RESUMEN
Stiff-person syndrome (SPS) usually manifests as an autoimmune neuromuscular disorder characterised by pronounced and advancing rigidity, primarily affecting the trunk and proximal muscles. There are various clinical subtypes like classic SPS (truncal stiffness, generalised rigidity and muscle spasms), partial SPS (stiff-limb syndrome) and uncommon forms including progressive encephalomyelitis with rigidity and myoclonus. Camptocormia, defined as forward flexion of the spine in the upright position that disappears in the supine position, without fixed deformity, has been described only in two cases as an initial presentation of Anti glutamic acid decarboxylase (GAD) autoimmunity. We encountered a young male presenting with a progressive forward-leaning posture and involuntary rhythmic movements in the lower limb. Diagnostic workup included MRI, blood routines, autoimmune screening, genetic testing, lumbar puncture and electromyography. Elevated serum anti-GAD antibody levels, inflammatory CSF and certain other clinical features supported the diagnosis of SPS. Treatment involved benzodiazepines, muscle relaxants and immunotherapy with intravenous immunoglobulin. This case underscores the importance of considering immune-mediated causes, such as SPS, in patients presenting with camptocormia.
Asunto(s)
Glutamato Descarboxilasa , Atrofia Muscular Espinal , Curvaturas de la Columna Vertebral , Síndrome de la Persona Rígida , Humanos , Masculino , Síndrome de la Persona Rígida/inmunología , Síndrome de la Persona Rígida/diagnóstico , Síndrome de la Persona Rígida/complicaciones , Curvaturas de la Columna Vertebral/inmunología , Curvaturas de la Columna Vertebral/complicaciones , Curvaturas de la Columna Vertebral/etiología , Glutamato Descarboxilasa/inmunología , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , Adulto , Rigidez Muscular/inmunología , Rigidez Muscular/tratamiento farmacológico , Rigidez Muscular/diagnóstico , Electromiografía , Imagen por Resonancia MagnéticaRESUMEN
Spinal Muscular Atrophy (SMA), a neurodegenerative disorder, extends its impact beyond the nervous system. The central protein implicated in SMA, Survival Motor Neuron (SMN) protein, is ubiquitously expressed and functions in fundamental processes such as alternative splicing, translation, cytoskeletal dynamics and signaling. These processes are relevant for all cellular systems, including cells of the immune system such as macrophages. Macrophages are capable of modulating their splicing, cytoskeleton and expression profile in order to fulfil their role in tissue homeostasis and defense. However, less is known about impairment or dysfunction of macrophages lacking SMN and the subsequent impact on the immune system of SMA patients. We aimed to review the potential overlaps between SMN functions and macrophage mechanisms highlighting the need for future research, as well as the current state of research addressing the role of macrophages in SMA.
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Macrófagos , Atrofia Muscular Espinal , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/inmunología , Animales , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by hypomorphic loss of function in the survival motor neuron (SMN) protein. SMA presents across a broad spectrum of disease severity. Unfortunately, genetic models of intermediate SMA have been difficult to generate in vertebrates and are thus unable to address key aspects of disease etiology. To address these issues, we developed a Drosophila model system that recapitulates the full range of SMA severity, allowing studies of pre-onset biology as well as late-stage disease processes. RESULTS: Here, we carried out transcriptomic and proteomic profiling of mild and intermediate Drosophila models of SMA to elucidate molecules and pathways that contribute to the disease. Using this approach, we elaborated a role for the SMN complex in the regulation of innate immune signaling. We find that mutation or tissue-specific depletion of SMN induces hyperactivation of the immune deficiency (IMD) and Toll pathways, leading to overexpression of antimicrobial peptides (AMPs) and ectopic formation of melanotic masses in the absence of an external challenge. Furthermore, the knockdown of downstream targets of these signaling pathways reduced melanotic mass formation caused by SMN loss. Importantly, we identify SMN as a negative regulator of a ubiquitylation complex that includes Traf6, Bendless, and Diap2 and plays a pivotal role in several signaling networks. CONCLUSIONS: In alignment with recent research on other neurodegenerative diseases, these findings suggest that hyperactivation of innate immunity contributes to SMA pathology. This work not only provides compelling evidence that hyperactive innate immune signaling is a primary effect of SMN depletion, but it also suggests that the SMN complex plays a regulatory role in this process in vivo. In summary, immune dysfunction in SMA is a consequence of reduced SMN levels and is driven by cellular and molecular mechanisms that are conserved between insects and mammals.
Asunto(s)
Modelos Animales de Enfermedad , Inmunidad Innata , Atrofia Muscular Espinal , Transducción de Señal , Animales , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/inmunología , Drosophila melanogaster/inmunología , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismoRESUMEN
Spinal muscular atrophy (SMA) is an inherited lower motor neuron disease. SMA occurs secondary to alterations in the survival motor neuron 1 gene (SMN1), which is the main driver of SMN protein production. The severity of the disease is determined by the number of copies of the SMN2 gene, which is a homolog to SMN1 but not as efficient in protein production. Three medications have recently been approved for the treatment of SMA. Nusinersen is an intrathecal antisense oligonucleotide that alters SMN2 pre-mRNA, onasemnogene abeparvovec-xioi is an intravenous SMN1 gene replacement therapy, and risdiplam is an oral small molecule splicing modifier of SMN2. No head-to-head studies have been conducted comparing these medications, so selection of one of these medications for an individual with SMA can be challenging. In this article we outline the efficacy, safety, and other pertinent factors to consider when selecting a therapy for an individual with SMA. The age of the individual and comorbidities, such as liver or kidney disease, help guide treatment choices. All three of these medications are efficacious, and early initiation is critical for obtaining the best outcomes.
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Atrofia Muscular Espinal/tratamiento farmacológico , Fármacos Neuromusculares/administración & dosificación , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos/administración & dosificación , Animales , Compuestos Azo/administración & dosificación , Compuestos Azo/inmunología , Productos Biológicos/administración & dosificación , Productos Biológicos/inmunología , Humanos , Atrofia Muscular Espinal/epidemiología , Atrofia Muscular Espinal/inmunología , Fármacos Neuromusculares/inmunología , Oligonucleótidos/inmunología , Oligonucleótidos Antisentido/inmunología , Pirimidinas/administración & dosificación , Pirimidinas/inmunología , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/inmunología , Resultado del TratamientoAsunto(s)
Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Autoantígeno Ku/inmunología , Atrofia Muscular Espinal/inmunología , Miositis/inmunología , Curvaturas de la Columna Vertebral/inmunología , Enfermedades del Nervio Trigémino/inmunología , Anciano , Autoanticuerpos/sangre , Enfermedades Autoinmunes/sangre , Femenino , Humanos , Autoantígeno Ku/sangre , Atrofia Muscular Espinal/sangre , Miositis/sangre , Miositis/diagnóstico por imagen , Curvaturas de la Columna Vertebral/sangre , Enfermedades del Nervio Trigémino/sangreRESUMEN
Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease that is the leading genetic cause of infantile death. It is caused by a severe deficiency of the ubiquitously expressed Survival Motor Neuron (SMN) protein. SMA is characterized by α-lower motor neuron loss and muscle atrophy, however, there is a growing list of tissues impacted by a SMN deficiency beyond motor neurons. The non-neuronal defects are observed in the most severe Type I SMA patients and most of the widely used SMA mouse models, however, as effective therapeutics are developed, it is unclear whether additional symptoms will be uncovered in longer lived patients. Recently, the immune system and inflammation has been identified as a contributor to neurodegenerative diseases such as ALS. To determine whether the immune system is comprised in SMA, we analyzed the spleen and immunological components in SMA mice. In this report, we identify: a significant reduction in spleen size in multiple SMA mouse models and a pathological reduction in red pulp and extramedullary hematopoiesis. Additionally, red pulp macrophages, a discrete subset of yolk sac-derived macrophages, were found to be altered in SMA spleens even in pre-symptomatic post-natal day 2 animals. These cells, which are involved in iron metabolism and the phagocytosis of erythrocytes and blood-borne pathogens are significantly reduced prior to the development of the neurodegenerative hallmarks of SMA, implying a differential role of SMN in myeloid cell ontogeny. Collectively, these results demonstrate that SMN deficiency impacts spleen development and suggests a potential role for immunological development in SMA.
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Desarrollo Embrionario/genética , Inflamación/genética , Atrofia Muscular Espinal/genética , Bazo/metabolismo , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Animales , Modelos Animales de Enfermedad , Desarrollo Embrionario/inmunología , Eritrocitos/inmunología , Eritrocitos/metabolismo , Eritrocitos/patología , Hematopoyesis Extramedular , Humanos , Inflamación/inmunología , Inflamación/patología , Hierro/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Neuronas Motoras/inmunología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Atrofia Muscular Espinal/inmunología , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Fagocitosis/genética , Fagocitosis/inmunología , Bazo/crecimiento & desarrollo , Bazo/inmunología , Bazo/patología , Proteína 1 para la Supervivencia de la Neurona Motora/biosíntesisRESUMEN
Spinal muscular atrophy (SMA) has long been solely considered a neurodegenerative disorder. However, recent work has highlighted defects in many other cell types that could contribute to disease aetiology. Interestingly, the immune system has never been extensively studied in SMA. Defects in lymphoid organs could exacerbate disease progression by neuroinflammation or immunodeficiency. Smn depletion led to severe alterations in the thymus and spleen of two different mouse models of SMA. The spleen from Smn depleted mice was dramatically smaller at a very young age and its histological architecture was marked by mislocalization of immune cells in the Smn2B/- model mice. In comparison, the thymus was relatively spared in gross morphology but showed many histological alterations including cortex thinning in both mouse models at symptomatic ages. Thymocyte development was also impaired as evidenced by abnormal population frequencies in the Smn2B/- thymus. Cytokine profiling revealed major changes in different tissues of both mouse models. Consistent with our observations, we found that survival motor neuron (Smn) protein levels were relatively high in lymphoid organs compared to skeletal muscle and spinal cord during postnatal development in wild type mice. Genetic introduction of one copy of the human SMN2 transgene was enough to rescue splenic and thymic defects in Smn2B/- mice. Thus, Smn is required for the normal development of lymphoid organs, and altered immune function may contribute to SMA disease pathogenesis.
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Atrofia Muscular Espinal/inmunología , Proteína 1 para la Supervivencia de la Neurona Motora/inmunología , Timocitos/inmunología , Timo/inmunología , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Timocitos/patología , Timo/patologíaRESUMEN
INTRODUCTION: Sural nerve biopsy is an important means of establishing the diagnosis of inflammatory neuropathies. We investigated the diagnostic value of endoneurial edema. METHODS: Diagnostic sural nerve biopsies from 42 patients with inflammatory and 28 patients with noninflammatory neuropathies were re-evaluated for the presence of endoneurial edema. Edema was assessed on hematoxylin-eosin stained paraffin and frozen sections and on azure II-methylene blue stained semithin sections. We determined the area of endoneurial edema on digitized images in relation to the entire endoneurial area of each fascicle. RESULTS: Edema was more extensive in neuropathies with short disease duration (≤12 months) as compared to long duration (>12 months; P < 0.01). Edema in inflammatory neuropathies of ≤12 months duration covered a larger area than in noninflammatory neuropathies (P < 0.01), and the extent of edema correlated negatively with disease duration (P < 0.05). CONCLUSIONS: Endoneurial edema may be a useful additional disease marker in inflammatory neuropathies of recent onset.
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Edema/patología , Enfermedades del Sistema Nervioso Periférico/patología , Nervio Sural/patología , Adulto , Anciano , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/patología , Biopsia , Estudios de Casos y Controles , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/inmunología , Neuropatías Diabéticas/patología , Edema/etiología , Edema/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/inmunología , Atrofia Muscular Espinal/patología , Polineuropatía Paraneoplásica/complicaciones , Polineuropatía Paraneoplásica/inmunología , Polineuropatía Paraneoplásica/patología , Nervios Periféricos/inmunología , Nervios Periféricos/patología , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/complicaciones , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/patología , Nervio Sural/inmunologíaRESUMEN
Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN.
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Inmunoglobulina M/sangre , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/inmunología , Paraproteinemias/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Bases de Datos Bibliográficas/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Indices of neuroinflammation are found in a variety of diseases of the CNS including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Over the years, neuroinflammation, in degenerative disorders of the CNS, has evolved from being regarded as an innocent bystander accomplishing its housekeeping function secondary to neurodegeneration to being considered as a bona fide contributor to the disease process and, in some situations, as a putative initiator of the disease. Herein, we will review neuroinflammation in both ALS and SMA not only from the angle of neuropathology but also from the angle of its potential role in the pathogenesis and treatment of these two dreadful paralytic disorders.
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Esclerosis Amiotrófica Lateral/inmunología , Gliosis/inmunología , Atrofia Muscular Espinal/inmunología , Mielitis/inmunología , Neuroglía/inmunología , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/fisiopatología , Astrocitos/inmunología , Citoprotección/fisiología , Gliosis/genética , Gliosis/fisiopatología , Humanos , Microglía/inmunología , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatología , Mielitis/genética , Mielitis/fisiopatología , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/fisiopatología , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1RESUMEN
The idea that point mutations in exons may affect splicing is intriguing and adds an additional layer of complexity when evaluating their possible effects. Even in the best-studied examples, the molecular mechanisms are not fully understood. Here, we use patient cells, model minigenes, and in vitro assays to show that a missense mutation in exon 5 of the medium-chain acyl-CoA dehydrogenase (MCAD) gene primarily causes exon skipping by inactivating a crucial exonic splicing enhancer (ESE), thus leading to loss of a functional protein and to MCAD deficiency. This ESE functions by antagonizing a juxtaposed exonic splicing silencer (ESS) and is necessary to define a suboptimal 3' splice site. Remarkably, a synonymous polymorphic variation in MCAD exon 5 inactivates the ESS, and, although this has no effect on splicing by itself, it makes splicing immune to deleterious mutations in the ESE. Furthermore, the region of MCAD exon 5 that harbors these elements is nearly identical to the exon 7 region of the survival of motor neuron (SMN) genes that contains the deleterious silent mutation in SMN2, indicating a very similar and finely tuned interplay between regulatory elements in these two genes. Our findings illustrate a mechanism for dramatic context-dependent effects of single-nucleotide polymorphisms on gene-expression regulation and show that it is essential that potential deleterious effects of mutations on splicing be evaluated in the context of the relevant haplotype.
Asunto(s)
Acil-CoA Deshidrogenasa/genética , Elementos de Facilitación Genéticos/genética , Exones/genética , Errores Innatos del Metabolismo Lipídico/inmunología , Polimorfismo de Nucleótido Simple , Empalme del ARN/genética , Elementos Silenciadores Transcripcionales/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Cartilla de ADN/genética , Femenino , Genes BRCA1/fisiología , Humanos , Inmunidad , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/genética , Datos de Secuencia Molecular , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/inmunología , Mutación Missense/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Estabilidad del ARN/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas del Complejo SMN , Homología de Secuencia de Ácido Nucleico , Proteína 2 para la Supervivencia de la Neurona Motora , Transcripción GenéticaRESUMEN
Legionella pneumophila is an intracellular pathogen that causes Legionnaires' disease in humans. Inbred mouse strains are uniformly resistant to L. pneumophila infection with the notable exception of A/J, where the chromosome 13 locus Lgn1 renders A/J macrophages permissive to L. pneumophila replication. The mouse Lgn1 region is syntenic with the spinal muscular atrophy (SMA) locus on human chromosome 5 and includes several copies of the neuronal apoptosis inhibitory protein (Naip) gene. We have analyzed a possible link among Lgn1, Naip, and macrophage function. RNA expression studies show that Naip (mostly copy 2) mRNA transcripts are expressed in macrophage-rich tissues, such as spleen, lung, and liver and are abundant in primary macrophages. Immunoblotting and immunoprecipitation analyses identify Naip protein expression in mouse macrophages and in macrophage cell lines RAW 264.7 and J774A. Interestingly, macrophages from permissive A/J mice express significantly less Naip protein than their nonpermissive C57BL/6J counterpart. Naip protein expression is increased after phagocytic events. Naip protein levels during infection with either virulent or avirulent strains of L. pneumophila increase during the first 6 h postinfection and remain elevated during the 48-h observation period. This enhanced expression is also observed in macrophages infected with Salmonella typhimurium. Likewise, an increase in Naip protein levels in macrophages is observed 24 h after phagocytosis of Latex beads. The cosegregation of Lgn1 and Naip together with the detected Naip protein expression in host macrophages as well as its modulation after phagocytic events and during intracellular infection make it an attractive candidate for the Lgn1 locus.
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Apoptosis/inmunología , Líquido Intracelular/inmunología , Líquido Intracelular/metabolismo , Legionella pneumophila/inmunología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Fagocitosis/inmunología , Animales , Humanos , Líquido Intracelular/microbiología , Macrófagos Peritoneales/microbiología , Ratones , Ratones Endogámicos A , Ratones Endogámicos C57BL , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/inmunología , Atrofia Muscular Espinal/microbiología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteína Inhibidora de la Apoptosis Neuronal , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , ARN Mensajero/biosíntesisRESUMEN
We report a 63-year-old man who died of respiratory failure. He was well until 1992 (57 years of his age), when he had an onset of progressive weakness of the bilateral upper limbs. He showed no improvement with TRH administration in other hospital. On January 12, 1994, he admitted to our department because of the progressive muscle weakness. Neurologic examination revealed a muscular atrophy associated with severe weakness and hyporeflexia in both upper limbs, and fasciculation were seen in his tongue. Electrophysiological studies revealed mild conduction block in the left medial nerve, and F-waves were not evoked in the left ulnar nerve and bilateral median nerves. After an administration of 25 g/day of human gamma-immunoglobulin for 5 days, conduction block as well as F-wave abnormalities in the left median and left ulnar nerve were improved, yet no improvement of muscle weakness was seen. The anti-GM1 IgG titer was transiently elevated in the patient's serum after gamma-immunoglobulin therapy. On September 8, 1994, subtotal gastrectomy was performed because of the early stage gastric cancer. Histological examination showed poorly differentiated adenocarcinoma (signet-ring cell carcinoma). His muscle weakness had been gradually extended to the lower limbs and he couldn't walk himself on January, 1998. On March, 1998, he developed tetraplegia, mild dysphagia, dysuria and the respiratory disturbance. On April 12, 1998, he admitted to our department for the second time. Neurologic examination revealed a muscular atrophy and fasciculation associated with severe weakness in all of his limbs, tongue and musclus masseter. Neither deep tendon reflex nor pathologic reflex was evoked in his upper and lower extremities. His ocular movements and sensations were well preserved. He died of respiratory failure on May 1, 1998. The patient was presented in a neurological CPC. Neurological and laboratory findings suggested a spinal progressive muscular atrophy (SPMA). However, there were several unusual points as a typical SPMA in this case, that is, an improvement of the electrophysiological abnormalities by gamma-globulin treatment, as well as transient elevation of anti-GM1 antibody. The clinical neurologists have arrived at the conclusion that the patient had lower motor neuron syndrome associated with anti-ganglioside antibody and cause of death was ascribed to the respiratory failure. We discussed whether this case was SPMA or multifocal motor neuropathy. Postmortem examination revealed numerous diverticulums in the ascending colon and lymphothyroiditis. No recurrent carcinoma was detected. Neuropathologically, both severe atrophy of the anterior spinal roots, and severe gliosis and neuronal loss in the anterior horn of the spinal cord were observed. Onuf nuclei were not affected. Neurogenic muscular atrophy was detected in the tongue, diaphragm, and limb muscles. Motor neurons of the brainstem were relatively preserved, but skein-like inclusions as detected by anti-ubiquitin antibody, were present in the facial and hypoglossal nuclei. Neither motor cortex nor cortico-spinal tracts were affected. Demyelination, remyelination or cellular infiltrations were not apparent in the right median nerve and sciatic nerves. The neuropathologic features were compatible with SPMA.
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Atrofia Muscular Espinal/patología , Autoanticuerpos/análisis , Carcinoma de Células en Anillo de Sello/patología , Diagnóstico Diferencial , Divertículo del Colon/patología , Gangliósido G(M1)/inmunología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/diagnóstico , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/inmunología , Neoplasias Gástricas/patología , Tiroiditis/patología , gammaglobulinas/uso terapéuticoAsunto(s)
Atrofia Muscular Espinal/genética , Proteínas del Tejido Nervioso/genética , Empalme Alternativo , Línea Celular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Amplificación de Genes , Expresión Génica , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ , Humanos , Atrofia Muscular Espinal/inmunología , Atrofia Muscular Espinal/metabolismo , Mutación , Proteínas del Tejido Nervioso/metabolismo , Fenotipo , ARN/genética , ARN/metabolismo , Proteínas de Unión al ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas del Complejo SMN , Proteína 2 para la Supervivencia de la Neurona MotoraRESUMEN
Increased titers of anti-GM1 antibodies have been associated with motor neuron disease and motor neuropathy with or without conduction block. To investigate the pathogenetic role of anti-GM1 antibodies we injected into rat tibial nerves sera from patients with multifocal motor neuropathy and conduction block (MMN) or progressive spinal muscular atrophy (PMA), both presenting anti-GM1 antibodies. Sera of patients with MMN produced reduction of amplitude and dispersion of compound muscle action potential from proximal stimulation. Morphometry revealed demyelination in 6.2% of fibers. Sera of patients with PMA did not produce clear-cut electrophysiological or morphological changes. Differential effects of sera from patients presenting high-titer anti-GM1 antibodies, but with distinct clinical syndromes, might depend on differences in anti-GM1 antibody affinity, valency, or ability to fix complement. Alternatively, circulating factors other than, or in addition to, anti-GM1 antibodies present in sera of patients with MMN, but not of PMA patients, might be responsible for conduction abnormalities and reproduce them after passive transfer.
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Anticuerpos/farmacología , Enfermedades Desmielinizantes/etiología , Gangliósido G(M1)/farmacología , Enfermedad de la Neurona Motora/fisiopatología , Atrofia Muscular Espinal/fisiopatología , Conducción Nerviosa/fisiología , Animales , Gangliósido G(M1)/inmunología , Humanos , Masculino , Enfermedad de la Neurona Motora/inmunología , Enfermedad de la Neurona Motora/patología , Atrofia Muscular Espinal/inmunología , Atrofia Muscular Espinal/patología , Conducción Nerviosa/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Nervio Tibial/efectos de los fármacos , Nervio Tibial/patología , Nervio Tibial/fisiopatologíaRESUMEN
Serum neutralizing antibodies for type 1, 2 and 3 poliovirus were studied in 15 Chinese patients in Taiwan with juvenile distal spinal muscular atrophy of the upper extremities and 15 age-matched normal subjects. Significantly lower serum antibody titers were found in the study group, suggesting that patients with this chronic focal form of acquired motor neuron disease are, to some degree, immunologically unresponsive to the neutralizing epitope of poliovirus.
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Anticuerpos Antivirales/sangre , Atrofia Muscular Espinal/inmunología , Poliovirus/inmunología , Adolescente , Adulto , Femenino , Humanos , Masculino , Atrofia Muscular Espinal/sangre , Pruebas de Neutralización , Valores de ReferenciaRESUMEN
Immunoglobulin (Ig)-mediated activity in plasma directed towards normal blood type matched red blood cells (RBC) inducing haemolysis in vitro has earlier been demonstrated to be a characteristic feature in ALS-patients. In this study, saliva of ALS-patients, normal and diseased controls was tested with the same in vitro test. An increased degree of haemolysis was induced by the ALS-patient as compared with control samples. The activity thus found in saliva had the same basic characteristics as that earlier described for plasma; it reacted similarly to serial dilution and was retained in salivary Ig. The effect on red blood cells of saliva from patients with bulbar paralysis was larger than that of saliva from ALS-patients lacking bulbar symptoms. It is discussed whether cytotoxic Ig in saliva could be pathophysiologically active in bulbar paralysis by means of passage through the oral mucosa and local action on motor end plates in perioral muscles.
Asunto(s)
Esclerosis Amiotrófica Lateral/inmunología , Autoanticuerpos/metabolismo , Parálisis Bulbar Progresiva/inmunología , Membrana Eritrocítica/inmunología , Atrofia Muscular Espinal/inmunología , Saliva/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Enfermedades Autoinmunes/inmunología , Neuronas Motoras/inmunología , Enfermedades Neuromusculares/inmunología , Esclerosis Amiotrófica Lateral/inmunología , Animales , Autoanticuerpos/análisis , Gangliósidos/inmunología , Humanos , Inmunidad Celular/inmunología , Atrofia Muscular Espinal/inmunología , Paraproteinemias/inmunologíaRESUMEN
Antibodies to HTLV-I were assayed in sera of 9 patients with progressive myelopathy, 11 with multiple sclerosis, 5 with myopathy and in 10 HIV-seropositive intravenous heroin abusers. Clinical features in 9 cases with progressive myelopathy were not different from those previously described in tropical spastic paraparesis associated with HTLV-I infection. No detectable HTLV-1 antibody was found in the sera of any of the 35 patients studied.