Atypical parkinsonism in C9orf72 expansions: a case report and systematic review of 45 cases from the literature

Wilke, Carlo; Pomper, Jörn K.; Biskup, Saskia; Puskás, C.; Berg, Daniela; Synofzik, Matthis

doi:10.1007/s00415-016-8021-7

Cited by 37 publications

(35 citation statements)

References 56 publications

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“…Why C9 causes some people to get pure ALS or FTD or a mixture of both is a mystery. Further complicating matters, C9 has also been associated with Parkinson's disease (PD) (Wilke et al 2016) and schizophrenia (Galimberti et al 2014), and neuronal loss and gliosis have been described quite broadly throughout the brain and spinal cord in C9 ALS (Cooper-Knock et al 2014).…”

Section: Rna-centric Mechanisms In C9orf72 Als-ftdmentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

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Section: Rna-centric Mechanisms In C9orf72 Als-ftdmentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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“…We identified a few cases reported either separately or as part of larger cohorts. The phenotypes include corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) The characteristics and results of studies on smaller or larger cohorts of patients with atypical parkinsonism are presented in Table .…”

Section: Resultsmentioning

confidence: 99%

“…In most instances, authors were very cautious to suggest genetic testing for C9orf72 , especially for typical PD cases. Overall, the most commonly reported features that increased the possibility of positive C9orf72 testing in patients with typical or atypical parkinsonism included early cognitive and/or behavioral symptoms, positive family history of ALS or FTD or other neurodegenerative syndromes, and the presence of UMN and LMN signs …”

Section: Resultsmentioning

confidence: 99%

“…A few reports presented radiographic features of patients with parkinsonism that carry the C9orf72 expansion. A systematic review concluded that cerebral atrophy is the most commonly reported imaging finding (90%), including frontotemporal atrophy in 53% of the cases, temporal atrophy (37%), parietal atrophy (13%), and generalized cerebral atrophy (30%) …”

Section: Resultsmentioning

confidence: 99%

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

Bourinaris

Houlden

2018

Movement Disord Clin Pract

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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.

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“…One clear example of this is the occurrence of repeat expansions in the C9ORF72 locus that increase risk for both amyotrophic lateral sclerosis and fronto-temporal dementia. C9ORF72 repeat expansion have also been identified in a low percentage of cases with Alzheimer diagnosis (Harms et al, 2013) and in cases with atypical Parkinsonism (Wilke et al, 2016) and in cases with corticobasal syndrome.…”

Section: Neurodegenerative Diseases Risk Factors Revealed Through Gementioning

confidence: 99%

DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously

Smith

2017

Front. Mol. Biosci.

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Delineation of underlying genomic and genetic factors in a specific disease may be valuable in establishing a definitive diagnosis and may guide patient management and counseling. In addition, genetic information may be useful in identification of at risk family members. Gene mapping and initial genome sequencing data enabled the development of microarrays to analyze genomic variants. The goal of this review is to consider different generations of sequencing techniques and their application to exome sequencing and whole genome sequencing and their clinical applications. In recent decades, exome sequencing has primarily been used in patient studies. Discussed in some detail, are important measures that have been developed to standardize variant calling and to assess pathogenicity of variants. Examples of cases where exome sequencing has facilitated diagnosis and led to improved medical management are presented. Whole genome sequencing and its clinical relevance are presented particularly in the context of analysis of nucleotide and structural genomic variants in large population studies and in certain patient cohorts. Applications involving analysis of cell free DNA in maternal blood for prenatal diagnosis of specific autosomal trisomies are reviewed. Applications of DNA sequencing to diagnosis and therapeutics of cancer are presented. Also discussed are important recent diagnostic applications of DNA sequencing in cancer, including analysis of tumor derived cell free DNA and exosomes that are present in body fluids. Insights gained into underlying pathogenetic mechanisms of certain complex common diseases, including schizophrenia, macular degeneration, neurodegenerative disease are presented. The relevance of different types of variants, rare, uncommon, and common to disease pathogenesis, and the continuum of causality, are addressed. Pharmogenetic variants detected by DNA sequence analysis are gaining in importance and are particularly relevant to personalized and precision medicine.

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Atypical parkinsonism in C9orf72 expansions: a case report and systematic review of 45 cases from the literature

Cited by 37 publications

References 56 publications

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

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

DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously

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