Recent advances in understanding dominant spinocerebellar ataxias from clinical and genetic points of view

Abstract

Spinocerebellar ataxias (SCAs) are rare types of cerebellar ataxia with a dominant mode of inheritance. To date, 47 SCA subtypes have been identified, and the number of genes implicated in SCAs is continually increasing. Polyglutamine (polyQ) expansion diseases ( ATXN1/SCA1, ATXN2/SCA2, ATXN3/SCA3, CACNA1A/SCA6, ATXN7/SCA7, TBP/SCA17, and ATN1/DRPLA) are the most common group of SCAs. No preventive or curative treatments are currently available, but various therapeutic approaches, including RNA-targeting treatments, such as antisense oligonucleotides (ASOs), are being developed. Clinical trials of ASOs in SCA patients are already planned. There is, therefore, a need to identify valid outcome measures for such studies. In this review, we describe recent advances towards identifying appropriate biomarkers, which are essential for monitoring disease progression and treatment efficacy. Neuroimaging biomarkers are the most powerful markers identified to date, making it possible to reduce sample sizes for clinical trials. Changes on brain MRI are already evident at the premanifest stage in SCA1 and SCA2 carriers and are correlated with CAG repeat size. Other potential biomarkers have also been developed, based on neurological examination, oculomotor study, cognitive assessment, and blood and cerebrospinal fluid analysis. Longitudinal studies based on multimodal approaches are required to establish the relationships between parameters and to validate the biomarkers identified.

DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder

“…Whilst the exact pathophysiology of DRPLA is unclear, the literature overall points towards the idea that the expanded polyQ stretch leads to a "gain-of-toxic" function of the mutant protein on neuronal cells [89]. To downregulate the levels of the pathological polyQ proteins, RNA-targeting therapies may hold promise in the treatment of DRPLA, in particular, antisense oligonucleotides (ASO) therapy [16]. Therapeutic ASOs are singlestranded synthetic DNA molecules that work by binding to complementary target mRNA through Watson and Crick hybridization to interfere with normal gene expression and protein synthesis.…”

“…Before clinically meaningful interventions can be discovered, a greater understanding of DRPLA disease progression and the identification of wet biomarkers must be pursued. Despite the significant advancements made for other neurodegenerative diseases, such as HD and AD, biomarkers in biological fluid, such as blood and CSF, have not been found for DRPLA [16]. Potential biomarkers including glial fibrillary acidic protein, DJ-1, and tau have been studied in SCA1, SCA2, and SCA6 patients, where only CSF tau was significantly higher in patients than controls, though levels did not correlate with CAG repeat size and disease severity [9].…”

Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population

“…Cognitive dysfunction, predominantly involving executive ability, visuospatial performance, and memory, has been reported in SCA patients as a result of impairment in subcortical structures and connections between the cerebellum and cerebral cortex (Coarelli et al, 2018;Fancellu et al, 2013). Among the various SCA subtypes, cognitive dysfunction is more common and severe in SCA17 than other subtypes of SCA.…”

“…of specific nonataxic clinical presentations may be regarded as clinical clues to specific subtypes of SCA (Coarelli, Brice, & Durr, 2018;Rossi, Perez-Lloret, Doldan, et al, 2014;Sullivan et al, 2018). For example, slow saccade is frequently identified in patients with SCA2, whereas seizure is more suggestive of SCA10 (Storey, 2016).…”

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

“…Spinocerebellar ataxias (SCAs) represent a group of autosomal dominant cerebellar ataxias (ADCAs) characterized first of all by a progressive ataxia because of the degeneration of the cerebellum and the cerebellar pathways [1][2][3][4][5]. To date, about 47 SCA subtypes have been described, and 35 causal genes have been identified [24]. The prevalence of SCAs is estimated to be 1 to 5 per 100,000 [2,5], but can vary markedly depending on the geography and ethnicity [2,3,5].…”