Common Spinocerebellar Ataxias Research Articles

Diagnosis of hereditary ataxias: a real-world single center experience.

This study aims to evaluate our experience in the diagnosis of hereditary ataxias (HAs), to analyze data from a real-world scenario. This is a retrospective, cross-sectional, descriptive study conducted at a single Italian adult neurogenetic outpatient clinic, in 147 patients affected by ataxia with a suspicion of hereditary forms, recruited from November 1999 to February 2024. A stepwise approach for molecular diagnostics was applied: targeted gene panel (TP) next-generation sequencing (NGS) and/or clinical exome sequencing (CES) were performed in the case of inconclusive first-line genetic testing, such as short tandem repeat expansions (TREs) testing for most common spinocerebellar ataxias (SCA1-3, 6-8,12,17, DRPLA), other forms [Fragile X-associated tremor/ataxia syndrome (FXTAS), Friedreich ataxia (FRDA) and mitochondrial DNA-related ataxia, RFC1-related ataxia/CANVAS] or inconclusive phenotype-guided specific single gene sequencing. A definitive diagnosis was reached in 36.7% of the cases. TREs testing was diagnostic in 30.4% of patients. The three most common TREs ataxias were FRDA (36.1%), SCA2 (27.8%), and RFC1-related ataxia/CANVAS (11.1%). In five patients, the molecular diagnosis was achieved by single gene sequencing and causative mutations were identified in POLG (2), SACS (1), DARS2 (1), MT-ATP6 (1). Of 94 patients with a suspicion of HAs of indeterminate genetic origin, 68 underwent new molecular evaluation using the NGS approach. In 28 of these cases, CES was performed after the TP sequencing resulted negative. In 13 patients, the diagnosis was achieved by NGS approach. In 7 of these 13 patients, the diagnosis was made by CES. Genes mutations identified as causative of HAs were found in SPG7 (4), SACS (1), CACNA1A (1), CACNA1G (1), EEF2 (1), PRKCG (1), KCNC3 (1), ADCK3 (1), SYNE1 (1), ITPR1 (1). A positive family history of ataxia and early onset of symptoms were associated with a higher likelihood of obtaining a definite diagnosis. The molecular diagnosis of HAs remains a significant challenge for neurologists. Our data indicate that, in most cases, a diagnosis of HA can be established through first line genetic testing, particularly TREs testing. However, for patients with a clinical diagnosis of HA who do not achieve a molecular diagnosis through initial genetic tests, the use of NGS proves to be a valuable tool, providing a definitive diagnosis in approximately 20% of cases. Therefore, when feasible in clinical practice, integrating NGS testing, especially exome sequencing, into the diagnostic decision-making process for unsolved cases is crucial.

F-Wave Features in Most Common Chinese Spinocerebellar Ataxias.

The use of F-wave study may help to gain insight into electrophysiological significance of spinocerebellar Ataxias (SCAs). Particularly, the difference of F-wave features between Chinese SCA1, SCA2 and SCA3 patients were scarcely reported. 20 SCA1, 20 SCA2, 46 SCA3 patients and 30 healthy controls underwent nerve (median, ulnar, tibial) conduction and F-wave studies, and electrophysiology parameters were compared between them. Clinical data including ataxia and non-ataxia features was recorded. The study revealed peripheral neuropathological involvement in 80% of SCA1, 100% of SCA2, and 50% of SCA3 Chinese patients. Most patients of all subtypes presented with sensory neuropathy, and F-wave changes. We observed that SCA1 patients had prolonged F-wave latency as well as increased maximum F-wave amplitude and F/M amplitude ratio compared to controls for the first time. Besides, SCA2 patients had decreased F-wave persistence as well as increased maximum F-wave amplitude, F/M amplitude ratio and frequency of giant F-wave. The maximum amplitude of SCA1 correlated positively with disease severity and disease duration. The value of F/M amplitude ratio of SCA2 correlated positively with disease duration. In all subtypes, F-wave of the tibial nerve was the most sensitive measurement index. This study exhibits F-wave characteristics and inter-group differences of the most common Chinese SCAs. F-wave may be a potential biomarker for evaluating the progression of SCAs.

Global and Regional Brain Grey and White Matter Morphometry Alterations in Type 1, 2, and 3 Spinocerebellar Ataxias (SCAs) Patients.

Spinocerebellar ataxias (SCAs) types 1, 2, and 3 are the most common subtypes of SCAs. However, the atrophy patterns of these three subtypes still need to be fully clarified. In this study, a total of 130 genetically confirmed SCA patients (SCA1: n = 16; SCA2: n = 13; symptomatic SCA3: n = 76; pre-symptomatic SCA3: n = 25) along with 65 age- and sex-matched healthy controls (HCs) were enrolled. MR volumetric analysis was used to explore the different atrophied patterns in these three SCA subtypes and the associations between significant morphometry alterations and clinical variables were further analyzed. Compared with HCs, the global brain grey matter (GM) of the three SCA subtypes and white matter (WM) volumes of the SCA2 and SCA3 were significantly reduced. SCA2 had significantly more severe GM volume atrophy than symptomatic SCA3. For local GM and WM volumes, all three subtypes of SCA have significant atrophy in infra- and supratentorial areas than HCs. The pre-symptomatic SCA3 patients had already demonstrated substantial WM atrophy. The SCAs subgroup comparisons showed that compared with symptomatic SCA3, SCA1 and SCA2 demonstrated more severe atrophy in regions of the cerebral and cerebellum, but symptomatic SCA3 had significantly atrophied bilateral lenticular nuclei. Besides, no significant difference was found in the local GM or WM volume between SCA1 and SCA2. Furthermore, some affected GM and WM regions, especially the damaged cerebellar peduncles, showed significant correlations with disease duration and severity in SCA1 and symptomatic SCA3. Our research results indicate differences in MRI brain injury patterns among common SCA subtypes, which might shed light on the deeper understanding of the pathophysiological mechanisms of SCAs.

Spinocerebellar Ataxias: Phenotypic Spectrum of PolyQ versus Non-Repeat Expansion Forms

Spinocerebellar ataxias (SCA) are most frequently due to (CAG)n (coding for polyglutamine, polyQ) expansions and, less so, to expansion of other oligonucleotide repeats (non-polyQ) or other type of variants (non-repeat expansion SCA). In this study we compared polyQ and non-repeat expansion SCA, in a cohort of patients with hereditary ataxia followed at a tertiary hospital. From a prospective study, 88 patients (51 families) with SCA were selected, 74 (40 families) of whom genetically diagnosed. Thirty-eight patients (51.4%, 19 families) were confirmed as having a polyQ (no other repeat-expansions were identified) and 36 (48.6%, 21 families) a non-repeat expansion SCA. Median age-at-onset was 39.5 [30.0-45.5] for polyQ and 7.0 years [1.00-21.50] for non-repeat expansion SCA. PolyQ SCA were associated with cerebellar onset, and non-repeat expansion forms with non-cerebellar onset. Time to diagnosis was longer for non-repeat expansion SCA. The most common polyQ SCA were Machado-Joseph disease (MJD/SCA3) (73.7%) and SCA2 (15.8%); whereas in non-repeat expansion SCA ATX-CACNA1A (14.3%), ATP1A3-related ataxia, ATX-ITPR1, ATX/HSP-KCNA2, and ATX-PRKCG (9.5% each) predominated. Disease duration (up to inclusion) was significantly higher in non-repeat expansion SCA, but the difference in SARA score was not statistically significant. Cerebellar peduncles and pons atrophy were more common in polyQ ataxias, as was axonal neuropathy. SCA had a wide range of genetic etiology, age-at-onset and presentation. Proportion of polyQ and non-repeat expansion SCA was similar; the latter had a higher genetic heterogeneity. While polyQ ataxias were typically linked to cerebellar onset in adulthood, non-repeat expansion forms associated with early onset and non-cerebellar presentations.

Cross-Sectional Analysis of Exome Sequencing Diagnosis in Patients With Neurologic Phenotypes Facing Barriers to Clinical Testing.

Exome sequencing (ES) demonstrates a 20-50 percent diagnostic yield for patients with a suspected monogenic neurologic disease. Despite the proven efficacy in achieving a diagnosis for such patients, multiple barriers for obtaining exome sequencing remain. This study set out to assess the efficacy of ES in patients with primary neurologic phenotypes who were appropriate candidates for testing but had been unable to pursue clinical testing. A total of 297 patients were identified from the UCLA Clinical Neurogenomics Research Center Biobank, and ES was performed, including bioinformatic assessment of copy number variation and repeat expansions. Information regarding demographics, clinical indication for ES, and reason for not pursuing ES clinically were recorded. To assess diagnostic efficacy, variants were interpreted by a multidisciplinary team of clinicians, bioinformaticians, and genetic counselors in accordance with the American College of Medical Genetics and Genomics variant classification guidelines. We next examined the specific barriers to testing for these patients, including how frequently insurance-related barriers such as coverage denials and inadequate coverage of cost were obstacles to pursuing exome sequencing. The cohort primarily consisted of patients with sporadic conditions (n = 126, 42.4%) of adult-onset (n = 239, 80.5%). Cerebellar ataxia (n = 225, 75.8%) was the most common presenting neurologic phenotype. Our study found that in this population of mostly adult patients with primary neurologic phenotypes that were unable to pursue exome sequencing clinically, 47 (15.8%) had diagnostic results while an additional 24 patients (8.1%) had uncertain results. Of the 297 patients, 206 were initially recommended for clinical exome but 88 (42.7%) could not pursue ES because of insurance barriers, of whom 14 (15.9%) had diagnostic findings, representing 29.8% of all patients with diagnostic findings. In addition, the incorporation of bioinformatic repeat expansion testing was valuable, identifying a total of 8 pathogenic repeat expansions (17.0% of all diagnostic findings) including 3 of the common spinocerebellar ataxias and 2 patients with Huntington disease. These findings underscore the importance and value of clinical ES as a diagnostic tool for neurogenetic disease and highlight key barriers that prevent patients from receiving important clinical information with potential treatment and psychosocial implications for patients and family members.

Early-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China.

Essential tremor (ET) is a neurological disease characterized by action tremor in upper arms. Although its high heritability and prevalence worldwide, its etiology and association with other diseases are still unknown. We investigated 10 common spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA36, dentatorubral-pallidoluysian atrophy (DRPLA) in 92 early-onset familial ET pedigrees in China collected from 2016 to 2022. We found one SCA12 proband carried 51 CAG repeats within PPP2R2B gene and one SCA3 proband with intermediate CAG repeats (55) with ATXN3 gene. The other 90 ET probands all had normal repeat expansions. Tremor can be the initial phenotype of certain SCA. For early-onset, familial ET patients, careful physical examinations are needed before genetic SCA screening.

Disease progression of spinocerebellar ataxia types 1, 2, 3 and 6 before and after ataxia onset.

Our aim was to study the evolution of ataxia and neurological symptoms before and after ataxia onset in the most common spinocerebellar ataxias (SCAs), SCA1, SCA2, SCA3 and SCA6. We therefore jointly analysed the data of the EUROSCA and RISCA studies, which recruited ataxic and non-ataxic mutation carriers. We used mixed effect models to analyse the evolution of Scale for the Rating and Assessment of Ataxia (SARA) scores, SCA Functional Index (SCAFI) and Inventory of Non-Ataxia Signs (INAS) counts. We applied multivariable modelling to identify factors associated with SARA progression. In the time interval 5 years prior to and after ataxia onset, we calculated sensitivity to change ratios (SCS) of SARA, SCAFI and INAS. 2740 visits of 677 participants were analysed. All measures showed non-linear progression that was best fitted by linear mixed models with linear, quadratic and cubic time effects. R2 values indicating quality of the fit ranged from 0.70 to 0.97. CAG repeat was associated with faster progression in SCA1, SCA2 and SCA3, but not SCA6. 5 years prior to and after ataxia onset, SARA had the highest SCS of all measures with a mean of 1.21 (95% CI: 1.20, 1.21) in SCA1, 0.94 (0.93, 0.94) in SCA2 and 1.23 (1.22, 1.23) in SCA3. Our data have important implications for the understanding of disease progression in SCA1, SCA2, SCA3 and SCA6 across the lifespan. Furthermore, our study provides information for the design of interventional trials, especially in pre-ataxic mutation carriers close to ataxia onset and patients in early disease stages.

SCAview: an Intuitive Visual Approach to the Integrative Analysis of Clinical Data in Spinocerebellar Ataxias

With SCAview, we present a prompt and comprehensive tool that enables scientists to browse large datasets of the most common spinocerebellar ataxias intuitively and without technical effort. Basic concept is a visualization of data, with a graphical handling and filtering to select and define subgroups and their comparison. Several plot types to visualize all data points resulting from the selected attributes are provided. The underlying synthetic cohort is based on clinical data from five different European and US longitudinal multicenter cohorts in spinocerebellar ataxia type 1, 2, 3, and 6 (SCA1, 2, 3, and 6) comprising > 1400 patients with overall > 5500 visits. First, we developed a common data model to integrate the clinical, demographic, and characterizing data of each source cohort. Second, the available datasets from each cohort were mapped onto the data model. Third, we created a synthetic cohort based on the cleaned dataset. With SCAview, we demonstrate the feasibility of mapping cohort data from different sources onto a common data model. The resulting browser-based visualization tool with a thoroughly graphical handling of the data offers researchers the unique possibility to visualize relationships and distributions of clinical data, to define subgroups and to further investigate them without any technical effort. Access to SCAview can be requested via the Ataxia Global Initiative and is free of charge.

Demographics and Clinical Characteristics of Autosomal Dominant Spinocerebellar Ataxia in Canada.

Autosomal dominant (AD) spinocerebellar ataxias (SCAs) encompass a large group of rare disorders, which occurs in individuals of different ethnic backgrounds. To date, demographics, and clinical descriptions of AD SCA in Canada are lacking. A retrospective chart review of patients with a genetically confirmed diagnosis of AD SCAs was performed at five tertiary centers across Canada in the provinces of Quebec, Alberta, and Ontario. Demographic, genetic, and clinical information were collected and analyzed. A total of 203 patients with AD SCA were identified. Weighted estimated prevalence of AD SCA in three large Canadian provinces was calculated (2.25 cases per 100.000) which is in keeping with the figures documented worldwide. We found that the distribution of the most common SCA differed when comparing provinces. The most prevalent SCA diagnosis in Ontario was SCA3 (49%), while the most prevalent SCA diagnosis in Alberta and Quebec was SCA2 in26% and 47%, respectively. SCA6 was the third most prevalent SCA subtype in Quebec (14%), which was not seen as commonly in other provinces. SCA1 was uncommonly seen in both Alberta and Quebec, despite being common in Ontario. In this largest Canadian study, we describe the prevalence, distribution, and clinical characteristics of AD SCA. We found that the distribution of the most common SCA differed in the three provinces studied. This finding reflects the heterogenous nature of the Canadian population.

Primena magnetne rezonancije u dijagnostici najčešćih spinocerebelarnih ataksija

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominant ataxias characterized by a dominantly progressive evolution of the cerebellar syndrome and other extra-cerebellar symptoms and signs. Today there are approximately 40 genetic SCAs and this review aims to describe the clinical picture and magnetic resonance imaging (MRI) findings of the most common SCA subtypes in Europe and Serbia. This is a group of polyglutamine diseases caused by mutations resulting from the expansion of the CAG repeats and accompanied by the loss of neural volume mainly of the cerebellum and the spinal cord. Magnetic resonance has a vital role in the diagnosis since it excludes structural damage as one of the potential causes of ataxia. In addition to this, the loss of volume, as demonstrated by MRI, serves as a biomarker that helps to monitor the natural progression of different subtypes of the disease. Typical findings in these MRI scans include cortico-cerebellar atrophy, spinal cord atrophy, olivopontocerebellar atrophy, and different combinations of the said atrophies. Unfortunately, there are no distinct pathognomonic MRI signs or combinations of signs to facilitate diagnosis. There are, however, similarities in the MRI findings of some of the SCA subtypes, especially at disease onset. The ability to differentiate one pattern of atrophy from another and observe other clinical characteristics can have an important role and can be of significant help in the diagnostic process.

CerebNet: A fast and reliable deep-learning pipeline for detailed cerebellum sub-segmentation

Quantifying the volume of the cerebellum and its lobes is of profound interest in various neurodegenerative and acquired diseases. Especially for the most common spinocerebellar ataxias (SCA), for which the first antisense oligonculeotide-base gene silencing trial has recently started, there is an urgent need for quantitative, sensitive imaging markers at pre-symptomatic stages for stratification and treatment assessment. This work introduces CerebNet, a fully automated, extensively validated, deep learning method for the lobular segmentation of the cerebellum, including the separation of gray and white matter. For training, validation, and testing, T1-weighted images from 30 participants were manually annotated into cerebellar lobules and vermal sub-segments, as well as cerebellar white matter. CerebNet combines FastSurferCNN, a UNet-based 2.5D segmentation network, with extensive data augmentation, e.g. realistic non-linear deformations to increase the anatomical variety, eliminating additional preprocessing steps, such as spatial normalization or bias field correction. CerebNet demonstrates a high accuracy (on average 0.87 Dice and 1.742mm Robust Hausdorff Distance across all structures) outperforming state-of-the-art approaches. Furthermore, it shows high test-retest reliability (average ICC >0.97 on OASIS and Kirby) as well as high sensitivity to disease effects, including the pre-ataxic stage of spinocerebellar ataxia type 3 (SCA3). CerebNet is compatible with FreeSurfer and FastSurfer and can analyze a 3D volume within seconds on a consumer GPU in an end-to-end fashion, thus providing an efficient and validated solution for assessing cerebellum sub-structure volumes. We make CerebNet available as source-code (https://github.com/Deep-MI/FastSurfer).

Single-Tube Screen for Rapid Detection of Repeat Expansions in Seven Common Spinocerebellar Ataxias.

The autosomal dominantly inherited and genetically heterogeneous spinocerebellar ataxias (SCAs) exhibit highly similar clinical presentations. Many are caused by repeat expansions, of which at least 8 involve CAG repeats. Repeat expansion detection is the only method to confirm disease status in symptomatic individuals. We present a novel strategy to simultaneously screen for the presence of CAG repeat expansion in the genes responsible for SCAs 1, 2, 3, 6, 7, 12, and dentatorubral-pallidoluysian atrophy using a simplified single-tube assay. The method employs differentially labeled locus-specific primers and a common triplet-primed primer. Amplified products from each locus are distinguished by a combination of the product size and the fluorophore tag. The upper size limit of the normal allele range was used as the cutoff for distinguishing normal from potentially affected samples, with repeat expansion detected by presence of electrophoretic peaks extending beyond the cutoff. Blinded evaluation of the assay on 60 genotype-known DNA samples correctly detected repeat expansion in the expected SCA repeat locus for all 31 DNA samples. In principle, this strategy can be applied to the simultaneous screening of any group of disease genes sharing the same repetitive units and/or their reverse complement.

Prevalence of Fragile X-Associated Tremor/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan

The presence of fragile X mental retardation 1 (FMR1) premutation has been linked to patients with a certain type of cerebellar ataxia, the fragile X-associated tremor/ataxia syndrome (FXTAS). However, its prevalence in Japan has yet to be clarified. The aim of the present study is to determine the prevalence of FXTAS in Japanese patients with cerebellar ataxia and to describe their clinical characteristics. DNA samples were collected from 1328 Japanese patients with cerebellar ataxia, referred for genetic diagnosis. Among them, 995 patients with negative results for the most common spinocerebellar ataxia subtypes were screened for FMR1 premutation. Comprehensive clinical and radiological analyses were performed for the patients harbouring FMR1 premutation. We herein identified FMR1 premutation from one female and two male patients, who satisfied both clinical and radiological criteria of FXTAS (0.3%; 3/995) as well. Both male patients presented with high signal intensity of corticomedullary junction on diffusion-weighted magnetic resonance imaging, a finding comparable to that of neuronal intranuclear inclusion disease. The female patient mimicked multiple system atrophy in the early stages of her disease and developed aseptic meningitis with a suspected immune-mediated mechanism after the onset of FXTAS, which made her unique. Despite the lower prevalence rate in Japan than the previous reports in other countries, the present study emphasises the necessity to consider FXTAS with undiagnosed ataxia, regardless of men or women, particularly for those cases presenting with similar clinical and radiological findings with multiple system atrophy or neuronal intranuclear inclusion disease.

Molecular spectrum, family screening and genetic counselling of Spinocerebellar Ataxia (SCA) cases in an Indian scenario

Spinocerebellar Ataxia (SCA) is a heterogeneous adult-onset disorder with an autosomal dominant inheritance pattern mainly caused by triplet repeat expansions. Clinical diagnosis of SCA is based on phenotypic features followed by confirmation through molecular diagnosis. To identify status of repeat range in Indian SCA cases and provide extended family screening, we enrolled 70 clinical SCA suspects. For molecular diagnosis, multiplex PCR (M-PCR) was used for common Indian SCA subtypes 1, 2, 3, 6, 7, 10, 12 and 17. TP-PCR was further used in SCA2, 7 and 10 to identify larger expansions. Eighteen out of 70 SCA suspects (25%) were found to be positive for various SCA subtypes- (5 SCA1 (28%), 6 SAC2 (34%), 2 SCA3 (12%), 3 SCA7 (16%) and one each for SCA6 (1%) and SCA17 (1%) subtypes). Genetic counselling and extended family screening were offered to all positive cases and yielded additional nine cases. We have established M-PCR and TP-PCR to detect the CAG repeat expansion in SCA suspects. This method can confirm SCA subtypes in a reliable, rapid and cost-effective way. Genetic characterization of SCA-related genes has great clinical relevance, as it could provide additional information and guidance to clinicians and family members regarding prognosis.

Evidence and practices of the use of next generation sequencing in patients with undiagnosed autosomal dominant cerebellar ataxias: a review.

Autosomal dominant cerebellar ataxias (ADCA) are heterogeneous diseases with a highly variable phenotype and genotype. They can be divided into episodic ataxia and spinocerebellar ataxia (SCA); the latter is considered the prototype of the ADCA. Most of the ADCA are caused by polyglutamine expansions, mainly SCA 1, 2, 3, 6, 7, 17 and Dentatorubral-pallidoluysian atrophy (DRPLA). However, 30% of patients remain undiagnosed after testing for these most common SCA. Recently, several studies have demonstrated that the new generation of sequencing methods are useful for the diagnose of these patients. This review focus on searching evidence on the literature, its usefulness in clinical practice and future perspectives.

Ophthalmic Manifestations and Genetics of the Polyglutamine Autosomal Dominant Spinocerebellar Ataxias: A Review.

Spinocerebellar ataxia (SCA) is a part of the cerebellar neurodegenerative disease group that is diverse in genetics and phenotypes. It usually shows autosomal dominant inheritance. SCAs, always together with the cerebellar degeneration, may exhibit clinical deficits in brainstem or eye, especially retina or optic nerve. Interestingly, autosomal dominant SCAs share a common genetic mechanism; the length of the glutamine chain is abnormally expanded due to the increase in the cytosine–adenine–guanine (CAG) repeats of the disease causing gene. Studies have suggested that the mutant ataxin induces alteration of protein conformation and abnormal aggregation resulting in nuclear inclusions, and causes cellular loss of photoreceptors through a toxic effect. As a result, these pathologic changes induce a downregulation of genes involved in the phototransduction, development, and differentiation of photoreceptors such as CRX, one of the photoreceptor transcription factors. However, the exact mechanism of neuronal degeneration by mutant ataxin restricted to only certain type of neuronal cell including cerebellar Purkinje neurons and photoreceptor is still unclear. The most common SCAs are types 1, 2, 3, 6, 7, and 17 which contain about 80% of autosomal dominant SCA cases. Various aspects of eye movement abnormalities are evident depending on the degree of cerebellar and brainstem degeneration in SCAs. In addition, certain types of SCAs such as SCA7 are characterized by both cerebellar ataxia and visual loss mainly due to retinal degeneration. The severity of the retinopathy can vary from occult macular photoreceptor disruption to extensive retinal atrophy and is correlated with the number of CAG repeats. The value of using optical coherence tomography in conjunction with electrodiagnostic and genetic testing is emphasized as the combination of these tests can provide critical information regarding the etiology, morphological evaluation, and functional significances. Therefore, ophthalmologists need to recognize and differentiate SCAs in order to properly diagnose and evaluate the disease. In this review, we have described and discussed SCAs showing ophthalmic abnormalities with particular attention to their ophthalmic features, neurodegenerative mechanisms, genetics, and future perspectives.

Natural history of most common spinocerebellar ataxia: a systematic review and meta-analysis.

Spinocerebellar ataxias (SCAs) are rare dominantly inherited neurodegenerative disorders that lead to severe disability and premature death. To better characterize the natural history of the most common SCAs, SCA1, SCA2, SCA3 and SCA6, we performed a meta-analysis of literature to determine disease progression, provide data for sample-sizes calculations for interventional trials and study the impact of geographical locations and study follow-up on disease progression. A systematic literature search from MEDLINE and EMBASE databases for longitudinal natural history studies of SCA patients was conducted. Studies using the Scale for the Assessment and Rating Ataxia (SARA) as outcome measure were considered. Random-effect (RE) meta-analysis was applied to estimate pooled disease progression. Six studies with 1215 SCA patients enrolled between 2005 and 2016 were finally selected. Annual pooled SARA score increase was 1.83 (1.46-2.20) in patients with SCA1, 1.40 (1.19-1.61) in patients with SCA2, 1.41 (0.97-1.84) in patients with SCA3, and 0.81 (0.66-0.97) in patients with SCA6. For patients with SCA3, disease progression was faster in studies located in Asia and Europe than in the US. Two-arm interventional trials of 1-year duration to achieve 80% power and α level of 5% would require 92 patients per group with SCA1, 97 with SCA2, 115 with SCA3, and 430 with SCA6 to detect a 50% reduction in disease progression. This meta-analysis provides quantitative data on the progression of the most common spinocerebellar ataxias based on patient numbers that exceed those of previous studies and confirms that disease progression is faster in SCA1, intermediate in SCA2 and SCA3 and slower in SCA6, with similar rates of disease progression in SCA2 and SCA3 between different populations, suggesting a possibility of international collaborative studies. Nevertheless, individual-patient data meta-analysis is needed to better understand the risk factors that influence disease progression and improve patient stratification in interventional trials.

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families.

Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive-affective syndrome (CCAS), named SCA48. Molecular screening was performed in a cohort of 235 unrelated patients with adult-onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole-exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico-diagnostic findings were reviewed to define the phenotypic spectrum. Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. Our results support SCA48 as a significant cause of adult-onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.

What is the best way to keep walking and moving around for individuals with Machado-Joseph disease? A scoping review through the lens of Aboriginal families with Machado-Joseph disease in the Top End of Australia

ObjectivesMachado-Joseph disease (MJD) is the most common spinocerebellar ataxia worldwide. Prevalence is highest in affected remote Aboriginal communities of the Top End of Australia. Aboriginal families with MJD from Groote...

Moving Towards Therapy in SCA1: Insights from Molecular Mechanisms, Identification of Novel Targets, and Planning for Human Trials.

The spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders inherited in an autosomal dominant fashion. The SCAs result in progressive gait imbalance, incoordination of the limbs, speech changes, and oculomotor dysfunction, among other symptoms. Over the past few decades, significant strides have been made in understanding the pathogenic mechanisms underlying these diseases. Although multiple efforts using a combination of genetics and pharmacology with small molecules have been made towards developing new therapeutics, no FDA approved treatment currently exists. In this review, we focus on SCA1, a common SCA subtype, in which some of the greatest advances have been made in understanding disease biology, and consequently potential therapeutic targets. Understanding of the underlying basic biology and targets of therapy in SCA1 is likely to give insight into treatment strategies in other SCAs. The diversity of the biology in the SCAs, and insight from SCA1 suggests, however, that both shared treatment strategies and specific approaches tailored to treat distinct genetic causes of SCA are likely needed for this group of devastating neurological disorders.