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1.
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
2.
Neurotherapeutics ; 16(4): 1106-1114, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31755042

RESUMO

Spinocerebellar ataxia type 31 (SCA31) is one of the autosomal-dominant neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom. This disease is caused by a 2.5- to 3.8-kb-long complex pentanucleotide repeat containing (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n in an intron of the gene called BEAN1 (brain expressed, associated with Nedd4). By comparing various pentanucleotide repeats in this particular locus among control Japanese and Caucasian populations, it was found that (TGGAA)n was the only sequence segregating with SCA31, strongly suggesting the pathogenicity of (TGGAA)n. The complex repeat also lies in an intron of another gene, TK2 (thymidine kinase 2), which is transcribed in the opposite direction, indicating that the complex repeat is bi-directionally transcribed as noncoding repeats. In SCA31 human brains, (UGGAA)n, the BEAN1 transcript of SCA31 mutation was found to form abnormal RNA structures called RNA foci in cerebellar Purkinje cell nuclei. Subsequent RNA pulldown analysis disclosed that (UGGAA)n binds to RNA-binding proteins TDP-43, FUS, and hnRNP A2/B1. In fact, TDP-43 was found to co-localize with RNA foci in human SCA31 Purkinje cells. To dissect the pathogenesis of (UGGAA)n in SCA31, we generated transgenic fly models of SCA31 by overexpressing SCA31 complex pentanucleotide repeats in Drosophila. We found that the toxicity of (UGGAA)n is length- and expression level-dependent, and it was dampened by co-expressing TDP-43, FUS, and hnRNP A2/B1. Further investigation revealed that TDP-43 ameliorates (UGGAA)n toxicity by directly fixing the abnormal structure of (UGGAA)n. This led us to propose that TDP-43 acts as an RNA chaperone against toxic (UGGAA)n. Further research on the role of RNA-binding proteins as RNA chaperones may provide a novel therapeutic strategy for SCA31.


Assuntos
Modelos Animais de Doenças , Repetições de Microssatélites/fisiologia , Mutação/fisiologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Animais , Sequência de Bases , Previsões , Humanos , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Ataxias Espinocerebelares/metabolismo
3.
Stereotact Funct Neurosurg ; 97(4): 241-243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31743916

RESUMO

The beneficial effect of thalamic deep brain stimulation (DBS) on action tremor has been reported in a few cases of spinocerebellar ataxia (SCA); however, several factors should be taken into account regarding the indication for DBS in advanced cases. We performed DBS of the ventral intermediate nucleus (Vim) of the thalamus for treatment of coarse action tremor in a patient with SCA2 (spinocerebellar ataxia type 2) in the wheelchair-bound stage. Although improvement of the tremor of the proximal part was incomplete, the patient regained substantial parts of daily functioning. The effect lasted for more than 6 years, and the suppression of tremor significantly contributed to maintaining the level of the patient's expression into the bedridden stage. Vim DBS can be a treatment option for tremor in SCA patients, even in the advanced stage, as long as the tremor is depriving the patient of behavioral expression. As residual proximal tremor may hamper functional recovery, DBS of other targets or multi-targets should be further explored to attain a better outcome.


Assuntos
Estimulação Encefálica Profunda/métodos , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/terapia , Tremor/diagnóstico por imagem , Tremor/terapia , Núcleos Ventrais do Tálamo/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Ataxias Espinocerebelares/fisiopatologia , Fatores de Tempo , Tremor/fisiopatologia , Núcleos Ventrais do Tálamo/fisiopatologia
4.
Neurotherapeutics ; 16(4): 1050-1073, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31435879

RESUMO

The effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment. A better understanding of the uncovered molecular mechanisms of the disease allowed the scientific community to develop strategies of potential therapy and helped to create some promising therapeutic approaches for SCA2 treatment. Recent progress in this field will be discussed in this review article.


Assuntos
Ataxina-2/genética , Peptídeos/genética , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Animais , Ataxina-2/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Mutação/fisiologia , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Estresse Oxidativo/fisiologia , Peptídeos/metabolismo , Ataxias Espinocerebelares/metabolismo , Transplante de Células-Tronco
5.
Neurotherapeutics ; 16(4): 1074-1096, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31432449

RESUMO

Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disorder characterized by progressive neuronal loss in the cerebellum, brainstem, and retina, leading to cerebellar ataxia and blindness as major symptoms. SCA7 is due to the expansion of a CAG triplet repeat that is translated into a polyglutamine tract in ATXN7. Larger SCA7 expansions are associated with earlier onset of symptoms and more severe and rapid disease progression. Here, we summarize the pathological and genetic aspects of SCA7, compile the current knowledge about ATXN7 functions, and then focus on recent advances in understanding the pathogenesis and in developing biomarkers and therapeutic strategies. ATXN7 is a bona fide subunit of the multiprotein SAGA complex, a transcriptional coactivator harboring chromatin remodeling activities, and plays a role in the differentiation of photoreceptors and Purkinje neurons, two highly vulnerable neuronal cell types in SCA7. Polyglutamine expansion in ATXN7 causes its misfolding and intranuclear accumulation, leading to changes in interactions with native partners and/or partners sequestration in insoluble nuclear inclusions. Studies of cellular and animal models of SCA7 have been crucial to unveil pathomechanistic aspects of the disease, including gene deregulation, mitochondrial and metabolic dysfunctions, cell and non-cell autonomous protein toxicity, loss of neuronal identity, and cell death mechanisms. However, a better understanding of the principal molecular mechanisms by which mutant ATXN7 elicits neurotoxicity, and how interconnected pathogenic cascades lead to neurodegeneration is needed for the development of effective therapies. At present, therapeutic strategies using nucleic acid-based molecules to silence mutant ATXN7 gene expression are under development for SCA7.


Assuntos
Ataxina-7/genética , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/tendências , Marcação de Genes/tendências , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Animais , Ataxina-7/metabolismo , Autofagia/fisiologia , Encéfalo/metabolismo , Encéfalo/patologia , Sistemas de Liberação de Medicamentos/métodos , Marcação de Genes/métodos , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Neurônios/metabolismo , Neurônios/patologia , Peptídeos/genética , Peptídeos/metabolismo , Ataxias Espinocerebelares/metabolismo
6.
Neurotherapeutics ; 16(4): 999-1008, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31338702

RESUMO

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


Assuntos
Ataxina-1/genética , Ensaios Clínicos como Assunto/métodos , Sistemas de Liberação de Medicamentos/tendências , Marcação de Genes/tendências , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Animais , Ataxina-1/antagonistas & inibidores , Ataxina-1/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Fármacos Atuantes sobre Aminoácidos Excitatórios/administração & dosagem , Fármacos Atuantes sobre Aminoácidos Excitatórios/metabolismo , Marcação de Genes/métodos , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Interferência de RNA/efeitos dos fármacos , Interferência de RNA/fisiologia , Ataxias Espinocerebelares/metabolismo
7.
Neurotherapeutics ; 16(4): 1097-1105, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31317427

RESUMO

Spinocerebellar ataxia type 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP), which functions as a general transcription factor. Like other polyQ expansion-mediated diseases, SCA17 is characterized by late-onset and selective neurodegeneration, despite the disease protein being ubiquitously expressed in the body. To date, the pathogenesis of polyQ diseases is not fully understood, and there are no effective treatments for these devastating disorders. The well-characterized function of TBP and typical neurodegeneration in SCA17 give us opportunities to understand how polyQ expansion causes selective neurodegeneration and to develop effective therapeutics. In this review, we discuss the molecular mechanisms behind SCA17, focusing on transcriptional dysregulation as its major cause. Mounting evidence suggests that reversing transcriptional alterations induced by mutant TBP and reducing the expression of mutant TBP are promising strategies to treat SCA17.


Assuntos
Modelos Animais de Doenças , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Proteína de Ligação a TATA-Box/genética , Transcrição Genética/fisiologia , Expansão das Repetições de Trinucleotídeos/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Ataxias Espinocerebelares/metabolismo , Proteína de Ligação a TATA-Box/metabolismo
8.
Nat Rev Dis Primers ; 5(1): 24, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975995

RESUMO

The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of autosomal dominantly inherited progressive disorders, the clinical hallmark of which is loss of balance and coordination accompanied by slurred speech; onset is most often in adult life. Genetically, SCAs are grouped as repeat expansion SCAs, such as SCA3/Machado-Joseph disease (MJD), and rare SCAs that are caused by non-repeat mutations, such as SCA5. Most SCA mutations cause prominent damage to cerebellar Purkinje neurons with consecutive cerebellar atrophy, although Purkinje neurons are only mildly affected in some SCAs. Furthermore, other parts of the nervous system, such as the spinal cord, basal ganglia and pontine nuclei in the brainstem, can be involved. As there is currently no treatment to slow or halt SCAs (many SCAs lead to premature death), the clinical care of patients with SCA focuses on managing the symptoms through physiotherapy, occupational therapy and speech therapy. Intense research has greatly expanded our understanding of the pathobiology of many SCAs, revealing that they occur via interrelated mechanisms (including proteotoxicity, RNA toxicity and ion channel dysfunction), and has led to the identification of new targets for treatment development. However, the development of effective therapies is hampered by the heterogeneity of the SCAs; specific therapeutic approaches may be required for each disease.


Assuntos
Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/terapia , Fatores Etários , Progressão da Doença , Humanos , Programas de Rastreamento/métodos , Fármacos Neuroprotetores/uso terapêutico , Equilíbrio Postural/fisiologia , Riluzol/uso terapêutico , Distúrbios da Fala/etiologia , Ataxias Espinocerebelares/epidemiologia
9.
CNS Neurol Disord Drug Targets ; 18(4): 279-293, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30864514

RESUMO

BACKGROUND & OBJECTIVE: The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides. CONCLUSION: The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few year's promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future.


Assuntos
Ataxias Espinocerebelares/diagnóstico , Expansão das Repetições de Trinucleotídeos , Animais , Terapia Genética , Humanos , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Avaliação de Sintomas
10.
Neuropathol Appl Neurobiol ; 45(6): 531-537, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30636067

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the SACS gene, which encodes for SACSIN. Although animal models are still necessary to investigate the role of SACSIN in the pathology of this disease, more reliable human cellular models need to be generated to better understand the cerebellar pathophysiology of ARSACS. The discovery of human induced pluripotent stem cells (hiPSC) has permitted the derivation of patient-specific cells. These cells have an unlimited self-renewing capacity and the ability to differentiate into different neural cell types, allowing studies of disease mechanism, drug discovery and cell replacement therapies. In this study, we discuss how the hiPSC-derived cerebellar organoid culture offers novel strategies for targeting the pathogenic mutations related to ARSACS. We also highlight the advantages and challenges of this 3D cellular model, as well as the questions that still remain unanswered.


Assuntos
Doenças Cerebelares/patologia , Cerebelo/patologia , Espasticidade Muscular/patologia , Ataxias Espinocerebelares/congênito , Animais , Doenças Cerebelares/terapia , Humanos , Células-Tronco Pluripotentes Induzidas , Modelos Teóricos , Espasticidade Muscular/terapia , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/terapia
11.
J Neurol ; 266(2): 533-544, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30284037

RESUMO

Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative ataxic disorders with autosomal dominant inheritance. We aim to provide an update on the recent clinical and scientific progresses in SCA where numerous novel genes have been identified with next-generation sequencing techniques. The main disease mechanisms of these SCAs include toxic RNA gain-of-function, mitochondrial dysfunction, channelopathies, autophagy and transcription dysregulation. Recent studies have also demonstrated the importance of DNA repair pathways in modifying SCA with CAG expansions. In addition, we summarise the latest technological advances in detecting known and novel repeat expansion in SCA. Finally, we discuss the roles of antisense oligonucleotides and RNA-based therapy as potential treatments.


Assuntos
Ataxias Espinocerebelares/diagnóstico , Humanos , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/terapia
12.
Medicine (Baltimore) ; 97(36): e12148, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30200108

RESUMO

RATIONALE: Spinocerebellar ataxia (SCA), a genetically inherited heterogeneous disorder, is characterized by gait ataxia, dysarthria, parkinsonism, choreic movements, dystonia, epilepsy, cognitive and psychiatric symptoms. Spinocerebellar ataxia-42 (SCA42), caused by heterozygous mutation in the calcium channel 1G (CACNA1G) gene, is a rare SCA subtype and the transmission pattern is autosomal dominant inheritance. PATIENT CONCERNS: We presented a novel mutation (c.4721T>A; p.Met1574Lys) in 3 patients from a Chinese family using whole-exome sequencing. All patients exhibited cerebellar ataxia and the clinical manifestations were similar to those that were previously reported in the French and Japanese families. In addition, cerebral magnetic resonance imaging (MRI) showed cerebellar atrophy, and the hot cross bun sign of brainstem was found in the proband and her sister. DIAGNOSES: The clinical features and MRI findings indicated the diagnosis of SCA. Taken together, the symptoms, MRI findings, as well as whole-exome sequencing made the diagnosis of SCA42 most likely candidate. INTERVENTIONS AND OUTCOMES: The patient was treated with cobamamide (1.5 mg once daily) for nerve nutrition and further physical therapy. At the 4-month follow-up visit, the patient's condition did not improve obviously. LESSONS: Recently, a missense mutation in CACNA1G gene (c.5144G4A; p.Arg1715His) was identified in French and Japanese families with SCA42. However, there has been no report of SCA42 or its mutant loci in Chinese patients. Our finding showed a novel mutation in CACNA1G gene and provided important insights into the pathogenesis of SCA42.


Assuntos
Canais de Cálcio Tipo T/genética , Mutação , Ataxias Espinocerebelares/genética , Família , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/terapia
13.
Artigo em Inglês | MEDLINE | ID: mdl-30191086

RESUMO

Background: Access to medical care in many regions is limited by socioeconomic status, at both the individual and the community level. This report describes the diagnostic process of a family residing on an underserved Caribbean island where routine neurological care is typically addressed by general practitioners, and genetic diagnosis is not available through regular medical channels. The diagnosis and management of neurodegenerative disorders is especially challenging in this setting. Case Report: We diagnosed a family with spinocerebellar ataxia type 3 (SCA3) in an underdeveloped nation with limited access to genetic medicine and no full-time neurologist. Discussion: Molecular diagnosis of the SCAs can be challenging, even in developed countries. In the Caribbean, genetic testing is generally only available at a small number of academic centers. Diagnosis in this family was ultimately made by utilizing an international, pro bono, research-based collaborative process. Although access to appropriate resources, such as speech, physical, and occupational therapies, is limited on this island because of economic and geographical factors, the provision of a diagnosis appeared to be ultimately beneficial for this family. Identification of affected families highlights the need for access to genetic diagnosis in all communities, and can help direct resources where needed.


Assuntos
Gerenciamento Clínico , Saúde da Família , Ataxias Espinocerebelares/diagnóstico , Adulto , Ataxina-3/genética , Feminino , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Expansão das Repetições de Trinucleotídeos/genética , Índias Ocidentais
14.
Arq Neuropsiquiatr ; 76(8): 555-562, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30231129

RESUMO

Spinocerebellar ataxias (SCA) are a clinically and genetically heterogeneous group of monogenic diseases that share ataxia and autosomal dominant inheritance as the core features. An important proportion of SCAs are caused by CAG trinucleotide repeat expansions in the coding region of different genes. In addition to genetic heterogeneity, clinical features transcend motor symptoms, including cognitive, electrophysiological and imaging aspects. Despite all the progress in the past 25 years, the mechanisms that determine how neuronal death is mediated by these unstable expansions are still unclear. The aim of this article is to review, from an historical point of view, the first CAG-related ataxia to be genetically described: SCA 1.


Assuntos
Ataxina-1/genética , Ataxias Espinocerebelares/genética , Ataxina-1/história , Disfunção Cognitiva/fisiopatologia , Depressão/fisiopatologia , História do Século XX , Humanos , Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Transtornos do Sono-Vigília/fisiopatologia , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/história , Ataxias Espinocerebelares/terapia , Expansão das Repetições de Trinucleotídeos/genética
15.
J Neurol ; 265(9): 2040-2051, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29959555

RESUMO

INTRODUCTION: To study the long-term evolution of patient-reported outcome measures (PROMs) in the most common spinocerebellar ataxias (SCAs), we analyzed 8 years follow-up data of the EUROSCA Natural History Study, a cohort study of 526 patients with SCA1, SCA2, SCA3 and SCA6. METHODS: To assess the functional capacity in daily living, we used the functional assessment (part IV) of the Unified Huntington's Disease Rating Scale (UHDRS-IV), for health-related quality of life the visual analogue scale of the EuroQol Five Dimensions Questionnaire (EQ-5D VAS), and for depressive symptoms the Patient Health Questionnaire (PHQ-9). Severity of ataxia was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and neurological symptoms other than ataxia with the Inventory of Non-Ataxia Signs (INAS). RESULTS: UHDRS-IV [SCA1: - 1.35 (0.12); SCA2: - 1.15 (0.11); SCA3: - 1.16 (0.11); SCA6: - 0.99 (0.12)] and EQ-5D [SCA1: - 2.88 (0.72); SCA2: - 1.97 (0.49); SCA3: - 2.06 (0.55); SCA6: - 1.03 (0.57)] decreased linearly, whereas PHQ-9 increased [SCA1: 0.15 (0.04); SCA2: 0.09 (0.03); SCA3: 0.06 (0.04); SCA6: 0.07 (0.04)] during the observational period. Standard response means (SRMs) of UHDRS-IV (0.473-0.707) and EQ-5D VAS (0.053-0.184) were lower than that of SARA (0.404-0.979). In SCA1, higher SARA scores [- 0.0288 (0.01), p = 0.0251], longer repeat expansions [- 0.0622 (0.02), p = 0.0002] and the presence of cognitive impairment at baseline [- 0.5381 (0.25), p = 0.0365] were associated with faster UHDRS-IV decline. In SCA3, higher INAS counts were associated with a faster UHDRS-IV decline [- 0.05 (0.02), p = 0.0212]. In SCA1, PHQ-9 progression was faster in patients with cognitive impairment [0.14 (0.07); p = 0.0396]. CONCLUSIONS: In the common SCAs, PROMs give complementary information to the information provided by neurological scales. This underlines the importance of PROMs as additional outcome measures in future interventional trials.


Assuntos
Atividades Cotidianas , Qualidade de Vida , Ataxias Espinocerebelares/terapia , Idoso , Depressão , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Índice de Gravidade de Doença , Ataxias Espinocerebelares/fisiopatologia , Ataxias Espinocerebelares/psicologia
16.
J Neurol ; 265(9): 2060-2070, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29968200

RESUMO

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early onset neurodegenerative disease that typically results in ataxia, upper motor neuron dysfunction and sensorimotor peripheral neuropathy. Dysarthria and dysphagia are anecdotally described as key features of ARSACS but the nature, severity and impact of these deficits in ARSACS are not known. A comprehensive quantitative and qualitative characterization of speech and swallowing function will support diagnostics, provide insights into the underlying pathology, and guide day-to-day clinical management. METHODS: 11 consecutive non-Quebec ARSACS patients were recruited, and compared to healthy participants from several published and unpublished cohorts. A comprehensive behavioural assessment including objective acoustic analysis and expert perceptual ratings of motor speech, the Clinical Assessment of Dysphagia in Neurodegeneration (CADN), videofluoroscopy and standardized tests of dysarthria and swallowing related quality of life was conducted. RESULTS: Speech in this ARSACS cohort is characterized by pitch breaks, prosodic deficits including reduced rate and prolonged intervals, and articulatory deficits. The swallowing profile was characterized by delayed initiation of the swallowing reflex and late epiglottic closure. Four out of ten patients were observed aspirating thin liquids on videofluoroscopy. Patients report that they regularly cough or choke on thin liquids and solids during mealtimes. Swallowing and speech-related quality of life was worse than healthy controls on all domains except sleep. CONCLUSIONS: The dysphagia and dysarthria profile of this ARSACS cohort reflects impaired coordination and timing. Dysphagia contributes to a significant impairment in functional quality of life in ARSACS, and appears to manifest distinctly from other ARSACS dysfunctions such as ataxia or spasticity.


Assuntos
Transtornos de Deglutição/fisiopatologia , Espasticidade Muscular/fisiopatologia , Distúrbios da Fala/fisiopatologia , Ataxias Espinocerebelares/congênito , Adolescente , Adulto , Criança , Deglutição , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/terapia , Pesquisa Qualitativa , Qualidade de Vida , Fala , Distúrbios da Fala/diagnóstico por imagem , Distúrbios da Fala/etiologia , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/fisiopatologia , Ataxias Espinocerebelares/terapia , Fatores de Tempo , Adulto Jovem
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(2): 284-287, 2018 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-29653012

RESUMO

Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal dominant progressive degenerative disease of the nervous system, which is characterized by a progressive cerebellar syndrome associated with saccadic eye scan, peripheral neuropathy, cognitive disorders, and other multisystem features. The gene predisposing to SCA2 has been mapped, which encodes the ataxin 2 protein. A CAG repeat expansion in the coding region of ATXN2 gene can cause extension of polyglutamine chain in the protein. This paper reviews recent progress made in the research on SCA2 in regard to its clinical features, pathology, etiology, pathogenesis and treatment.


Assuntos
Ataxias Espinocerebelares/genética , Animais , Ataxina-2/genética , Humanos , Ataxias Espinocerebelares/etiologia , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/terapia
18.
Adv Exp Med Biol ; 1049: 135-145, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29427101

RESUMO

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, inherited disease that leads to degeneration of Purkinje cells of the cerebellum and culminates in death 10-30 years after disease onset. SCA1 is caused by a CAG repeat mutation in the ATXN1 gene, encoding the ATXN1 protein with an abnormally expanded polyglutamine tract. As neurodegeneration progresses, other brain regions become involved and contribute to cognitive deficits as well as problems with speech, swallowing, and control of breathing. The fundamental basis of pathology is an aberration in the normal function of Purkinje cells affecting regulation of gene transcription and RNA splicing. Glutamine-expanded ATXN1 is highly stable and more resistant to degradation. Moreover, phosphorylation at S776 in ATXN1 is a post-translational modification known to influence protein levels. SCA1 remains an untreatable disease managed only by palliative care. Preclinical studies are founded on the principle that mutant protein load is toxic and attenuating ATXN1 protein levels can alleviate disease. Two approaches being pursued are targeting gene expression or protein levels. Viral delivery of miRNAs harnesses the RNAi pathway to destroy ATXN1 mRNA. This approach shows promise in mouse models of disease. At the protein level, kinase inhibitors that block ATXN1-S776 phosphorylation may lead to therapeutic clearance of unphosphorylated ATXN1.


Assuntos
Ataxina-1 , Processamento de Proteína Pós-Traducional , Células de Purkinje , Processamento de RNA , Ataxias Espinocerebelares , Transcrição Genética , Animais , Ataxina-1/biossíntese , Ataxina-1/genética , Terapia Genética/métodos , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Fosforilação , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Estabilidade de RNA/genética , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/terapia
19.
Adv Exp Med Biol ; 1049: 197-218, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29427104

RESUMO

Spinocerebellar Ataxia type 7 (SCA7, OMIM # 164500) is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive cerebellar ataxia and blindness. SCA7 is part of the large family of autosomal dominant cerebellar ataxias (ADCAs), and was estimated to account for 1-11.7% of ADCAs in diverse populations. The frequency of SCA7 is higher where local founder effects were observed as in Scandinavia, Korea, South Africa and Mexico. SCA7 is pathomechanistically related to the group of CAG/polyglutamine (polyQ) expansion disorders, which includes other SCAs (1-3, 6 and 17), Huntington's disease, spinal bulbar muscular atrophy and dentatorubro pallidoluysian atrophy. Two distinctive characteristics of SCA7 are the strong anticipation by which earlier onset and more severe symptoms are observed in successive generations of affected families, and the loss of visual acuity due to cone-rod dystrophy of the retina. The pathology is caused by an unstable CAG repeat expansion coding for a polyQ stretch in Ataxin-7 (ATXN7). PolyQ expansion in ATXN7 confers toxic properties and leads to selective neuronal degeneration in the cerebellum, the brain stem and the retina. Herein, we summarize the genetic, clinical and pathological features of SCA7 and review our current knowledge of pathomechanisms and preclinical studies.


Assuntos
Tronco Encefálico , Cerebelo , Peptídeos , Retina , Ataxias Espinocerebelares , Expansão das Repetições de Trinucleotídeos , Animais , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Efeito Fundador , Humanos , Peptídeos/genética , Peptídeos/metabolismo , Retina/metabolismo , Retina/patologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/terapia
20.
Handb Clin Neurol ; 147: 173-185, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29325610

RESUMO

Spinocerebellar ataxias (SCAs) are a genetically diverse group of dominantly inherited disorders that share clinical features that result from dysfunction and degeneration of the cerebellum and its associated pathways. Although nearly 40 genes are currently recognized to result in SCA, shared mechanisms for disease pathogenesis exist among subsets of the SCAs. The most common SCAs result from a glutamine-encoding CAG repeat in the respective disease genes. This chapter discusses the varied genetic etiology of SCA and attempts to categorize these disorders based on shared mechanisms of disease. We also summarize evaluation and management for the SCAs.


Assuntos
Genes Dominantes/genética , Proteínas do Tecido Nervoso/genética , Ataxias Espinocerebelares , Expansão das Repetições de Trinucleotídeos/genética , Cerebelo/patologia , Variação Genética , Humanos , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/fisiopatologia , Ataxias Espinocerebelares/terapia
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