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Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (â¼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that â¼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.
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Testes Genéticos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Testes Genéticos/métodos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Glucosilceramidase/genética , alfa-Sinucleína/genética , Predisposição Genética para Doença , Ubiquitina-Proteína Ligases/genética , Estudos de Coortes , Proteínas Quinases/genética , Mutação , AdultoRESUMO
BACKGROUND: Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD). OBJECTIVE: The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. METHODS: We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60. RESULTS: tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. CONCLUSIONS: tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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BACKGROUND: Impulse-control and related behavioral disorders (ICBDs) significantly impact the lives of Parkinson's disease (PD) patients and caregivers, with lasting consequences if undiagnosed and untreated. While ICBD pathophysiology and risk factors are well-studied, a standardized severity definition and treatment evidence remain elusive. OBJECTIVE: This work aimed to establish international expert consensus on ICBD treatment strategies. To comprehensively address diverse treatment availabilities, experts from various continents were included. METHODS: From 2021 to 2023, global movement disorders specialists engaged in a Delphi process. A core expert group initiated surveys, involving a larger panel in three iterations, leading to refined severity definitions and treatment pathways. RESULTS: Experts achieved consensus on defining ICBD severity, emphasizing regular PD patient screenings for early detection. General treatment recommendations focused on continuous monitoring, collaboration with significant others, and seeking specialist advice for legal or financial challenges. For mild to severe ICBDs, gradual reduction in dopamine agonists was endorsed, followed by reductions in other PD medications. Second-line treatment strategies included diverse approaches like reversing the last medication change, cognitive behavior therapy, subthalamic nucleus deep brain stimulation, and specific medications like quetiapine, clozapine, and antidepressants. The panel reached consensus on distinct treatment pathways for punding and dopamine dysregulation syndrome, formulating therapy recommendations. Comprehensive discussions addressed management strategies for the exacerbation of either motor or non-motor symptoms following the proposed treatments. CONCLUSION: The consensus offers in-depth insights into ICBD management, presenting clear severity criteria and expert consensus treatment recommendations. The study highlights the critical need for further research to enhance ICBD management. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Estimulação Encefálica Profunda , Transtornos Disruptivos, de Controle do Impulso e da Conduta , Transtornos Mentais , Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Doença de Parkinson/tratamento farmacológico , Consenso , Transtornos Mentais/terapia , Dopamina/metabolismo , Agonistas de Dopamina/uso terapêutico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/terapiaRESUMO
This document presents a consensus on the diagnosis and classification of isolated cervical dystonia (iCD) with a review of proposed terminology. The International Parkinson and Movement Disorder Society Dystonia Study Group convened a panel of experts to review the main clinical and diagnostic issues related to iCD and to arrive at a consensus on diagnostic criteria and classification. These criteria are intended for use in clinical research, but also may be used to guide clinical practice. The benchmark is expert clinical observation and evaluation. The criteria aim to systematize the use of terminology as well as the diagnostic process, to make it reproducible across centers and applicable by expert and non-expert clinicians. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations, which are incorporated into the current criteria. Three iCD presentations are described in some detail: idiopathic (focal or segmental) iCD, genetic iCD, and acquired iCD. The relationship between iCD and isolated head tremor is also reviewed. Recognition of idiopathic iCD has two levels of certainty, definite or probable, supported by specific diagnostic criteria. Although a probable diagnosis is appropriate for clinical practice, a higher diagnostic level may be required for specific research studies. The consensus retains elements proven valuable in previous criteria and omits aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of iCD expands, these criteria will need continuous revision to accommodate new advances. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Distúrbios Distônicos , Doença de Parkinson , Torcicolo , Humanos , Doença de Parkinson/diagnóstico , Torcicolo/diagnóstico , Distúrbios Distônicos/genética , Tremor , Consenso , Classificação Internacional de DoençasRESUMO
BACKGROUND: More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them. OBJECTIVE: This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for "defining the riddle" will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD. CONCLUSION: Accuracy in defining endophenotypes of "typical PD" across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Humanos , Doença de Parkinson/genética , Síndrome , Biomarcadores , Previsões , Sistema Nervoso Central/patologiaRESUMO
BACKGROUND: Dystonia is associated with disabling nonmotor symptoms like chronic pain (CP), which is prevalent in dystonia and significantly impacts the quality of life (QoL). There is no validated tool for assessing CP in dystonia, which substantially hampers pain management. OBJECTIVE: The aim was to develop a CP classification and scoring system for dystonia. METHODS: A multidisciplinary group was established to develop the Dystonia-Pain Classification System (Dystonia-PCS). The classification of CP as related or unrelated to dystonia was followed by the assessment of pain severity score, encompassing pain intensity, frequency, and impact on daily living. Then, consecutive patients with inherited/idiopathic dystonia of different spatial distribution were recruited in a cross-sectional multicenter validation study. Dystonia-PCS was compared to validated pain, mood, QoL, and dystonia scales (Brief Pain Inventory, Douleur Neuropathique-4 questionnaire, European QoL-5 Dimensions-3 Level Version, and Burke-Fahn-Marsden Dystonia Rating Scale). RESULTS: CP was present in 81 of 123 recruited patients, being directly related to dystonia in 82.7%, aggravated by dystonia in 8.8%, and nonrelated to dystonia in 7.5%. Dystonia-PCS had excellent intra-rater (Intraclass Correlation Coefficient - ICC: 0.941) and inter-rater (ICC: 0.867) reliability. In addition, pain severity score correlated with European QoL-5 Dimensions-3 Level Version's pain subscore (r = 0.635, P < 0.001) and the Brief Pain Inventory's severity and interference scores (r = 0.553, P < 0.001 and r = 0.609, P < 0.001, respectively). CONCLUSIONS: Dystonia-PCS is a reliable tool to categorize and quantify CP impact in dystonia and will help improve clinical trial design and management of CP in patients affected by this disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Distonia , Distúrbios Distônicos , Transtornos dos Movimentos , Humanos , Distonia/diagnóstico , Distonia/complicações , Qualidade de Vida , Estudos Transversais , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Distúrbios Distônicos/complicações , Distúrbios Distônicos/diagnóstico , Transtornos dos Movimentos/complicações , DorRESUMO
BACKGROUND: To compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as 'levodopa equivalent dose' (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed. OBJECTIVES: To update LED conversion formulae based on a systematic review. METHODS: The MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency. RESULTS: The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon. CONCLUSIONS: The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Levodopa , Doença de Parkinson , Humanos , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. OBJECTIVE: The objective of this study was to perform the first X-chromosome-wide association study for PD risk in a Latin American cohort. METHODS: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. RESULTS: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478-0.77], P = 3.13 × 10-5 replication odds ratio: 0.60 [0.37-0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome-wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. CONCLUSIONS: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Cromossomos Humanos X , Doença de Parkinson , Feminino , Humanos , Masculino , Estudo de Associação Genômica Ampla , Hispânico ou Latino , América Latina , Doença de Parkinson/genética , Fatores Sexuais , Cromossomos Humanos X/genética , Desequilíbrio de Ligação/genéticaRESUMO
BACKGROUND: Parkinsonism is strongly associated with ageing, and many studies have suggested that parkinsonian signs may affect up to half of older adults and is associated with a wide range of adverse health outcomes. We compared clinical and functional characteristics of oldest-old community-dwelling individuals with parkinsonism (parkinsonian group [PG]) to individuals without parkinsonism (non-parkinsonian group [NPG]. METHODS: The Pietà study is a population-based study conducted in Caeté, southeast Brazil, involving 607 individuals aged 75 + years submitted to an extensive clinical evaluation. A subset of 65 PG individuals (61.5% women, median age of 82 years) was compared to 542 NPG individuals (64.8% women, median age of 80 years). RESULTS: PG individuals had significantly more functional impairment, clinical comorbidities (including number of falls, loss of bladder control and dysphagia) and major depression. Multivariate analysis revealed that older age, higher UPDRSm scores, lower category fluency test (animals/minute) and delayed recall memory scores were associated with PG. This group was also more cognitively impaired, with lower performance than NPG individuals in the Mini-Mental State Examination, category fluency test (animals/minute), clock drawing and in delayed recall (p < 0.001 for all tests). UPDRSm scores were the most contributing factor to cognition that independently explained variability in functionality of the entire sample. CONCLUSION: Individuals aged 75 + years with parkinsonism were significantly more clinically and functionally impaired in this population-based sample. Cognitive dysfunction explained most of the loss of functionality in these patients. UPDRS-m scores contributed independently to explain variability in functionality in the whole sample.
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Disfunção Cognitiva , Transtornos Parkinsonianos , Feminino , Animais , Masculino , Transtornos Parkinsonianos/epidemiologia , Envelhecimento , Brasil/epidemiologia , CogniçãoRESUMO
PURPOSE: Eyelid spasms might be associated with elevated intraocular pressure (IOP) in hemifacial spasm (HFS) patients. IOP assessment using a Goldmann applanation tonometer (GAT) is often compromised by eyelid spasms. This study aimed to assess the effect of HFS on IOP measurements using the transpalpebral tonometer Diaton® before and after treatment with botulinum toxin type A (BTX-A) and compared Diaton® and GAT measurements after treatment with BTX-A. METHODS: IOP measurements were obtained with Diaton® in 27 patients with moderate-to-severe HFS before and after treatment with BTX-A. After treatment, the IOP was also measured using GAT and the results were compared with the ones measured with a Diaton®. The patients underwent automated perimetry, OCT, and pachymetry for screening to glaucoma. RESULTS: Mean IOP with Diaton® was 11 ± 3.42 mmHg before treatment in the affected eye and 9 ± 2.98 mmHg in the contralateral eye. This difference was statistically significant (P = 0.012). However, after treatment with BTX-A, no interocular difference was found in IOP obtained with Diaton® (P = 0.204) or GAT (P = 0.971). Comparison between GAT and Diaton® measurements showed no significant differences after BTX-A treatment between the affected (P = 0.212) and contralateral eye (P = 0.971). CONCLUSIONS: A significant reduction in IOP measurements on the affected side of HFS patients was observed after treatment with BTX-A, demonstrating that eyelid spasms may increase the IOP. No significant difference was observed between Diaton® and GAT measurements after the application of BTX-A. No differences were found in automated perimetry, OCT, and CCT when comparing affected eyes with contralateral eyes.
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Blefarospasmo , Toxinas Botulínicas , Glaucoma , Espasmo Hemifacial , Humanos , Pressão Intraocular , Reprodutibilidade dos Testes , Tonometria Ocular/métodos , Glaucoma/diagnóstico , Córnea , Blefarospasmo/diagnóstico , Blefarospasmo/tratamento farmacológico , PálpebrasRESUMO
BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. OBJECTIVES: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. METHODS: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. RESULTS: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. CONCLUSIONS: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.
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Apatia , Coreia , Doença de Huntington , Transtornos dos Movimentos , Humanos , Doença de Huntington/tratamento farmacológico , Doença de Huntington/terapia , Transtornos dos Movimentos/tratamento farmacológico , Tetrabenazina/uso terapêuticoRESUMO
BACKGROUND: Episodic memory impairment may occur in progressive supranuclear palsy (PSP). However, it remains uncertain whether this is due to executive dysfunction or to the involvement of brain areas responsible for memory. OBJECTIVES: To investigate the specific brain regions underlying episodic memory impairment in PSP. METHODS: Twenty-one patients with PSP and 20 healthy controls underwent the Figure Memory Test (FMT) from the Brief Cognitive Screening Battery and brain MRI. We explored correlations between gray matter volumes and memory scores in PSP patients, adjusting for age and performance on the Frontal Assessment Battery. RESULTS: PSP patients performed worse than controls (p < 0.001) on delayed recall in the FMT. Delayed recall scores correlated to bilateral hippocampal and parahippocampal volumes in PSP patients. CONCLUSIONS: Medial temporal structures may play a role in episodic memory impairment in PSP, suggesting that amnesia in PSP is not solely due to executive dysfunction.
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Memória Episódica , Paralisia Supranuclear Progressiva , Encéfalo/diagnóstico por imagem , Humanos , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/etiologia , Neuroimagem , Testes Neuropsicológicos , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/diagnóstico por imagemRESUMO
Chorea is defined by the presence of abnormal, involuntary, continuous, random movements that results from a number of autoimmune, hereditary, vascular, metabolic, drug-induced and functional (psychogenic) causes. Chorea may present at all stages of life, from newborns to elderly individuals. While Huntington disease is the main suspicion in adults presenting with chorea, once a drug-induced or parkinsonian dyskinesia have been ruled out; Huntington disease exceptionally presents with chorea in children. Sydenham chorea is considered the most common cause of acute childhood-onset chorea, but its prevalence has decreased in Western countries. However, in younger children other etiologies such as dyskinetic cerebral palsy, anti-NMDAR receptor encephalitis, other autoimmune conditions, or mutations in NKX2-1, ADCY-5, FOXG1, GNAO1, GPR88, SLC2A1, SQSTM1, ATP8A2, or SYT-1 should be considered. In this manuscript, we review the main causes, diagnosis and management of chorea in children.
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Doenças Autoimunes , Coreia , Doença de Huntington , Causalidade , Criança , Coreia/diagnóstico , Coreia/etiologia , Coreia/terapia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP , Humanos , MutaçãoRESUMO
There are many rare movement disorders, and new ones are described every year. Because they are not well recognized, they often go undiagnosed for long periods of time. However, early diagnosis is becoming increasingly important. Rapid advances in our understanding of the biological mechanisms responsible for many rare disorders have enabled the development of specific treatments for some of them. Well-known historical examples include Wilson disease and dopa-responsive dystonia, for which specific and highly effective treatments have life-altering effects. In recent years, similarly specific and effective treatments have been developed for more than 30 rare inherited movement disorders. These treatments include specific medications, dietary changes, avoidance or management of certain triggers, enzyme replacement therapy, and others. This list of treatable rare movement disorders is likely to grow during the next few years because a number of additional promising treatments are actively being developed or evaluated in clinical trials. © 2017 International Parkinson and Movement Disorder Society.
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Transtornos dos Movimentos/genética , Transtornos dos Movimentos/terapia , Doenças Raras/genética , Doenças Raras/terapia , Ensaios Clínicos como Assunto/métodos , Humanos , Resultado do TratamentoRESUMO
Chorea, a movement disorder characterised by a continuous flow of unpredictable muscle contractions, has a myriad of genetic and non-genetic causes. Although autoimmune processes are rare aetiology of chorea, they are relevant both for researchers and clinicians. The aim of this article is to provide a review of the epidemiology, clinical and laboratory features, pathogenesis and management of the most common autoimmune causes of chorea. Emphasis is given particularly to Sydenham's chorea, systemic lupus erythematosus, primary antiphospolipid antibody syndrome, paraneoplastic chorea and anti-N-methyl-d-aspartate receptor encephalitis.
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Doenças Autoimunes do Sistema Nervoso/diagnóstico , Coreia/epidemiologia , Coreia/imunologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Doenças Autoimunes do Sistema Nervoso/etiologia , Humanos , Lúpus Eritematoso Sistêmico/diagnósticoRESUMO
PACT is a stress-modulated activator of the interferon-induced double-stranded RNA-activated protein kinase (PKR). Stress-induced phosphorylation of PACT is essential for PACT's association with PKR leading to PKR activation. PKR activation leads to phosphorylation of translation initiation factor eIF2α inhibition of protein synthesis and apoptosis. A recessively inherited form of early-onset dystonia DYT16 has been recently identified to arise due to a homozygous missense mutation P222L in PACT. To examine if the mutant P222L protein alters the stress-response pathway, we examined the ability of mutant P222L to interact with and activate PKR. Our results indicate that the substitution mutant P222L activates PKR more robustly and for longer duration albeit with slower kinetics in response to the endoplasmic reticulum stress. In addition, the affinity of PACT-PACT and PACT-PKR interactions is enhanced in dystonia patient lymphoblasts, thereby leading to intensified PKR activation and enhanced cellular death. P222L mutation also changes the affinity of PACT-TRBP interaction after cellular stress, thereby offering a mechanism for the delayed PKR activation in response to stress. Our results demonstrate the impact of a dystonia-causing substitution mutation on stress-induced cellular apoptosis.
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Apoptose , Distonia , Mutação de Sentido Incorreto , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , eIF-2 Quinase/metabolismo , Substituição de Aminoácidos , Distonia/genética , Distonia/metabolismo , Distonia/patologia , Feminino , Células HeLa , Humanos , Masculino , eIF-2 Quinase/genéticaRESUMO
UNLABELLED: Influenza virus neuraminidase (NA) is an interesting target of small-molecule antiviral drugs. We isolated a set of H5N1 NA-specific single-domain antibodies (N1-VHHm) and evaluated their in vitro and in vivo antiviral potential. Two of them inhibited the NA activity and in vitro replication of clade 1 and 2 H5N1 viruses. We then generated bivalent derivatives of N1-VHHm by two methods. First, we made N1-VHHb by genetically joining two N1-VHHm moieties with a flexible linker. Second, bivalent N1-VHH-Fc proteins were obtained by genetic fusion of the N1-VHHm moiety with the crystallizable region of mouse IgG2a (Fc). The in vitro antiviral potency against H5N1 of both bivalent N1-VHHb formats was 30- to 240-fold higher than that of their monovalent counterparts, with 50% inhibitory concentrations in the low nanomolar range. Moreover, single-dose prophylactic treatment with bivalent N1-VHHb or N1-VHH-Fc protected BALB/c mice against a lethal challenge with H5N1 virus, including an oseltamivir-resistant H5N1 variant. Surprisingly, an N1-VHH-Fc fusion without in vitro NA-inhibitory or antiviral activity also protected mice against an H5N1 challenge. Virus escape selection experiments indicated that one amino acid residue close to the catalytic site is required for N1-VHHm binding. We conclude that single-domain antibodies directed against influenza virus NA protect against H5N1 virus infection, and when engineered with a conventional Fc domain, they can do so in the absence of detectable NA-inhibitory activity. IMPORTANCE: Highly pathogenic H5N1 viruses are a zoonotic threat. Outbreaks of avian influenza caused by these viruses occur in many parts of the world and are associated with tremendous economic loss, and these viruses can cause very severe disease in humans. In such cases, small-molecule inhibitors of the viral NA are among the few treatment options for patients. However, treatment with such drugs often results in the emergence of resistant viruses. Here we show that single-domain antibody fragments that are specific for NA can bind and inhibit H5N1 viruses in vitro and can protect laboratory mice against a challenge with an H5N1 virus, including an oseltamivir-resistant virus. In addition, plant-produced VHH fused to a conventional Fc domain can protect in vivo even in the absence of NA-inhibitory activity. Thus, NA of influenza virus can be effectively targeted by single-domain antibody fragments, which are amenable to further engineering.
Assuntos
Antivirais/uso terapêutico , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Infecções por Orthomyxoviridae/prevenção & controle , Anticorpos de Domínio Único/uso terapêutico , Animais , Antivirais/imunologia , Modelos Animais de Doenças , Feminino , Virus da Influenza A Subtipo H5N1/imunologia , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Anticorpos de Domínio Único/imunologia , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the clinical and radiological features of vascular parkinsonism (VP) and Parkinson's disease (PD). METHODS: Cross-sectional study where 15 patients with VP (8 (53.3%) men; aged 75.7 ± 10.4 years) and 30 patients with PD (17 (56.7%) men; aged 67.3 ± 7.5 years) underwent motor and cognitive evaluation and brain MRI. RESULTS: Patients with VP were, on average, 8.4 years older (p = 0.004); all had arterial hypertension. They presented with a sudden onset of parkinsonism (80%) and a rapidly progressive clinical course (53.3%). Predominant lower body parkinsonism (p<0.001), postural instability (p=0.003) with freezing of gait (p<0.001) and falls (p<0.001), urinary incontinence (p < 0.001) and pyramidal signs (p<0.001) were more common in patients with VP. Movement Disorders Society's Unified PD Rating Scale (MDS-UPDRS) scores were higher in patients with VP (p=0.005 in 'OFF' state and p<0.001 in 'ON' state). They had greater cognitive impairment and 12 (80%) fulfilled diagnostic criteria for probable vascular dementia. Most patients with VP had brain MRI changes: multiple lacunar infarcts (66.7%) or extensive white matter disease (26.7%). CONCLUSIONS: VP can be clinically distinguished from PD based on sudden onset of parkinsonism at an older age, characterised by lower body predominance, urinary incontinence, pyramidal signs, postural instability with freezing of gait and falls, and dementia.