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"Ataxia"
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The inherited cerebellar ataxias: an update
This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis strategies and recent therapeutic developments. Initial approach facing a patient with cerebellar ataxia requires family medical history, physical examination, exclusions of acquired causes and genetic analysis, including Next-Generation Sequencing (NGS). To guide diagnosis, several algorithms and a new genetic nomenclature for recessive cerebellar ataxias have been proposed. The challenge of NGS analysis is the identification of causative variant, trio analysis being usually the most appropriate option. Public genomic databases as well as pathogenicity prediction software facilitate the interpretation of NGS results. We also report on key clinical points for the diagnosis of the main ICAs, including Friedreich ataxia, CANVAS, polyglutamine spinocerebellar ataxias, Fragile X-associated tremor/ataxia syndrome. Rarer forms should not be neglected because of diagnostic biomarkers availability, disease-modifying treatments, or associated susceptibility to malignancy. Diagnostic difficulties arise from allelic and phenotypic heterogeneity as well as from the possibility for one gene to be associated with both dominant and recessive inheritance. To complicate the phenotype, cerebellar cognitive affective syndrome can be associated with some subtypes of cerebellar ataxia. Lastly, we describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.
Journal Article
Cellular functions of the protein kinase ATM and their relevance to human disease
The protein kinase ataxia telangiectasia mutated (ATM) is a master regulator of double-strand DNA break (DSB) signalling and stress responses. For three decades, ATM has been investigated extensively to elucidate its roles in the DNA damage response (DDR) and in the pathogenesis of ataxia telangiectasia (A-T), a human neurodegenerative disease caused by loss of ATM. Although hundreds of proteins have been identified as ATM phosphorylation targets and many important roles for this kinase have been identified, it is still unclear how ATM deficiency leads to the early-onset cerebellar degeneration that is common in all individuals with A-T. Recent studies suggest the existence of links between ATM deficiency and other cerebellum-specific neurological disorders, as well as the existence of broader similarities with more common neurodegenerative disorders. In this Review, we discuss recent structural insights into ATM regulation, and possible aetiologies of A-T phenotypes, including reactive oxygen species, mitochondrial dysfunction, alterations in transcription, R-loop metabolism and alternative splicing, defects in cellular proteostasis and metabolism, and potential pathogenic roles for hyper-poly(ADP-ribosyl)ation.Deficiency in the protein kinase ATM — a master regulator of double-strand DNA breaks and stress responses — causes ataxia telangiectasia (A-T). Recent studies link A-T with other neurodegenerative disorders, and implicate reactive oxygen species, mitochondrial dysfunction, defects in proteostasis and metabolism, and increased poly(ADP-ribosyl)ation in the aetiology of A-T.
Journal Article
The Autosomal Recessive Cerebellar Ataxias
Autosomal recessive cerebellar ataxia must be considered in any child or young adult with a progressive disorder of gait or balance or with hypotonia or excessive clumsiness. This review presents a practical approach to these neurodegenerative diseases.
The autosomal recessive cerebellar ataxias are a group of little known and often neglected diseases that are best understood by following a practical, multidisciplinary approach that focuses on clinical rather than molecular considerations. This review focuses on the main forms in which cerebellar ataxia is a prominent sign. It does not attempt to revisit all of the ataxias of this type. Cerebellar ataxia (from the Greek words “a,” meaning “not,” and “taxis,” meaning “order”) is characterized by an incoordination of movement and unsteadiness (see Video 1, available with the full text of this article at NEJM.org) due to cerebellar dysfunction. . . .
Journal Article
3604 Levodopa responsive parkinsonism in Spinocerebellar ataxia 27B
BackgroundSpinocerebellar ataxia type 27B (SCA27B) is a recently characterised cause of individuals presenting with late onset cerebellar ataxia. It is a rare autosomal dominant neurodegenerative disorder caused by mutations in the Fibroblast Growth Factor 14 (FGF14) gene. Here, we present a case of late onset cerebellar ataxia with associated Parkinsonism that is responsive to levodopa.CaseA 65 year-old female presents with a progressive deterioration in her gait secondary to truncal ataxia since the age of 62 years. Throughout the course of her illness, she developed asymmetrical parkinsonism, bowel and bladder incontinence, and had a background of parasomnias preceding her presentation and also a family history of late onset parkinsonism and early onset cognitive impairment. Brain magnetic resonance imaging revealed atrophy of the midbrain, PONS, and middle cerebellar peduncles. Genetic testing confirmed a pathogenic triplet repeat within the FGF14 gene consistent with a diagnosis of SCA27B. Levodopa was commenced for her parkinsonism, with improvement in the speed and amplitude of her movements, and restoration of partial independence. On discharge, fampridine was introduced to support continued functional restoration.ConclusionSCA27B should be considered in individuals presenting with late onset ataxia, and may mimic alternate neurodegenerative conditions. This case report demonstrates that associated parkinsonism may be responsive to levodopa.
Journal Article
Spanish Translation and Pilot Validation of the Scale for the Assessment and Rating of Ataxia (SARA)
Introduction: Ataxias are a heterogeneous group of disorders with multiple etiologies. Despite the existence of several rating scales, no validated Spanish version of the SARA scale has been available. Given that more than 480 million people worldwide are Spanish speakers, the absence of such a tool represents a gap in clinical practice and research. Methods:The SARA scale was translated and cross-culturally adapted following ITC guidelines. A pilot test was conducted in 13 patients with genetically confirmed (n=11) or immune-mediated (n=2) ataxia. Internal consistency was assessed using Cronbach’s alpha, and external validity was evaluated against Barthel index, disease stage, and disease duration. Results:The Spanish version of SARA showed good internal consistency (Cronbach’s alpha = 0.87). A significant negative correlation with Barthel index (r=-0.94, p<0.01) and a positive correlation with disease stage (r=0.921, p<0.01) were observed. Correlation with disease duration was weak and not significant (r=0.55, p=0.51). Discussion:This pilot study demonstrates the feasibility of a Spanish adaptation of SARA, aligning with results from international validations (Portuguese, Japanese, Chinese, French). Although preliminary, these findings suggest that this tool may provide a reliable measure for clinical and research purposes in Spanish-speaking populations. We generated a Spanish version of the SARA scale with promising preliminary results in terms of reliability and validity. Further multicenter studies with larger cohorts are warranted to confirm its definitive validation.
Journal Article
The neurological update: therapies for cerebellar ataxias in 2020
Cerebellar ataxias (CAs) represent a heterogeneous group of sporadic or inherited disorders. The clinical spectrum of CAs is continuously expanding. Our understanding of the mechanisms leading to the clinical deficits has improved over these last decades, in particular thanks to progress in genetics, neuroimaging and the advent of relevant animal models allowing the identification of the pathophysiological pathways leading to CAs. The rationale behind treatments is now established for most of the CAs encountered during daily practice worldwide. In this update, we will discuss the symptomatic, physical and occupational therapies now being trialled along with individualized exercises, and present key emerging issues on immune-mediated cerebellar ataxias, hereditary cerebellar ataxias. Finally, we will discuss novel therapeutic approaches, including cerebellar non-invasive stimulation and treatments acting on RNA/proteins. So far, no state-of-the art randomized placebo-controlled clinical trial has shown a convincing clinically relevant efficacy of any drug, with the exception of 4-aminopyridine for the symptomatic treatment of episodic ataxia type 2 and downbeat nystagmus (placebo-controlled trials).
Journal Article
Spinocerebellar ataxia 27B: a frequent and slowly progressive autosomal-dominant cerebellar ataxia—experience from an Italian cohort
Background
Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in
FGF14
(SCA27B) is a recent, relatively common form of late-onset ataxia.
Objective
Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies.
Methods
We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases.
Results
In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment.
Conclusion
Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies.
Journal Article
How to distinguish spinocerebellar ataxia 27B from late onset cerebellar ataxia: insights from a case–control study
Background
Spinocerebellar ataxia 27B is the most common genetic late onset cerebellar ataxia (LOCA). However, it commonly overlaps with other genetic LOCA as with the cerebellar form of multiple system atrophy (MSA-C).
Objectives
To pinpoint which clinical signs and symptoms best discriminate between
FGF14
+ from
FGF14
− patients at symptoms’ onset.
Methods
Twenty SCA27B (≥ 250 GAA repeat expansion) patients were retrospectively matched by gender and age at disease onset with 20 negative
FGF14
(−) LOCA patients and with 20 MSA-C patients. Clinical features were ranked based on their contribution towards distinguishing between the groups (feature importance ranking).
Results
SCA27B patients had significantly higher rates of episodic symptoms, cerebellar oculomotor signs, dysdiadochokinesia, and alcohol intolerance than LOCA-
FGF14
− ataxia patients. The lack of autonomic symptoms and MRI signs in SCA27B patients were the most discriminating features from MSA-C. An AUC of 0.87 was obtained if using the “top 3 clinical features model” (episodic symptoms, cerebellar oculomotor signs and dysdiadochokinesia) to distinguish SCAB27 from LCOA
FGF14
− . Regarding MRI findings, no significant differences were found between SCA27B and
FGF14
− patients, while a positive hot cross buns sign and the presence of brainstem atrophy were key distinguishing features between SCA27B from MSA-C patients (
p
< 0.005).
Conclusion
Our pilot case–control study contributes to the identification of early clinical symptoms to differentiate SCA27B to LOCA patients including
FGF14
- and MSA-C ones. From a feature perspective, while clinical features are crucial, identifying surrogate biomarkers—such as ocular or gait parameters—could aid in the early diagnosis and follow-up of SCA27B patients.
Journal Article
Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia
In this study, a large repeat expansion in a noncoding part of
FGF14
was found to cause late-onset cerebellar ataxia, which underscores the importance of noncoding regions in the search for causes of disease.
Journal Article