Spinocerebellar ataxia: relationship between phenotype and genotype – a review

Sun, Yi‐Min; Lü, Chuan-Zhen; Wu, Zhi‐Ying

doi:10.1111/cge.12808

Cited by 121 publications

(102 citation statements)

References 121 publications

(177 reference statements)

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“…Common symptoms associated with SCA are ataxic gait, osculomotor disorders, dysarthria and cognitive impairment, which can ultimately cause death. Over 20 types of SCAs have been identified based on genetic descriptions [131–133]. An expansion of repeated CAG trinucleotides accounts for the major pathogenic mutation in SCA [132].…”

Section: Oxidative Stress In Spinocerebellar Ataxia Diseasementioning

confidence: 99%

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications

Liu

Zhou

Ziegler

et al. 2017

Oxidative Medicine and Cellular Longevity

649

472

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Increasing numbers of individuals, particularly the elderly, suffer from neurodegenerative disorders. These diseases are normally characterized by progressive loss of neuron cells and compromised motor or cognitive function. Previous studies have proposed that the overproduction of reactive oxygen species (ROS) may have complex roles in promoting the disease development. Research has shown that neuron cells are particularly vulnerable to oxidative damage due to their high polyunsaturated fatty acid content in membranes, high oxygen consumption, and weak antioxidant defense. However, the exact molecular pathogenesis of neurodegeneration related to the disturbance of redox balance remains unclear. Novel antioxidants have shown great potential in mediating disease phenotypes and could be an area of interest for further research. In this review, we provide an updated discussion on the roles of ROS in the pathological mechanisms of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia, as well as a highlight on the antioxidant-based therapies for alleviating disease severity.

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Section: Oxidative Stress In Spinocerebellar Ataxia Diseasementioning

confidence: 99%

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications

Liu

Zhou

Ziegler

et al. 2017

Oxidative Medicine and Cellular Longevity

649

472

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“…More than 40 SCA subtypes have been reported, and 34 genes have been identified so far. Three main categories are defined on the basis of the mutation type,4 namely those due to CAG‐coding polyglutamine repeat expansion, noncoding repeat expansions, and conventional mutations (http://neuromuscular.wustl.edu/ataxia/domatax.html). …”

mentioning

confidence: 99%

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

Manes

Alberici

Gregorio

et al. 2017

Annals of Neurology

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ObjectiveSpinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.MethodsWe enrolled 10 SCA38 patients, and carried out a double‐blind randomized placebo‐controlled study for 16 weeks, followed by an open‐label study with overall 40‐week DHA treatment. At baseline and at follow‐up visit, patients underwent standardized clinical assessment, brain 18‐fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis.ResultsAfter 16 weeks, we showed a significant pre–post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40‐week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients’ blood at 40 weeks as compared to baseline. No side effect was recorded.InterpretationDHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615–621

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“…This classification system was introduced by AE Harding in 1982 to account for the varying degree of heterogeneity between the dominantly inherited ataxias [42]. Although, the classification is somewhat out-dated due to the genetically classified SCA system used in the present day, it is of some benefit to mention, as the system broadly classifies all ADCA into three discrete categories [43,44]. These categories were created on the basis of separating dominant ataxias by their complex phenotypes of ataxic and non-ataxic clinical manifestations; termed ADCA type I, II and III (Table 1) [42,45].…”

Section: Autosomal Dominant Cerebellar Ataxia (Adca) Type Classificationmentioning

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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Spinocerebellar ataxia: relationship between phenotype and genotype – a review

Cited by 121 publications

References 121 publications

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

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

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