the direct causal role of C9orf72 and suggesting the possibility of being a susceptibility factor, while the presence of the expansion in normal controls questions its clinical significance. Finally, studies on pathology reveal a distinctive broad range of C9orf72-related neurodegeneration that could explain the wide phenotypic variation.

Keywords: C9orf72; Parkinson's disease; movement disorders; parkinsonism; repeat expansion disorders.

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Figures

Figure 1
Figure 1
Calculated frequencies of C9orf72 expansion carriers based on aggregate data of reviewed studies. Frequency and number of cases for ALS and FTD as reported elsewhere (see text).
See this image and copyright information in PMC

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