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Coenzyme Q2, polyprenyltransferase (COQ2) variants have been reported to be associated with multiple system atrophy (MSA). However, the relationship between COQ2 variants and familial Parkinson's disease (PD) remains unclear. We investigated the frequency of COQ2 variants and clinical symptoms among familial PD and MSA. We screened COQ2 using the Sanger method in 123 patients with familial PD, 52 patients with sporadic PD, and 39 patients with clinically diagnosed MSA. Clinical information was collected from medical records for the patients with COQ2 variants. Allele frequencies of detected rare non-synonymous variants were compared by public database of the Exome Aggregation Consortium (ExAC) and Japanese genetic variation database, using Fisher's exact test. We detected two probands with rare variants in COQ2, the p.P157S from Family A, whose patient was clinically diagnosed as having juvenile PD, and the p.H15 N/p.G331S from Family B, whose patients shared common symptoms of PD. Furthermore, in an association study comparing these familial PD and MSA cases with a public variant database, eight non synonymous variants were detected in COQ2. Three of these were very rare variants, namely, p.P157S, p.L261Qfs*4, and p.G331S, and one variant, p.G21S, was found to show a significant association with familial PD. COQ2 variants rarely may associate with the disease onset of familial PD. Our findings contribute to an understanding of COQ2 variants in neurodegenerative disorders.
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Alquil e Aril Transferases/genética , Predisposição Genética para Doença/genética , Atrofia de Múltiplos Sistemas/genética , Doença de Parkinson/genética , Adulto , Idoso , Animais , Povo Asiático/genética , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , CoelhosRESUMO
OBJECTIVE: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). METHODS: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. RESULTS: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. CONCLUSIONS: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.
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Painless Legs and Moving Toes Syndrome (PoLMT) is a rare movement disorder characterized by flexion, extension, abduction, adduction, and torsion of toes without pain. It is considered a variant of Painful Legs and Moving Toes Syndrome (PLMT), which is characterized by similar movements but with pain. Although neuropathy and several central nervous system (CNS) involvements have been reported to be associated with PoLMT, the actual cause and mechanism remain unclear. Here we describe the first case of PoLMT in Parkinson's Disease (PD), parallel to parkinsonism in severity, who demonstrated a good response to dopaminergic therapy.
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BACKGROUND: Nonketotic hyperglycemia often causes seizures. Recently, seizures associated with nonketotic hyperglycemia have been found to be associated with subcortical T2 hypointensity on magnetic resonance imaging, especially in the occipital lobes. However, the mechanism remains unclear, although iron accumulation is suggested. We present a case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the hypothesis that the mechanism of subcortical T2 hypointensity is iron accumulation using gradient-echo T2*-weighted magnetic resonance imaging. CASE PRESENTATION: A 65-year-old Japanese man complained of intermittent pastel-colored flashing lights. On neurological examination, he also had lower right-side quadrant hemianopia. No other abnormal neurological findings were found. On laboratory analysis, his blood glucose level was 370 mg/dL, HbA1c was 11.4 %, and serum osmolarity was 326 mOsm/L. No ketones were detected in urine. A magnetic resonance imaging scan of his head showed subcortical T2 and T2* hypointensity in his left occipital lobe. Single-photon emission computed tomography with I123-N-isopropyl-iodoamphetamine revealed hyperperfusion in the left dominant occipital lobe. These magnetic resonance imaging abnormalities resolved during clinical recovery and treatment to control his blood sugar level. Therefore, a diagnosis of occipital lobe seizures associated with nonketotic hyperglycemia was made. CONCLUSIONS: To the best of our knowledge, this is the first case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the role of iron accumulation as a mechanism for subcortical T2 hypointensity using T2*-magnetic resonance imaging.
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Hiperglicemia/complicações , Lobo Occipital/diagnóstico por imagem , Convulsões/complicações , Convulsões/diagnóstico por imagem , Idoso , Humanos , Japão , Imageamento por Ressonância Magnética , MasculinoRESUMO
BACKGROUND: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. METHODS: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. DISCUSSION: This study will confirm whether H2 water can improve PD symptoms. TRIAL REGISTRATION: UMIN000010014 (February, 13, 2013).
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Hidrogênio/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Água , Idoso , Antiparkinsonianos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
We herein report the case of a 49-year-old man with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated with Legionnaires' disease due to Legionella pneumophila serogroup 2. Past reports suggest that Legionella infection is frequent in cases of MERS-associated pneumonia. Obtaining an early diagnosis of legionella infection is a challenge, especially if a Legionella pneumophila serogroup other than serogroup 1 contains the causative agent. In this case, the splenial lesion played an important role in recognizing the legionella infection. We suggest that legionella infection should be considered as a differential diagnosis in cases of splenial lesions associated with pneumonia.
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Corpo Caloso/patologia , Legionella pneumophila/isolamento & purificação , Doença dos Legionários/diagnóstico , Doença dos Legionários/patologia , Encefalite/etiologia , Humanos , Doença dos Legionários/complicações , Masculino , Pessoa de Meia-IdadeAssuntos
Carbidopa/farmacologia , Coreia/etiologia , Agonistas de Dopamina/farmacologia , Levodopa/farmacologia , Mielinólise Central da Ponte/complicações , Transtornos Parkinsonianos/tratamento farmacológico , Carbidopa/administração & dosagem , Progressão da Doença , Agonistas de Dopamina/administração & dosagem , Combinação de Medicamentos , Humanos , Hipocinesia/tratamento farmacológico , Hipocinesia/etiologia , Levodopa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Rigidez Muscular/tratamento farmacológico , Rigidez Muscular/etiologia , Transtornos Parkinsonianos/etiologiaRESUMO
BACKGROUND: Hemichorea is usually caused by a structural lesion in the contralateral basal ganglia or subthalamic nuclei or it develops as a form of a neurologic complication including hyperglycemia. We report a rare case of a patient who developed choreic movement in the right upper extremity associated with a contralateral middle cerebral artery (MCA) occlusion. METHODS: A 76-year-old man presented with chorea in the right upper limb, known as monochorea, which occurred after recovery from losing consciousness while standing. He was found to have idiopathic orthostatic hypotension. His diffusion-weighted magnetic resonance imaging did not show signal changes indicative of acute ischemic lesions. A left carotid artery angiogram showed occlusion of the left MCA. (123)I-N-isopropyl-4-iodoamphetamine single-photon emission computed tomography of the brain showed marked hypoperfusion in the left MCA territory. His cerebrovascular reserve capacity determined using acetazolamide was relatively decreased in this territory. This decrease in cerebrovascular reserve capacity, however, did not require surgical treatment, such as extracranial-intracranial bypass surgery. RESULTS: The recurrence of chorea was not observed after antiplatelet therapy and instruction on how to cope with orthostatic hypotension. CONCLUSIONS: It is considered that transient hemodynamic ischemia in the right basal ganglia-thalamocortical circuits because of the combination of MCA occlusion and hypotension was the underlying cause of the monochorea in this patient.Vascular imaging studies for early identification of occlusion or severe stenosis of cerebral major arteries should be carried out in patients acutely presenting with chorea, even in the absence of other clinical signs.
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Coreia/etiologia , Coreia/patologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/diagnóstico , Extremidade Superior/fisiopatologia , Idoso , Imagem de Difusão por Ressonância Magnética , Humanos , Imageamento Tridimensional , Angiografia por Ressonância Magnética , MasculinoAssuntos
Equilíbrio Postural/fisiologia , Transtornos de Sensação/etiologia , Paralisia Supranuclear Progressiva/complicações , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Inosina Monofosfato/metabolismo , Imageamento por Ressonância Magnética , Masculino , Transtornos de Sensação/diagnóstico por imagem , Transtornos de Sensação/patologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
INTRODUCTION: Mitochondrial complex I deficiencies have been found in post-mortem brains of patients with Parkinson's disease (PD). Coenzyme Q10 (CoQ10) is the electron acceptor found in complexes I and II, and is a potent antioxidant. A recent trial of the oxidized form of CoQ10 for PD failed to show benefits; however, the reduced form of CoQ10 (ubiquinol-10) has shown better neuroprotective effects in animal models. METHODS: Randomized, double-blind, placebo-controlled, parallel-group pilot trials were conducted to assess the efficacy of ubiquinol-10 in Japanese patients with PD. Participants were divided into two groups: PD experiencing wearing off (Group A), and early PD, without levodopa (with or without a dopamine agonist) (Group B). Participants took 300 mg of ubiquinol-10 or placebo per day for 48 weeks (Group A) or 96 weeks (Group B). RESULTS: In Group A, total Unified Parkinson's Disease Rating Scale (UPDRS) scores decreased in the ubiquinol-10 group (n = 14; mean ± SD [-4.2 ± 8.2]), indicating improvement in symptoms. There was a statistically significant difference (p < 0.05) compared with the placebo group (n = 12; 2.9 ± 8.9). In Group B, UPDRS increased in the ubiquinol-10 group (n = 14; 3.9 ± 8.0), as well as in the placebo group (n = 8; 5.1 ± 10.3). CONCLUSIONS: This is the first report showing that ubiquinol-10 may significantly improve PD with wearing off, as judged by total UPDRS scores, and that ubiquinol-10 is safe and well tolerated.
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Antioxidantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Ubiquinona/análogos & derivados , Idoso , Antioxidantes/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Projetos Piloto , Resultado do Tratamento , Ubiquinona/administração & dosagem , Ubiquinona/farmacologiaAssuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Terapia Combinada , Granulomatose Linfomatoide/tratamento farmacológico , Granulomatose Linfomatoide/radioterapia , Adulto , Ciclofosfamida/uso terapêutico , Citarabina/uso terapêutico , Dexametasona/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Rituximab/uso terapêuticoRESUMO
INTRODUCTION: Painless legs and moving toes syndrome (PoLMT) is a rare movement disorder characterized by flexion, extension, abduction, adduction, and torsion of toes in the absence of pain. It is considered a variant of painful legs and moving toes syndrome, which is characterized by similar movements but is accompanied by pain. Although neuropathy, spinal cord compression, brain tumor, cerebral infarction, and Wilson's disease have been reported to be associated with PoLMT, the actual cause, trigger, and mechanism remain unclear. Therefore, a standardized treatment for PoLMT is not established yet. CASE PRESENTATION: We describe a 64-year-old Japanese woman with no past medical history who presented with nonrhythmic repetitive involuntary toe movement of the left foot in the absence of pain. She was diagnosed with idiopathic PoLMT and treated with a low dose of clonazepam (0.5 mg/day). The involuntary movement disappeared completely several days after treatment. CONCLUSION: A low dose of clonazepam is effective in the treatment of PoLMT.
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Mutations in p150glued cause hereditary motor neuropathy with vocal cord paralysis (HMN7B) and Perry syndrome (PS). Here we show that both overexpression of p150glued mutants and knockdown of endogenous p150glued induce apoptosis. Overexpression of a p150glued plasmid containing either a HMN7B or PS mutation resulted in cytoplasmic p150glued-positive aggregates and was associated with cell death. Cells containing mutant p150glued aggregates underwent apoptosis that was characterized by an increase in cleaved caspase-3- or Annexin V-positive cells and was attenuated by both zVAD-fmk (a pan-caspase inhibitor) application and caspase-3 siRNA knockdown. In addition, overexpression of mutant p150glued decreased mitochondrial membrane potentials and increased levels of translocase of the mitochondrial outer membrane (Tom20) protein, indicating accumulation of damaged mitochondria. Importantly, siRNA knockdown of endogenous p150glued independently induced apoptosis via caspase-8 activation and was not associated with mitochondrial morphological changes. Simultaneous knockdown of endogenous p150glued and overexpression of mutant p150glued had additive apoptosis induction effects. These findings suggest that both p150glued gain-of-toxic-function and loss-of-physiological-function can cause apoptosis and may underlie the pathogenesis of p150glued-associated disorders.
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Apoptose/genética , Caspase 3/metabolismo , Caspase 8/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Clorometilcetonas de Aminoácidos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores de Caspase/farmacologia , Complexo Dinactina , Células HeLa , Humanos , Proteínas Associadas aos Microtúbulos/genética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismoRESUMO
Mitochondrial fission is mediated by the dynamin-related protein Drp1 in metazoans. Drp1 is recruited from the cytosol to mitochondria by the mitochondrial outer membrane protein Mff. A second mitochondrial outer membrane protein, named Fis1, was previously proposed as recruitment factor, but Fis1(-/-) cells have mild or no mitochondrial fission defects. Here we show that Fis1 is nevertheless part of the mitochondrial fission complex in metazoan cells. During the fission cycle, Drp1 first binds to Mff on the surface of mitochondria, followed by entry into a complex that includes Fis1 and endoplasmic reticulum (ER) proteins at the ER-mitochondrial interface. Mutations in Fis1 do not normally affect fission, but they can disrupt downstream degradation events when specific mitochondrial toxins are used to induce fission. The disruptions caused by mutations in Fis1 lead to an accumulation of large LC3 aggregates. We conclude that Fis1 can act in sequence with Mff at the ER-mitochondrial interface to couple stress-induced mitochondrial fission with downstream degradation processes.
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Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Membrana/genética , Dinâmica Mitocondrial , Proteínas Mitocondriais/genética , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Retículo Endoplasmático/metabolismo , Células HCT116 , Células HeLa , Humanos , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/metabolismo , Músculos/citologia , Mutação de Sentido Incorreto , ProteóliseRESUMO
Mitochondria continually change shape through the combined actions of fission, fusion, and movement along cytoskeletal tracks. The lengths of mitochondria and the degree to which they form closed networks are determined by the balance between fission and fusion rates. These rates are influenced by metabolic and pathogenic conditions inside mitochondria and by their cellular environment. Fission and fusion are important for growth, for mitochondrial redistribution, and for maintenance of a healthy mitochondrial network. In addition, mitochondrial fission and fusion play prominent roles in disease-related processes such as apoptosis and mitophagy. Three members of the Dynamin family are key components of the fission and fusion machineries. Their functions are controlled by different sets of adaptor proteins on the surface of mitochondria and by a range of regulatory processes. Here, we review what is known about these proteins and the processes that regulate their actions.