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AIM: This study aimed to analyze two cases of marked hypo-high-density lipoprotein (HDL) cholesterolemia to identify mutations in ATP-binding cassette transporter A1 (ABCA1) and elucidate the molecular mechanism by which these novel pathological mutations contribute to hypo-HDL cholesterolemia in Tangier disease. METHODS: Wild type and mutant expression plasmids containing a FLAG tag inserted at the C-terminus of the human ABCA1 gene were generated and transfected into HEK293T cells. ABCA1 protein expression and cholesterol efflux were evaluated via Western blotting and efflux assay. The difference in the rate of change in protein expression was evaluated when proteolytic and protein-producing systems were inhibited. RESULTS: In case 1, a 20-year-old woman presented with a chief complaint of gait disturbance. Her HDL-C level was only 6.2 mg/dL. Tangier disease was suspected because of muscle weakness, decreased nerve conduction velocity, and splenomegaly. Whole-exome analysis showed compound heterozygosity for a W484* nonsense mutation and S1343I missense mutation, which confirmed Tangier disease. Cholesterol efflux decreased by a mixture of W484* and S1343I mutations. The S1343I mutation decreased the protein production rate but increased the degradation rate, decreasing the protein levels. This patient also had Krabbe disease. The endogenous ABCA1 protein level of macrophage cell decreased by knocking down its internal galactocerebrosidase.Case 2, a 51-year-old woman who underwent tonsillectomy presented with peripheral neuropathy, corneal opacity, and HDL-C of 3.4 mg/dL. Whole-exome analysis revealed compound heterozygosity for R579* and R1572* nonsense mutations, which confirmed Tangier disease. CONCLUSION: Case 1 is a new ABCA1 mutation with complex pathogenicity, namely, a W484*/S1343I compound heterozygote with marked hypo-HDL cholesterolemia. Analyses of the compound heterozygous mutations indicated that decreases in ABCA1 protein levels and cholesterol efflux activity caused by the novel S1343I mutation combined with loss of W484* protein activity could lead to marked hypo-HDL cholesterolemia. Galactocerebrosidase dysfunction could also be a potential confounding factor for ABCA1 protein function.
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Background: Neuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria for inflammatory demyelinating central nervous system diseases included symptomatic narcolepsy; however, no relevant case-control studies exist. We aimed to examine the relationship among cerebrospinal fluid orexin-A (CSF-OX) levels, cataplexy and diencephalic syndrome; determine risk factors for low-and-intermediate CSF-OX levels (≤200 pg/mL) and quantify hypothalamic intensity using MRI. Methods: This ancillary retrospective case-control study included 50 patients with hypersomnia and 68 controls (among 3000 patients) from Akita University, the University of Tsukuba and community hospitals (200 facilities). Outcomes were CSF-OX level and MRI hypothalamus-to-caudate-nucleus-intensity ratio. Risk factors were age, sex, hypersomnolence and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130%. Logistic regression was performed for the association between the risk factors and CSF-OX levels ≤200 pg/mL. Results: The hypersomnia group (n=50) had significantly more cases of NMOSD (p<0.001), diencephalic syndrome (p=0.006), corticosteroid use (p=0.011), hypothalamic lesions (p<0.023) and early treatment (p<0.001). No cataplexy occurred. In the hypersomnia group, the median CSF-OX level was 160.5 (IQR 108.4-236.5) pg/mL and median MRI hypothalamus-to-caudate-nucleus-intensity ratio was 127.6% (IQR 115.3-149.1). Significant risk factors were hypersomnolence (adjusted OR (AOR) 6.95; 95% CI 2.64 to 18.29; p<0.001) and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% (AOR 6.33; 95% CI 1.18 to 34.09; p=0.032). The latter was less sensitive in predicting CSF-OX levels ≤200 pg/mL. Cases with MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% had a higher rate of diencephalic syndrome (p<0.001, V=0.59). Conclusions: Considering orexin as reflected by CSF-OX levels and MRI hypothalamus-to-caudate-nucleus-intensity ratio may help diagnose hypersomnia with diencephalic syndrome.
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BACKGROUND: Among eye movements in amyotrophic lateral sclerosis (ALS), we identified the characteristics of square-wave jerks (SWJs) seen during times without visual fixation (VF) and analyzed their relationships with clinical parameters. MATERIALS AND METHODS: Clinical symptoms were evaluated and eye movements were tested using electronystagmography in 15 patients with ALS (10 men, 5 women; mean age, 66.9 ± 10.5 years). SWJs with and without VF were recorded, and their characteristics were identified. Relationships between each SWJ parameter and clinical symptoms were evaluated. Results were compared with eye movement data from 18 healthy individuals. RESULTS: The frequency of SWJs without VF was significantly higher in the ALS group than in the healthy group (P < 0.001). When the condition was changed from VF to no-VF in the ALS group, the frequency of SWJs was significantly higher in healthy subjects (P = 0.004). A positive correlation was seen between frequency of SWJs and percentage predicted forced vital capacity (%FVC) (R = 0.546, P = 0.035). CONCLUSION: The frequency of SWJs was higher with VF in healthy people, and was suppressed without VF. In contrast, the frequency of SWJs was not suppressed without VF in ALS patients. This suggests that SWJs without VF have some clinical significance in ALS patients. Moreover, a relationship was noted between the parameters of SWJs without VF in ALS patients and results of pulmonary function tests, suggesting that SWJs during times without VF may offer a clinical parameter of ALS.
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Esclerose Lateral Amiotrófica , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Movimentos Sacádicos , Fixação Ocular , Capacidade Vital/fisiologia , BiomarcadoresRESUMO
A 51-year-old man with the chief complaint of glove- and stocking-type dysesthesia for >3 years was diagnosed with Waldenström's macroglobulinemia (WM) based on IgM-type M-proteinemia, bone marrow infiltration of plasmacytoid B cells, multiple lymphadenopathies, and splenomegaly. A nerve conduction examination suggested demyelinating neuropathy. Serum anti-myelin-associated glycoprotein antibody was negative. Sural nerve biopsy showed myelin thinning, suggesting demyelination. Axonal damage and tumor cell infiltration in the intrafascicular epineurium were also observed. After chemotherapies with rituximab and bendamustine, M-proteinemia and lymphadenopathies disappeared. However, abnormalities in the nerve conduction examination and dysesthesia were only slightly alleviated. As articles describing patients with WM with peripheral nerve infiltration are limited, we report this case with a literature review.
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Linfadenopatia , Doenças do Sistema Nervoso Periférico , Macroglobulinemia de Waldenstrom , Masculino , Humanos , Pessoa de Meia-Idade , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Parestesia/complicações , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/patologia , Rituximab/uso terapêutico , Linfadenopatia/complicações , Imunoglobulina MRESUMO
OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.
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Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/tratamento farmacológico , Método Duplo-Cego , Humanos , Nitrilas , Piridonas/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: In a previous study on Alzheimer's disease (AD), we showed that vestibular dysfunction derived from cerebral disorders contributes to balance disorders. No previous clinical study has attempted to prevent the progression of balance disorders in dementia patients through vestibular stimulation using an air caloric device. OBJECTIVE: The purpose of this pilot study was to delay the progression of balance disorders by inducing vestibular compensation, specifically by utilizing the effect of vestibular stimulation to activate the cerebrum. METHODS: Fifteen individuals were randomized and classified into a stimulation group or a nonstimulation group. Eight AD patients underwent vestibular stimulation every 2 weeks for 6 months in the stimulation group. Seven AD patients participated in the nonstimulation group (the control group). Both groups were subsequently evaluated using a Mini-Mental State Examination (MMSE), stepping test, caloric test, and smooth pursuit eye movement test just before starting the study and 6 months later. RESULTS: For balance parameters, the various tests did not show any significant differences between the two groups. However, in the stepping test, the decline rate tended to be higher in the nonstimulation group than in the stimulation group. The stimulation group's rate of decline in MMSE scores was lower than that of the nonstimulation group (p=0.015). No adverse events were tracked during the present study. CONCLUSION: Repeated vestibular stimulation might help patients retain greater balance and higher function. To prove these effects, the future clinical application will require an increased number of cases and longer periods of vestibular stimulation. This study showed that vestibular stimulation by air caloric device is safe and tolerable in patients with AD.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Síndrome de Miller Fisher/induzido quimicamente , Nivolumabe/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , MasculinoRESUMO
To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.
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Estudos de Associação Genética , Variação Genética/genética , Heterozigoto , Homozigoto , Doença de Parkinson/genética , Proteínas Quinases/genética , Fatores Etários , Idade de Início , Feminino , Frequência do Gene , Coração/diagnóstico por imagem , Humanos , Masculino , Mediastino/diagnóstico por imagem , Mediastino/patologia , Imagem de Perfusão do Miocárdio , Miocárdio/patologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/epidemiologia , Doença de Parkinson/patologiaRESUMO
Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3' splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.
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Esclerose Lateral Amiotrófica/genética , Predisposição Genética para Doença/genética , Cinesinas/genética , Mutação/genética , Adulto , Esclerose Lateral Amiotrófica/diagnóstico , Povo Asiático/genética , Feminino , Estudos de Associação Genética , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. PATIENTS AND METHODS: We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. RESULTS: The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients' ability to conduct everyday activities was also improved by the treatment. CONCLUSION: Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.
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Bezafibrato/uso terapêutico , Síndrome Congênita de Insuficiência da Medula Óssea/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Doenças Musculares/tratamento farmacológico , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/genética , Adulto , Bezafibrato/metabolismo , Criança , Síndrome Congênita de Insuficiência da Medula Óssea/fisiopatologia , Feminino , Humanos , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Masculino , Doenças Mitocondriais/fisiopatologia , Doenças Musculares/fisiopatologiaRESUMO
Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.
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Encéfalo/patologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Adolescente , Adulto , Autoanticorpos/imunologia , Autoantígenos/imunologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with aceruloplasminemia might respond to deferasirox in less than one year.
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Anemia Ferropriva/tratamento farmacológico , Ceruloplasmina/deficiência , Deferasirox/uso terapêutico , Quelantes de Ferro/uso terapêutico , Distúrbios do Metabolismo do Ferro/complicações , Distúrbios do Metabolismo do Ferro/tratamento farmacológico , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/tratamento farmacológico , Adulto , Ceruloplasmina/análise , Cobre/sangue , Feminino , Humanos , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemAssuntos
Encefalite/diagnóstico por imagem , Encefalite/tratamento farmacológico , Esteroides/administração & dosagem , Cerebelo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Pedúnculo Cerebelar Médio/diagnóstico por imagem , Ponte/diagnóstico por imagem , Prednisolona/administração & dosagemRESUMO
GDF-15, a member of the transforming growth factor beta superfamily, regulates inflammatory and apoptotic pathways in various diseases, such as heart failure, kidney dysfunction, and cancer. We aimed to clarify potentially confounding variables affecting GDF-15 and demonstrate its utility as a mitochondrial biomarker using serum samples from 15 patients with mitochondrial diseases (MD), 15 patients with limbic encephalitis (LE), 10 patients with multiple sclerosis/neuromyelitis optica spectrum disorders (MS/NMOSD), and 19 patients with amyotrophic lateral sclerosis (ALS). GDF-15 and FGF-21 were significantly elevated in MD. GDF-15 and FGF-21 showed a good correlation in MD but not in LE, MS, and ALS. GDF-15 was potentially influenced by age in LE, MS/NMOSD, and ALS but not in MD. FGF-21 was not correlated with age in MS/NMOSD, ALS, LE, and MD. GDF-15 was not correlated with clinical features in LE or BMI or body weight in ALS. GDF-15 positively correlated with the Expanded Disability Status Scale (EDSS) in MS/NMOSD, while EDSS showed no correlation with age. In conclusion, the results revealed that GDF-15 may be influenced by EDSS in MS/NMOPSD and by age in LE, MS/NMOSD, and ALS but not in MD. Mitochondrial damage in MS/NMOSD is a potentially confounding variable affecting GDF-15.
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Fatores de Crescimento de Fibroblastos/sangue , Fator 15 de Diferenciação de Crescimento/sangue , Doenças Mitocondriais/sangue , Esclerose Múltipla/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/sangue , Biomarcadores/sangue , Avaliação da Deficiência , Feminino , Humanos , Encefalite Límbica/sangue , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/sangue , Adulto JovemRESUMO
INTRODUCTION: Fatty acid oxidation disorders (FAODs) are rare diseases caused by a defective mitochondrial fatty acid oxidation (FAO) enzyme. We recently reported that bezafibrate improved patient quality of life (QOL) based on the SF-36 questionnaire score in patients with FAODs during a 50-week, open-label, clinical trial. Herein we conducted further survey assessments of the trial patients to define the long-term efficacy and safety of bezafibrate. MATERIALS AND METHODS: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in five patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and one patient with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 15.9â¯years; range, 5.8-26.4â¯years). The bezafibrate administration was continued for a further 102-174â¯weeks after the 24-week treatment described in our previous study. QOL was quantitated using the 36-Item Short Form Health Survey (SF-36) questionnaire, which constitutes eight components: physical functioning (PF), role limitation due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitation due to emotional problems, and mental health. RESULTS: PF was elevated in all patients and continued to rise during the study, with the total QOL scores increased from baseline in five of the six cases. In particular, three patients older than 20â¯years showed treatment efficacy, and all subcategories of QOL were elevated in two of these cases. CONCLUSION: Our findings supported one of the stated benefits of bezafibrate in improving QOL for patients with FAODs.