<i>C9orf72</i> repeat expansions as genetic modifiers for depression in spinocerebellar ataxias

Figueroa, Karla P.; Gan, Shi Rui; Perlman, Susan; Wilmot, George; Gómez, Christopher M.; Schmahmann, Jeremy D.; Paulson, Henry L.; Shakkottai, Vikram G.; Ying, Sarah H.; Zesiewicz, Theresa; Bushara, Khalaf; Geschwind, Michael D.; Xia, Guangbin; Subramony, S. H.; Ashizawa, Tetsuo; Pulst, Stefan M.; Kuo, Sheng Han

doi:10.1002/mds.27258

Cited by 5 publications

(5 citation statements)

References 7 publications

(9 reference statements)

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“…The possibility that the C9orf72 hexanucleotide expansion could interact with other repeat expansion disorders, including the CAG expansions disorders of several SCA genes and HD, possibly altering the phenotypic expression of either condition, has been suggested in some papers . This finding could mean that C9orf72 expansion, either in the pathogenic or in the intermediate size of repeat units, could act as a genetic modifier of other repeat expansion disorders and vice versa.…”

Section: Resultsmentioning

confidence: 99%

“…79 A study on genetically confirmed SCA patients identified seven cases with concomitant C9orf72 hexanucleotide expansions within the pathogenic range, defined as >30 repeat units, in a cohort of 277 patients diagnosed with pathogenic CAG expansions in SCA1, SCA2, SCA3, and SCA6. 80 All were reported to have various degrees of motor neuron signs, but none had ALS. The same study reported that 40% of the patients had intermediate expansions in C9orf72 and studied their phenotype.…”

Section: Prevalence Of C9orf72 In Other Movement Disordersmentioning

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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Section: Resultsmentioning

confidence: 99%

Section: Prevalence Of C9orf72 In Other Movement Disordersmentioning

confidence: 99%

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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“…Specifically, clinical presentations of tremor and dystonia could be influenced by the repeat expansions outside of the pathological SCA allele ( 17 , 18 ). We also recently identified that the pathological repeat expansions of C9orf72 occur in a small subset of SCA patients, and the intermediate repeat expansions of C9orf72 can be a genetic modifier for depressive symptoms ( 22 ), further underscoring the importance of repeat interactions. Another discovery related to genetic modifiers is that ethnicity can play a role in SCA disease progression ( 23 ).…”

Section: Crc-scamentioning

confidence: 94%

Collaborative Efforts for Spinocerebellar Ataxia Research in the United States: CRC-SCA and READISCA

2020

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Spinocerebellar ataxias are progressive neurodegenerative disorders primarily affecting the cerebellum. Although the first disease-causing gene was identified nearly 30 years ago, there is no known cure to date, and only a few options exist for symptomatic treatment, with modest effects. The recently developed tools in molecular biology, such as CRISPR/Cas9 and antisense oligonucleotides, can directly act on the disease mechanisms at the genomic or RNA level in disease models. In a nutshell, we are finally just one step away from clinical trials with therapies targeting the underlying genetic cause. However, we still face the challenges for rare neurodegenerative diseases: difficulty in obtaining a large cohort size for sufficient statistical power and the need for biomarkers and clinical outcome assessments (COA) with adequate sensitivity to reflect progression or treatment responses. To overcome these obstacles, ataxia experts form research networks for clinical trial readiness. In this review, we retrace our steps of the collaborative efforts among ataxia researchers in the United States over the years to study and treat these relentless disorders and the future directions of such research networks.

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“…171,172 SCA3 patients often have dystonia, depression, restless leg syndrome, and levodopa-responsive parkinsonism. 197,198 SCA6 patients are classically considered "pure ataxia" without extra-cerebellar symptoms, and SCA7 patients invariably have vision loss due to macular degeneration. SCA17 patients have complex symptoms, including dementia, chorea, and dystonia.…”

Section: Autosomal Dominant Cerebellar Ataxiasmentioning

confidence: 99%

Ataxias: Hereditary, Acquired, and Reversible Etiologies

Lin

Kuo

2023

Semin Neurol

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A variety of etiologies can cause cerebellar dysfunction, leading to ataxia symptoms. Therefore, the accurate diagnosis of the cause for cerebellar ataxia can be challenging. A step-wise investigation will reveal underlying causes, including nutritional, toxin, immune-mediated, genetic, and degenerative disorders. Recent advances in genetics have identified new genes for both autosomal dominant and autosomal recessive ataxias, and new therapies are on the horizon for targeting specific biological pathways. New diagnostic criteria for degenerative ataxias have been proposed, specifically for multiple system atrophy, which will have a broad impact on the future clinical research in ataxia. In this article, we aim to provide a review focus on symptoms, laboratory testing, neuroimaging, and genetic testing for the diagnosis of cerebellar ataxia causes, with a special emphasis on recent advances. Strategies for the management of cerebellar ataxia is also discussed.

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C9orf72 repeat expansions as genetic modifiers for depression in spinocerebellar ataxias

Cited by 5 publications

References 7 publications

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

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

Collaborative Efforts for Spinocerebellar Ataxia Research in the United States: CRC-SCA and READISCA

Ataxias: Hereditary, Acquired, and Reversible Etiologies

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