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

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.

C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease

“…In addition to ALS and FTD, the C9orf72 gene expansion mutation has been linked with other neurodegenerative and psychiatric disorders, although etiological roles remain unknown [118][119][120][121][122][123]. We have shown that SMCR8, whose cellular levels positively correlate with C9orf72 protein expression, associates not only with many factors of protein metabolism and stress granule dynamics, but also with numerous products of genes linked with a range CNS disorders (65/340 in total, Table 2).…”

An update on genetic frontotemporal dementia

“…PPA is a rare phenotype but is usually a nonfluent variant when present, and similarly parkinsonian disorders can occur but are infrequent as a presenting syndrome. Also unlike the other genetic groups, hyperkinetic movement disorders may occur, and C9orf72 is said to be associated with a Huntington’s disease-like phenotype on some occasions [29].…”

Interrelation between Sarcopenia and the Number of Motor Neurons in Patients with Parkinsonian Syndromes

“…This hypothesis was first introduced 1995 by Uitti et al [9] as “neurodegenerative overlap syndrome” in patients presenting with multiple symptoms from the spectrum of iPD, motor neuron diseases, and Alzheimer disease. Some of the cases mentioned may, however, fall into one of the more recently developed diagnoses, such as PSP and C9ORF72 gene carriers [21, 22]. Nevertheless, the concept is still referred to today; it has been extended to include neurogenic sarcopenia and describes the role of motor unit loss in the onset of sarcopenia [4].…”