SCA-LSVD: A repeat-oriented locus-specific variation database for genotype to phenotype correlations in spinocerebellar ataxias

Faruq, Mohammed; Scaria, Vinod; Singh, Inder; Tyagi, Shivani; Srivastava, Achal K.; Mukerji, Mitali

doi:10.1002/humu.21006

Cited by 28 publications

(13 citation statements)

References 58 publications

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“…These findings are to some extent similar to data reported from Italy, where SCA1 and SCA2 are by far the commonest SCAs in contrast to SCA3 and SCA6, which are very rare [7]. SCA3 also seems to be rare in India, where SCA6 is virtually absent [8]. SCA6 is also only rarely found in Spain and France [9,10].…”

Section: Discussionsupporting

confidence: 89%

Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia

Pemble

Sweeney

Paudel³

et al. 2012

Journal of the Neurological Sciences

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The relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. No data exist at present on the frequency of different SCAs in the Greek population. In the present study we investigated the presence of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in a cohort of 83 Greek patients with slowly progressive cerebellar ataxia. Twenty patients came from autosomal dominant (AD) pedigrees, seven displayed recessive or unclear inheritance and 56 were sporadic. We found four patients with pathological SCA expansions, all from AD pedigrees. Two patients had SCA1, one SCA2 and one SCA7 (10.0, 5.0 and 5.0% of the AD group, respectively). The clinical features of these patients were within the expected spectrum. In total, a pathological expansion was detected in 20% of patients from AD pedigrees. Interestingly, no cases of SCA3 or SCA6 were detected in the AD group. No expansions were found in other familial cases or in sporadic patients. Overall, no cases of SCA3, SCA6, SCA12, SCA17 or DRPLA were identified in the Greek population. In conclusion, SCA1, SCA2 and SCA7 are present in Greek patients with AD cerebellar ataxia in frequencies similar to those observed in other populations. SCA3 and SCA6 appear however to be rare in Greece. The genetic cause for the majority of AD ataxias remains to be identified.

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Section: Discussionsupporting

confidence: 89%

Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia

Pemble

Sweeney

Paudel³

et al. 2012

Journal of the Neurological Sciences

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“…The disease is progressive and patients become dependent on others within a few years of onset. SCA-2 is among the three (with SCA3 and SCA6) most frequent types of SCAs worldwide [1,7,8,] whereas it has been reported as the most common SCA phenotype in India [9,10,11,12]. …”

Section: Introductionmentioning

confidence: 99%

Quantitative Profiling and Identification of Plasma Proteins of Spinocerebellar Ataxia Type 2 Patients

Swarup

Srivastava²,

Padma³

et al. 2013

Neurodegener Dis

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Background: Spinocerebellar ataxia type 2 (SCA2) is an autosomal-dominant hereditary ataxia characterized by progressive gait and limb ataxia, dysarthria, slow saccades, neuropathy and dementia. The expansion of trinucleotide CAG repeats in the coding region of the ATXN-2 gene leads to expanded polyglutamine stretch in the mutated protein which causes neuronal death. Objective: In this study, we investigated the blood plasma of SCA2 patients to find protein biomarkers. Methods: Thirty-two ataxia patients clinically suspected for SCA2 were evaluated by the International Co-operative Ataxia Rating Scale followed by genetic analysis using PCR. Plasma proteomics of SCA2 patients and age- and gender-matched healthy controls was done using 2D-difference in-gel electrophoresis, LC-MS/MS and Western blot. Results: Genetic analysis confirmed 10 of 32 suspected SCA2 patients. Proteomic data revealed nine differentially expressed proteins in SCA2. These proteins find good association with oxidative stress, calcium-dependent apoptosis, neuropathy, and cognitive impairment in SCA2 patients. Interestingly, the elevated levels of the voltage-dependent calcium channel γ-3 subunit showed a direct correlation with calcium-generated apoptosis of Purkinje cells. The cognitive deficit, a common symptom in SCA2 patients, seems to correlate with decreased levels of transthyretin and retinol-binding protein-4. Conclusions: Some of these identified proteins in SCA2 can be useful for therapeutic, diagnostic and prognostic purposes.

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“…Several geographically localised studies have been conducted on the prevalence of ADCAs, with the focus on the six SCA diseases. With regards to SCA3, the prevalence is at its highest in Brazil (69% of SCA cases), Portugal (58%) and China (49%) and relatively low in USA (21%), India (3%) and Italy (1%) [77,[79][80][81][82][83]. An interesting case is the founder effect of SCA7 in South Africa, where this disease represents 26.6% of SCA diseases [84], a figure that is significantly higher than the 2% occurrence worldwide [78].…”

Section: Prevalence and Incidencementioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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SCA-LSVD: A repeat-oriented locus-specific variation database for genotype to phenotype correlations in spinocerebellar ataxias

Cited by 28 publications

References 58 publications

Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia

Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia

Quantitative Profiling and Identification of Plasma Proteins of Spinocerebellar Ataxia Type 2 Patients

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

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