Articles de revues : « SCA28 »

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Tulli, Susanna, Andrea Del Bondio, Valentina Baderna, Davide Mazza, Franca Codazzi, Tyler Mark Pierson, Alessandro Ambrosi et al. « Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation ». Journal of Medical Genetics 56, n^o 8 (25 mars 2019) : 499–511. http://dx.doi.org/10.1136/jmedgenet-2018-105766.

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BackgroundSpinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in AFG3L2. The AFG3L2 protein is a subunit of mitochondrial m-AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date.MethodsWe derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p.F664S and p.M666T, p.G671R, p.Y689H and a truncating frameshift p.L556fs) and analysed multiple aspects of mitochondrial physiology. As reference of residual m-AAA activity, we included SPAX5 patient fibroblasts with homozygous p.Y616C pathogenic variant, AFG3L2+/− HEK293 T cells by CRISPR/Cas9-genome editing and Afg3l2−/− murine fibroblasts.ResultsWe found that SCA28 cells carrying missense changes have normal levels of assembled m-AAA complexes, while the cells with a truncating pathogenic variant had only half of this amount. We disclosed inefficient mitochondrial fusion in SCA28 cells caused by increased OPA1 processing operated by hyperactivated OMA1. Notably, we found altered mitochondrial proteostasis to be the trigger of OMA1 activation in SCA28 cells, with pharmacological attenuation of mitochondrial protein synthesis resulting in stabilised levels of OMA1 and OPA1 long forms, which rescued mitochondrial fusion efficiency. Secondary to altered mitochondrial morphology, mitochondrial calcium uptake resulted decreased in SCA28 cells.ConclusionOur data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and AFG3L2+/− cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants.

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Charif, Majida, Arnaud Chevrollier, Naïg Gueguen, Céline Bris, David Goudenège, Valérie Desquiret-Dumas, Stéphanie Leruez et al. « Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy ». Neurology Genetics 6, n^o 3 (20 mai 2020) : e428. http://dx.doi.org/10.1212/nxg.0000000000000428.

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ObjectiveTo improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.MethodsExonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.ResultsWe identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.ConclusionsOur results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.

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Politi, Letterio Salvatore, Stefania Bianchi Marzoli, Claudia Godi, Marta Panzeri, Paola Ciasca, Gianluca Brugnara, Anna Castaldo et al. « MRI Evidence of Cerebellar and Extraocular Muscle Atrophy Differently Contributing to Eye Movement Abnormalities in SCA2 and SCA28 Diseases ». Investigative Opthalmology & ; Visual Science 57, n^o 6 (19 mai 2016) : 2714. http://dx.doi.org/10.1167/iovs.15-18732.

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Maltecca, Francesca, Elisa Baseggio, Francesco Consolato, Davide Mazza, Paola Podini, Samuel M. Young, Ilaria Drago et al. « Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model ». Journal of Clinical Investigation 125, n^o 1 (8 décembre 2014) : 263–74. http://dx.doi.org/10.1172/jci74770.

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Di Bella, Daniela, Federico Lazzaro, Alfredo Brusco, Massimo Plumari, Giorgio Battaglia, Annalisa Pastore, Adele Finardi et al. « Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28 ». Nature Genetics 42, n^o 4 (7 mars 2010) : 313–21. http://dx.doi.org/10.1038/ng.544.

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Cagnoli, Claudia, Caterina Mariotti, Franco Taroni, Marco Seri, Alessandro Brussino, Chiara Michielotto, Marina Grisoli et al. « SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22–q11.2 ». Brain 129, n^o 1 (26 octobre 2005) : 235–42. http://dx.doi.org/10.1093/brain/awh651.

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Szpisjak, Laszlo, Viola L. Nemeth, Noemi Szepfalusi, Denes Zadori, Zoltan Maroti, Tibor Kalmar, Laszlo Vecsei et Peter Klivenyi. « Neurocognitive Characterization of an SCA28 Family Caused by a Novel AFG3L2 Gene Mutation ». Cerebellum 16, n^o 5-6 (28 juin 2017) : 979–85. http://dx.doi.org/10.1007/s12311-017-0870-9.

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Jia, Dandan, Beisha Tang, Zhao Chen, Yuting Shi, Zhanfang Sun, Li Zhang, Junling Wang, Kun Xia et Hong Jiang. « Spinocerebellar Ataxia Type 28 (SCA28) is an Uncommon Cause of Dominant Ataxia Among Chinese Kindreds ». International Journal of Neuroscience 122, n^o 10 (26 janvier 2012) : 560–62. http://dx.doi.org/10.3109/00207454.2012.690796.

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Mancini, Cecilia, Eriola Hoxha, Luisa Iommarini, Alessandro Brussino, Uwe Richter, Francesca Montarolo, Claudia Cagnoli et al. « Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity ». Neurobiology of Disease 124 (avril 2019) : 14–28. http://dx.doi.org/10.1016/j.nbd.2018.10.018.

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Park, Hyeyoung, Han-Joon Kim et Beom S. Jeon. « Parkinsonism in Spinocerebellar Ataxia ». BioMed Research International 2015 (2015) : 1–11. http://dx.doi.org/10.1155/2015/125273.

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Spinocerebellar ataxia (SCA) presents heterogeneous clinical phenotypes, and parkinsonism is reported in diverse SCA subtypes. Both levodopa responsive Parkinson disease (PD) like phenotype and atypical parkinsonism have been described especially in SCA2, SCA3, and SCA17 with geographic differences in prevalence. SCA2 is the most frequently reported subtype of SCA related to parkinsonism worldwide. Parkinsonism in SCA2 has unique genetic characteristics, such as low number of expansions and interrupted structures, which may explain the sporadic cases with low penetrance. Parkinsonism in SCA17 is more remarkable in Asian populations especially in Korea. In addition, an unclear cutoff of the pathologic range is the key issue in SCA17 related parkinsonism. SCA3 is more common in western cohorts. SCA6 and SCA8 have also been reported with a PD-like phenotype. Herein, we reviewed the epidemiologic, clinical, genetic, and pathologic features of parkinsonism in SCAs.

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Svenstrup, Kirsten, Troels Tolstrup Nielsen, Frederik Aidt, Nina Rostgaard, Morten Duno, Flemming Wibrand, Tua Vinther-Jensen et al. « SCA28 : Novel Mutation in the AFG3L2 Proteolytic Domain Causes a Mild Cerebellar Syndrome with Selective Type-1 Muscle Fiber Atrophy ». Cerebellum 16, n^o 1 (11 février 2016) : 62–67. http://dx.doi.org/10.1007/s12311-016-0765-1.

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Edener, Ulf, Janine Wöllner, Ute Hehr, Zacharias Kohl, Stefan Schilling, Friedmar Kreuz, Peter Bauer, Veronica Bernard, Gabriele Gillessen-Kaesbach et Christine Zühlke. « Early onset and slow progression of SCA28, a rare dominant ataxia in a large four-generation family with a novel AFG3L2 mutation ». European Journal of Human Genetics 18, n^o 8 (31 mars 2010) : 965–68. http://dx.doi.org/10.1038/ejhg.2010.40.

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Kraft, Scott, Sarah Furtado, Ranjit Ranawaya, Jillian Parboosingh, Stacey Bleoo, Karen McElligott, Peter Bridge, Sian Spacey, Shyamal Das et Oksana Suchowersky. « Adult Onset Spinocerebellar Ataxia in a Canadian Movement Disorders Clinic ». Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 32, n^o 4 (mai 2005) : 450–58. http://dx.doi.org/10.1017/s0317167100004431.

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ABSTRACT:Background:The spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of neurodegenerative disorders. Relative frequencies vary within different ethnic groups and geographical locations.Objectives:1) To determine the frequencies of hereditary and sporadic adult onset SCAs in the Movement Disorders population; 2) to assess if the fragile X mental retardation gene 1 (FMR1) premutation is found in this population.Methods:A retrospective chart review of individuals with a diagnosis of adult onset SCA was carried out. Testing for SCA types 1, 2, 3, 6, 7, and 8, Dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich ataxia and the FMR1 expansion was performed.Results:A total of 69 patients in 60 families were identified. Twenty-one (35%) of the families displayed autosomal dominant and two (3.3%) showed autosomal recessive (AR) pattern of inheritance. A positive but undefined family history was noted in nine (15%). The disorder appeared sporadic in 26 patients (43.3%). In the AD families, the most common mutation was SCA3 (23.8%) followed by SCA2 (14.3%) and SCA6 (14.3%). The SCA1 and SCA8 were each identified in 4.8%. FA was found in a pseudodominant pedigree, and one autosomal recessive pedigree. One sporadic patient had a positive test (SCA3).Dentatorubral-pallidoluysian atrophy and FMR1 testing was negative.Conclusion:A positive family history was present in 53.3% of our adult onset SCA patients. A specific genetic diagnosis could be given in 61.9% of dominant pedigrees with SCA3 being the most common mutation, followed by SCA2 and SCA6. The yield in sporadic cases was low. The fragile X premutation was not found to be responsible for SCA.

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Patturajan, Meera, Xiangyun Wei, Ronald Berezney et Jeffry L. Corden. « A Nuclear Matrix Protein Interacts with the Phosphorylated C-Terminal Domain of RNA Polymerase II ». Molecular and Cellular Biology 18, n^o 4 (1 avril 1998) : 2406–15. http://dx.doi.org/10.1128/mcb.18.4.2406.

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ABSTRACT Yeast two-hybrid screening has led to the identification of a family of proteins that interact with the repetitive C-terminal repeat domain (CTD) of RNA polymerase II (A. Yuryev et al., Proc. Natl. Acad. Sci. USA 93:6975–6980, 1996). In addition to serine/arginine-rich SR motifs, the SCAFs (SR-like CTD-associated factors) contain discrete CTD-interacting domains. In this paper, we show that the CTD-interacting domain of SCAF8 specifically binds CTD molecules phosphorylated on serines 2 and 5 of the consensus sequence Tyr1Ser2Pro3Thr4Ser5Pro6Ser7. In addition, we demonstrate that SCAF8 associates with hyperphosphorylated but not with hypophosphorylated RNA polymerase II in vitro and in vivo. This result suggests that SCAF8 is not present in preinitiation complexes but rather associates with elongating RNA polymerase II. Immunolocalization studies show that SCAF8 is present in granular nuclear foci which correspond to sites of active transcription. We also provide evidence that SCAF8 foci are associated with the nuclear matrix. A fraction of these sites overlap with a subset of larger nuclear speckles containing phosphorylated polymerase II. Taken together, our results indicate a possible role for SCAF8 in linking transcription and pre-mRNA processing.

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Miterski, B., J. T. Epplen, D. Poehlau, E. Sindern et M. Haupts. « SCA2 ». Neurogenetics 2, n^o 4 (2000) : 0235. http://dx.doi.org/10.1007/s100480050070.

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Yang, Lu, Ya-Ru Shao, Xiao-Yan Li, Yin Ma, Yi Dong et Zhi-Ying Wu. « Association of the Level of Neurofilament Light With Disease Severity in Patients With Spinocerebellar Ataxia Type 2 ». Neurology 97, n^o 24 (27 octobre 2021) : e2404-e2413. http://dx.doi.org/10.1212/wnl.0000000000012945.

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Background and ObjectivesFew biochemical markers have been identified in spinocerebellar ataxia type 2 (SCA2). This study aimed to determine the levels of neurofilament light (NfL) in patients with SCA2 and to identify whether they are associated with disease severity.MethodsParticipants were recruited from 1 medical center in China, and individuals with SCA2 were genetically diagnosed. NfL levels were assessed with the single molecule array method. Disease severity was evaluated with the Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the Inventory of Non-Ataxia Symptoms (INAS). Cerebellum and brainstem volumes were calculated from neuroimaging measurements. We used the Pearson correlation and partial correlation for correlation analyses.ResultsForty-nine patients with manifest SCA2, 10 preclinical individuals with SCA2, and 92 controls were enrolled. A high consistency was identified between serum and CSF NfL (r = 0.868, p < 0.0001). In individuals with SCA2, levels of serum NfL were associated with disease severity (SARA: r = 0.425, p = 0.003; ICARS: r = 0.383, p = 0.009; INAS:, r = 0.390, p = 0.007; cerebellum volume: r = −0.393, p = 0.024) after adjustment for age. NfL levels were higher close to the expected age at onset in preclinical individuals with SCA2 (R2 = 0.43, p = 0.04).DiscussionLevels of serum NfL were correlated with disease intensity in individuals with SCA2 and were higher close to the estimated age at onset in preclinical SCA2. Therefore, NfL is a potential serum biomarker of disease severity in SCA2.Classification of EvidenceThis study provides Class II evidence that elevated NfL levels are associated with disease severity in individuals with SCA2.

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Burdekin, Emma D., Brent L. Fogel, Shafali S. Jeste, Julian Martinez, Jessica E. Rexach, Charlotte DiStefano, Carly Hyde, Tabitha Safari et Rujuta B. Wilson. « The Neurodevelopmental and Motor Phenotype of SCA21 (ATX-TMEM240) ». Journal of Child Neurology 35, n^o 14 (24 juillet 2020) : 953–62. http://dx.doi.org/10.1177/0883073820943488.

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Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) is a rare form of cerebellar ataxia that commonly presents with motor, cognitive, and behavioral impairments. Although these features have been identified as part of the clinical manifestations of SCA21, the neurodevelopmental disorders associated with SCA21 have not been well studied or described. Here we present extensive phenotypic data for 3 subjects from an SCA21 family in the United States. Genetic testing demonstrated the c.196 G>A (p.Gly66Arg) variant to be a second recurrent mutation associated with the disorder. Standardized developmental assessment revealed significant deficits in cognition, adaptive function, motor skills, and social communication with 2 of the subjects having diagnoses of autism spectrum disorder, which has never been described in SCA21. Quantitative gait analysis showed markedly abnormal spatiotemporal gait variables indicative of poor gait control and cerebellar as well as noncerebellar dysfunction. Clinical evaluation also highlighted a striking variability in clinical symptoms, with greater ataxia correlating with greater severity of neurodevelopmental disorder diagnoses. Notably, neurodevelopmental outcomes have improved with intervention over time. Taken together, this case series identifies that the manifestation of neurodevelopmental disorders is a key feature of SCA21 and may precede the presence of motor abnormalities. Furthermore, the coexistence of ataxia and neurodevelopmental disorders in these subjects suggests a role for spinocerebellar pathways in both outcomes. The findings in this study highlight the importance of evaluation of neurodevelopmental concerns in the context of progressive motor abnormalities and the need for timely intervention to ultimately improve quality of life for individuals with SCA21.

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Ledezma-Lozano, I. Y., J. J. Padilla-Martínez, S. D. Leyva-Torres, I. Parra-Rojas, M. G. Ramírez-Dueñas, Ana Laura Pereira-Suárez, H. Rangel-Villalobos, S. L. Ruiz-Quezada, P. E. Sánchez-Hernández et J. F. Muñoz-Valle. « Association of CD28 IVS3 +17T/C Polymorphism with Soluble CD28 in Rheumatoid Arthritis ». Disease Markers 30, n^o 1 (2011) : 25–29. http://dx.doi.org/10.1155/2011/620849.

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Objective:Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology in which inflammatory pathology involves T cell activation and the CD28 costimulatory molecule involved in T cell presentation. The gene includes the CD28 IVS3 +17T/C polymorphism that could be associated with susceptibility to RA whereas the soluble concentrations of CD28 (sCD28) could be related to clinical activity.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Results:RA patients had significantly higher frequencies of the CD28 T allele compared to HS (p= 0.032 OR = 1.59, C.I. 1.02–2.49). In addition, the IVS3 +17 T/T genotype frequency was also increased in RA vs. HS (p= 0.026). The RA patients showed higher sCD28 serum levels than HS (p= 0.001). Carriers of the T/T genotype in RA patients showed higher sCD28 levels than C/C carriers (p= 0.047). In addition, a correlation between sCD28 and Spanish HAQ-DI (correlation, 0.272;p= 0.016), was found.Conclusion:The T allele in CD28 IVS3 +17T/C polymorphism is associated with a susceptibility to RA in Western Mexico. In addition, increased sCD28 levels are related to T/T genotype in RA patients.

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Vogel, Adam P., Michelle Magee, Reidenis Torres-Vega, Jacqueline Medrano-Montero, Melissa P. Cyngler, Megan Kruse, Sandra Rojas et al. « Features of speech and swallowing dysfunction in pre-ataxic spinocerebellar ataxia type 2 ». Neurology 95, n^o 2 (11 juin 2020) : e194-e205. http://dx.doi.org/10.1212/wnl.0000000000009776.

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ObjectiveTo determine whether objective and quantitative assessment of dysarthria and dysphagia in spinocerebellar ataxia type 2 (SCA2), specifically at pre-ataxic and early disease phases, can act as sensitive disease markers.MethodsForty-six individuals (16 with pre-ataxic SCA2, 14 with early-stage ataxic SCA2, and 16 healthy controls) were recruited in Holguin, Cuba. All participants underwent a comprehensive battery of assessments including objective acoustic analysis, clinician-derived ratings of speech function and swallowing, and quality of life assessments of swallowing.ResultsReduced speech agility manifest at the pre-ataxic stage was observed during diadochokinetic tasks, with the magnitude of speech deficit augmented in the early ataxic stage. Speech rate was slower in early-stage ataxic SCA2 compared with pre-ataxic SCA2 and healthy controls. Reduced speech agility and speech rate correlated with disease severity and time to ataxia onset, verifying that speech deficits occur prior to ataxia onset and increase in severity as the disease progresses. Whereas dysphagia was observed in both pre-ataxic and ataxic SCA2, it was not associated with swallowing-related quality of life, disease severity, or time to ataxia onset.ConclusionsSpeech and swallowing deficits appear sensitive to disease progression in early-stage SCA2, with syllabic rate a viable marker. Findings provide insight into mechanisms of disease progression in early-stage SCA2, signaling an opportunity for stratifying early-stage SCA2 and identifying salient markers of disease onset as well as outcome measures in future early-stage therapeutic studies.

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John, Prescilla D., Erica F. Weiss, Diana Bronshteyn, David M. Masur, John J. McGinley et Ronda F. Facchini. « A-81 Neuropsychological Profile of Child with Spinocerebellar Ataxia, Type 29 ». Archives of Clinical Neuropsychology 36, n^o 6 (30 août 2021) : 1126. http://dx.doi.org/10.1093/arclin/acab062.99.

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Abstract Objective Spinocerebellar ataxia 29 (SCA29) is a rare autosomal dominant disorder resulting in infantile-onset hypertonia, gross motor delay and cognitive impairment. SCA29 causes cerebellar dysfunction and atrophy manifested by poor hand coordination, instability of gait, impaired articulation, poor hand-eye coordination, language delay, and a wide legged, unsteady walk. Slow improvement across childhood is common, but the limited available research suggests significant clinical heterogeneity among individuals diagnosed with SCA29. We report the case of a six-year-old first grade girl to highlight the cognitive profile of SCA29 and determine its consistency with the literature. Methods Full neuropsychological evaluation was conducted, including examination of overall cognitive ability, academic achievement, and behavior. Results The patient demonstrated delayed cognitive and motor skills, slow processing, reduced reading fluency, and weak reading comprehension. Impaired verbal comprehension and limited fund of knowledge was seen. Working memory and visual spatial ability were relative individual strengths, though normatively weak. Untimed and non-motor academic skills were well below peers. Performances met criteria for ADHD and Language Disorder. Conclusion Six-year-old girl with SCA29 with expected motor difficulties including gross motor delay, hypotonia, ataxia, poor ocular fixation evidenced global impairments with expected weakness with verbal comprehension and receptive language skills. This is consistent with the findings in the SCA29 literature. Comorbid diagnoses of ADHD and Language Disorder were present. Given clinical heterogeneity, this case serves to expand existing knowledge on case variability, and adds the consideration of wider comorbidities in this rare condition.

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Hernandez-Castillo, Carlos R., Israel Vaca-Palomares, Víctor Galvez, Aurelio Campos-Romo, Rosalinda Diaz et Juan Fernandez-Ruiz. « Cognitive Deficits Correlate with White Matter Deterioration in Spinocerebellar Ataxia Type 2 ». Journal of the International Neuropsychological Society 22, n^o 4 (18 février 2016) : 486–91. http://dx.doi.org/10.1017/s1355617716000084.

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AbstractObjectives: The aim of this study was to explore the relationship between cognitive and white matter deterioration in a group of participants with spinocerebellar ataxia type 2 (SCA2). Methods: Fourteen genetically confirmed participants with SCA2 and 14 aged-matched controls participated in the study. Diffusion tensor imaging tract-based spatial statistics were performed to analyze structural white matter integrity. Significant group differences in the mean diffusivity were correlated with SCA2 cognitive deficits. Results: Our analysis revealed higher mean diffusivity in the SCA2 group in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Cognitive scores correlated with white matter mean diffusivity in the parahippocampal area, inferior frontal and supramarginal gyri and the stria terminalis. Conclusions: Our findings show significant correlations between white matter microstructural damage in key areas affected in SCA2 and cognitive deficits. These findings result in a more comprehensive understanding of the effect of the neurodegenerative process in people with SCA2. (JINS, 2016, 22, 486–491)

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Yamada, Kesuke J., Hirotomo Takatsuka, Junya Hirota, Keto Mineta, Yuji Nomoto et Masaki Ito. « Members of SIAMESE-RELATED Class Inhibitor Proteins of Cyclin-Dependent Kinase Retard G2 Progression and Increase Cell Size in Arabidopsis thaliana ». Life 12, n^o 9 (31 août 2022) : 1356. http://dx.doi.org/10.3390/life12091356.

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Cell size requires strict and flexible control as it significantly impacts plant growth and development. Unveiling the molecular mechanism underlying cell size control would provide fundamental insights into plants’ nature as sessile organisms. Recently, a GRAS family transcription factor SCARECROW-LIKE28 (SCL28) was identified as a determinant of cell size in plants; specifically, SCL28 directly induces a subset of SIAMESE-RELATED (SMR) family genes encoding plant-specific inhibitors of cyclin-dependent kinases (i.e., SMR1, SMR2, SMR6, SMR8, SMR9, SMR13, and SMR14), thereby slowing down G2 phase progression to provide the time to increase cell volume. Of the SMR genes regulated by SCL28, genetic analysis has demonstrated that SMR1, SMR2, and SMR13 cooperatively regulate the cell size downstream of SCL28 in roots and leaves, whereas other SMR members’ contribution remains unexplored. This study shows that in root meristematic cells, SMR9 redundantly participates in cell size control with SMR1, SMR2, and SMR13. Moreover, our cell cycle analysis provides the first experimental evidence that SMR proteins inhibit the G2 progression of proliferating cells. Overall, these findings illuminate the diverse yet overlapping roles of SMR proteins in cell cycle regulation while reinforcing that SMRs are essential downstream effectors of SCL28 to modulate G2 progression and cell size.

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Pakdaman, Yasaman, Siren Berland, Helene J. Bustad, Sigrid Erdal, Bryony A. Thompson, Paul A. James, Kjersti N. Power et al. « Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16 ». International Journal of Molecular Sciences 22, n^o 11 (30 mai 2021) : 5870. http://dx.doi.org/10.3390/ijms22115870.

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Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.

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Yoshii, Fumihito, Hitoshi Tomiyasu, Ryo Watanabe et Masafuchi Ryo. « MRI Signal Abnormalities of the Inferior Olivary Nuclei in Spinocerebellar Ataxia Type 2 ». Case Reports in Neurology 9, n^o 3 (10 novembre 2017) : 267–71. http://dx.doi.org/10.1159/000481303.

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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant spinocerebellar degeneration, associated with extended repeats of the trinucleotide CAG in the ATXN2 gene on the long arm of chromosome 12. Magnetic resonance imaging (MRI) of SCA2 showed significant atrophies of the brainstem, middle cerebellar peduncles, and cerebellum. We report two genetically proven SCA2 patients who showed hypertrophy of the inferior olivary nuclei on proton density- and T2-weighted MRI. This pattern has never been reported in patients with SCA1, SCA3, or SCA6, and may make it possible to differentiate SCA2 from other hereditary spinocerebellar ataxias.

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Vaca-Palomares, Israel, Rosalinda Díaz, Roberto Rodríguez-Labrada, Jacqueline Medrano-Montero, Raúl Aguilera-Rodríguez, Yaimeé Vázquez-Mojena, Juan Fernandez-Ruiz et Luis Velázquez-Pérez. « Strategy Use, Planning, and Rule Acquisition Deficits in Spinocerebellar Ataxia Type 2 Patients ». Journal of the International Neuropsychological Society 21, n^o 3 (mars 2015) : 214–20. http://dx.doi.org/10.1017/s1355617715000132.

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AbstractOur goal was to improve spinocerebellar ataxia type 2 (SCA2) cognitive profile characterization by testing the hypothesis that strategy, planning and rule acquisition capacities are affected in SCA2. Forty one patients with SCA2 were evaluated with the Spatial Working Memory (SWM), the Stockings of Cambridge (SOC), and the Intra-Extra Dimensional Shift (IED) tests of the Executive module of the Cambridge Neuropsychological Testing Automated Battery (CANTAB). Paired Associates Learning (PAL) and Delayed Matching to Sample (DMS) from the CANTAB memory module were also assessed to corroborate previous findings. Motor deterioration was measured using the Scale for the Assessment and Rating of Ataxia (SARA). We found significant SCA2 related deficits in strategy, planning, and rule acquisition. Our results also corroborated significant memory deficits in these patients with SCA2. Further analysis also showed that patients with large motor deterioration had poorer associative learning and spatial planning scores. Patients with SCA2 show strategy, planning, and rule acquisition deficits as revealed with the CANTAB battery. These deficits should be noted when planning an effective therapy for these patients. (JINS, 2015, 21, 1–7)

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Cardwell, Marissa M., et Juan J. Martinez. « The Sca2 Autotransporter Protein from Rickettsia conorii Is Sufficient To Mediate Adherence to and Invasion of Cultured Mammalian Cells ». Infection and Immunity 77, n^o 12 (5 octobre 2009) : 5272–80. http://dx.doi.org/10.1128/iai.00201-09.

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ABSTRACT Obligate intracellular bacteria of the genus Rickettsia must adhere to and invade the host endothelium in order to establish an infection. These processes require the interaction of rickettsial surface proteins with mammalian host cell receptors. A previous bioinformatic analysis of sequenced rickettsial species identified a family of at least 17 predicted “surface cell antigen” (sca) genes whose products resemble autotransporter proteins. Two members of this family, rOmpA and rOmpB of spotted fever group (SFG) rickettsiae have been identified as adhesion and invasion factors, respectively; however, little is known about the putative functions of the other sca gene products. An intact sca2 gene is found in the majority of pathogenic SFG rickettsiae and, due to its sequence conservation among these species, we predict that Sca2 may play an important function at the rickettsial surface. Here we have shown that sca2 is transcribed and expressed in Rickettsia conorii and have used a heterologous gain-of-function assay in E. coli to determine the putative role of Sca2. Using this system, we have demonstrated that expression of Sca2 at the outer membrane of nonadherent, noninvasive E. coli is sufficient to mediate adherence to and invasion of a panel of mammalian cells, including endothelial cells. Furthermore, soluble Sca2 protein is capable of diminishing R. conorii invasion of cultured mammalian cells. This is the first evidence that Sca2 participates in the interaction between SFG rickettsiae and host cells and suggests that in addition to other surface proteins, Sca2 may play a critical role in rickettsial pathogenesis.

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Szpisjak, László, András Salamon, Viola L. Németh, Noémi Szépfalusi, Zoltán Maróti, Tibor Kalmár, Aliz Zimmermann, Dénes Zádori et Péter Klivényi. « Novel heterozygous STUB1 gene mutation causes SCA48 in a Hungarian patient ». Ideggyógyászati szemle 76, n^o 1-2 (2023) : 63–72. http://dx.doi.org/10.18071/isz.76.0063.

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Spinocerebellar ataxia type 48 (SCA48) is an autosomal dominantly inherited disease characterized by gait and limb ataxia, cerebellar dysarthria, cognitive impairment, psychiatric abnormalities and variable types of movement disorders. To date, more than 30 STUB1 gene (NM_005861.4) mutations have been described in the genetic background of SCA48. The aim of this short report was to demonstrate the first Hungarian SCA48 patient caused by a novel STUB1 missense mutation (c.788G>C, p.Arg263Pro). The characteristics of detailed neurological phenotype, brain MRI and genetic assessment are presented and compared to previously published cases. The most important neurological findings of the patient were gait ataxia, dysarthria, cognitive decline and psychiatric problems including depression, anxiety and mild impulsivity. The brain MRI demonstrated cerebellar atrophy with posterolateral predominance and frontal lobe cortical atrophy. Clinical exome sequencing examination identified the above-mentioned missense variant located in the significant ubiquitinase domain of the CHIP protein. In this paper the first Hungarian SCA48 patient was described with characteristic neuropsychiatric signs and brain MRI abnormalities, due to a novel STUB1 gene missense mutation.

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Afonso, Inês T., Patrícia Lima, André Conceição, Carlos A. Matos et Clévio Nóbrega. « Mutant Ataxin-2 Expression in Aged Animals Aggravates Neuropathological Features Associated with Spinocerebellar Ataxia Type 2 ». International Journal of Molecular Sciences 23, n^o 19 (7 octobre 2022) : 11896. http://dx.doi.org/10.3390/ijms231911896.

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Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal, dominantly inherited disease, in which the affected individuals have a disease onset around their third life decade. The molecular mechanisms underlying SCA2 are not yet completely understood, for which we hypothesize that aging plays a role in SCA2 molecular pathogenesis. In this study, we performed a striatal injection of mutant ataxin-2 mediated by lentiviral vectors, in young and aged animals. Twelve weeks post-injection, we analyzed the striatum for SCA2 neuropathological features and specific aging hallmarks. Our results show that aged animals had a higher number of mutant ataxin-2 aggregates and more neuronal marker loss, compared to young animals. Apoptosis markers, cleaved caspase-3, and cresyl violet staining also indicated increased neuronal death in the aged animal group. Additionally, mRNA levels of microtubule-associated protein 1 light-chain 3B (LC3) and sequestosome-1 (SQSTM1/p62) were altered in the aged animal group, suggesting autophagic pathway dysfunction. This work provides evidence that aged animals injected with expanded ataxin-2 had aggravated SCA2 disease phenotype, suggesting that aging plays an important role in SCA2 disease onset and disease progression.

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Li, Shu-Ting, et Yang Zhou. « Spinocerebellar ataxia type 2 presenting with involuntary movement : a diagnostic dilemma ». Journal of International Medical Research 47, n^o 12 (27 novembre 2019) : 6390–96. http://dx.doi.org/10.1177/0300060519889457.

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Spinocerebellar ataxia type 2 (SCA2) is a rare disease characterized by slowly progressive ataxia, dysarthria, ophthalmoplegia, and slow saccade. SCA2 can present with a complex combination of hyperkinetic and hypokinetic movement disorders. Here, we describe a patient with SCA2 that partly mimicked the clinical manifestations of Huntington’s disease; similar symptoms had previously occurred in the patient’s family members. The findings in this report indicate that, when a patient exhibits choreiform movement (i.e., accompanying cerebellar ataxia), an SCA2-related mutation could be responsible for the onset of disease. In addition, this knowledge of the potential for extrapyramidal involvement in such patients is critical for clinicians.

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Scoles, Daniel R., Warunee Dansithong, Lance T. Pflieger, Sharan Paul, Mandi Gandelman, Karla P. Figueroa, Frank Rigo, C. Frank Bennett et Stefan M. Pulst. « ALS-associated genes in SCA2 mouse spinal cord transcriptomes ». Human Molecular Genetics 29, n^o 10 (20 avril 2020) : 1658–72. http://dx.doi.org/10.1093/hmg/ddaa072.

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Abstract The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.

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van der Put, Johanna, Dalia Daugeliene, Åsa Bergendal, Malin Kvarnung, Per Svenningsson et Martin Paucar. « On Spinocerebellar Ataxia 21 as a Mimicker of Cerebral Palsy ». Neurology Genetics 8, n^o 3 (31 mai 2022) : e668. http://dx.doi.org/10.1212/nxg.0000000000000668.

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ObjectivesSporadic variants in ataxia genes may mimic cerebral palsy (CP). Spinocerebellar ataxia 21 (SCA21), a very rare autosomal dominant disease, was discovered to be associated with variants in the transmembrane protein 240 (TMEM240) gene in 2014. In this report, we present 2 patients with sporadic SCA21, one of them diagnosed with ataxic CP.MethodsPatients provided oral and written consent. Comprehensive clinical evaluation, neuroimaging studies, review of previous psychometric evaluations, and whole-genome sequencing were applied in both cases.ResultsBoth patients presented with early-onset ataxia and exhibited mild parkinsonian features. Patient 1 experienced motor and speech delay, autism, and dyslexia, whereas patient 2 experienced dyslexia. Neuroimaging was normal in both cases. In patient 1, the previously reported pathogenic c.509C>T (Pro170Leu) variant in TMEM240 was detected, whereas patient 2 harbored the novel c.182_188delinsGGAT (Val61_Pro63delinsGlyMet) variant in the same gene. Both genetic variants were sporadic.DiscussionOur findings support the notion that SCA21 is a neurodevelopmental syndrome and a mimicker of ataxic CP. Both lack of a family history of ataxia and congenital presentation were reasonable arguments to consider ataxic CP. However, lack of convincing perinatal incidents, progressive symptoms, and the common presence of cerebellar atrophy should alert neurologists about SCA21.

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Kim, Youg Sung, Sangjin Lee et Hae-Won Shin. « A Patient with Spinocerebellar Ataxia 2 Presenting with Multiple System Atrophy ». Journal of the Korean Neurological Association 38, n^o 1 (1 février 2020) : 33–36. http://dx.doi.org/10.17340/jkna.2020.1.6.

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Spinocerebellar ataxia type-2 (SCA2) is an autosomal dominant cerebellar ataxia that occurs due to expanded CAG trinucleotide repeats in the ATXN2 gene. Clinical features of parkinsonism in SCA2 vary from phenotypes of levodopa-responsive parkinsonism to multiple system atrophy. We described a patient with SCA2 presenting typical clinical manifestations of multiple system atrophy-c type with levodopa responsive parkinsonism whose dopamine transporter (DAT) image showed atypically reduced DAT uptake in in the striatum.

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Zhou, Y. X., G. X. Wang, B. S. Tang, W. D. Li, D. A. Wang, H. S. Lee, N. Sambuughin et al. « Spinocerebellar ataxia type 2 in China ». Neurology 51, n^o 2 (août 1998) : 595–98. http://dx.doi.org/10.1212/wnl.51.2.595.

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Sixteen patients from nine Chinese families with spinocerebellar ataxia type 2 (SCA2) were heterozygous for a CAG repeat expansion in the SCA2 gene containing 37 to 56 repeats, whereas the normal alleles carried 14 to 28 repeats. One or two CAA triplets within the CAG tract were seen in normal, but not in the expanded alleles. A strong inverse correlation was established between the number of CAG repeats and the age of disease onset. SCA2 accounted for 12% of the known Chinese families with spinocerebellar ataxia.

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Scarabino, Daniela, Liana Veneziano, Alessia Fiore, Suran Nethisinghe, Elide Mantuano, Hector Garcia-Moreno, Gianmarco Bellucci et al. « Leukocyte Telomere Length Variability as a Potential Biomarker in Patients with PolyQ Diseases ». Antioxidants 11, n^o 8 (24 juillet 2022) : 1436. http://dx.doi.org/10.3390/antiox11081436.

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SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington’s Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient’s age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.

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Dennis, Almaguer-Gotay, Luis E. Almaguer-Mederos, Rodríguez-Aguilera Raúl, Rodríguez-Labrada Roberto, Velázquez-Pérez Luis, Cuello-Almarales Dany, González-Zaldívar Yanetza et al. « Redox Imbalance Associates with Clinical Worsening in Spinocerebellar Ataxia Type 2 ». Oxidative Medicine and Cellular Longevity 2021 (19 février 2021) : 1–9. http://dx.doi.org/10.1155/2021/9875639.

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Background. Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease presenting with redox imbalance. However, the nature and implications of redox imbalance in SCA2 physiopathology have not been fully understood. Objective. The objective of this study is to assess the redox imbalance and its association with disease severity in SCA2 mutation carriers. Methods. A case-control study was conducted involving molecularly confirmed SCA2 patients, presymptomatic individuals, and healthy controls. Several antioxidant parameters were assessed, including serum thiol concentration and the superoxide dismutase, catalase, and glutathione S-transferase enzymatic activities. Also, several prooxidant parameters were evaluated, including thiobarbituric acid-reactive species and protein carbonyl concentrations. Damage, protective, and OXY scores were computed. Clinical correlates were established. Results. Significant differences were found between comparison groups for redox markers, including protein carbonyl concentration ( F = 3.30 ; p = 0.041 ), glutathione S-transferase activity ( F = 4.88 ; p = 0.009 ), and damage ( F = 3.20 ; p = 0.045 ), protection ( F = 12.75 ; p < 0.001 ), and OXY ( F = 7.29 ; p = 0.001 ) scores. Protein carbonyl concentration was positively correlated with CAG repeat length ( r = 0.27 ; p = 0.022 ), while both protein carbonyl concentration ( r = − 0.27 ; p = 0.018 ) and OXY score ( r = − 0.25 ; p = 0.013 ) were inversely correlated to the disease duration. Increasing levels of antioxidants and decreasing levels of prooxidant parameters were associated with clinical worsening. Conclusions. There is a disruption of redox balance in SCA2 mutation carriers which depends on the disease stage. Besides, redox changes associate with markers of disease severity, suggesting a link between disruption of redox balance and SCA2 physiopathology.

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Seshagiri, Doniparthi V., Pramod Kumar Pal, Sanjeev Jain et Ravi Yadav. « Optokinetic nystagmus in patients with SCA ». Neurology 91, n^o 13 (29 août 2018) : e1255-e1261. http://dx.doi.org/10.1212/wnl.0000000000006250.

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ObjectiveTo characterize the clinical features in patients with spinocerebellar ataxia (SCA) type 1, SCA2, and SCA3 and to evaluate the oculomotor dysfunction by using optokinetic nystagmus (OKN) testing, which may be a sensitive marker.MethodsIn this prospective observational study, all patients underwent detailed neurologic examination with special emphasis on eye movements. OKN was evaluated with a tape. Disease severity was measured with the International Co-Operative Ataxia Rating Scale (ICARS).ResultsA total of 73 genetically confirmed patients were included, of whom 28, 30, and 15 patients were positive for SCA1, SCA2, and SCA3, respectively. Dystonia was more common in patients with SCA3 (46%), and absent ankle jerk was more common in those with SCA2 (21.4%). Brisk deep tendon reflexes were common in patients with SCA1 (46.6%), followed by patients with SCA3 (26.6%) and SCA2 (7.1%). Vertical OKN was impaired in all patients and absent in 86.6% of patients with SCA1, 96% of those with SCA2, and 80% of those with SCA3. Horizontal OKN was absent in 30% of patients with SCA1, 57% of patients with SCA2, and 33% of those with SCA3. Higher motor disability (posture and gait, kinetic functions [Motor Disability] subscore on the ICARS) was associated with higher oculomotor dysfunction measured by OKN-saccades impairment grading but not with the Ocular Disorder subscore of ICARS (ICARS-OD).ConclusionOKN-saccades are a better and sensitive bedside clinical tool to quantify oculomotor dysfunction in neurodegenerative ataxias. Its role needs to be tested further in presymptomatic carriers. The current ICARS-OD scale to grade oculomotor dysfunction in degenerative ataxias need to be modified.

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Satterfield, Terrence F., Stephen M. Jackson et Leo J. Pallanck. « A Drosophila Homolog of the Polyglutamine Disease Gene SCA2 Is a Dosage-Sensitive Regulator of Actin Filament Formation ». Genetics 162, n^o 4 (1 décembre 2002) : 1687–702. http://dx.doi.org/10.1093/genetics/162.4.1687.

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Abstract Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract in ataxin-2, the SCA2 gene product. The normal cellular function of ataxin-2 and the mechanism by which polyglutamine expansion of ataxin-2 causes neurodegeneration remain unknown. In this study we have used genetic and molecular approaches to investigate the function of a Drosophila homolog of the SCA2 gene (Datx2). Like human ataxin-2, Datx2 is found throughout development in a variety of tissue types and localizes to the cytoplasm. Mutations that reduce Datx2 activity or transgenic overexpression of Datx2 result in female sterility, aberrant sensory bristle morphology, loss or degeneration of tissues, and lethality. These phenotypes appear to result from actin filament formation defects occurring downstream of actin synthesis. Further studies demonstrate that Datx2 does not assemble with actin filaments, suggesting that the role of Datx2 in actin filament formation is indirect. These results indicate that Datx2 is a dosage-sensitive regulator of actin filament formation. Given that loss of cytoskeleton-dependent dendritic structure defines an early event in SCA2 pathogenesis, our findings suggest the possibility that dysregulation of actin cytoskeletal structure resulting from altered ataxin-2 activity is responsible for neurodegeneration in SCA2.

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Egorova, Polina A., Olga A. Zakharova, Olga L. Vlasova et Ilya B. Bezprozvanny. « In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model ». Journal of Neurophysiology 115, n^o 6 (1 juin 2016) : 2840–51. http://dx.doi.org/10.1152/jn.00913.2015.

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Cerebellar Purkinje cells (PCs) are primarily affected in many spinocerebellar ataxias (SCA). In this study we investigated functional activity of PCs in transgenic mouse model of SCA2, a polyglutamine neurodegenerative hereditary disorder. In our studies we used extracellular single-unit recording method to compare spontaneous activity of PCs in age-matched wild-type mice and SCA2-58Q transgenic mice. We discovered that the fraction of PCs with bursting and an irregular pattern of spontaneous activity dramatically increases in aged SCA2-58Q mice compared with wild-type littermates. Small-conductance calcium-activated potassium (SK) channels play an important role in determining firing rate of PCs. Indeed, we demonstrated that intraperitoneal (IP) injection of SK channel inhibitor NS8593 induces an irregular pattern of PC activity in wild-type mice. Furthermore, we demonstrated that IP injection of SK channel-positive modulator chlorzoxazone (CHZ) decreases spontaneous firing rate of cerebellar PCs. Finally, we have shown that IP injections with CHZ normalize firing activity of cerebellar PCs from aging SCA2-58Q mice. We propose that alterations in PC firing patterns is one of potential causes of ataxic symptoms in SCA2 and in other SCAs and that positive modulators of SK channels can be used to normalize activity of PCs and alleviate ataxic phenotype in patients with SCA.

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Ando, Hideaki, Matsumi Hirose et Katsuhiko Mikoshiba. « Aberrant IP3 receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29 ». Proceedings of the National Academy of Sciences 115, n^o 48 (14 novembre 2018) : 12259–64. http://dx.doi.org/10.1073/pnas.1811129115.

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Spinocerebellar ataxia type 29 (SCA29) is autosomal dominant congenital ataxia characterized by early-onset motor delay, hypotonia, and gait ataxia. Recently, heterozygous missense mutations in an intracellular Ca2+ channel, inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1), were identified as a cause of SCA29. However, the functional impacts of these mutations remain largely unknown. Here, we determined the molecular mechanisms by which pathological mutations affect IP3R1 activity and Ca2+ dynamics. Ca2+ imaging using IP3R-null HeLa cells generated by genome editing revealed that all SCA29 mutations identified within or near the IP3-binding domain of IP3R1 completely abolished channel activity. Among these mutations, R241K, T267M, T267R, R269G, R269W, S277I, K279E, A280D, and E497K impaired IP3 binding to IP3R1, whereas the T579I and N587D mutations disrupted channel activity without affecting IP3 binding, suggesting that T579I and N587D compromise channel gating mechanisms. Carbonic anhydrase-related protein VIII (CA8) is an IP3R1-regulating protein abundantly expressed in cerebellar Purkinje cells and is a causative gene of congenital ataxia. The SCA29 mutation V1538M within the CA8-binding site of IP3R1 completely eliminated its interaction with CA8 and CA8-mediated IP3R1 inhibition. Furthermore, pathological mutations in CA8 decreased CA8-mediated suppression of IP3R1 by reducing protein stability and the interaction with IP3R1. These results demonstrated the mechanisms by which pathological mutations cause IP3R1 dysfunction, i.e., the disruption of IP3 binding, IP3-mediated gating, and regulation via the IP3R-modulatory protein. The resulting aberrant Ca2+ homeostasis may contribute to the pathogenesis of cerebellar ataxia.

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Kleba, Betsy, Tina R. Clark, Erika I. Lutter, Damon W. Ellison et Ted Hackstadt. « Disruption of the Rickettsia rickettsii Sca2 Autotransporter Inhibits Actin-Based Motility ». Infection and Immunity 78, n^o 5 (1 mars 2010) : 2240–47. http://dx.doi.org/10.1128/iai.00100-10.

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ABSTRACT Rickettsii rickettsii, the etiologic agent of Rocky Mountain spotted fever, replicates within the cytosol of infected cells and uses actin-based motility to spread inter- and intracellularly. Although the ultrastructure of the actin tail and host proteins associated with it are distinct from those of Listeria or Shigella, comparatively little is known regarding the rickettsial proteins involved in its organization. Here, we have used random transposon mutagenesis of R. rickettsii to generate a small-plaque mutant that is defective in actin-based motility and does not spread directly from cell to cell as is characteristic of spotted fever group rickettsiae. The transposon insertion site of this mutant strain was within Sca2, a member of a family of large autotransporter proteins. Sca2 exhibits several features suggestive of its apparent role in actin-based motility. It displays an N-terminal secretory signal peptide, a C-terminal predicted autotransporter domain, up to four predicted Wasp homology 2 (WH2) domains, and two proline-rich domains, one with similarity to eukaryotic formins. In a guinea pig model of infection, the Sca2 mutant did not elicit fever, suggesting that Sca2 and actin-based motility are virulence factors of spotted fever group rickettsiae.

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Zu, Tao, Brian Gibbens, Noelle S. Doty, Mário Gomes-Pereira, Aline Huguet, Matthew D. Stone, Jamie Margolis et al. « Non-ATG–initiated translation directed by microsatellite expansions ». Proceedings of the National Academy of Sciences 108, n^o 1 (20 décembre 2010) : 260–65. http://dx.doi.org/10.1073/pnas.1013343108.

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Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.

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Li, Yangyang, Li Jin, Jing Yan, Hong Zhang, Rong Zhang et Cheng Hu. « CD28 Genetic Variants Increase Susceptibility to Diabetic Kidney Disease in Chinese Patients with Type 2 Diabetes : A Cross-Sectional Case Control Study ». Mediators of Inflammation 2021 (17 avril 2021) : 1–10. http://dx.doi.org/10.1155/2021/5521050.

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Few studies have illuminated the genetic role of T cell costimulatory molecule CD28/CD80/CTLA4 variants in diabetic kidney disease (DKD) susceptibility. We aimed to investigate the causal role of genetic polymorphisms in CD28/CD80/CTLA4 with DKD susceptibility in patients with T2DM. A total of 3253 patients with T2DM were recruited for genotyping: including 204 DKD patients and 371 controls in stage 1 and 819 DKD patients and 563 controls in stage 2; besides, 1296 T2DM patients were selected for the analysis of association between loci and DKD-related traits. A subset of 227 T2DM patients (118 patients with DKD and 109 patients without DKD) from the total population above were selected to assess serum soluble CD28 (sCD28) levels. Then, we performed a candidate gene association study to identify single-nucleotide polymorphisms (SNPs) associated with DKD susceptibility and further used those SNPs to perform Mendelian randomization analyses of serum sCD28 level and DKD susceptibility. Under additive genetic models, CD28-rs3116494 ( OR = 1.29 [95% CI 1.11, 1.51], P = 0.0011 ) and CD80-rs3850890 ( OR = 1.16 [95% CI 1.02, 1.31], P = 0.0283 ) were associated with DKD susceptibility adjusted for age, gender, body mass index (BMI), duration of diabetes, and HbA1c. CD28-rs3116494 was associated with serum sCD28 level ( β = 0.26 [95% CI 0.08, 0.44], P = 0.0043 ). The Mendelian randomization analysis showed that CD28-rs3116494 played a causal role in DKD by influencing serum sCD28 levels ( β = 1.15 [95% CI 0.46, 1.83], P = 0.0010 ). In conclusion, we identified that two novel SNPs, CD28-rs3116494 and CD80-rs3850890, were associated with DKD susceptibility. Using the Mendelian randomization analysis, our study provided evidence for a causal relationship between serum CD28 levels and DKD with T2DM in the Chinese population.

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Baviera-Muñoz, Raquel, Lidón Carretero-Vilarroig, Juan Francisco Vázquez-Costa, Carlos Morata-Martínez, Marina Campins-Romeu, Nuria Muelas, Isabel Sastre-Bataller et al. « Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain ». Neurology Genetics 8, n^o 6 (14 novembre 2022) : e200038. http://dx.doi.org/10.1212/nxg.0000000000200038.

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Background and ObjectivesTo determine the diagnostic efficacy of clinical exome-targeted sequencing (CES) and spinocerebellar ataxia 36 (SCA36) screening in a real-life cohort of patients with cerebellar ataxia (CA) from Eastern Spain.MethodsA total of 130 unrelated patients with CA, negative for common trinucleotide repeat expansions (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, dentatorubral pallidoluysian atrophy [DRPLA], and Friedreich ataxia), were studied with CES. Bioinformatic and genotype-phenotype analyses were performed to assess the pathogenicity of the variants encountered. Copy number variants were analyzed when appropriate. In undiagnosed dominant and sporadic cases, repeat primed PCR was used to screen for the presence of a repeat expansion in theNOP56gene.ResultsCES identified pathogenic or likely pathogenic variants in 50 families (39%), including 23 novel variants. Overall, there was a high genetic heterogeneity, and the most frequent genetic diagnosis wasSPG7(n = 15), followed bySETX(n = 6),CACNA1A(n = 5),POLR3A(n = 4), andSYNE1(n = 3). In addition, 17 families displayed likely pathogenic/pathogenic variants in 14 different genes:KCND3(n = 2),KIF1C(n = 2),CYP27A1A(n = 2),AFG3L2(n = 1),ANO10(n = 1),CAPN1(n = 1),CWF19L1(n = 1),ITPR1(n = 1),KCNA1(n = 1),OPA1(n = 1),PNPLA6(n = 1),SPG11(n = 1),SPTBN2(n = 1), andTPP1(n = 1). Twenty-two novel variants were characterized. SCA36 was diagnosed in 11 families, all with autosomal dominant (AD) presentation. SCA36 screening increased the total diagnostic rate to 47% (n = 61/130). Ultimately, undiagnosed patients showed delayed age at onset (p< 0.05) and were more frequently sporadic.DiscussionOur study provides insight into the genetic landscape of CA in Eastern Spain. Although CES was an effective approach to capture genetic heterogeneity, most patients remained undiagnosed. SCA36 was found to be a relatively frequent form and, therefore, should be tested prior to CES in familial AD presentations in particular geographical regions.

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Munhoz, Renato P., Hélio A. Teive, Salmo Raskin et André R. Troiano. « Atypical parkinsonism and SCA8 ». Parkinsonism & ; Related Disorders 12, n^o 3 (avril 2006) : 191–92. http://dx.doi.org/10.1016/j.parkreldis.2005.10.001.

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Baba, Yasuhiko, Ryan J. Uitti, Matthew J. Farrer et Zbigniew K. Wszolek. « Atypical Parkinsonism and SCA8 ». Parkinsonism & ; Related Disorders 12, n^o 6 (septembre 2006) : 396. http://dx.doi.org/10.1016/j.parkreldis.2006.06.001.

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Lastres-Becker, Isabel, Udo Rüb et Georg Auburger. « Spinocerebellar ataxia 2 (SCA2) ». Cerebellum 7, n^o 2 (3 avril 2008) : 115–24. http://dx.doi.org/10.1007/s12311-008-0019-y.

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Mascalchi, Mario, et Alessandra Vella. « Neuroimaging Biomarkers in SCA2 Gene Carriers ». International Journal of Molecular Sciences 21, n^o 3 (4 février 2020) : 1020. http://dx.doi.org/10.3390/ijms21031020.

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A variety of Magnetic Resonance (MR) and nuclear medicine (NM) techniques have been used in symptomatic and presymptomatic SCA2 gene carriers to explore, in vivo, the physiopathological biomarkers of the neurological dysfunctions characterizing the associated progressive disease that presents with a cerebellar syndrome, or less frequently, with a levodopa-responsive parkinsonian syndrome. Morphometry performed on T1-weighted images and diffusion MR imaging enable structural and microstructural evaluation of the brain in presymptomatic and symptomatic SCA2 gene carriers, in whom they show the typical pattern of olivopontocerebellar atrophy observed at neuropathological examination. Proton MR spectroscopy reveals, in the pons and cerebellum of SCA2 gene carriers, a more pronounced degree of abnormal neurochemical profile compared to other spinocerebellar ataxias with decreased NAA/Cr and Cho/Cr, increased mi/Cr ratios, and decreased NAA and increased mI concentrations. These neurochemical abnormalities are detectable also in presymtomatic gene carriers. Resting state functional MRI (rsfMRI) demonstrates decreased functional connectivity within the cerebellum and of the cerebellum with fronto-parietal cortices and basal ganglia in symptomatic SCA2 subjects. 18F-fluorodeoxyglucose Positron Emission Tomography (PET) shows a symmetric decrease of the glucose uptake in the cerebellar cortex, the dentate nucleus, the brainstem and the parahippocampal cortex. Single photon emission tomography and PET using several radiotracers have revealed almost symmetric nigrostriatal dopaminergic dysfunction irrespective of clinical signs of parkinsonism which are already present in presymtomatic gene carriers. Longitudinal small size studies have proven that morphometry and diffusion MR imaging can track neurodegeneration in SCA2, and hence serve as progression biomarkers. So far, such a capability has not been reported for proton MR spectroscopy, rsfMRI and NM techniques. A search for the best surrogate marker for future clinical trials represents the current challenge for the neuroimaging community.

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Amarante, Thiago R. Padilha, Sibele Y. M. Takeda, Hélio A. G. Teive et Marise Bueno Zonta. « Impact of disease duration on functional status of patients with spinocerebellar ataxia type 2 ». Arquivos de Neuro-Psiquiatria 75, n^o 11 (novembre 2017) : 773–77. http://dx.doi.org/10.1590/0004-282x20170146.

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ABSTRACT Objective: To correlate disease duration in spinocerebellar ataxia type 2 (SCA2) with disease severity, balance and functionality. Method: Sixteen SCA2 patients were analyzed for: disease duration, disease severity (SARA score), balance (Berg balance scale score) and functionality (FIM and Lawton scores). Results: Greater severity was correlated with worse functionality (Lawton: r = −0.0561, FIM: r = −0.6402) and balance (r = −0.7188). Longer disease duration was correlated with greater severity (p = 0.0002) and reduced functionality (FIM: p = 0.005; Lawton: p = 0.0402) and balance (p = 0.0036). A year increase in disease duration corresponded to a 0.8-point increase on the SARA scale, a 1.38-point decrease in FIM score, a 2.30-point decrease on the Berg balance scale and a 0.45-point decrease on the Lawton scale. Conclusion: Longer disease duration in this series of SCA2 patients was correlated with greater disease severity, worse balance and greater functional dependency.

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Hirano, Makito, Makoto Samukawa, Chiharu Isono, Kazumasa Saigoh, Yusaku Nakamura et Susumu Kusunoki. « Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene ». Neurology Genetics 4, n^o 4 (août 2018) : e252. http://dx.doi.org/10.1212/nxg.0000000000000252.

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ObjectiveTo assess the contribution of noncoding repeat expansions in Japanese patients with amyotrophic lateral sclerosis (ALS).MethodsSporadic ALS in Western countries is frequently associated with noncoding repeat expansions in the C9ORF72 gene. Spinocerebellar ataxia type 8 (SCA8) is another noncoding repeat disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Although the involvement of upper and lower motor neurons in SCA8 has been reported, a positive association between SCA8 and ALS remains unestablished. Spinocerebellar ataxia type 36 is a recently identified disease caused by noncoding repeat expansions in the NOP56 gene and is characterized by motor neuron involvement. We collected blood samples from 102 Japanese patients with sporadic ALS and analyzed the ATXN8OS gene by the PCR–Sanger sequencing method and the C9ORF72 and NOP56 genes by repeat-primed PCR assay.ResultsThree patients with ALS (3%) had mutations in the ATXN8OS gene, whereas no patient had a mutation in the C9ORF72 or NOP56 gene. The mutation-positive patients were clinically characterized by neck weakness or bulbar-predominant symptoms. None of our patients had apparent cerebellar atrophy on MRI, but 2 had nonsymptomatic abnormalities in the white matter or putamen.ConclusionsOur finding reveals the importance of noncoding repeat expansions in Japanese patients with ALS and extends the clinical phenotype of SCA8. Three percent seems small but is still relatively large for Japan, considering that the most commonly mutated genes, including the SOD1 and SQSTM1 genes, only account for 2%–3% of sporadic patients each.

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De Michele, Giovanna, Elena Salvatore, Sirio Cocozza, Alessandro Filla et Filippo M. Santorelli. « Of cognition and cerebellum in SCA48 ». neurogenetics 21, n^o 2 (3 février 2020) : 145–46. http://dx.doi.org/10.1007/s10048-020-00603-8.

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