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1.
Gene ; 771: 145360, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33333218

RESUMO

Variants in SETX have been implicated in recessively and dominantly inherited disorders, ataxia with oculomotor apraxia type 2 (AOA2 OMIM# 606002) and amyotrophic lateral sclerosis (ALS4, OMIM# 602433) respectively, in humans. We report two novel bi-allelic pathogenic variants in SETX in patients suffering from ataxia with oculomotor apraxia type 2, extending the allelic spectrum of the gene variants. We also discuss the pathogenicity of SETX variants in relation to the evolutionary conservation status of the affected amino acids. Our analyses suggest that variants of some amino acids which are not fully conserved in evolution, may cause a disorder in humans, provided the particular pathogenic variant is absent in other orthologues.


Assuntos
Esclerose Amiotrófica Lateral/genética , DNA Helicases/genética , Enzimas Multifuncionais/genética , Mutação de Sentido Incorreto , RNA Helicases/genética , Ataxias Espinocerebelares/congênito , Adolescente , DNA Helicases/química , Evolução Molecular , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Enzimas Multifuncionais/química , Linhagem , Domínios Proteicos , RNA Helicases/química , Análise de Sequência de DNA , Ataxias Espinocerebelares/genética , Adulto Jovem
2.
BMJ Case Rep ; 13(12)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33318253

RESUMO

A 4-year-old girl was referred to the geneticist with a history of ataxia associated with intention tremor of the hands, strabismus and hypermetropy. Her symptoms presented about 2 years earlier with inability to walk unaided and lower limbs hypotonia. Cognitive functions were normal. Brain MRI showed a cerebellar and vermian hypoplasia with enlargement of both the cerebrospinal fluid spaces and the IV brain ventricle. Family history was unremarkable. A genetic screening using a 42-gene panel for hereditary ataxia/spastic paraparesis identified a de novo c.1438C>T - p.(Arg480Trp) missense change in the SPTBN2 gene (NM_006946.2). This variant is reported to be associated with congenital ataxia, later evolving into ataxia and intellectual disability. This case further supports the existence of a specific SPTBN2 p.(Arg480Trp)-associated phenotype, with a de novo recurrence of this variant in the heterozygous state.


Assuntos
Encéfalo/patologia , Espectrina/genética , Ataxias Espinocerebelares/genética , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual , Imagem por Ressonância Magnética , Mutação de Sentido Incorreto , Fenótipo , Espectrina/metabolismo
3.
BMC Bioinformatics ; 21(Suppl 21): 542, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33371889

RESUMO

BACKGROUND: Short tandem repeat (STR), or "microsatellite", is a tract of DNA in which a specific motif (typically < 10 base pairs) is repeated multiple times. STRs are abundant throughout the human genome, and specific repeat expansions may be associated with human diseases. Long-read sequencing coupled with bioinformatics tools enables the estimation of repeat counts for STRs. However, with the exception of a few well-known disease-relevant STRs, normal ranges of repeat counts for most STRs in human populations are not well known, preventing the prioritization of STRs that may be associated with human diseases. RESULTS: In this study, we extend a computational tool RepeatHMM to infer normal ranges of 432,604 STRs using 21 long-read sequencing datasets on human genomes, and build a genomic-scale database called RepeatHMM-DB with normal repeat ranges for these STRs. Evaluation on 13 well-known repeats show that the inferred repeat ranges provide good estimation to repeat ranges reported in literature from population-scale studies. This database, together with a repeat expansion estimation tool such as RepeatHMM, enables genomic-scale scanning of repeat regions in newly sequenced genomes to identify disease-relevant repeat expansions. As a case study of using RepeatHMM-DB, we evaluate the CAG repeats of ATXN3 for 20 patients with spinocerebellar ataxia type 3 (SCA3) and 5 unaffected individuals, and correctly classify each individual. CONCLUSIONS: In summary, RepeatHMM-DB can facilitate prioritization and identification of disease-relevant STRs from whole-genome long-read sequencing data on patients with undiagnosed diseases. RepeatHMM-DB is incorporated into RepeatHMM and is available at https://github.com/WGLab/RepeatHMM .


Assuntos
Genômica , Repetições de Microssatélites/genética , Sequenciamento Completo do Genoma , Humanos , Masculino , Ataxias Espinocerebelares/genética
6.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 235-239, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981278

RESUMO

Objective: To investigate the effects of exogenous NaHS on myelin basic protein (MBP) and learning and memory of hippocampal neurons in mice with spinocerebellar ataxia type 3 (SCA3) and its therapeutic significance.Methods: Twelve male normal mice were randomly selected as normal control group (NC Group), and 48 SCA3 mice were randomly selected as SCA3 model group (M Group), low dose group (NL Group, 10 µmol/kg), medium dose group (NM Group, 50µmol/kg) and high dose group (NH Group, 100 µmol/kg), 12 rats in each group. The drug treated groups were injected with NaHS intraperitoneally once a day for 4 weeks. The changes of learning and memory ability of SCA3 mice before and after the intervention of different doses of NaHS were determined by Morris water maze, the content of hydrogen sulfide (H2S) in hippocampus was measured by spectrophotometry, the expression of MBP was detected by immunohistochemistry, and the morphological changes of neuron myelin sheath were observed by electron microscope. Results: Compared with the control group, the learning and memory ability of SCA3 mice was decreased significantly (P<0.05), and the content of H2S in hippocampus was decreased (P<0.05). After different doses of exogenous NaHS treatment, the learning and memory ability was improved in different degrees (P<0.05), and the contents of H2S and MBP in hippocampus of SCA3 mice were also improved in different degrees (P<0.05). Conclusion: Exogenous NaHS may increase the contents of H2S and MBP in the hippocampus of SCA3 mice, which may have a protective effect on the neurons, and then improve the learning and memory ability of SCA3 mice, and provide a new idea for the treatment of SCA3.


Assuntos
Sulfeto de Hidrogênio , Aprendizagem , Memória , Ataxias Espinocerebelares , Sulfetos , Animais , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Proteína Básica da Mielina , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ataxias Espinocerebelares/tratamento farmacológico , Sulfetos/farmacologia , Sulfetos/uso terapêutico
7.
Brain Nerve ; 72(9): 947-959, 2020 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-32934184

RESUMO

Cortical cerebellar atrophy (CCA) contains hereditary spinocerebellar degeneration (hSCD) and genetic testing is necessary for an accurate diagnosis. Screening for frequent hSCDs (triplet repeat disease and SCA31) was performed. Panel analysis and whole exome analysis using a next-generation sequencer were also performed. The Japan Consortium for Ataxias, J-CAT, contributes to the elucidation of the genetic epidemiology of CCA. The elucidation of CCA would be promoted by comprehensive gene analysis, including whole genome analysis.


Assuntos
Ataxias Espinocerebelares , Degenerações Espinocerebelares , Atrofia/patologia , Cerebelo , Humanos , Japão , Degenerações Espinocerebelares/patologia
8.
Rehabilitación (Madr., Ed. impr.) ; 54(3): 200-210, jul.-sept. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-196736

RESUMO

Las evidencias sobre la efectividad de las intervenciones rehabilitadoras en las ataxias espinocerebelosas son escasas y variables. OBJETIVO: Recopilar las evidencias existentes sobre dicha efectividad. Material y MÉTODOS: Se han analizado todos los ensayos clínicos publicados hasta la fecha y evaluado los resultados obtenidos en cuanto a la mejora del equilibrio, marcha y realización de actividades diarias postratamiento. Encontramos una mejora significativa de la postura (p <0,008), marcha (p <0,02), así como una reducción de la puntuación de la subescala SARAg&p (marcha y postura) e índice SCAFI 8MW (velocidad de marcha) (p = 0,02). También observamos mejora en desórdenes del habla (p = 0,02), síntomas depresivos (p <0,0001) y caídas accidentales (p <0,005). CONCLUSIONES: A pesar de la controversia en aspectos relacionados con la intensidad, la temporalidad y la duración de las mejoras conseguidas, queda constatada la efectividad clínica del tratamiento rehabilitador en estos pacientes, especialmente en aspectos como la marcha y el equilibrio


Evidence of the effectiveness of rehabilitation interventions in spinocerebellar ataxia is scarce and variable. OBJECTIVES: The aim of this systematic review was to gather the existing evidence on the effectiveness of these interventions. MATERIAL AND METHODS: To do this, we analysed all the clinical trials published to date and assessed their results in terms of improved balance, gait, and performance of daily activities after treatment. Significant improvements were found for posture (P<.008) and gait (P<.02), as well as a reduction in the scores for the SARAg&p subscale (gait and posture) and SCAFI 8MW index (gait speed) (P=.02). We also observed improvements in speech disorders (P=.02), depressive symptoms (P<.0001) and accidental falls (P<.005)


Assuntos
Humanos , Degenerações Espinocerebelares/reabilitação , Ataxias Espinocerebelares/reabilitação , Transtornos das Sensações/reabilitação , Transtornos Neurológicos da Marcha/reabilitação , Equilíbrio Postural/fisiologia , Atividades Cotidianas/classificação , Postura/fisiologia
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 1043-1047, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820527

RESUMO

Spinocerebellar ataxia (SCA) is a group of autosomal dominant hereditary diseases. Based on their inheritance pattern, they can be divided into SCAs caused by expansion of microsatellite repeats or point mutations. Although SCAs may be diagnosed based on their clinical characteristics and results of genetic testing, their treatment still remains as a challenge. So far no drug has been approved by the US Food and Drug Administration or the European Medicines Agency. Strict preclinical trials are critical for the development of disease-modifying drugs.


Assuntos
Ataxias Espinocerebelares , Testes Genéticos , Humanos , Repetições de Microssatélites , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia
10.
Lancet Neurol ; 19(9): 738-747, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32822634

RESUMO

BACKGROUND: Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative diseases. Our aim was to study the conversion to manifest ataxia among apparently healthy carriers of mutations associated with the most common SCAs (SCA1, SCA2, SCA3, and SCA6), and the sensitivity of clinical and functional measures to detect change in these individuals. METHODS: In this prospective, longitudinal, observational cohort study, based at 14 referral centres in seven European countries, we enrolled children or siblings of patients with SCA1, SCA2, SCA3, or SCA6. Eligible individuals were those without ataxia, defined by a score on the Scale for the Assessment and Rating of Ataxia (SARA) of less than 3; participants had to be aged 18-50 years for children or siblings of patients with SCA1, SCA2, or SCA3, and 35-70 years for children or siblings of patients with SCA6. Study visits took place at recruitment and after 2, 4, and 6 years (plus or minus 3 months). We did genetic testing to identify mutation carriers, with results concealed to the participant and clinical investigator. We assessed patients with clinical scales, questionnaires of patient-reported outcome measures, a rating of the examiner's confidence of presence of ataxia, and performance-based coordination tests. Conversion to ataxia was defined by an SARA score of 3 or higher. We analysed the association of factors at baseline with conversion to ataxia and the evolution of outcome parameters on temporal scales (time from inclusion and time to predicted age at ataxia onset) in the context of mutation status and conversion status. This study is registered with ClinicalTrials.gov, NCT01037777. FINDINGS: Between Sept 13, 2008, and Oct 28, 2015, 302 participants were enrolled. We analysed data for 252 participants with at least one follow-up visit. 83 (33%) participants were from families affected by SCA1, 99 (39%) by SCA2, 46 (18%) by SCA3, and 24 (10%) by SCA6. In participants who carried SCA mutations, 26 (52%) of 50 SCA1 carriers, 22 (59%) of 37 SCA2 carriers, 11 (42%) of 26 SCA3 carriers, and two (13%) of 15 SCA6 carriers converted to ataxia. One (3%) of 33 SCA1 non-carriers and one (2%) of 62 SCA2 non-carriers converted to ataxia. Owing to the small number of people who met our criteria for ataxia, subsequent analyses could not be done in carriers of the SCA6 mutation. Baseline factors associated with conversion were age (hazard ratio 1·13 [95% CI 1·03-1·24]; p=0·011), CAG repeat length (1·25 [1·11-1·41]; p=0·0002), and ataxia confidence rating (1·72 [1·23-2·41]; p=0·0015) for SCA1; age (1·08 [1·02-1·14]; p=0·0077) and CAG repeat length (1·65 [1·27-2·13]; p=0·0001) for SCA2; and age (1·27 [1·09-1·50]; p=0·0031), confidence rating (2·60 [1·23-5·47]; p=0·012), and double vision (14·83 [2·15-102·44]; p=0·0063) for SCA3. From the time of inclusion, the SARA scores of SCA1, SCA2, and SCA3 mutation carriers increased, whereas they remained stable in non-carriers. On a timescale defined by the predicted time of ataxia onset, SARA progression in SCA1, SCA2, and SCA3 mutation carriers was non-linear, with marginal progression before ataxia and increasing progression after ataxia onset. INTERPRETATION: Our study provides quantitative data on the conversion of non-ataxic SCA1, SCA2, and SCA3 mutation carriers to manifest ataxia. Our data could prove useful for the design of preventive trials aimed at delaying the onset of ataxia by aiding sample size calculations and stratification of study participants. FUNDING: European Research Area Network for Research Programmes on Rare Diseases, Polish Ministry of Science and Higher Education, Italian Ministry of Health, European Community's Seventh Framework Programme.


Assuntos
Progressão da Doença , Mutação/genética , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Adulto , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
12.
Neurology ; 95(9): e1199-e1210, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611635

RESUMO

OBJECTIVES: With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid motor biomarkers are highly warranted. In this observational study, we aimed to unravel and validate markers of ataxic gait in real life by using wearable sensors. METHODS: We assessed gait characteristics of 43 patients with degenerative cerebellar disease (Scale for the Assessment and Rating of Ataxia [SARA] 9.4 ± 3.9) compared with 35 controls by 3 body-worn inertial sensors in 3 conditions: (1) laboratory-based walking; (2) supervised free walking; (3) real-life walking during everyday living (subgroup n = 21). Movement analysis focused on measures of spatiotemporal step variability and movement smoothness. RESULTS: A set of gait variability measures was identified that allowed us to consistently identify ataxic gait changes in all 3 conditions. Lateral step deviation and a compound measure of spatial step variability categorized patients vs controls with a discrimination accuracy of 0.86 in real life. Both were highly correlated with clinical ataxia severity (effect size ρ = 0.76). These measures allowed detecting group differences even for patients who differed only 1 point in the clinical SARAposture&gait subscore, with highest effect sizes for real-life walking (d = 0.67). CONCLUSIONS: We identified measures of ataxic gait that allowed us not only to capture the gait variability inherent in ataxic gait in real life, but also to demonstrate high sensitivity to small differences in disease severity, with the highest effect sizes in real-life walking. They thus represent promising candidates for motor markers for natural history and treatment trials in ecologically valid contexts. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that a set of gait variability measures, even if accessed in real life, correlated with the clinical severity of ataxia in patients with degenerative cerebellar disease.


Assuntos
Análise da Marcha/métodos , Ataxias Espinocerebelares/fisiopatologia , Dispositivos Eletrônicos Vestíveis , Adulto , Idoso , Ataxia Telangiectasia/fisiopatologia , Feminino , Análise da Marcha/instrumentação , Humanos , Masculino , Pessoa de Meia-Idade , Equilíbrio Postural , Índice de Gravidade de Doença , Caminhada , Adulto Jovem
13.
Nat Commun ; 11(1): 3298, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620747

RESUMO

Communication between organelles is essential for their cellular homeostasis. Neurodegeneration reflects the declining ability of neurons to maintain cellular homeostasis over a lifetime, where the endolysosomal pathway plays a prominent role by regulating protein and lipid sorting and degradation. Here we report that TMEM16K, an endoplasmic reticulum lipid scramblase causative for spinocerebellar ataxia (SCAR10), is an interorganelle regulator of the endolysosomal pathway. We identify endosomal transport as a major functional cluster of TMEM16K in proximity biotinylation proteomics analyses. TMEM16K forms contact sites with endosomes, reconstituting split-GFP with the small GTPase RAB7. Our study further implicates TMEM16K lipid scrambling activity in endosomal sorting at these sites. Loss of TMEM16K function led to impaired endosomal retrograde transport and neuromuscular function, one of the symptoms of SCAR10. Thus, TMEM16K-containing ER-endosome contact sites represent clinically relevant platforms for regulating endosomal sorting.


Assuntos
Anoctaminas/metabolismo , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Lisossomos/metabolismo , Animais , Anoctaminas/genética , Transporte Biológico , Células COS , Linhagem Celular Tumoral , Células Cultivadas , Chlorocebus aethiops , Retículo Endoplasmático/ultraestrutura , Endossomos/ultraestrutura , Células HEK293 , Humanos , Metabolismo dos Lipídeos , Lisossomos/ultraestrutura , Camundongos Knockout , Microscopia Eletrônica , Mutação , Transporte Proteico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo
14.
Nat Commun ; 11(1): 3343, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620905

RESUMO

The expanded polyglutamine (polyQ) tract form of ataxin-1 drives disease progression in spinocerebellar ataxia type 1 (SCA1). Although known to form distinctive intranuclear bodies, the cellular pathways and processes that polyQ-ataxin-1 influences remain poorly understood. Here we identify the direct and proximal partners constituting the interactome of ataxin-1[85Q] in Neuro-2a cells, pathways analyses indicating a significant enrichment of essential nuclear transporters, pointing to disruptions in nuclear transport processes in the presence of elevated levels of ataxin-1. Our direct assessments of nuclear transporters and their cargoes confirm these observations, revealing disrupted trafficking often with relocalisation of transporters and/or cargoes to ataxin-1[85Q] nuclear bodies. Analogous changes in importin-ß1, nucleoporin 98 and nucleoporin 62 nuclear rim staining are observed in Purkinje cells of ATXN1[82Q] mice. The results highlight a disruption of multiple essential nuclear protein trafficking pathways by polyQ-ataxin-1, a key contribution to furthering understanding of pathogenic mechanisms initiated by polyQ tract proteins.


Assuntos
Ataxina-1/metabolismo , Núcleo Celular/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Células de Purkinje/metabolismo , Transporte Ativo do Núcleo Celular/genética , Animais , Ataxina-1/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HeLa , Humanos , Camundongos , Mutação , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Transporte Nucleocitoplasmático/genética , Peptídeos/genética , Ligação Proteica , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Expansão das Repetições de Trinucleotídeos/genética
15.
Adv Exp Med Biol ; 1207: 149-161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671744

RESUMO

Polyglutamine (polyQ) disease is a type of fatal neurodegenerative disease caused by an expansion of CAG repeats in a specific gene, resulting in a protein with an abnormal polyQ fragment. The age of onset and the degree of pathological deterioration are related to the length of the polyQ fragment. At least 9 kinds of polyglutamine diseases have been discovered, including Huntington disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinobulbar muscular atrophy (SBMA) and six spinocerebellar ataxia (SCA) such as SCA1, 2, 3, 6, 7 and 17 subtypes (Table 9.1). Previous studies suggest that autophagy plays a major role in the quality control of disease proteins in polyQ diseases. In this chapter, we majorly focused on three representative polyQ diseases, including spinocerebellar Ataxia type 3 (SCA3), spinocerebellar ataxia type 7 (SCA7) and Huntington's disease (HD). The relationship of the ubiquitin-proteasome system and autophagy involved in disease protein accumulation were summarized.


Assuntos
Autofagia , Atrofia Bulboespinal Ligada ao X , Doença de Huntington , Epilepsias Mioclônicas Progressivas , Peptídeos/metabolismo , Ataxias Espinocerebelares , Humanos
16.
Neurol Neurochir Pol ; 54(4): 350-355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687595

RESUMO

AIM OF THE STUDY: Multiple system atrophy (MSA) and spinocerebellar ataxia (SCA) share similar symptomatology. We describe a rare occurrence of familial MSA that proved to be SCA6 upon genetic analysis. MATERIALS AND METHODS: Eighty MSA patients were enrolled in our study; blood samples were collected and genetic screening of the familial case for known SCA loci was performed. RESULTS: A 68-year-old woman presented with recurrent and severe episodes of light-headedness, imbalance, frequent falls, neck and lower back stiffness, subjective arm and leg weakness, and numbness and tingling in both feet. One year later, her condition had declined; she experienced more falls, worsening instability, again more generalised but still subjective weakness, impaired fine motor movements, slurred speech, difficulty swallowing, episodes of choking, bladder incontinence, and constipation. Clinical suspicion included parkinsonism, MSA, and SCA. The patient was enrolled in our MSA study and was found to have 22 and 12 CAG repeats in CACNA1A. The other 79 clinical MSA patients were negative for SCA6 screening. CONCLUSIONS AND CLINICAL IMPLICATIONS: While MSA and SCA may have similar presentations during early disease stages, the presence of both conditions on the list of differential diagnoses can be a diagnostic dilemma. Further analysis will aid in developing a biomarker to distinguish between the two conditions and guide proper management.


Assuntos
Atrofia de Múltiplos Sistemas , Ataxias Espinocerebelares , Idoso , Ataxia , Feminino , Testes Genéticos , Humanos
19.
Nucleic Acids Res ; 48(13): 7557-7568, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32520333

RESUMO

Spinocerebellar ataxia type 10 (SCA10) is a progressive genetic disorder caused by ATTCT pentanucleotide repeat expansions in intron 9 of the ATXN10 gene. ATTCT repeats have been reported to form unwound secondary structures which are likely linked to large-scale repeat expansions. In this study, we performed high-resolution nuclear magnetic resonance spectroscopic investigations on DNA sequences containing two to five ATTCT repeats. Strikingly, we found the first two repeats of all these sequences well folded into highly compact minidumbbell (MDB) structures. The 3D solution structure of the sequence containing two ATTCT repeats was successfully determined, revealing the MDB comprises a regular TTCTA and a quasi TTCT/A pentaloops with extensive stabilizing loop-loop interactions. We further carried out in vitro primer extension assays to examine if the MDB formed in the primer could escape from the proofreading function of DNA polymerase. Results showed that when the MDB was formed at 5-bp or farther away from the priming site, it was able to escape from the proofreading by Klenow fragment of DNA polymerase I and thus retained in the primer. The intriguing structural findings bring about new insights into the origin of genetic instability in SCA10.


Assuntos
Ataxina-10/genética , Repetições de Microssatélites , Ataxias Espinocerebelares/genética , Replicação do DNA , Humanos , Espectroscopia de Ressonância Magnética
20.
Neurology ; 95(2): e194-e205, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32527970

RESUMO

OBJECTIVE: To 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. METHODS: Forty-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. RESULTS: Reduced 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. CONCLUSIONS: Speech 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.


Assuntos
Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Distúrbios da Fala/etiologia , Distúrbios da Fala/fisiopatologia , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/fisiopatologia , Adolescente , Adulto , Biomarcadores , Transtornos de Deglutição/psicologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Testes de Articulação da Fala , Distúrbios da Fala/psicologia , Ataxias Espinocerebelares/psicologia , Adulto Jovem
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