RESUMEN
Background and objectives: Antiglycine receptor (anti-GlyR) antibody mediates multiple immune-related diseases. This study aimed to summarize the clinical features to enhance our understanding of anti-GlyR antibody-related disease. Methods: By collecting clinical information from admitted patients positive for glycine receptor (GlyR) antibody, the clinical characteristics of a new patient positive for GlyR antibody were reported in this study. To obtain additional information regarding anti-GlyR antibody-linked illness, clinical data and findings on both newly reported instances in this study and previously published cases were merged and analyzed. Results: A new case of anti-GlyR antibody-related progressive encephalomyelitis with rigidity and myoclonus (PERM) was identified in this study. A 20-year-old man with only positive cerebrospinal fluid anti-GlyR antibody had a good prognosis with first-line immunotherapy. The literature review indicated that the common clinical manifestations of anti-GlyR antibody-related disease included PERM or stiff-person syndrome (SPS) (n = 179, 50.1%), epileptic seizure (n = 94, 26.3%), and other neurological disorders (n = 84, 24.5%). Other neurological issues included demyelination, inflammation, cerebellar ataxia and movement disorders, encephalitis, acute psychosis, cognitive impairment or dementia, celiac disease, Parkinson's disease, neuropathic pain and allodynia, steroid-responsive deafness, hemiballism/tics, laryngeal dystonia, and generalized weakness included respiratory muscles. The group of PERM/SPS exhibited a better response to immunotherapy than others. Conclusions: The findings suggest the presence of multiple clinical phenotypes in anti-GlyR antibody-related disease. Common clinical phenotypes include PERM, SPS, epileptic seizure, and paraneoplastic disease. Patients with RERM/SPS respond well to immunotherapy.
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Autoanticuerpos , Encefalomielitis , Rigidez Muscular , Receptores de Glicina , Humanos , Masculino , Receptores de Glicina/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Adulto Joven , Encefalomielitis/inmunología , Encefalomielitis/diagnóstico , Rigidez Muscular/inmunología , Rigidez Muscular/etiología , Rigidez Muscular/diagnóstico , Mioclonía/inmunología , Mioclonía/diagnóstico , Síndrome de la Persona Rígida/inmunología , Síndrome de la Persona Rígida/diagnóstico , Síndrome de la Persona Rígida/terapia , AdultoAsunto(s)
Trastornos Parkinsonianos , Síndrome de la Persona Rígida , Humanos , Síndrome de la Persona Rígida/inmunología , Síndrome de la Persona Rígida/diagnóstico , Trastornos Parkinsonianos/inmunología , Receptores de Glicina/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Masculino , Femenino , Persona de Mediana Edad , Trastornos de la Visión/inmunología , Trastornos de la Visión/etiologíaRESUMEN
This case report describes a 54-year-old woman with naming deficits, comprehension impairment, and memory loss. Initial physical and neurological examination results were unremarkable.
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Afasia Progresiva Primaria , Autoanticuerpos , Receptores de Glicina , Humanos , Autoanticuerpos/inmunología , Afasia Progresiva Primaria/inmunología , Receptores de Glicina/inmunología , Masculino , Femenino , Persona de Mediana Edad , AncianoRESUMEN
BACKGROUND AND OBJECTIVES: Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRß subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRß making it not unlikely that GlyRß-specific autoantibody (aAb) exist and contribute to the disease pathology. METHODS: In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRß. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRß binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRß aAb binding were resolved by whole-cell patch-clamp recordings. RESULTS: Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRß aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRß colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRß aAb from both patients to its target impair glycine efficacy. DISCUSSION: Our study establishes GlyRß as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRß impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRß aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.
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Enfermedades Autoinmunes , Receptores de Glicina , Síndrome de la Persona Rígida , Humanos , Autoanticuerpos , Glicina , Receptores de Glicina/inmunología , Receptores de Glicina/metabolismo , Síndrome de la Persona Rígida/inmunologíaRESUMEN
INTRODUCTION: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare disorder. However, the outcome is still variable with different serological and tumor associations, and the elements to good response with less relapse is yet to be elucidated. METHOD: We present a case and obtain a literature review of patients with PERM and make comparisons based on different serological groups. We also analyze patients with idiopathic PERM that had detailed medical records. RESULTS: 81 patients were collected and analyzed. The largest group were glycine receptor-antibody (GlyR-Ab)-positive (70%), and the seropositive-GlyR-Ab-negative group had better response to immunotherapy. Malignancy can occur up to 2 years from the presentation of PERM. Among the 18 cases with detailed records, the patients who had good outcome initiate immunotherapy within 2 months from presentation. 9 of the 12 patients who experienced no relapse had non-steroid immunotherapy. The maximal interval time of relapse was 24 months. CONCLUSION: We recommend tumor surveillance up to 2 years in patients with PERM and early administration of immunotherapies and maintain with non-steroid immunotherapy with or without oral corticosteroid for a minimum of 2 years to reduce the risk of relapse in GlyR-Ab-positive patients.
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Autoanticuerpos , Encefalomielitis/diagnóstico , Rigidez Muscular/diagnóstico , Receptores de Glicina/inmunología , Encefalomielitis/inmunología , Femenino , Humanos , Persona de Mediana Edad , Rigidez Muscular/inmunologíaRESUMEN
AIMS: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a life-threatening condition often associated with highly raised serum antibodies to glycine receptors (GlyRs); these bind to the surface of large neurons and interneurons in rodent brain and spinal cord sections and, in vitro, inhibit function and reduce surface expression of the GlyRs. The effects in vivo have not been reported. METHODS: Purified plasma IgG from a GlyR antibody-positive patient with PERM, and a healthy control (HC), was injected daily into the peritoneal cavity of mice for 12 days; lipopolysaccharide (LPS) to open the blood-brain barrier, was injected on days 3 and 8. Based on preliminary data, behavioural tests were only performed 48 h post-LPS on days 5-7 and 10-12. RESULTS: The GlyR IgG injected mice showed impaired ability on the rotarod from days 5 to 10 but this normalized by day 12. There were no other behavioural differences but, at termination (d13), the GlyR IgG-injected mice had IgG deposits on the neurons that express GlyRs in the brainstem and spinal cord. The IgG was not only on the surface but also inside these large GlyR expressing neurons, which continued to express surface GlyR. CONCLUSIONS: Despite the partial clinical phenotype, not uncommon in passive transfer studies, the results suggest that the antibodies had accessed the GlyRs in relevant brain regions, led to antibody-mediated internalization and increased GlyR synthesis, compatible with the temporary loss of function.
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Autoanticuerpos/farmacología , Encefalomielitis/inmunología , Inmunoglobulina G/farmacología , Neuronas Motoras/metabolismo , Rigidez Muscular/inmunología , Receptores de Glicina/metabolismo , Animales , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Autoantígenos/metabolismo , Tronco Encefálico/inmunología , Tronco Encefálico/metabolismo , Encefalomielitis/metabolismo , Humanos , Inmunoglobulina G/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas Motoras/inmunología , Rigidez Muscular/metabolismo , Mioclonía/inmunología , Mioclonía/metabolismo , Receptores de Glicina/inmunología , Médula Espinal/inmunología , Médula Espinal/metabolismoAsunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Benserazida/farmacología , Dopaminérgicos/farmacología , Encefalomielitis/tratamiento farmacológico , Levodopa/farmacología , Rigidez Muscular/tratamiento farmacológico , Mioclonía/tratamiento farmacológico , Receptores de Glicina/inmunología , Adulto , Autoanticuerpos , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Benserazida/administración & dosificación , Dopaminérgicos/administración & dosificación , Combinación de Medicamentos , Encefalomielitis/inmunología , Encefalomielitis/fisiopatología , Humanos , Levodopa/administración & dosificación , Masculino , Rigidez Muscular/inmunología , Rigidez Muscular/fisiopatología , Mioclonía/inmunología , Mioclonía/fisiopatologíaRESUMEN
OBJECTIVE: Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. METHODS: A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. RESULTS: Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues 29 A to 62 G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. INTERPRETATION: Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544-561.
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Autoanticuerpos/inmunología , Encefalomielitis/inmunología , Rigidez Muscular/inmunología , Receptores de Glicina/metabolismo , Síndrome de la Persona Rígida/inmunología , Adulto , Anciano , Animales , Autoanticuerpos/farmacología , Autoantígenos/inmunología , Conducta Animal/efectos de los fármacos , Encefalomielitis/metabolismo , Epítopos de Linfocito B/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rigidez Muscular/metabolismo , Receptores de Glicina/inmunología , Síndrome de la Persona Rígida/metabolismo , Pez CebraRESUMEN
OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions. METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters. RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention. CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.
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Autoanticuerpos , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Técnicas de Diagnóstico Neurológico/normas , Glutamato Descarboxilasa/inmunología , Pruebas Inmunológicas/normas , Péptidos y Proteínas de Señalización Intracelular/inmunología , Proteínas de la Membrana/inmunología , Trastornos Mentales/diagnóstico , Proteínas del Tejido Nervioso/inmunología , Neurópilo/inmunología , Canales de Potasio con Entrada de Voltaje/inmunología , Receptores AMPA/inmunología , Receptores de GABA-B/inmunología , Receptores de Glicina/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/análisis , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Niño , Preescolar , Femenino , Células HEK293 , Humanos , Lactante , Masculino , Trastornos Mentales/sangre , Trastornos Mentales/líquido cefalorraquídeo , Trastornos Mentales/inmunología , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Adulto JovenRESUMEN
Stiff person spectrum disorders (SPSD) are a broad group of immune-mediated disorders. Clinical presentations include classical stiff person syndrome (SPS), focal SPS, and progressive encephalomyelitis with rigidity and myoclonus (PERM). The most frequently associated antibodies are anti-GAD65, anti-GlyR, anti-amphiphysin, and anti-DPPX. Immunotherapy is the primary treatment modality. We present an illustrative case series of three patients: anti-GlyR antibody-mediated PERM presenting as rapidly progressive dementia; anti-amphiphysin antibody-mediated SPS; and SPS presentation with anti-Zic4 antibodies, spasmodic laryngeal stridor and fluctuating eyelid ptosis. Clinical characteristics, CSF findings, neurophysiological features, adequate immunological assays and a high suspicion index are essential for prompt diagnosis and management.
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Diversidad de Anticuerpos , Autoanticuerpos/inmunología , Síndrome de la Persona Rígida/inmunología , Anciano , Anciano de 80 o más Años , Especificidad de Anticuerpos , Autoantígenos/inmunología , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/inmunología , Diarrea/etiología , Diplopía/etiología , Resultado Fatal , Trastornos Neurológicos de la Marcha/etiología , Humanos , Inmunosupresores/uso terapéutico , Inmunoterapia , Masculino , Persona de Mediana Edad , Rigidez Muscular/etiología , Mioclonía/etiología , Proteínas del Tejido Nervioso/inmunología , Neuroimagen , Fenotipo , Receptores de Glicina/inmunología , Convulsiones/etiología , Síndrome de la Persona Rígida/complicaciones , Síndrome de la Persona Rígida/diagnóstico por imagen , Síndrome de la Persona Rígida/terapia , Factores de Transcripción/inmunología , Temblor/etiologíaRESUMEN
Background: Glycine is a classical neurotransmitter that has role in both inhibitory and excitatory synapses. To understand whether glycinergic inputs are involved in the regulation of the hypophysiotropic thyrotropin-releasing hormone (TRH) neurons, the central controllers of the hypothalamic-pituitary-thyroid axis, the glycinergic innervation of the TRH neurons was studied in the hypothalamic paraventricular nucleus (PVN). Methods: Double-labeling immunocytochemistry and patch-clamp electrophysiology were used to determine the role of glycinergic neurons in the regulation of TRH neurons in the PVN. Anterograde and retrograde tracing methods were used to determine the sources of the glycinergic input of TRH neurons. Results: Glycine transporter-2 (GLYT2), a marker of glycinergic neurons, containing axons were found to establish symmetric type of synapses on TRH neurons in the PVN. Furthermore, glycine receptor immunoreactivity was observed in these TRH neurons. The raphe magnus (RMg) and the ventrolateral periaqueductal gray (VLPAG) were found to be the exclusive sources of the glycinergic innervation of the TRH neurons within the PVN. Patch-clamp electrophysiology using sections of TRH-IRES-tdTomato mice showed that glycine hyperpolarized the TRH neurons and completely blocked the firing of these neurons. Glycine also markedly hyperpolarized the TRH neurons in the presence of tetrodotoxin demonstrating the direct effect of glycine. In more than 60% of the TRH neurons, spontaneous inhibitory postsynaptic currents (sIPSCs) were observed, even after the pharmacological inhibition of glutamatergic and GABAergic neuronal transmission. The glycine antagonist, strychnine, almost completely abolished these sIPSCs, demonstrating the inhibitory nature of the glycinergic input of TRH neurons. Conclusions: These data demonstrate that TRH neurons in the PVN receive glycinergic inputs from the RMg and the VLPAG. The symmetric type of synaptic connection and the results of the electrophysiological experiments demonstrate the inhibitory nature of these inputs.
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Glicina/fisiología , Neuronas/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Hormona Liberadora de Tirotropina/farmacología , Animales , Glicina/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática , Masculino , Ratones , Ratones Transgénicos , Técnicas de Placa-Clamp , Receptores de Glicina/efectos de los fármacos , Receptores de Glicina/inmunología , Sinapsis/efectos de los fármacos , Tetrodotoxina/farmacologíaRESUMEN
A 48-year-old woman with a 3-month history of spontaneously resolving stiff leg symptom at the age of 43 years presented with progressive onset of leg rigidity, walking difficulty, and myoclonic jerks. On admission she had marked stiffness in her foot joints with symmetric sustained dorsiflexion of the ankles and toes, with spontaneous and reflex myoclonic jerks easily provoked by knee tendon tap. She appeared to have a spastic gait due to stiffness in her legs. Needle electromyogram (EMG) examination revealed continuous motor unit activity in the tibialis anterior muscle at rest even when voluntary contraction of the gastrocnemius muscle was instructed, but no myokimic discharge or acute denervation sign was seen. The laboratory tests were unremarkable, including glutamic acid decarboxylase antibody. Cerebrospinal fluid (CSF) examination was also normal, without oligoclonal bands or elevated IgG index. She was diagnosed with stiff-limb syndrome based on neurologic examination and needle EMG findings, and she was treated with intravenous high-dose methylprednisolone (500â mg/day, 3 days), resulting in marked improvement in her symptoms. Anti-glycine receptor antibodies were subsequently identified in her archived serum and CSF obtained before immunotherapy. She was then started on oral prednisolone (30â mg/day) and had been free of symptoms.
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Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Receptores de Glicina/inmunología , Síndrome de la Persona Rígida/diagnóstico , Síndrome de la Persona Rígida/tratamiento farmacológico , Administración Oral , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Electromiografía , Femenino , Glucocorticoides/administración & dosificación , Humanos , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Prednisolona/administración & dosificación , Quimioterapia por Pulso , Síndrome de la Persona Rígida/inmunología , Resultado del TratamientoRESUMEN
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an autoimmune disorder involving the brainstem and spinal cord and is sometimes associated with thymoma. We encountered a 75-year-old woman with typical PERM features, glycine receptor antibody, and thymoma. Her neurologic symptoms improved after thymectomy, but she unexpectedly developed anasarca with massive pleural effusions and hypoalbuminemia and finally succumbed to death. The autopsy showed edema and mononuclear infiltration in the pleura but no neuropathological findings typical of PERM. Effective treatment of PERM can reverse the neuropathological signs of encephalomyelitis. The autoimmune nature of anasarca is possible but not proven.
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Enfermedades Autoinmunes/complicaciones , Edema/etiología , Encefalomielitis/complicaciones , Rigidez Muscular/complicaciones , Mioclonía/complicaciones , Timectomía/efectos adversos , Timoma/complicaciones , Timoma/cirugía , Neoplasias del Timo/complicaciones , Neoplasias del Timo/cirugía , Anciano , Autoanticuerpos/sangre , Enfermedades Autoinmunes/cirugía , Autopsia , Edema/inmunología , Encefalomielitis/cirugía , Resultado Fatal , Femenino , Humanos , Rigidez Muscular/cirugía , Mioclonía/cirugía , Derrame Pleural/etiología , Derrame Pleural/inmunología , Complicaciones Posoperatorias , Receptores de Glicina/inmunología , Albúmina Sérica/análisisRESUMEN
BACKGROUND AND PURPOSE: Antibodies to glycine receptors (GlyR-Abs) were first defined in progressive encephalopathy with rigidity and myoclonus (PERM) but were subsequently identified in other clinical presentations. Our aim was to assess the clinical associations of all patients identified with GlyR-Abs in Queensland, Australia, between April 2014 and May 2017 and to compare these to cases reported in the literature. METHODS: A literature review identified the clinical features of all published GlyR-Ab-positive cases through online databases. A case series was undertaken via collection of clinical information from all patients diagnosed or known to immunology, pathology or neurological services in Queensland during the study period of 3 years. RESULTS: In all, 187 GlyR-Ab-positive cases were identified in the literature. The majority (47.6%) had PERM, 22.4% had epilepsy, but the remaining 30% included mixed phenotypes consisting of cerebellar ataxia, movement disorders, demyelination and encephalitis/cognitive dysfunction. By contrast, in our series of 14 cases, eight had clinical presentations consistent with seizures and epilepsy and only three cases had classical features of PERM. There was one case each of global fatiguable weakness with sustained clonus, laryngeal dystonia and movement disorder with hemiballismus and tics. The rate of response to immune therapy was similar in all groups. CONCLUSION: Antibodies to glycine receptors are linked to a spectrum of neurological disease. The results of the literature review and our case series suggest a greater relationship between GlyR-Abs and epilepsy than previously reported.
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Autoanticuerpos , Rigidez Muscular/inmunología , Mioclonía/inmunología , Receptores de Glicina/inmunología , Adolescente , Adulto , Anciano , Australia , Niño , Preescolar , Encefalitis/inmunología , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/inmunología , Fenotipo , Adulto JovenRESUMEN
Stiff-person syndrome (SPS) is a disorder characterized by fluctuating muscle rigidity and painful spasms that occur spontaneously or are triggered by diverse stimuli. Partial or segmental forms of the disorder, such as stiff-limb syndrome (SLS) and a more severe disease called progressive encephalomyelitis with rigidity and myoclonus (PERM), are usually considered within the spectrum of SPS. SPS responds to immunotherapies, and several autoantigens have been identified. Most patients with SPS have a high-titer of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of γ-aminobutyric acid (GABA), and up to 15% have antibodies to the glycine receptor α-subunit. This review explains milestones in defining SPS including autoantibodies.
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Autoanticuerpos/inmunología , Síndrome de la Persona Rígida/diagnóstico , Síndrome de la Persona Rígida/inmunología , Encefalomielitis/inmunología , Glutamato Descarboxilasa/inmunología , Humanos , Rigidez Muscular , Receptores de Glicina/inmunologíaRESUMEN
It may be challenging to distinguish autoimmune encephalitis associated with anti-neuronal autoantibodies from primary psychiatric disorders. Here, serum was drawn from patients with a first-episode psychosis (n=70) or a clinical high-risk for psychosis (n=6) and controls (n=34). We investigated the serum prevalence of 24 anti-neuronal autoantibodies: IgG antibodies for anti-N-methyl-d-aspartate-type glutamate receptor (anti-NMDAR), glutamate and γ-aminobutyric acid alpha and beta receptors (GABA-a, GABA-b), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), glycine receptor (GlyR), metabotropic glutamate receptor 1 and 5 (mGluR1, mGluR5), anti-Tr/Delta/notch-like epidermal growth factor-related receptor (DNER), contactin-associated protein-like 2 (CASPR2), myelin oligodendrocyte glycoprotein (MOG), glutamic acid decarboxylase-65 (GAD65), collapsin response mediator protein 5/crossveinless-2 (CV2), aquaporin-4 (AQP4), anti-dipeptidyl-peptidase-like protein-6 (DPPX), type 1 anti-neuronal nuclear antibody (ANNA-1, Hu), Ri, Yo, IgLON5, Ma2, zinc finger protein 4 (ZIC4), Rho GTPase-activating protein 26, amphiphysin, and recoverin, as well as IgA and IgM for dopamine-2-receptor (DRD2). Anti-NMDA IgG antibodies were positive with serum titer 1:320 in one patient with a clinical high risk for psychosis. He did not receive a diagnosis of encephalitis after comprehensive neurological evaluation. All other antineuronal autoantibodies were negative and there were no additional findings with immunohistochemistry of brain issues.
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Autoanticuerpos/sangre , Síntomas Prodrómicos , Trastornos Psicóticos/sangre , Trastornos Psicóticos/inmunología , Receptores de Glutamato/inmunología , Adolescente , Adulto , Acuaporina 4 , Femenino , Estudios de Seguimiento , Humanos , Masculino , Proteínas de la Membrana/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Proteínas del Tejido Nervioso/inmunología , Escalas de Valoración Psiquiátrica , Receptores de GABA/inmunología , Receptores de Glicina/inmunología , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE OF REVIEW: This review highlights the recent discovery of antibodies to glycine receptor (GlyR-Ab) and discusses the relationship between these antibodies and neurological disorders. RECENT FINDINGS: Since the initial description in 2008 of antibodies to glycine receptors (GlyR-Abs) in a patient with progressive encephalomyelitis with rigidity and myoclonus (PERM), these antibodies have been found in PERM and in some patients with a variety of stiff person spectrum (SPS) or related disorders. Patients with GlyR-Abs often improve with aggressive immunotherapy, and antibody titres correlate with disease severity. Around 25% of patients have another autoimmune condition and 10-20% have an underlying malignancy. GlyR-Abs bind to extracellular determinants, are mainly Immunoglobulin G1 subclass and induce GlyR internalization in Human embryonic kidney 293 cells, suggesting pathogenicity. The spectrum of neurological disease associated with GlyR-Abs has not been fully characterized, and lower titres may not be syndrome specific, but GlyR-Abs, like antibodies to other neuronal cell-surface antigens, define immunotherapy-responsive disease and are likely to be pathogenic. This distinguishes them from the glutamic acid decarboxylase antibodies that can also be found at high titres in patients with classical stiff person syndrome which is more often chronic and relatively resistant to immunological treatments. SUMMARY: Irrespective of the clinical features, GlyR-Abs are helpful in the diagnosis of patients who very often have a subacute, progressive and life-threatening disorder which shows a favourable response to immunotherapy.
Asunto(s)
Autoanticuerpos/análisis , Encefalomielitis/inmunología , Rigidez Muscular/inmunología , Mioclonía/inmunología , Receptores de Glicina/inmunología , Encefalomielitis/complicaciones , Encefalomielitis/terapia , Humanos , Rigidez Muscular/etiología , Rigidez Muscular/terapia , Mioclonía/etiología , Mioclonía/terapia , Síndrome de la Persona Rígida/inmunologíaRESUMEN
BACKGROUND: Antibody-associated disorders of the central nervous system are increasingly recognised in adults and children. Some are known to be paraneoplastic, whereas in others an infective trigger is postulated. They include disorders associated with antibodies to N-methyl-d-aspartate receptor (NMDAR), voltage-gated potassium channel-complexes (VGKC-complex), GABAB receptor or glycine receptor (GlyR). With antibodies to NMDAR or VGKC-complexes, distinct clinical patterns are well characterised, but as more antibodies are discovered, the spectra of associated disorders are evolving. GlyR antibodies have been detected in patients with progressive encephalopathy with rigidity and myoclonus (PERM), or stiff man syndrome, both rare but disabling conditions. CASE REPORT: We report a case of a young child with focal seizures and progressive dyskinesia in whom GlyR antibodies were detected. Anticonvulsants and immunotherapy were effective in treating both the seizures and movement disorder with good neurological outcome and with a decline in the patient's serum GlyR-Ab titres. CONCLUSION: Glycine receptor antibodies are associated with focal status epilepticus and seizures, encephalopathy and progressive dyskinesia and should be evaluated in autoimmune encephalitis.
Asunto(s)
Discinesias/tratamiento farmacológico , Discinesias/inmunología , Receptores de Glicina/inmunología , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/inmunología , Anticonvulsivantes/uso terapéutico , Autoanticuerpos/sangre , Preescolar , Discinesias/complicaciones , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Rigidez Muscular/complicaciones , Rigidez Muscular/tratamiento farmacológico , Rigidez Muscular/inmunología , Mioclonía/complicaciones , Mioclonía/tratamiento farmacológico , Mioclonía/inmunología , Fenotipo , Estado Epiléptico/complicacionesRESUMEN
Our patient was a previously normal boy who presented to his local hospital with an explosive onset of prolonged seizures and encephalopathy. He was treated for a presumed central nervous system infection and initial neuroimaging was normal. Despite treatment with antibiotics and antiepileptic drugs (AEDs), he remained encephalopathic and became ataxic over the next 48â hours, not related to medication. The seizures also proved resistant to treatment despite polytherapy with AEDs, and he required immune-modulatory treatment, intravenous methylprednisolone and intravenous immunoglobulin, in addition to the AEDs to achieve seizure control. The ataxia also improved following treatment. The initial EEG was normal but subsequent EEGs, separated by a week each, were abnormal and revealed subtle atypical 'delta-brush-like waves'. The patient's serum and cerebrospinal fluid were tested for autoantibodies, and he was found to be positive for glycine receptor antibodies that are neuronal antibodies.
Asunto(s)
Anticuerpos/sangre , Receptores de Glicina/inmunología , Convulsiones/inmunología , Anticonvulsivantes/uso terapéutico , Ataxia/inmunología , Encefalopatías/inmunología , Preescolar , Quimioterapia Combinada , Glucocorticoides/uso terapéutico , Humanos , Masculino , Prednisolona/uso terapéutico , Convulsiones/tratamiento farmacológicoRESUMEN
IMPORTANCE: Thymoma is commonly recognized in association with paraneoplastic autoimmune myasthenia gravis (MG), an IgG-mediated impairment of synaptic transmission targeting the nicotinic acetylcholine receptor of muscle. Newly identified synaptic autoantibodies may expand the serological profile of thymoma. OBJECTIVE: To investigate the frequency of potentially pathogenic neural synaptic autoantibodies in patients with thymoma. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients with histopathologically confirmed thymoma and serum available to test for synaptic autoantibodies (collected 1986-2014) at the Mayo Clinic Neuroimmunology Laboratory. We identified and classified 193 patients with thymoma into 4 groups: (1) lacking neurological autoimmunity (n = 43); (2) isolated MG (n = 98); (3) MG plus additional autoimmune neurological manifestations (n = 26); and (4) neurological autoimmunity other than MG (n = 26). MAIN OUTCOMES AND MEASURES: Clinical presentation and serum profile of autoantibodies reactive with molecularly defined synaptic plasma membrane proteins of muscle, peripheral, and central nervous systems. RESULTS: Of the 193 patients with thymoma, mean patient age was 52 years and did not significantly differ by sex (106 women) or group. Myasthenia gravis was the most prevalent clinical manifestation (64%) followed by dysautonomia (16 patients [8%]) and encephalopathy (15 patients [8%]); 164 patients (85%) had at least 1 synaptic autoantibody, and 63 of these patients (38%) had at least 1 more. Muscle acetylcholine receptor was most frequent (78%), followed by ganglionic acetylcholine receptor (20%), voltage-gated Kv1 potassium channel-complex (13%), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (5%). Less frequent were aquaporin-4, voltage-gated Kv1 potassium channel-complex related proteins (leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2), glycine receptor, and γ-aminobutyric acid-A receptor. Synaptic autoantibodies were significantly more frequent in patients with neurological autoimmunity than in those without and were most frequent in patients with neurological manifestations other than or in addition to MG. CONCLUSIONS AND RELEVANCE: Synaptic autoantibodies, particularly those reactive with ion channels of the ligand-gated nicotinic acetylcholine receptor superfamily (namely α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, glycine, and γ-aminobutyric acid-A receptors), were prevalent in patients with thymoma. Autoantibodies of this extended spectrum may enhance autoimmune serological testing as an aid to preoperative thymoma diagnosis. Detection of currently known synaptic autoantibody specificities absent from this profile have potential algorithmic usefulness as negative predictors for thymoma (as recognized for neuronal voltage-gated calcium channel autoantibodies).