Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 95
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Oncologist ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615948

RESUMO

Platinum-based chemotherapy is commonly associated with toxic sensory neuropathies, but also, although rarely, with Guillain-Barré syndrome (GBS). We describe five patients who developed GBS while receiving platinum-based chemotherapy for a solid tumor and report the five cases published so far. Most patients had received cumulative platinum doses below known neurotoxic levels, and all of them had an optimal outcome after platinum discontinuation, associated in most cases with administration of intravenous immunoglobulin. Clinical presentation, electroneuromyography, and cerebrospinal fluid analysis help clinicians to differentiate GBS from toxic neuropathy. Platinum compounds are the only chemotherapeutic agents used for solid tumors that have been associated to GBS. Thus, we propose that GBS may constitute a non-dose-dependent side effect of platinum drugs and that awareness needs to be raised among oncologists on this rare but potentially life-threatening complication of platinum chemotherapy. IMPLICATIONS FOR PRACTICE: Many patients on platinum-based chemotherapy for solid tumors develop sensory neuropathy, a common dose-dependent side effect. The authors propose that Guillain-Barré syndrome may constitute an immune-mediated, non-dose-related side effect of platinum-based chemotherapy. Prompt diagnosis of Guillain-Barré syndrome and distinction from classical toxic neuropathy are crucial for optimal treatment. Platinum discontinuation, associated if needed to intravenous immunoglobulin administration, radically changes the course of the disease and minimizes neurological sequelae.

2.
Neurol Genet ; 5(2): e321, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31119192

RESUMO

Objective: To study the genetic and phenotypic spectrum of patients harboring recessive mutations in BVES. Methods: We performed whole-exome sequencing in a multicenter cohort of 1929 patients with a suspected hereditary myopathy, showing unexplained limb-girdle muscular weakness and/or elevated creatine kinase levels. Immunohistochemistry and mRNA experiments on patients' skeletal muscle tissue were performed to study the pathogenicity of identified loss-of-function (LOF) variants in BVES. Results: We identified 4 individuals from 3 families harboring homozygous LOF variants in BVES, the gene that encodes for Popeye domain containing protein 1 (POPDC1). Patients showed skeletal muscle involvement and cardiac conduction abnormalities of varying nature and severity, but all exhibited at least subclinical signs of both skeletal muscle and cardiac disease. All identified mutations lead to a partial or complete loss of function of BVES through nonsense-mediated decay or through functional changes to the POPDC1 protein. Conclusions: We report the identification of homozygous LOF mutations in BVES, causal in a young adult-onset myopathy with concomitant cardiac conduction disorders in the absence of structural heart disease. These findings underline the role of POPDC1, and by extension, other members of this protein family, in striated muscle physiology and disease. This disorder appears to have a low prevalence, although it is probably underdiagnosed because of its striking phenotypic variability and often subtle yet clinically relevant manifestations, particularly concerning the cardiac conduction abnormalities.

5.
Mitochondrion ; 45: 22-28, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29474836

RESUMO

Mutations in the gene encoding polymerase gamma (POLG) are a common cause of mitochondrial diseases in adults. We retrospectively analyzed volumetric and diffusion tensor imaging data from 20 adult POLG-mutated patients compared to healthy controls. We used an original clinical binary load score and electroneuromyography to evaluate disease severity. Patients showed atrophy in the basal ganglia, amygdala, and brainstem (p < 0.05) compared to controls, as well as decreased fractional anisotropy (FA) in the cingulate gyrus, the internal capsule and the corona radiata (p < 0.05). Clinical scores correlated with decreased FA and increased radial diffusivity in several brain regions (p < 0.05).


Assuntos
Biomarcadores/análise , Polimerase do DNA Mitocondrial/genética , Imagem de Tensor de Difusão/métodos , Doenças Mitocondriais/diagnóstico por imagem , Mutação , Adolescente , Adulto , Idoso , Animais , Gânglios da Base/patologia , Tronco Encefálico/patologia , Feminino , Giro do Cíngulo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Miografia/métodos , Estudos Retrospectivos , Adulto Jovem
6.
J Peripher Nerv Syst ; 23(4): 235-240, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30203907

RESUMO

We aimed to analyse the response to rituximab in a cohort of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients with associated disorders. We conducted a clinical and electrophysiological retrospective monocentric study in 28 CIDP patients. Response to rituximab was defined as (a) a five-point increase in the Medical Research Council sum score or a one-point decrease in the Overall Neuropathy Limitations Scale score, compared to the score at the first rituximab infusion, or (b) the discontinuation of, or reduced need for, the last treatments before rituximab initiation. Twenty-one patients (75%) were responders to rituximab. The median time before response was 6 months (1-10 months). Only two patients needed to be treated again during a median follow-up of 2.0 years (0.75-9 years). Interestingly, the response rate was good in patients with associated autoimmune disease (5/8) and similar to the response rate observed in patients with a haematological disease (16/20) (P = 0.63). A shorter disease duration was associated with a better clinical response to rituximab (odds ratio 0.81, P = 0.025) and the response rate was better (P = 0.05) in common forms (83.3%) than in sensory forms (42.9%). No major adverse events were recorded. Rituximab is efficacious in CIDP patients with haematological or autoimmune disease. It improves clinical response and decreases dependence on first-line treatments.


Assuntos
Imunossupressores/uso terapêutico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/complicações , Terapia Combinada , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Seguimentos , Doenças Hematológicas/complicações , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
7.
Neurology ; 91(10): e985-e994, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30089619

RESUMO

OBJECTIVE: To report the clinicopathologic features and outcome of myositis in patients treated with immune checkpoint inhibitors (ICIs) (irMyositis). METHODS: We retrospectively analyzed patients diagnosed with irMyositis in tertiary centers in Paris, France, and Berlin, Germany, from January 2015 to July 2017. The main outcomes were clinical manifestations and muscle histology, which included major histocompatibility complex class I (MHC-I), C5b-9, CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L) 1, and programmed cell death 1 ligand 2 (PD-L2). RESULTS: Ten patients with metastatic cancer were included; median age was 73 (range 56-87) years. Median follow-up duration was 48 (range 16-88) weeks. Six patients developed myositis during nivolumab therapy, 1 patient during pembrolizumab, 1 patient during durvalumab, and 2 patients during combined nivolumab and ipilimumab. Median delay between ICI initiation and myositis onset was 25 (range 5-87) days. Clinical manifestations were dominated by acute or subacute myalgia (8 patients) and limb-girdle (7), axial (7), and oculomotor (7) weakness. Four patients had evidence of myocarditis. In all patients, creatine kinase levels were elevated (median 2,668, range 1,059-16,620 U/L), while anti-acetylcholine receptor and myositis-associated antibodies were negative. Electrodiagnostic studies showed myopathic process without decrement in all patients. Muscle biopsy constantly showed multifocal necrotic myofibers, sarcolemmal MHC-I, and endomysial inflammation, consisting mainly of CD68+ cells expressing PD-L1 and CD8+ cells expressing PD-1. ICI treatment was withdrawn in all patients; 9 patients received immunosuppressive therapy, which consistently led to marked clinical improvement. CONCLUSIONS: irMyositis presents with remarkably homogeneous and unique clinicopathologic features, expanding the nosologic spectrum of inflammatory myopathies in patients with cancer. ICI withdrawal and treatment with corticosteroids improve outcome.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Citocinas/metabolismo , Miocardite/etiologia , Miosite/etiologia , Neoplasias/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Creatina Quinase/metabolismo , Eletromiografia , Europa (Continente) , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Miocárdio/patologia , Miosite/diagnóstico por imagem , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Estudos Retrospectivos , Adulto Jovem
8.
J Neuropathol Exp Neurol ; 77(9): 769-781, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30011033

RESUMO

Infiltration of the peripheral nervous system (PNS) by lymphoma, called neurolymphomatosis, is a rare condition among the spectrum of lymphoma-associated neuropathies; its diagnosis is challenging. Cerebrospinal fluid (CSF) analysis is of great value, but nerve biopsy (NB) may be necessary to prove invasion by malignant cells. Clonality polymerase chain reaction (PCR)-based analysis is a validated method in the diagnosis of hematological malignancies, but there are very little data on its diagnostic yield on NB samples. We explored the contribution of NB with clonality analysis to the diagnosis of neurolymphomatosis in 15 patients with negative CSF analysis. Moreover, we assessed the performance of clonality testing in a case-control manner, using patients with inflammatory infiltrates on NB as controls. Neurolymphomatosis was the first manifestation of lymphoma in 60% and could be diagnosed on routine histology alone in 40%. Clonality testing showed monoclonal rearrangement in 86.7% and was unsuccessful in 8.1%. Performance of clonality testing was as follows: 92.9% positive predictive value, 90% negative predictive value, 86.7% sensitivity, 94.7% specificity. This study confirms the diagnostic challenge of neurolymphomatosis, the usefulness of NB in patients with negative CSF analysis, and highlights the high yield of PCR-based clonality testing to assess the malignant nature of PNS lymphoid infiltrates.


Assuntos
Biópsia/métodos , Neurolinfomatose/genética , Neurolinfomatose/patologia , Nervos Periféricos/patologia , Reação em Cadeia da Polimerase , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Feminino , Fluordesoxiglucose F18 , Humanos , Imunomodulação , Masculino , Pessoa de Meia-Idade , Condução Nervosa/fisiologia , Neurolinfomatose/líquido cefalorraquidiano , Neurolinfomatose/terapia , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
9.
Neurol Neuroimmunol Neuroinflamm ; 5(3): e452, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29845092

RESUMO

Objectives: To describe clinicopathologic features of muscular sarcoidosis and the associated sarcoidosis phenotype through a nationwide multicenter study. Methods: Patients were included if they had histologically proven sarcoidosis and symptomatic muscular involvement confirmed by biological, imaging, or histologic examinations. Results: Forty-eight patients (20 males) were studied, with a median age at muscular symptoms onset of 45 years (range 18-71). Four patterns were identified: a nodular pattern (27%); smoldering phenotype (29%); acute, subacute, or progressive myopathic type (35%); and combined myopathic and neurogenic pattern (10%). In all patterns, sarcoidosis was multivisceral with a median of 3 extramuscular organs involved (mostly lungs, lymph nodes, eyes, and skin) and a prolonged course with long-term use of corticosteroids and immunosuppressive drugs. Muscular patterns differed according to clinical presentation (myalgia, nodules, or weakness), electromyographic findings, muscular MRI, and response to sarcoidosis treatment. The myopathic and neuromuscular patterns were more severe. Conclusion: This nationwide study of muscular sarcoidosis allowed the identification of 4 patterns of granulomatous myositis, which differed by phenotypes and the clinical course.

10.
J Neurol ; 265(7): 1590-1599, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29725842

RESUMO

Paraneoplastic motor neuron disorders (MND) are rare conditions; their exact clinical and electrophysiological phenotype have not been exhaustively described yet. The purpose of this study is to depict the main characteristics of paraneoplastic MND to highlight the features that may allow its diagnosis. Based on the description of eight original cases, and on the revision of 21 patients identified from a systematic review of the literature, the main features of paraneoplastic MND can be summarized as follows: (1) subacute; (2) lower motor neuron syndrome, associated or not with upper motor neuron involvement; (3) predominant asymmetric upper limb involvement; (4) presence of other non-motor neurological manifestations, including sensory neuronopathy; (5) signs of inflammation in the cerebrospinal fluid (CSF); (6) neurological improvement or stabilization after immunotherapy and tumor treatment. The diagnosis of paraneoplastic MND may be difficult because of its rarity, the absence of pathognomonic clinical features, and the frequent absence of prior tumor history. However, it is of capital importance to correctly identify patients with paraneoplastic MND, as this represents a potentially treatable condition. In the presence of subacute lower motor neuron impairment, especially when atypical clinical features for degenerative MND or other non-motor neurological manifestations are present, we recommend testing for onconeural antibodies. In the case, the search for onconeural antibodies is negative, but it exists a strong clinical suspicion for a paraneoplastic etiology; CSF analysis and total-body 18FDG-PET/CT imaging should be performed to circumstantiate diagnosis.


Assuntos
Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/etiologia , Síndromes Paraneoplásicas do Sistema Nervoso/complicações , Potenciais de Ação/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocinas/líquido cefalorraquidiano , Eletromiografia , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/terapia , Exame Neurológico , Síndromes Paraneoplásicas do Sistema Nervoso/terapia , Estudos Retrospectivos
11.
Acta Derm Venereol ; 98(9): 842-847, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-29738044

RESUMO

Livedoid vasculopathy is a rare thrombotic cutaneous disease. This observational study aimed to assess the clinical and biological features of livedoid vasculopathy and the efficacy of treatments. Patients enrolled had typical livedoid vasculopathy both clinically and histologically. Investigation of thrombophilia was performed. Electromyography was undertaken in the presence of symptoms suggesting peripheral neuropathy. Eighteen women and 8 men were included, with a mean age of 35.5 years at onset. Twenty patients had at least one thrombophilia factor. Ten patients had a peripheral neuropathy with 2 of these patients demonstrating a specific thrombo-occlusive vasculopathy on muscle biopsy. Anticoagulation with low molecular weight heparin was the most prescribed therapy and was associated with the best outcome (effective in 14 patients). Eight patients had severe disease refractory to anticoagulation and required intravenous immunoglobulins, producing a good response in 6 patients.


Assuntos
Anticoagulantes/administração & dosagem , Heparina de Baixo Peso Molecular/administração & dosagem , Imunoglobulinas Intravenosas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Livedo Reticular/tratamento farmacológico , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Coagulação Sanguínea/efeitos dos fármacos , Criança , Feminino , França/epidemiologia , Humanos , Livedo Reticular/sangue , Livedo Reticular/epidemiologia , Livedo Reticular/imunologia , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/epidemiologia , Fatores de Risco , Trombofilia/sangue , Trombofilia/tratamento farmacológico , Trombofilia/epidemiologia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
12.
J Peripher Nerv Syst ; 23(2): 143-146, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29542204

RESUMO

A 59-year-old woman presented with progressive paresthesias of all of her limbs for 4 years, associated with neuropathic pain, tingling in the tongue and allodynia, consistent with small fiber neuropathy (SFN). Several systemic symptoms and signs were found on clinical examination and laboratory work-up. Neurological investigations including neurophysiologic test and skin biopsy supported the diagnosis of SFN. Chronic exposure to N-hexane was then disclosed and suspected to be the cause of the disease. Following the discontinuation of chronic N-hexane exposure, the patient had a progressive improvement of all signs and symptoms, reinforcing the correlation between exposure to N-hexane, and development of SFN. Exposure to N-hexane may be considered as a novel reversible cause of SFN, which underlines the need to look for toxic etiologies in the diagnosis of SFN.


Assuntos
Hexanos/toxicidade , Exposição Ocupacional/efeitos adversos , Neuropatia de Pequenas Fibras/induzido quimicamente , Feminino , Humanos , Pessoa de Meia-Idade , Condução Nervosa/fisiologia , Pele/patologia , Neuropatia de Pequenas Fibras/patologia
13.
Neurol Neuroimmunol Neuroinflamm ; 5(3): e451, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29520367

RESUMO

Objective: To study the B-cell content, organization, and existence of distinct B-cell subpopulations in relation to the expression of type 1 interferon signature related genes in dermatomyositis (DM). Methods: Evaluation of skeletal muscle biopsies from patients with adult DM (aDM) and juvenile DM (jDM) by histology, immunohistochemistry, electron microscopy, and quantitative reverse-transcription PCR. Results: We defined 3 aDM subgroups-classic (containing occasional B cells without clusters), B-cell-rich, and follicle-like aDM-further elucidating IM B-lymphocyte maturation and immunity. The quantity of B cells and formation of ectopic lymphoid structures in a subset of patients with aDM were associated with a specific profile of cytokines and chemokines involved in lymphoid neogenesis. Levels of type 1 interferon signature related gene expression paralleled B-cell content and architectural organization and link B-cell immunity to the interferon type I signature. Conclusion: These data corroborate the important role of B cells in DM, highlighting the direct link between humoral mechanisms as key players in B-cell immunity and the role of type I interferon-related immunity.

14.
Neurology ; 90(6): e507-e517, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29330311

RESUMO

OBJECTIVE: To characterize muscle fiber necrosis in immune-mediated necrotizing myopathies (IMNM) with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) antibodies and to explore its underlying molecular immune mechanisms. METHODS: Muscle biopsies from patients with IMNM were analyzed and compared to biopsies from control patients with myositis. In addition to immunostaining and reverse transcription PCR on muscle samples, in vitro immunostaining on primary muscle cells was performed. RESULTS: Creatine kinase levels and muscle regeneration correlated with the proportion of necrotic fibers (r = 0.6, p < 0.001). CD68+iNOS+ macrophages and a Th-1 immune environment were chiefly involved in ongoing myophagocytosis of necrotic fibers. T-cell densities correlated with necrosis but no signs of cytotoxicity were detected. Activation of the classical pathway of the complement cascade, accompanied by deposition of sarcolemmal immunoglobulins, featured involvement of humoral immunity. Presence of SRP and HMGCR proteins on altered myofibers was reproduced on myotubes exposed to purified patient-derived autoantibodies. Finally, a correlation between sarcolemmal complement deposits and fiber necrosis was observed (r = 0.4 and p = 0.004). Based on these observations, we propose to update the pathologic criteria of IMNM. CONCLUSION: These data further corroborate the pathogenic role of anti-SRP and anti-HMGCR autoantibodies in IMNM, highlighting humoral mechanisms as key players in immunity and myofiber necrosis.


Assuntos
Autoanticorpos/sangue , Proteínas do Sistema Complemento/metabolismo , Hidroximetilglutaril-CoA Redutases/imunologia , Músculo Esquelético/patologia , Doenças Musculares/sangue , Doenças Musculares/complicações , Partícula de Reconhecimento de Sinal/imunologia , Antígenos CD/metabolismo , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Linfócitos/patologia , Macrófagos/patologia , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Miofibrilas/metabolismo , Miofibrilas/patologia , Necrose/etiologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/metabolismo , Partícula de Reconhecimento de Sinal/metabolismo
15.
Muscle Nerve ; 57(2): 330-334, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28224639

RESUMO

INTRODUCTION: Bcl-2-associated athanogene-3 (BAG3) mutations have been described in rare cases of rapidly progressive myofibrillar myopathies. Symptoms begin in the first decade with axial involvement and contractures and are associated with cardiac and respiratory impairment in the second decade. Axonal neuropathy has been documented but usually not as a key clinical feature. METHODS: We report a 24-year-old woman with severe rigid spine syndrome and sensory-motor neuropathy resembling Charcot-Marie-Tooth disease (CMT). RESULTS: Muscle MRI showed severe fat infiltration without any specific pattern. Deltoid muscle biopsy showed neurogenic changes and discrete myofibrillar abnormalities. Electrocardiogram and transthoracic echocardiography results were normal. Genetic analysis of a panel of 45 CMT genes showed no mutation. BAG3 gene screening identified the previously reported c.626C>T, pPro209Leu, mutation. DISCUSSION: This case indicates that rigid spine syndrome and sensory-motor axonal neuropathy are key clinical features of BAG3 mutations that should be considered even without cardiac involvement. Muscle Nerve, 57: 330-334, 2018.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Doença de Charcot-Marie-Tooth/genética , Neuropatia Hereditária Motora e Sensorial/genética , Corpos de Mallory/patologia , Distrofias Musculares/genética , Escoliose/genética , Biópsia , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/diagnóstico por imagem , Eletrodiagnóstico , Feminino , Cardiopatias/complicações , Neuropatia Hereditária Motora e Sensorial/complicações , Neuropatia Hereditária Motora e Sensorial/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Corpos de Mallory/genética , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Distrofias Musculares/complicações , Distrofias Musculares/diagnóstico por imagem , Mutação/genética , Escoliose/complicações , Escoliose/diagnóstico por imagem , Adulto Jovem
16.
Nat Commun ; 8(1): 1859, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29192144

RESUMO

Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and function but most showed limited efficacy. Here we show that the expression of components of the myostatin signaling pathway is downregulated in muscle wasting or atrophying diseases, with a decrease of myostatin and activin receptor, and an increase of the myostatin antagonist, follistatin. We also provide in vivo evidence in the congenital myotubular myopathy mouse model (knock-out for the myotubularin coding gene Mtm1) that a down-regulated myostatin pathway can be reactivated by correcting the underlying gene defect. Our data may explain the poor clinical efficacy of anti-myostatin approaches in several of the clinical studies and the apparent contradictory results in mice regarding the efficacy of anti-myostatin approaches and may inform patient selection and stratification for future trials.


Assuntos
Miostatina/metabolismo , Doenças Neuromusculares/metabolismo , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Folistatina/genética , Folistatina/metabolismo , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Miopatias Congênitas Estruturais/genética , Miostatina/sangue , Miostatina/genética , Doenças Neuromusculares/genética , Doenças Neuromusculares/terapia , Proteínas Tirosina Fosfatases não Receptoras/genética
17.
Melanoma Res ; 27(5): 511-515, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28692456

RESUMO

Therapeutic advances derived from targeted therapy and immune checkpoint inhibitors can improve melanoma prognosis. Since 2015, cobimetinib has been approved in combination with vemurafenib in the first-line treatment for BRAF-mutated melanoma. For NRAS-mutated melanomas, MEK inhibition seems to be a therapeutic target, and association with checkpoint inhibitor provides a further therapeutic perspective. Infraclinical creatine phosphokinase (CPK) elevation is an MEK inhibitor side effect. We describe a case of focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib, 1 month after its introduction. The clinical presentation comprised interscapular pain, axial fatigue with cervical hypotonia, CPK elevation, intense fluorine-18-fluorodeoxyglucose uptake in cervical muscles, and necrotizing myopathy was confirmed by muscle biopsy. Cobimetinib was temporarily discontinued, resulting in CPK normalization. Re-evaluation showed partial response, motivating continuation of combination therapy with a reduced dose of cobimetinib (40 mg/day). Because prescription of targeted therapies is likely to increase, this adverse event should be known.


Assuntos
Azetidinas/efeitos adversos , MAP Quinase Quinase 1/efeitos adversos , Melanoma/complicações , Doenças Musculares/etiologia , Piperidinas/efeitos adversos , Neoplasias Cutâneas/complicações , Idoso , Azetidinas/farmacologia , Humanos , MAP Quinase Quinase 1/farmacologia , Masculino , Melanoma/patologia , Doenças Musculares/patologia , Piperidinas/farmacologia , Neoplasias Cutâneas/patologia
18.
J Neurol ; 264(6): 1218-1226, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28536920

RESUMO

Multiple mononeuropathy (MM) occurs rarely during systemic lupus erythematosus (SLE) but may lead to major disability. The aim of this study was to investigate the clinic-pathological presentations of MM during SLE, as well as long-term outcomes. We conducted a multicentric retrospective study that included patients receiving a diagnosis of MM during SLE. Ten patients were included (8 women and 2 men, median age at MM diagnosis: 40.4 years). SLE was diagnosed before MM in 9/10 patients (median time 8.2 years). When MM occurred, the SLEDAI score was ≥6 for 6/9 patients. Presenting symptoms consisted of sensory deficits (n = 10), neuropathic pain (n = 9), and/or motor deficits (n = 9), sometimes symmetrical, affecting the lower limbs (10/10) and occasionally the upper limbs (5/10). All patients presented with uni- or bilateral damage of the common fibular nerve, with less frequent involvement of the tibial nerve. Serum cryoglobulinemia was positive in 5/9 patients. Electrophysiological studies confirmed the non-symmetrical involvement of multiple nerve trunks in all patients. Neuromuscular biopsy (performed in five patients) showed histological signs of vasculitis in two patients and perivascular lymphocytic inflammatory infiltrates in two others. All patients were treated with glucocorticosteroids combined with cyclophosphamide (n = 6), rituximab (n = 3), or mycophénolate-mofétil (n = 1). The median follow-up was 5 years. Two patients relapsed during follow-up. All patients had motor and/or sensory sequelae upon follow-up. MM associated with SLE is frequently caused by a vasculitis mechanism. Patients improve with steroids and immunosuppressive drugs. Long-term outcomes include frequent clinical sequelae and possible relapses.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Mononeuropatias/complicações , Adolescente , Corticosteroides/uso terapêutico , Adulto , Proteína C-Reativa/metabolismo , Eletromiografia , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Mononeuropatias/tratamento farmacológico , Mononeuropatias/patologia , Condução Nervosa/fisiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto Jovem
19.
Hum Mutat ; 38(5): 556-568, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28144995

RESUMO

In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C-terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins.


Assuntos
Estudos de Associação Genética , Proteínas de Choque Térmico Pequenas/genética , Mutação , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Biomarcadores , Linhagem Celular , Criança , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico/genética , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/genética , Família Multigênica , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA