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1.
Cell ; 172(5): 924-936.e11, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474920

RESUMO

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.


Assuntos
Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Haploinsuficiência/genética , Mutação/genética , Proteínas de Ligação a RNA/genética , Convulsões/genética , Adolescente , Adulto , Idade de Início , Idoso de 80 Anos ou mais , Animais , Sequência de Bases , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Evolução Molecular , Feminino , Deleção de Genes , Células HEK293 , Humanos , Lactente , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Estabilidade Proteica , Convulsões/diagnóstico por imagem
2.
Mov Disord ; 38(8): 1527-1535, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37310233

RESUMO

BACKGROUND: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing. OBJECTIVES: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations. METHODS: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership. RESULTS: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries. CONCLUSIONS: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Doença de Parkinson/psicologia , Testes Genéticos , Aconselhamento
3.
Mov Disord ; 38(8): 1384-1396, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37365908

RESUMO

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Testes Genéticos
4.
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.

5.
Can J Neurol Sci ; 49(1): 19-28, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33875038

RESUMO

Levodopa-carbidopa intestinal gel infusion (LCIG) is an established therapy for advanced Parkinson disease (PD), resulting in a significant improvement of quality of life. With increased LCIG adoption worldwide, potential complications due to abnormal vitamin absorption or metabolism have been reported in these patients. Neurologists are unfamiliar with vitamins physiology and pathophysiological mechanisms in case of their deficiency. Unfortunately, clinical and laboratory guidelines related to vitamin monitoring and supplementation in the context of treatment with LCIG are not available. We herein summarize the current knowledge on three vitamins that are reduced with LCIG therapy reporting on their physiology, laboratory testing, and clinical impact of their deficiency/excess. In addition, we proposed an opinion-based recommendation for clinicians treating LCIG patients. Patients and caregivers should be informed about the risk of vitamin deficiency. Vitamin B12, homocysteine, and methylmalonic acid (MMA) should be tested before starting LCIG, six months after and once/year thereafter. Vitamin B6 and folate testing is not universally available but it should be considered if homocysteine is elevated but MMA and/or total vitamin B12 are normal. Prophylaxis of vitamin deficiency should be started as soon as LCIG is implemented, possibly even before. Dietary recommendations are enough in most patients although a subgroup of patients is at higher risk and should receive Vitamin B12 regularly and cycles of B6. Finally, once diagnosed a vitamin deficiency should be readily treated and accompanied by clinical and laboratory monitoring. Resistant cases should receive non-oral routes of administration and possibly discontinue LCIG, even temporarily.


Assuntos
Carbidopa , Levodopa , Antiparkinsonianos/efeitos adversos , Humanos , Levodopa/efeitos adversos , Qualidade de Vida , Vitaminas/uso terapêutico
6.
Mov Disord ; 36(8): 1979-1983, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33983638

RESUMO

BACKGROUND: The Quality of Life in Neurological Disorders (Neuro-QoL) is a publicly available health-related quality-of-life measurement system. OBJECTIVE: The aim of this study was to evaluate the utility of Neuro-QoL item banks as outcome measures for clinical trials in Parkinson's disease. METHODS: An analysis of Neuro-QoL responsiveness to change and construct validity was performed in a multicenter clinical trial cohort. RESULTS: Among 310 participants over 3 years, changes in five of eight Neuro-QoL domains were significant (P < 0.05) but very modest. The largest effect sizes were seen in the cognition and mobility domains (0.35-0.39). The largest effect size for change over the year in which levodopa was initiated was -0.19 for lower extremity function-mobility. For a similarly designed clinical trial, estimated sample size required to demonstrate a 50% reduction in worsening ranged from 420 to more than 1000 participants per group. CONCLUSIONS: More sensitive tools will be required to serve as an outcome measure in early Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson , Qualidade de Vida , Cognição , Humanos , Avaliação de Resultados em Cuidados de Saúde , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Psicometria
7.
Mov Disord ; 36(7): 1664-1675, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33598982

RESUMO

BACKGROUND: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). OBJECTIVES: We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP. METHODS: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls. RESULTS: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. CONCLUSIONS: Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society.


Assuntos
Paraplegia Espástica Hereditária , Proteases Dependentes de ATP , ATPases Associadas a Diversas Atividades Celulares/genética , Canadá , Humanos , Metaloendopeptidases/genética , Mutação/genética , Paraplegia , Paraplegia Espástica Hereditária/genética , Fatores de Transcrição
8.
Eur J Neurol ; 28(12): 3999-4009, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34296504

RESUMO

BACKGROUND AND PURPOSE: Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread. METHODS: Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation ("dystonia-only") and one accepting dystonia OR tremor in any body part as disease manifestations ("dystonia OR tremor"). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping. RESULTS: Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62-0.70 and 0.62-0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread. CONCLUSIONS: This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals' risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.


Assuntos
Distonia , Distúrbios Distônicos , Adulto , Bases de Dados Factuais , Distonia/epidemiologia , Distúrbios Distônicos/complicações , Distúrbios Distônicos/epidemiologia , Humanos , Tremor/epidemiologia , Tremor/etiologia
9.
Genet Med ; 22(12): 2114-2119, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32741968

RESUMO

PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot-Marie-Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance. METHODS: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis. RESULTS: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA. CONCLUSION: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.


Assuntos
Doença de Charcot-Marie-Tooth , Paraplegia Espástica Hereditária , Alelos , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Humanos , Mutação , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Sequenciamento do Exoma
10.
Am J Hum Genet ; 98(5): 1038-1046, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27153400

RESUMO

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.


Assuntos
Axônios/patologia , Calpaína/genética , Predisposição Genética para Doença/genética , Neurônios Motores/patologia , Paraplegia Espástica Hereditária/genética , Adulto , Animais , Encéfalo/fisiologia , Caenorhabditis elegans/genética , Movimento Celular/genética , Modelos Animais de Doenças , Drosophila melanogaster/genética , Feminino , Humanos , Masculino , Neurônios Motores/citologia , Adulto Jovem , Peixe-Zebra/genética
11.
J Stroke Cerebrovasc Dis ; 27(1): 153-161, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28986199

RESUMO

OBJECTIVES: To determine the prevalence of vascular parkinsonism (VasP) in a stroke prevention clinic (SPC). BACKGROUND: VasP can be defined by an onset of parkinsonism with prominent gait problems occurring within 1 year of stroke. METHODS: We created a screening strategy based on the Tanner Questionnaire (TQ), a validated scale for parkinsonism, and the creation of a 4-point Five-Minute Assessment Scale (FMAS) operationalizing Zijlmans' criteria for the diagnosis of VasP. Consecutive stroke patients were screened over a 12-month period using the TQ and the FMAS. SAS statistical software was used. RESULTS: Two hundred forty patients (52.5% females) were screened (mean age of 65 years, standard deviation, 14.5). Twenty-five percent of patients had a TQ score ≥ 4 with a median FMAS of 2. In this group, 32.6% (15/46) were found to have parkinsonism. Seventeen percent (8/46) were diagnosed with VasP having an FMAS of 4. Seventy-five of the participants obtained a TQ ≤ 3, with a median FMAS of 1. Only 1 patient in this group had parkinsonism (1.9%; 1/194). Using a cutoff of 4 points in the TQ resulted in a sensitivity of 93.8%, a specificity of 86.2% for parkinsonism, and a sensitivity of 100% with a specificity of 83% for VasP. Patients with FMAS = 4 (VasP) attained higher scores in the TQ with a median of 5 (Spearman rank correlation coefficient for the TQ and the FMAS (rs) = .447, P < .0005). CONCLUSIONS: We documented a prevalence of 3% (8/240) for VasP in an SPC. We propose a new, easier, and unified 2-step TQ-FMAS screening strategy for this condition.


Assuntos
Ambulatório Hospitalar , Doença de Parkinson Secundária/diagnóstico , Doença de Parkinson Secundária/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Inquéritos e Questionários , Centros de Atenção Terciária , Adulto , Idoso , Idoso de 80 Anos ou mais , Alberta/epidemiologia , Estudos Transversais , Feminino , Marcha , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson Secundária/fisiopatologia , Valor Preditivo dos Testes , Prevalência , Desenvolvimento de Programas , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/prevenção & controle
12.
Am J Hum Genet ; 92(6): 946-54, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23664116

RESUMO

Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.


Assuntos
Proteínas de Transporte/genética , Atrofia Muscular Espinal/genética , Mutação de Sentido Incorreto , Adulto , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Transporte/metabolismo , Pré-Escolar , Sequência Conservada , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Genes Dominantes , Estudos de Associação Genética , Ligação Genética , Complexo de Golgi/metabolismo , Complexo de Golgi/patologia , Células HeLa , Humanos , Masculino , Proteínas Associadas aos Microtúbulos , Atrofia Muscular Espinal/congênito , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patologia , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
13.
Am J Hum Genet ; 93(1): 181-90, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-23830518

RESUMO

Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism.


Assuntos
Deficiência Intelectual/genética , Transtornos dos Movimentos/genética , Doenças Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Deleção de Sequência , Proteínas de Transporte Vesicular/metabolismo , Adolescente , Adulto , Ataxia/genética , Mapeamento Cromossômico , Consanguinidade , Creatina Quinase/sangue , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Exoma , Feminino , Complexo de Golgi/genética , Complexo de Golgi/metabolismo , Complexo de Golgi/patologia , Homozigoto , Humanos , Proteína 2 de Membrana Associada ao Lisossomo , Proteínas de Membrana Lisossomal/genética , Proteínas de Membrana Lisossomal/metabolismo , Lisossomos/metabolismo , Masculino , Transtornos dos Movimentos/patologia , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Doenças Musculares/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Linhagem , Ligação Proteica , Transporte Proteico , Sítios de Splice de RNA , Síria , Proteínas de Transporte Vesicular/genética , Adulto Jovem
14.
Can J Neurol Sci ; 43(3): 360-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26891024

RESUMO

BACKGROUND: Many Canadians with multiple sclerosis (MS) have recently travelled internationally to have procedures for a putative condition called chronic cerebrospinal venous insufficiency (CCSVI). Here, we describe where and when they went and describe the baseline characteristics of persons with MS who participated in this non-evidence-based medical tourism for CCSVI procedures. METHODS: We conducted a longitudinal observational study that used online questionnaires to collect patient-reported information about the safety, experiences, and outcomes following procedures for CCSVI. A convenience sample of all Albertans with MS was recruited between July 2011 and March 2013. RESULTS: In total, 868 individuals enrolled; 704 were included in this cross-sectional, baseline analysis. Of these, 128 (18.2%) participants retrospectively reported having procedures for CCSVI between April 2010 and September 2012. The proportion of participants reporting CCSVI procedures declined from 80 (62.5%) in 2010, to 40 (31.1%) in 2011, and 8 (6.3%) in 2012. In multivariable logistic regression analysis, CCSVI procedures were independently associated with longer disease duration, secondary progressive clinical course, and greater disability status. CONCLUSIONS: Although all types of people with MS pursued procedures for CCSVI, a major driver of participation was greater disability. This highlights that those with the greatest disability are the most vulnerable to unproven experimental procedures. Participation in CCSVI procedures waned over time possibly reflecting unmet expectations of treated patients, decreased media attention, or that individuals who wanted procedures had them soon after the CCSVI hypothesis was widely publicized.


Assuntos
Circulação Cerebrovascular/fisiologia , Turismo Médico/estatística & dados numéricos , Esclerose Múltipla/complicações , Insuficiência Venosa/complicações , Insuficiência Venosa/terapia , Adulto , Doença Crônica , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Sistemas On-Line , Índice de Gravidade de Doença , Inquéritos e Questionários
15.
Am J Hum Genet ; 90(3): 434-44, 2012 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-22387017

RESUMO

Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.


Assuntos
Cromossomos Humanos Par 4 , Doença de Huntington/genética , Idade de Início , Alelos , Estudos de Casos e Controles , Efeito Fundador , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Repetições de Trinucleotídeos
16.
Mov Disord ; 30(4): 500-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25545465

RESUMO

Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. L-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces L-dopa-plasma-level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day "off" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, "on" time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks.


Assuntos
Antiparkinsonianos/uso terapêutico , Carbidopa/uso terapêutico , Géis , Intestinos/fisiologia , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Adulto , Idoso , Combinação de Medicamentos , Feminino , Géis/uso terapêutico , Humanos , Intestinos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
17.
Hum Mutat ; 35(1): 45-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24108619

RESUMO

Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease genes for rare pediatric diseases using whole-exome sequencing. We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families, we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative.


Assuntos
Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Exoma , Análise de Sequência de DNA , Canadá , Criança , Pré-Escolar , Consanguinidade , Predisposição Genética para Doença , Variação Genética , Humanos , Técnicas de Diagnóstico Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos
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