Spinocerebellar ataxia: an update

Sullivan, Roisin; Yau, Wai Yan; O’Connor, Emer; Houlden, Henry

doi:10.1007/s00415-018-9076-4

Cited by 219 publications

(190 citation statements)

References 132 publications

(99 reference statements)

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“…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).…”

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confidence: 99%

Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population

et al. 2019

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Background Spinocerebellar ataxia (SCA) presents with variable clinical presentations in addition to ataxia. The aim of this study was to reappraise the diverse nonataxic clinical characteristics of the five most common SCA subtypes in the Asian population. Methods The clinical presentations of 90 patients with genetically confirmed SCA1, SCA2, SCA3, SCA6, or SCA17 were assessed retrospectively between November 2008 and September 2018 at a tertiary referral center in Taiwan. Results Parkinsonism was the most common nonataxic phenotype (21.1%), with a greater prevalence than Caucasian and other Asian SCA carriers. Patients with parkinsonism feature had fewer CAG repeats in SCA2 (31.0 ± 4.5 vs. 36.9 ± 6.0, p = .03) and SCA3 (65.6 ± 7.9 vs. 70.0 ± 4.2, p = .02) compared to those with pure ataxia presentation. The average age of symptom onset was significantly higher in the parkinsonism group of SCA2 (51.5 ± 8.9 vs. 35.3 ± 12.6 years, p = .007) than those with pure ataxia. Focal or segmental dystonia was identified in 4.4% of SCA patients (n = 2 each SCA2 and SCA3). Nonmotor symptoms, including impaired cognition (6.1% of SCA2 and 8.3% of SCA3 patients) and depression (9.1% of SCA2 and 8.3% of SCA3 patients), were also common nonataxic features in our SCA patients. Conclusions Parkinsonism, dystonia, and cognitive‐psychiatric symptoms are common features in patients with SCA mutations in our population. Our study identifies a different clinical spectrum of SCA1, SCA2, SCA3, SCA6, and SCA17 compared to Caucasians.

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confidence: 99%

Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population

et al. 2019

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“…In the ataxias more broadly, numerous diagnostic procedures such as MRI, nerve conduction studies and cognitive testing are performed, in part to inform diagnostic genetic testing. However our experience, and globally, is that despite these extensive investigations, a diagnosis is only achieved in at best ~30% of cases [27][28][29]. The diagnostic journey is long (up to 20 years) and often unsuccessful.…”

Section: Discussionmentioning

confidence: 99%

Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data

Rafehi

Szmulewicz

Pope

et al. 2019

Preprint

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Background: Spinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats (STRs). Recent methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. Objectives: To determine the genetic basis of ataxia in a large, multigenerational Australian pedigree, with autosomal dominant inheritance and possible anticipation. Methods and Results: WGS was performed on three affected relatives. The sequence data was screened for known pathogenic REs using three repeat expansion detection tools: exSTRa, ExpansionHunter and GangSTR. This screen provided a clear and rapid diagnosis (<5 days from receiving the sequencing data) of SCA36, a very rare form of ataxia which is caused by an intronic hexanucleotide GGCCTG RE in NOP56. Conclusions:We have demonstrated that diagnosis of rare ataxias caused by REs is highly feasible and cost effective with WGS. We propose a change in current clinical practice, such that WGS be implemented as the frontline, cost effective methodology for molecular testing of individuals with a clinical diagnosis of ataxia.

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“…In gain-of-function disorders, the main purpose is to decrease the mutated mRNA expression by use of single-stranded ASOs, by blocking translation or by a direct silencing effect [111]. In particular ASOs bind complementary mRNA using Watson-Crick hybridization; this process leads to RNase H enzymes recruitment [112]. In SCA3 fibroblasts the removal of central 88 amino-acid region of the ataxin-3 protein was realized with ASOs [112].…”

Section: Polyglutaminopathiesmentioning

confidence: 99%

“…In particular ASOs bind complementary mRNA using Watson-Crick hybridization; this process leads to RNase H enzymes recruitment [112]. In SCA3 fibroblasts the removal of central 88 amino-acid region of the ataxin-3 protein was realized with ASOs [112]. In a mouse model of SCA2 the administration of intrathecal ASOs decreased the levels of the mutated protein, improving the firing of Purkinje neurons as well as motor tasks [113].…”

Section: Polyglutaminopathiesmentioning

confidence: 99%

Recent Advances in the Treatment of Cerebellar Disorders

2019

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Various etiopathologies affect the cerebellum, resulting in the development of cerebellar ataxias (CAs), a heterogeneous group of disorders characterized clinically by movement incoordination, affective dysregulation, and cognitive dysmetria. Recent progress in clinical and basic research has opened the door of the ‘‘era of therapy” of CAs. The therapeutic rationale of cerebellar diseases takes into account the capacity of the cerebellum to compensate for pathology and restoration, which is collectively termed cerebellar reserve. In general, treatments of CAs are classified into two categories: cause-cure treatments, aimed at arresting disease progression, and neuromodulation therapies, aimed at potentiating cerebellar reserve. Both forms of therapies should be introduced as soon as possible, at a time where cerebellar reserve is still preserved. Clinical studies have established evidence-based cause-cure treatments for metabolic and immune-mediated CAs. Elaborate protocols of rehabilitation and non-invasive cerebellar stimulation facilitate cerebellar reserve, leading to recovery in the case of controllable pathologies (metabolic and immune-mediated CAs) and delay of disease progression in the case of uncontrollable pathologies (degenerative CAs). Furthermore, recent advances in molecular biology have encouraged the development of new forms of therapies: the molecular targeting therapy, which manipulates impaired RNA or proteins, and the neurotransplantation therapy, which delays cell degeneration and facilitates compensatory functions. The present review focuses on the therapeutic rationales of these recently developed therapeutic modalities, highlighting the underlying pathogenesis.

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Spinocerebellar ataxia: an update

Cited by 219 publications

References 132 publications

Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population

Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population

Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data

Recent Advances in the Treatment of Cerebellar Disorders

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