RESUMO
Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM1,2. The most common disease-causing mutation (DOK71124_1127 dup) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. Here we describe a mouse model of this common form of CM (Dok7CM mice) and a mouse with point mutations in the two tyrosine residues (Dok72YF). We show that Dok7CM mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in Dok7CM mice. These findings identify an unexpected cause for disease and a potential therapy for both DOK7 CM and other forms of CM caused by mutations in AGRIN, LRP4 or MUSK, and illustrate the potential of targeted therapy to rescue congenital lethality.
Assuntos
Proteínas Musculares/genética , Mutação , Síndromes Miastênicas Congênitas/tratamento farmacológico , Síndromes Miastênicas Congênitas/genética , Envelhecimento , Agrina/genética , Agrina/metabolismo , Animais , Animais Recém-Nascidos , Anticorpos/imunologia , Modelos Animais de Doenças , Feminino , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Masculino , Camundongos , Terapia de Alvo Molecular , Fibras Musculares Esqueléticas/química , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Síndromes Miastênicas Congênitas/imunologia , Fosforilação , Fosfotirosina/genética , Fosfotirosina/metabolismo , Proteínas Proto-Oncogênicas c-crk/metabolismo , Receptores Proteína Tirosina Quinases/agonistas , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/imunologia , Receptores Proteína Tirosina Quinases/metabolismo , Recidiva , Sinapses/metabolismoRESUMO
We report on four consecutive patients with Parkinson's disease, in whom anti-acetylcholine receptor (AChR) antibody positive bulbar myasthenia gravis (MG) turned out to be responsible for progressive dysphagia.
Assuntos
Transtornos de Deglutição/diagnóstico , Progressão da Doença , Miastenia Gravis/diagnóstico , Síndromes Miastênicas Congênitas/diagnóstico , Doença de Parkinson/diagnóstico , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Transtornos de Deglutição/classificação , Transtornos de Deglutição/imunologia , Diagnóstico Diferencial , Disartria/classificação , Disartria/diagnóstico , Disartria/imunologia , Humanos , Masculino , Miastenia Gravis/classificação , Miastenia Gravis/imunologia , Síndromes Miastênicas Congênitas/classificação , Síndromes Miastênicas Congênitas/imunologia , Doença de Parkinson/classificação , Doença de Parkinson/imunologia , Receptores Colinérgicos/imunologiaRESUMO
BACKGROUND: The role of antibodies in neuromuscular junction disorders is well established with antibodies to acetylcholine receptor, muscle-specific kinase, and voltage-gated calcium channels. The diseases associated with these antibodies, myasthenia gravis and the Lambert-Eaton myasthenic syndrome, respond well to symptomatic treatments (e.g., cholinesterase inhibitors) and to immunotherapies such as plasma exchange, intravenous immunoglobulin, oral steroids, and steroid-sparing drugs. The role of the antibodies has been established by a variety of in vitro and in vivo approaches. More recently, antibodies to voltage-gated potassium channels have been identified in patients with autoimmune forms of acquired neuromyotonia. Over the last decade, antibodies to CNS membrane receptors or ion channels have begun to be identified and these antibodies define antibody-mediated CNS diseases that also respond to immunotherapies. SUMMARY: The paradigms gained from the study of the peripheral conditions has led to a better appreciation of the role of antibodies in neurological disorders and a growing recognition of their role in central nervous system (CNS) diseases.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Canalopatias , Imunoterapia , Corticosteroides/uso terapêutico , Adulto , Aquaporina 4/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/terapia , Canais de Cálcio/imunologia , Canalopatias/imunologia , Canalopatias/terapia , Glutamato Descarboxilase/imunologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Recém-Nascido , Síndromes Miastênicas Congênitas/imunologia , Síndromes Miastênicas Congênitas/terapia , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/terapia , Troca Plasmática , Canais de Potássio de Abertura Dependente da Tensão da Membrana/imunologia , Receptores de Neurotransmissores/imunologiaRESUMO
Myasthenia gravis and myasthenic syndromes are diseases of the neuromuscular junction. Autoantibodies and toxins to or mutations in one of the synaptic proteins are the main causes of dysfunction. Myasthenic phenotypes can be classified according to the basic aetiological mechanisms or divided depending on the clinical phenotype.
Assuntos
Miastenia Gravis/imunologia , Miastenia Gravis/fisiopatologia , Junção Neuromuscular/fisiopatologia , Adulto , Idoso , Autoanticorpos/sangue , Autoanticorpos/imunologia , Feminino , Humanos , Recém-Nascido , Síndrome Miastênica de Lambert-Eaton/imunologia , Síndrome Miastênica de Lambert-Eaton/fisiopatologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Músculos/fisiopatologia , Mutação , Miastenia Gravis/epidemiologia , Síndromes Miastênicas Congênitas/imunologia , Síndromes Miastênicas Congênitas/fisiopatologia , Junção Neuromuscular/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/genética , Receptores Colinérgicos/imunologia , Transmissão SinápticaRESUMO
In 1960, John A. Simpson hypothesized that myasthenia gravis "is an 'auto-immune' response of muscle in which an antibody to end-plate protein may be formed." Simpson's speculation was subsequently shown to be correct. A review of Simpson's hypothesis from a historical perspective illustrates the role of analogy in science.
Assuntos
Miastenia Gravis/história , Ciência/métodos , Adulto , Formação de Anticorpos , Especificidade de Anticorpos , Autoanticorpos/imunologia , Feminino , História do Século XX , Humanos , Recém-Nascido , Masculino , Modelos Imunológicos , Modelos Neurológicos , Placa Motora/imunologia , Miastenia Gravis/imunologia , Síndromes Miastênicas Congênitas/história , Síndromes Miastênicas Congênitas/imunologia , Gravidez , Ciência/história , EscóciaRESUMO
Acetylcholine receptor (AChR) antibodies are present in around 85% of patients with myasthenia gravis (MG) as measured by the conventional radioimmunoprecipitation assay. Antibodies that block the fetal form of the AChR are occasionally present in mothers who develop MG after pregnancy, especially in those whose babies are born with arthrogryposis multiplex congenita. The antibodies cross the placenta and block neuromuscular transmission, leading to joint deformities and often stillbirth. In these mothers, antibodies made in the thymus are mainly specific for fetal AChR and show restricted germline origins, suggesting a highly mutated clonal response; subsequent spread to involve adult AChR could explain development of maternal MG in those cases who first present after pregnancy. In the 15% of "seronegative" MG patients without AChR antibodies (SNMG), there are serum factors that increase AChR phosphorylation and reduce AChR function, probably acting via a different membrane receptor. These factors are not IgG and could be IgM or even non-Ig serum proteins. In a proportion of SNMG patients, however, IgG antibodies to the muscle-specific kinase, MuSK, are present. These antibodies are not found in AChR antibody-positive MG and are predominantly IgG4. MuSK antibody positivity appears to be associated with more severe bulbar disease that can be difficult to treat effectively.