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1.
Mov Disord ; 38(3): 368-377, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36374860

RESUMO

Spinocerebellar ataxia type 17 or ATX-TBP is a CAG/CAA repeat expansion disorder characterized by marked clinical heterogeneity. Reports of affected carriers with subthreshold repeat expansions and of patients with Parkinson's disease (PD) with expanded repeats have cast doubt on the established cutoff values of the expansions and the phenotypic spectrum of this disorder. The objective of this systematic review was to explore the genotype-phenotype relationships for repeat expansions in TBP to delineate the ATX-TBP phenotype and reevaluate the pathological range of repeat expansions. The International Parkinson and Movement Disorder Society Genetic Mutation Database (MDSGene) standardized data extraction protocol was followed. Clinically affected carriers of reported ATX-TBP expansions were included. Publications that contained repeat sizes in screened cohorts of patients with PD and/or healthy individuals were included for a separate evaluation of cutoff values. Phenotypic and genotypic data for 346 ATX-TBP patients were curated. Overall, 97.7% of the patients had ≥41 repeats, while 99.6% of patients with PD and 99.9% of healthy individuals had ≤42 repeats, with a gray zone of reduced penetrance between 41 and 45 repeats. Pure parkinsonism was more common in ATX-TBP patients with 41 to 45 repeats than in the group with ≥46 repeats, which conversely more often presented with a complex phenotype with mixed movement disorders. An updated genotype-phenotype assessment for ATX-TBP is provided, and new repeat expansion cutoff values of reduced penetrance (41-45 expanded repeats) and full penetrance (46-66 expanded repeats) are proposed. These adjusted cutoff values will have diagnostic and counseling implications and may guide future clinical trial protocol. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson , Ataxias Espinocerebelares , Humanos , Estudos de Associação Genética , Doença de Parkinson/genética , Ataxias Espinocerebelares/genética , Proteína de Ligação a TATA-Box/genética , Expansão das Repetições de Trinucleotídeos
2.
Eur J Neurol ; 30(10): 3377-3393, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37422902

RESUMO

BACKGROUND: Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms. METHODS: We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/). RESULTS: Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'. CONCLUSION: Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.


Assuntos
Ataxia , Transtornos dos Movimentos , Humanos , Ataxia/genética , Genótipo , Fenótipo
3.
Can J Neurol Sci ; : 1-8, 2023 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-37462070

RESUMO

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) therapy has been shown to be a safe and effective treatment for advanced Parkinson's disease (PD). Limited data are available regarding long-term benefits and complications in Canada. Objective of the study was to review long-term experience and clinical outcomes in PD patients with LCIG therapy over 11 years in a multidisciplinary University clinic setting. METHODS: Chart review was done on PD patients with LCIG from 2011 to 2022. Data collected: dosing, UPDRS-III motor scores, OFF times, hours with dyskinesias, MoCA, complications, discontinuation reasons, and nursing time requirements. RESULTS: Thirty-three patients received LCIG therapy with a mean follow-up of 3.25±2.09 years. UPDRS-III scores showed reduction of 15% from baseline (mean 35.9) up to 4 years (mean 30.4). Daily OFF time improved from baseline (mean 7.1 ± 3.13 hours) up to 5 years (mean 3.3 ± 2.31 hours; -53.5%; p < 0.048), and dyskinesias remained stable. Nursing time averaged 22 hours per patient per year after PEG-J insertion and titration. Most common complications were PEG-J tube dislodgement and stoma site infection (0-3zero to three events/patient/year). Serious side effects were seen in four (12%) patients resulting in hospitalization and/or death. Nine patients (27.2%) discontinued the treatment due to lack of improved efficacy over oral therapy or development of dementia and 10 (30%) died of causes unrelated to LCIG infusion. CONCLUSION: Patients on LCIG showed improved motor function over 5-year follow-up. Serious complications were uncommon. Dedicated nursing time is required by LCIG-trained nurses in a multidisciplinary setting for optimum management.

4.
World Neurosurg ; 142: e89-e94, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32540287

RESUMO

BACKGROUND: Appropriate patient selection is critical for successful deep brain stimulation (DBS) for Parkinson disease (PD). Subcortical atrophy is a possible determinant of postoperative DBS outcomes in patients with idiopathic PD, but it has not been well evaluated for DBS of the globus pallidus interna (GPi). We investigated perioperative subcortical atrophy measures in patients with PD and their relationship to postoperative motor response in bilateral GPi-targeted DBS. METHODS: A retrospective cohort study examined correlations among indices of subcortical volumetry, disease duration, and age with postoperative outcomes at 6 months (Unified Parkinson's Disease Rating Scale Part III motor score quotient, levodopa equivalent daily dosing, and 39-item Parkinson's Disease Questionnaire mobility subscore). Subcortical volumetry was assessed by bicaudate ratio, Evans index, and third ventricular width on perioperative imaging. Linear regression models established correlations between preoperative variables and postoperative outcomes. RESULTS: Data from 34 patients with PD who were treated with GPi-targeted DBS were evaluated. Age was found to exhibit statistically significant positive correlations with all 3 measures of subcortical atrophy (P ≤ 0.002). None of the measures correlated with disease duration. Only Evans index and third ventricular width correlated with preoperative medication response (P < 0.05). Age and all 3 measures of atrophy exhibited statistically significant correlations with Unified Parkinson's Disease Rating Scale Part III motor score quotient (P ≤ 0.01), but not with levodopa equivalent daily dosing or 39-item Parkinson's Disease Questionnaire motor subscores (P > 0.05). CONCLUSIONS: Perioperative age and subcortical atrophy as measured in this study correlated with motor responsiveness at 6 months postoperatively among patients receiving bilateral GPi-targeted DBS stimulation for PD.


Assuntos
Encéfalo/diagnóstico por imagem , Núcleo Caudado/diagnóstico por imagem , Estimulação Encefálica Profunda/métodos , Globo Pálido , Doença de Parkinson/terapia , Idoso , Atrofia , Encéfalo/patologia , Núcleo Caudado/patologia , Estudos de Coortes , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
5.
Artigo em Inglês | MEDLINE | ID: mdl-29657900

RESUMO

OBJECTIVE: To determine whether occipital and cingulate hypometabolism is being under-reported or missed on 18-fluorodeoxyglucose positron emission tomography (FDG-PET) CT scans in patients with Dementia with Lewy Bodies (DLB). BACKGROUND: Recent studies have reported higher sensitivity and specificity for occipital and cingulate hypometabolism on FDG-PET of DLB patients. METHODS: This retrospective chart review looked at regions of interest (ROI's) in FDG-PET CT scan reports in 35 consecutive patients with a clinical diagnosis of probable, possible, or definite DLB as defined by the latest DLB Consortium Report. ROI's consisting of glucose hypometabolism in frontal, parietal, temporal, occipital, and cingulate areas were tabulated and charted separately by the authors from the reports. A blinded Nuclear medicine physician read the images independently and marked ROI's separately. A Cohen's Kappa coefficient statistic was calculated to determine agreement between the reports and the blinded reads. RESULTS: On the radiology reports, 25.71% and 17.14% of patients reported occipital and cingulate hypometabolism respectively. Independent reads demonstrated significant disagreement with the proportion of occipital and cingulate hypometabolism being reported on initial reads: 91.43% and 85.71% respectively. Cohen's Kappa statistic determinations demonstrated significant agreement only with parietal hypometabolism (p<0.05). CONCLUSION: Occipital and cingulate hypometabolism is under-reported and missed frequently on clinical interpretations of FDG-PET scans of patients with DLB, but the frequency of hypometabolism is even higher than previously reported. Further studies with more statistical power and receiver operating characteristic analyses are needed to delineate the sensitivity and specificity of these in vivo biomarkers.

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