Identification of FXTAS presenting with SCA 12 like phenotype in India

Faruq, Mohammed; Srivastava, Achal Kumar; Suroliya, Varun; Kumar, Deepak; Garg, Ajay; Shukla, Geeta; Behari, Madhuri

doi:10.1016/j.parkreldis.2014.07.001

Cited by 10 publications

(7 citation statements)

References 12 publications

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“…Rodriguez-Revenga et al, 2007;Seixas et al, 2005;Zühlke et al, 2004). However, two other SCA screenings found slightly higher PM frequencies of 4.1 and 5.1%, respectively (Macpherson, Waghorn, & Hammans, 2003;Van Esch et al, 2005), and another screening found an even higher frequency of 9% PM carriers who had a SCA12-like phenotype (Faruq et al, 2014). Of the studies in populations not yet genetically tested for the SCAs, three found no PM carriers (Kerber, Jen, & Perlman, 2005;Kraft, Furtado, & Ranawaya, 2005;Tan et al, 2004), and frequencies of the premutation were consistently low in two other cerebellar ataxia screenings, at 1.1 and 2.1%, respectively (Cellini et al, 2006;Wardle et al, 2009).…”

Section: E Case Reportsmentioning

confidence: 97%

“…Screening studies for cerebellar ataxia in patients with suspected SCA or MSA identified 32 PM carriers (Biancalana, Toft, & Le Ber, 2005;Brussino, Gellera, & Saluto, 2005;Cellini, Forleo, & Ginestroni, 2006;Faruq, Srivastava, & Suroliya, 2014;Kamm et al, 2005;L. Rodriguez-Revenga, Gómez-Anson, & Muñoz, 2007;Seixas, Maurer, & Lin, 2005;Seixas et al, 2011;Van Esch, Dom, & Bex, 2005;Wardle, Majounie, & Muzaimi, 2009;Zühlke et al, 2004).…”

Section: E Case Reportsmentioning

confidence: 99%

“…One exception is SCA12, which is the only SCA for which kinetic tremor is the presenting sign and most frequent symptom (Pulst, 2003). Given that the tremor in SCA12 may resemble the tremor of FXTAS, there is the potential for FXTAS tremor to be mistaken as SCA12 (Faruq et al, 2014). However, SCA12 has a very low prevalence rate, except in Northern India where it causes 7% of the dominant ataxias (E. Storey & Billimoria, 2005).…”

Section: G Comparison Between Fxtas and Sca And Msamentioning

confidence: 99%

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Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders

Robertson

Hall

McAsey

et al. 2016

The Clinical Neuropsychologist

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Section: E Case Reportsmentioning

confidence: 97%

Section: E Case Reportsmentioning

confidence: 99%

Section: G Comparison Between Fxtas and Sca And Msamentioning

confidence: 99%

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Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders

Robertson

Hall

McAsey

et al. 2016

The Clinical Neuropsychologist

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“…In a recent screening study in India of a cohort with progressive, late‐onset tremor/ataxia (109 patients and 173 control subjects), three premutation alleles were detected among the patient group; two of these individuals (96 and 102 CGG repeats) were being evaluated for SCA (spinocerebellar ataxia)‐12 and another (78 CGG repeats) for progressive gait ataxia. The frequency of FXTAS was 3.3% overall and 9% (2/23 cases) for SCA‐12–like presentation, underscoring the need to screen cases of apparent (test‐negative) SCA.…”

Section: Approaches To Treatment Of Fxtasmentioning

confidence: 99%

Fragile X–associated tremor/ataxia syndrome

Hagerman

2015

Annals of the New York Academy of Sciences

135

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some but not all carriers of small, non-coding CGG-repeat expansions (55–200 repeats; premutation) within the fragile X gene (FMR1). Principal features of FXTAS include intention tremor, cerebellar ataxia, Parkinsonism, memory and executive function deficits, autonomic dysfunction, brain atrophy with white matter disease, and cognitive decline. Although FXTAS was originally considered to be confined to the premutation range, rare individuals with a gray zone (45 to 54 repeats) or an unmethylated full mutation (>200 repeats) allele have now been described; the constant feature of the disorder remaining the requirement for FMR1 expression, in contradistinction to the gene silencing mechanism of fragile X syndrome. Although transcriptional activity is required for FXTAS pathogenesis, the specific trigger(s) for FXTAS pathogenesis remains elusive, highlighting the need for more research in this area. This need is underscored by recent neuroimaging findings of changes in the central nervous system that consistently appear well before the onset of clinical symptoms, thus creating an opportunity to delay or prevent the appearance of FXTAS.

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“…At the phenotypic level SCA12 is closely connected with other neurodegenerative disorders like Spinocerebellar ataxia type 1-3 & 17, Huntington's disease and Parkinson's disease. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), which is also considered a phenocopy of SCA12, is caused by TNR expansion of CGG repeats in the 5'UTR of FMR1, resulting into RNA toxicity (Hagerman, 2013;Faruq et al, 2014). RNA mediated toxicity has been implicated in many TNR diseases caused by repeat expansion either in the coding or non-coding region (Krzyzosiak et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Dynamics of a non-coding trinucleotide repeat expansion disorder SCA12 in iPSC derived neuronal cells: signatures of interferon induced response

Kumar

Dhapola

et al. 2017

Preprint

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Abstract:Spinocerebellar ataxia type-12 (SCA12) is a neurological disorder that exhibits a unique progressive tremor/ataxia syndrome induced by triplet (CAG) repeat expansion in 5' UTR of PPP2R2B. SCA12 is one of the most prominent SCA-subtype in India and till date no appropriate disease models have been described. Our aim was to establish human iPSC derived neuronal cell lines of SCA12 and study transcriptomic level alterations induced by CAG expansion. For translational application, peripheral blood transcriptomics of SCA12 patients was also performed. Lymphoblastoid cell lines of three SCA12 patients were reprogrammed to iPSCs and then re-differentiated into pan-neuronal lineage. RNAsequencing based comparative transcriptomics was performed for disease and control cell lineages. Microarray based transcriptomic profiling of peripheral blood of SCA12 patients was performed in a case/control (n=15/9) design. We have successfully created human neuronal cell lines of SCA12 patient as exhibited by their molecular profiling. Differential expression analysis of RNA-Seq data has shown enrichment for type-I interferon signaling and other relevant cellular processes in SCA12-neurons. At the splice-isoform level, we observed an upregulation of expanded CAG containing non-coding transcript of PPP2R2B.Peripheral blood transcriptomics analysis and targeted validation of RNA-Seq data has allowed us to identify inflammatory signatures as potential markers of molecular pathology in SCA12. Our study has allowed us to establish first iPSC based neuronal cell lines of SCA12.We have identified pro-inflammatory signatures in SCA12-neurons suggestive of a dsRNA mediated activation of interferon signaling and that corroborates with the emerging evidence of neuronal atrophy due to neuro-inflammation in common neurodegenerative diseases. This study involved development of an iPSCs derived neuronal cells of SCA12 and look through signatures of neurodegeneration by whole RNA sequencing. This model sheds light upon key role of RNA mediated induced response in Interferon signaling for neurodegeneration.peer-reviewed)

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Identification of FXTAS presenting with SCA 12 like phenotype in India

Cited by 10 publications

References 12 publications

Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders

Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders

Fragile X–associated tremor/ataxia syndrome

Transcriptomic Dynamics of a non-coding trinucleotide repeat expansion disorder SCA12 in iPSC derived neuronal cells: signatures of interferon induced response

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