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1.
Neurobiol Dis ; 199: 106571, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38901781

RESUMO

Leucine-rich repeat kinase 2 (LRRK2) is the most common gene responsible for familial Parkinson's disease (PD). The gene product of LRRK2 contains multiple protein domains, including armadillo repeat, ankyrin repeat, leucine-rich repeat (LRR), Ras-of-complex (ROC), C-terminal of ROC (COR), kinase, and WD40 domains. In this study, we performed genetic screening of LRRK2 in our PD cohort, detecting sixteen LRRK2 rare variants. Among them, we selected seven variants that are likely to be familial and characterized them in terms of LRRK2 protein function, along with clinical information and one pathological analysis. The seven variants were S1120P and N1221K in the LRR domain; I1339M, S1403R, and V1447M in the ROC domain; and I1658F and D1873H in the COR domain. The kinase activity of the LRRK2 variants N1221K, S1403R, V1447M, and I1658F toward Rab10, a well-known phosphorylation substrate, was higher than that of wild-type LRRK2. LRRK2 D1873H showed enhanced self-association activity, whereas LRRK2 S1403R and D1873H showed reduced microtubule-binding activity. Pathological analysis of a patient with the LRRK2 V1447M variant was also performed, which revealed Lewy pathology in the brainstem. No functional alterations in terms of kinase activity, self-association activity, and microtubule-binding activity were detected in LRRK2 S1120P and I1339M variants. However, the patient with PD carrying LRRK2 S1120P variant also had a heterozygous Glucosylceramidase beta 1 (GBA1) L444P variant. In conclusion, we characterized seven LRRK2 variants potentially associated with PD. Five of the seven variants in different LRRK2 domains exhibited altered properties in kinase activity, self-association, and microtubule-binding activity, suggesting that each domain variant may contribute to disease progression in different ways.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Humanos , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Mutação/genética , Células HEK293 , Predisposição Genética para Doença/genética , Estudos de Coortes
2.
Sci Rep ; 13(1): 17801, 2023 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-37853169

RESUMO

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.


Assuntos
Vestibulopatia Bilateral , Ataxia Cerebelar , Síndrome de Guillain-Barré , Doenças do Sistema Nervoso Periférico , Doenças Vestibulares , Humanos , Ataxia Cerebelar/genética , Mutação , Doenças do Sistema Nervoso Periférico/genética
3.
Intern Med ; 61(8): 1247-1252, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-34615817

RESUMO

We herein report a case of recurrent multifocal, distal-dominant-sensorimotor neuropathy with ophthalmoplegia, IgM anti-GM1 antibody, and pyrexia-associated relapse. The patient developed sensory disturbance in her limbs after febrile disease at 50 years old. She had experienced several similar episodes and was admitted to the hospital at 56 years old. Based on a pathological study and electrophysiological findings consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), maintenance IVIg therapy was administered and produced partial improvement with no relapse at one-year follow-up. Immunohistochemical studies suggested the presence of IgG (not IgM) anti-myelin antibodies. Chronic neuropathy with ophthalmoplegia and pyrexia-associated relapse may be a unique variant of CIDP.


Assuntos
Oftalmoplegia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Polirradiculoneuropatia , Doença Crônica , Feminino , Febre , Gangliosídeos , Humanos , Imunoglobulina M , Fenótipo , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Recidiva
4.
J Neuroimmunol ; 339: 577127, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31841738

RESUMO

Anti-myelin-associated glycoprotein (MAG) neuropathy is mediated by the binding of IgM M-proteins to the human natural killer-1 epitope of several glycoconjugates, including MAG and phosphacan. We recently reported that IgM M-proteins with a higher ratio of anti-phosphacan titer to anti-MAG titer (P/M ratio) were associated with a progressive clinical course. Herein, we investigated the temporal variability of the P/M ratio. The results showed that P/M ratios in worsened cases were significantly increased relative to stable or improved cases. Thus, temporal variability in the specificity of IgM M-proteins may be related to the disease course of anti-MAG neuropathy.


Assuntos
Autoanticorpos/sangue , Glicoproteína Associada a Mielina/sangue , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/diagnóstico , Idoso , Autoanticorpos/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Seguimentos , Humanos , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Glicoproteína Associada a Mielina/imunologia , Doenças do Sistema Nervoso Periférico/imunologia , Ligação Proteica/fisiologia
5.
Rinsho Shinkeigaku ; 58(1): 25-29, 2018 Jan 26.
Artigo em Japonês | MEDLINE | ID: mdl-29269694

RESUMO

A 19-year-old woman developed high fever, headache, and nausea after taking Loxoprofen for pharyngitis, followed by disturbed consciousness and nuchal stiffness. The patient and her mother had a history of Raynaud's phenomenon. Cerebrospinal fluid (CSF) examination indicated a diagnosis of aseptic meningitis and revealed high levels of Q albumin and IgG index. Anti-RNP antibodies were positive in serum and CSF. Her symptoms disappeared immediately after cessation of Loxoprofen and a drug lymphocyte stimulation test was negative, confirming a diagnosis of non-steroidal anti-inflammatory drugs (NSAIDs)-induced aseptic meningitis. It should be kept in mind that an immune abnormality such as serum and CSF anti-RNP antibodies may play a role in development of NSAIDs-induced aseptic meningitis. A history of usage of NSAIDs and a thorough examination of collagen diseases are useful for identification of the origin of aseptic meningitis in a young woman.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/líquido cefalorraquidiano , Meningite Asséptica/diagnóstico , Meningite Asséptica/etiologia , Fenilpropionatos/efeitos adversos , Ribonucleoproteínas/imunologia , Acetaminofen/administração & dosagem , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Autoimunidade , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Diagnóstico Diferencial , Substituição de Medicamentos , Feminino , Humanos , Resultado do Tratamento , Adulto Jovem
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