RESUMEN
Rasmussen's encephalitis (RE) stands as a rare neurological disorder marked by progressive cerebral hemiatrophy and epilepsy resistant to medical treatment. Despite extensive study, the primary cause of RE remains elusive, while its histopathological features encompass cortical inflammation, neuronal degeneration, and gliosis. The underlying molecular mechanisms driving disease progression remain largely unexplored. In this case study, we present a patient with RE who underwent hemispherotomy and has remained seizure-free for over six months, experiencing gradual motor improvement. Furthermore, we conducted molecular analysis on the excised brain tissue, unveiling a decrease in the expression of cell-cycle-associated genes coupled with elevated levels of BDNF and TNF-α proteins. These findings suggest the potential involvement of cell cycle regulators in the progression of RE.
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Encefalitis , Humanos , Encefalitis/genética , Encefalitis/patología , Encefalitis/metabolismo , Masculino , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/metabolismo , Femenino , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Ciclo Celular/genéticaRESUMEN
BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS. CASE PRESENTATION: A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week. CONCLUSIONS: This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.
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Ataxia , Encefalitis , Síndrome del Cromosoma X Frágil , Temblor , Humanos , Ataxia/diagnóstico , Ataxia/genética , Diagnóstico Diferencial , Encefalitis/diagnóstico , Encefalitis/complicaciones , Encefalitis/genética , Encefalitis/patología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/complicaciones , Cuerpos de Inclusión Intranucleares/patología , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/complicaciones , Temblor/diagnóstico , Temblor/genética , Temblor/etiologíaRESUMEN
INTRODUCTION: Patients with encephalitis following a viral infection are often thought to have a para infectious, inflammatory, or autoimmune cause for their presentation. These diagnoses usually result in treatments with immunosuppressant therapies which can have side effects. However, there is an increasing body of evidence demonstrating that patients can have a direct genetic cause mediating viral infection triggered encephalitis, where inflammation is a secondary response. These patients may benefit not from immunosuppressive therapies, but from protection from infection through dedicated immunisation programs and early antiviral therapies at times of infection. METHODS: A small case series of paediatric neurology patients (n = 2) from a single institution with infection induced encephalitis and an underlying genetic cause, is presented. Patients with a confirmed genetic cause of infection induced encephalitis were identified and consented by their treating neurologist for inclusion in this case series. Ethics approval was gained for this case series and review of the surrounding literature. CONCLUSION: A case of both DBR1 and NUP214 genetic changes resulting in infection induced encephalitis is presented. This case series raises awareness of this rare group of disorders and provides clues to their identification. Features to prompt clinician consideration of such genetic conditions are also highlighted. Although rare, identification of these patients is important due to implications on treatment, prognosis, and family planning.
Asunto(s)
Proteínas de Complejo Poro Nuclear , Humanos , Femenino , Masculino , Proteínas de Complejo Poro Nuclear/genética , Niño , Encefalitis Infecciosa/genética , Encefalitis Infecciosa/etiología , Preescolar , Encefalitis/genética , Encefalitis/etiología , LactanteRESUMEN
PURPOSE OF REVIEW: We summarize the recent discoveries on genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes (PNS), emphasizing clinical and pathophysiological implications. RECENT FINDINGS: The human leukocyte antigen (HLA) is the most studied genetic factor in autoimmune encephalitis and PNS. The HLA haplotype 8.1, which is widely known to be related to systemic autoimmunity, has been only weakly associated with a few types of autoimmune encephalitis and PNS. However, the strongest and most specific associations have been reported in a subgroup of autoimmune encephalitis that comprises antileucine-rich glioma-inactivated 1 (LGI1) limbic encephalitis, associated with DRB1∗07â:â01 , anticontactin-associated protein-like 2 (CASPR2) limbic encephalitis, associated with DRB1∗11â:â01 , and anti-IgLON5 disease, associated with DRB1∗10â:â01â¼DQA1∗01â¼DQB1∗05 . Non-HLA genes have been poorly investigated so far in autoimmune encephalitis, mainly in those lacking HLA associations such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, with only a few genome-wide association studies (GWAS) reporting equivocal results principally limited by small sample size. SUMMARY: Genetic predisposition seems to be driven mostly by HLA in a group of autoimmune encephalitis characterized by being nonparaneoplastic and having predominantly IgG4 autoantibodies. The contribution of non-HLA genes, especially in those diseases lacking known or strong HLA associations, will require large cohorts enabling GWAS to be powerful enough to render meaningful results.
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Encefalitis , Predisposición Genética a la Enfermedad , Enfermedad de Hashimoto , Síndromes Paraneoplásicos del Sistema Nervioso , Humanos , Autoanticuerpos/inmunología , Encefalitis/genética , Encefalitis/inmunología , Predisposición Genética a la Enfermedad/genética , Enfermedad de Hashimoto/genética , Enfermedad de Hashimoto/inmunología , Antígenos HLA/genética , Antígenos HLA/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/genética , Síndromes Paraneoplásicos del Sistema Nervioso/inmunologíaRESUMEN
Here we describe the second ever-reported case of familial anti-leucine-rich glioma-inactivated protein 1 (LGI1) limbic encephalitis (LE). Two elderly Caucasian sisters presented with psychiatric symptoms and cognitive impairment, followed by faciobrachial dystonic seizures. Anti-LGI1 antibodies were detected in their serum. Considering they had been living in distant regions for decades, environmental factors could be ruled out. Human leukocyte antigen (HLA) genotyping revealed that both carried HLA-DRB1*07, found in 90% of anti-LGI1 encephalitis patients, HLA-DQA1*02:01 and HLA-DQB1*03:03, commonly associated with DRB1*07:01. Considering the exceptional nature of familial cases, as-yet-unknown genetic contributors other than HLA might play a role in our siblings.
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Encefalitis , Encefalitis Límbica , Humanos , Anciano , Péptidos y Proteínas de Señalización Intracelular , Encefalitis/genética , Encefalitis/complicaciones , Convulsiones , Cadenas HLA-DRB1/genética , AutoanticuerposRESUMEN
Status epilepticus (SE) in humans is characterized by prolonged convulsive seizures that are generalized and often difficult to control. The current antiseizure drugs (ASDs) aim to stop seizures quickly enough to prevent the SE-induced brain inflammation, injury, and long-term sequelae. However, sole reliance on acute therapies is imprudent because prompt treatment may not always be possible under certain circumstances. The pathophysiological mechanisms underlying the devastating consequences of SE are presumably associated with neuroinflammatory reactions, where prostaglandin E2 (PGE2) plays a pivotal role. As the terminal synthase for pathogenic PGE2, the microsomal prostaglandin E synthase-1 (mPGES-1) is rapidly and robustly induced by prolonged seizures. Congenital deletion of mPGES-1 in mice is neuroprotective and blunts gliosis following chemoconvulsant seizures, suggesting the feasibility of mPGES-1 as a potential antiepileptic target. Herein, we investigated the effects of a dual species mPGES-1 inhibitor in a mouse pilocarpine model of SE. Treatment with the mPGES-1 inhibitor in mice after SE that was terminated by diazepam, a fast-acting benzodiazepine, time-dependently abolished the SE-induced PGE2 within the brain. Its negligible effects on cyclooxygenases, the enzymes responsible for the initial step of PGE2 biosynthesis, validated its specificity to mPGES-1. Post-SE inhibition of mPGES-1 also blunted proinflammatory cytokines and reactive gliosis in the hippocampus and broadly prevented neuronal damage in a number of brain areas. Thus, pharmacological inhibition of mPGES-1 by small-molecule inhibitors might provide an adjunctive strategy that can be implemented hours after SE, together with first-line ASDs, to reduce SE-provoked brain inflammation and injury.
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Encefalitis , Estado Epiléptico , Animales , Ratones , Dinoprostona , Modelos Animales de Enfermedad , Encefalitis/genética , Encefalitis/metabolismo , Encefalitis/prevención & control , Gliosis/complicaciones , Gliosis/tratamiento farmacológico , Prostaglandina-E Sintasas , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Convulsiones/metabolismo , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/genética , Estado Epiléptico/metabolismoRESUMEN
Rasmussen encephalitis (RE) is a rare childhood neurological disease characterized by progressive unilateral loss of function, hemispheric atrophy and drug-resistant epilepsy. Affected brain tissue shows signs of infiltrating cytotoxic T-cells, microglial activation, and neuronal death, implicating an inflammatory disease process. Recent studies have identified molecular correlates of inflammation in RE, but cell-type-specific mechanisms remain unclear. We used single-nucleus RNA-sequencing (snRNA-seq) to assess gene expression across multiple cell types in brain tissue resected from two children with RE. We found transcriptionally distinct microglial populations enriched in RE compared to two age-matched individuals with unaffected brain tissue and two individuals with Type I focal cortical dysplasia (FCD). Specifically, microglia in RE tissues demonstrated increased expression of genes associated with cytokine signaling, interferon-mediated pathways, and T-cell activation. We extended these findings using spatial proteomic analysis of tissue from four surgical resections to examine expression profiles of microglia within their pathological context. Microglia that were spatially aggregated into nodules had increased expression of dynamic immune regulatory markers (PD-L1, CD14, CD11c), T-cell activation markers (CD40, CD80) and were physically located near distinct CD4+ and CD8+ lymphocyte populations. These findings help elucidate the complex immune microenvironment of RE.
Asunto(s)
Encefalitis , Microglía , Niño , Humanos , Microglía/patología , Proteómica , Encefalitis/genética , Encefalitis/complicaciones , Inflamación/metabolismoRESUMEN
Pediatric encephalitis has significant morbidity and mortality, yet 50% of cases are unexplained. Host genetics plays a role in encephalitis' development; however, the contributing variants are poorly understood. One child with anti-NMDA receptor encephalitis and ten with unexplained encephalitis underwent whole genome sequencing to identify rare candidate variants in genes known to cause monogenic immunologic and neurologic disorders, and polymorphisms associated with increased disease risk. Using the professional Human Genetic Mutation Database (Qiagen), we divided the candidate variants into three categories: monogenic deleterious or potentially deleterious variants (1) in a disease-consistent inheritance pattern; (2) in carrier states; and (3) disease-related polymorphisms. Six patients (55%) had a deleterious or potentially deleterious variant in a disease-consistent inheritance pattern, five (45%) were heterozygous carriers for an autosomal recessive condition, and six (55%) carried a disease-related polymorphism. Finally, seven (64%) had more than one variant, suggesting possible polygenetic risk. Among variants identified were those implicated in atypical hemolytic uremic syndrome, common variable immunodeficiency, hemophagocytic lymphohistiocytosis, and systemic lupus erythematosus. This preliminary study shows genetic variation related to inborn errors of immunity in acute pediatric encephalitis. Future research is needed to determine if these variants play a functional role in the development of unexplained encephalitis.
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Encefalitis , Linfohistiocitosis Hemofagocítica , Humanos , Niño , Mutación , Heterocigoto , Polimorfismo Genético , Encefalitis/genética , Variación GenéticaRESUMEN
AIM: To evaluate clinical and imaging features in patients with acute necrotizing encephalopathy of childhood (ANEC) to identify predictors of RANBP2 mutations, influenza association, and long-term outcomes. METHOD: A retrospective chart review in patients with ANEC (2012-2020) seen at a tertiary pediatric center was performed. Children were included if they had acute inflammatory lesions in the basal ganglia and pons. Variables included presenting features, imaging characteristics, RANBP2 gene testing, nasopharyngeal swab findings, therapies, and long-term outcomes. RESULTS: Twenty patients were included (average age at presentation 3y 6mo, interquartile range 3y 7mo, SD 2y 8mo; 14 females, six males). Three of the 20 experienced recurrences; one of the 20 died. Ten patients were influenza positive. Seven patients were RANBP2 mutation positive. A higher likelihood of hemorrhage was observed in patients who were influenza positive compared to influenza negative (p=0.048). Patients with influenza had a higher degree of thalamic hemorrhage (2, p=0.035) and greater extent of diffusion restriction (3, p=0.035) in semiquantitive analysis. INTERPRETATION: Children with ANEC who are positive for influenza are more likely to have hemorrhage and greater thalamic swelling. RANBP2 status was predictive of relapse but not predictive of overall outcome.
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Encefalitis , Gripe Humana , Leucoencefalitis Hemorrágica Aguda , Chaperonas Moleculares , Proteínas de Complejo Poro Nuclear , Enfermedad Aguda , Niño , Encefalitis/genética , Femenino , Humanos , Gripe Humana/complicaciones , Gripe Humana/genética , Leucoencefalitis Hemorrágica Aguda/genética , Masculino , Chaperonas Moleculares/genética , Mutación , Proteínas de Complejo Poro Nuclear/genética , Estudios RetrospectivosRESUMEN
BACKGROUND AND OBJECTIVES: To study human leukocyte antigen (HLA) allele associations in anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis. METHODS: A multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using χ2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable. RESULTS: DRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e-50) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequently female (p = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, p = 4.57 × 10-6 and OR = 8.93, p = 2.50 × 10-3, respectively). DRB1*04:02 was also independently associated with younger age at onset (ß = -6.68, p = 9.78 × 10-3). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms. DISCUSSION: In addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.
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Enfermedades Autoinmunes del Sistema Nervioso , Encefalitis , Estudio de Asociación del Genoma Completo , Cadenas HLA-DRB1/genética , Péptidos y Proteínas de Señalización Intracelular/inmunología , Anciano , Autoanticuerpos , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Encefalitis/genética , Encefalitis/inmunología , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleAsunto(s)
Tronco Encefálico/patología , Cerebelo/patología , Encefalitis/diagnóstico , Adulto , Tronco Encefálico/diagnóstico por imagen , Proteínas Portadoras/sangre , Proteínas Portadoras/líquido cefalorraquídeo , Cerebelo/diagnóstico por imagen , Encefalitis/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Atrofia de Múltiples SistemasRESUMEN
This study was designed to determine the effect of acute caffeine (CAF) administration, which exerts a broad spectrum of anti-inflammatory activity, on the synthesis of pro-inflammatory cytokines and their receptors in the hypothalamus and choroid plexus (ChP) during acute inflammation caused by the injection of bacterial endotoxin-lipopolysaccharide (LPS). The experiment was performed on 24 female sheep randomly divided into four groups: control; LPS treated (iv.; 400 ng/kg of body mass (bm.)); CAF treated (iv.; 30 mg/kg of bm.); and LPS and CAF treated. The animals were euthanized 3 h after the treatment. It was found that acute administration of CAF suppressed the synthesis of interleukin (IL-1ß) and tumor necrosis factor (TNF)α, but did not influence IL-6, in the hypothalamus during LPS-induced inflammation. The injection of CAF reduced the LPS-induced expression of TNF mRNA in the ChP. CAF lowered the gene expression of IL-6 cytokine family signal transducer (IL6ST) and TNF receptor superfamily member 1A (TNFRSF1) in the hypothalamus and IL-1 type II receptor (IL1R2) in the ChP. Our study on the sheep model suggests that CAF may attenuate the inflammatory response at the hypothalamic level and partly influence the inflammatory signal generated by the ChP cells. This suggests the potential of CAF to suppress neuroinflammatory processes induced by peripheral immune/inflammatory challenges.
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Cafeína/administración & dosificación , Plexo Coroideo/inmunología , Citocinas/genética , Encefalitis/tratamiento farmacológico , Hipotálamo/inmunología , Lipopolisacáridos/efectos adversos , Administración Intravenosa , Animales , Cafeína/farmacología , Plexo Coroideo/efectos de los fármacos , Modelos Animales de Enfermedad , Encefalitis/inducido químicamente , Encefalitis/genética , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Interleucina-1beta/genética , Interleucina-6/metabolismo , Ovinos , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
High-fat diet (HFD)-induced comorbid cognitive and behavioural impairments are thought to be the result of persistent low-grade neuroinflammation. Metformin, a first-line medication for the treatment of type-2 diabetes, seems to ameliorate these comorbidities, but the underlying mechanism(s) are not clear. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective peptides endowed with anti-inflammatory properties. Alterations to the PACAP/VIP system could be pivotal during the development of HFD-induced neuroinflammation. To unveil the pathogenic mechanisms underlying HFD-induced neuroinflammation and assess metformin's therapeutic activities, (1) we determined if HFD-induced proinflammatory activity was present in vulnerable brain regions associated with the development of comorbid behaviors, (2) investigated if the PACAP/VIP system is altered by HFD, and (3) assessed if metformin rescues such diet-induced neurochemical alterations. C57BL/6J male mice were divided into two groups to receive either standard chow (SC) or HFD for 16 weeks. A further HFD group received metformin (HFD + M) (300 mg/kg BW daily for 5 weeks) via oral gavage. Body weight, fasting glucose, and insulin levels were measured. After 16 weeks, the proinflammatory profile, glial activation markers, and changes within the PI3K/AKT intracellular pathway and the PACAP/VIP system were evaluated by real-time qPCR and/or Western blot in the hypothalamus, hippocampus, prefrontal cortex, and amygdala. Our data showed that HFD causes widespread low-grade neuroinflammation and gliosis, with regional-specific differences across brain regions. HFD also diminished phospho-AKT(Ser473) expression and caused significant disruptions to the PACAP/VIP system. Treatment with metformin attenuated these neuroinflammatory signatures and reversed PI3K/AKT and PACAP/VIP alterations caused by HFD. Altogether, our findings demonstrate that metformin treatment rescues HFD-induced neuroinflammation in vulnerable brain regions, most likely by a mechanism involving the reinstatement of PACAP/VIP system homeostasis. Data also suggests that the PI3K/AKT pathway, at least in part, mediates some of metformin's beneficial effects.
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Dieta Alta en Grasa/efectos adversos , Encefalitis/tratamiento farmacológico , Metformina/administración & dosificación , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Estudios de Casos y Controles , Regulación hacia Abajo , Encefalitis/inducido químicamente , Encefalitis/genética , Encefalitis/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Metformina/farmacología , Ratones , Ratones Endogámicos C57BL , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/genética , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Transducción de Señal/efectos de los fármacos , Péptido Intestinal Vasoactivo/genéticaRESUMEN
Biallelic pathogenic variants in RNU4ATAC have been linked to microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Although children with MOPD1 have been reported to show profound, life-limiting clinical decompensation at the time of a febrile illness, these episodes including magnetic resonance imaging (MRI) findings have not been well characterized. We present acute MRI brain findings for a 10-year-old girl with homozygous variants in RNU4ATAC (NR_023343.1) n.55G>A, who presented with two episodes of clinical decompensation associated with a febrile illness in early childhood. The pathogenic variants were identified by whole genome sequencing as RNU4ATAC is not captured in most exome products. Her MRI of the brain revealed symmetric, diffusion restriction of the deep gray nuclei that initially pointed to a mitochondrial disease or acute necrotizing encephalopathy. Her phenotype included microcephaly and profound cognitive impairment that can be seen with MOPD1. However, she did not demonstrate clinical or radiographic evidence of a spondyloepimetaphyseal dysplasia or "primordial dwarfism" that is characteristic of this disease. As such, the predominant neurological presentation of this child represents an atypical variant of RNU4ATAC-associated disease and should be a diagnostic consideration for geneticists and neurologists caring for children, particularly in the event of an acute clinical decline.
Asunto(s)
Enanismo/genética , Encefalitis/genética , Retardo del Crecimiento Fetal/genética , Microcefalia/genética , Osteocondrodisplasias/genética , ARN Nuclear Pequeño/genética , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Niño , Preescolar , Enanismo/diagnóstico por imagen , Enanismo/patología , Encefalitis/diagnóstico por imagen , Encefalitis/patología , Exoma/genética , Femenino , Retardo del Crecimiento Fetal/diagnóstico por imagen , Retardo del Crecimiento Fetal/patología , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Microcefalia/diagnóstico por imagen , Microcefalia/patología , Mutación/genética , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/patología , Fenotipo , Secuenciación del Exoma , Secuenciación Completa del GenomaRESUMEN
Toll-like receptor (TLR) signaling plays a critical role in the induction and progression of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, experimental autoimmune encephalitis, type 1 diabetes mellitus and neurodegenerative diseases. Deciphering antigen recognition by antibodies provides insights and defines the mechanism of action into the progression of immune responses. Multiple strategies, including phage display and hybridoma technologies, have been used to enhance the affinity of antibodies for their respective epitopes. Here, we investigate the TLR4 antibody-binding epitope by computational-driven approach. We demonstrate that three important residues, i.e., Y328, N329, and K349 of TLR4 antibody binding epitope identified upon in silico mutagenesis, affect not only the interaction and binding affinity of antibody but also influence the structural integrity of TLR4. Furthermore, we predict a novel epitope at the TLR4-MD2 interface which can be targeted and explored for therapeutic antibodies and small molecules. This technique provides an in-depth insight into antibody-antigen interactions at the resolution and will be beneficial for the development of new monoclonal antibodies. Computational techniques, if coupled with experimental methods, will shorten the duration of rational design and development of antibody therapeutics.
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Anticuerpos Monoclonales/inmunología , Artritis Reumatoide/inmunología , Encefalitis/inmunología , Epítopos/genética , Enfermedad de Hashimoto/inmunología , Enfermedades Neurodegenerativas/inmunología , Receptor Toll-Like 4/genética , Secuencia de Aminoácidos/genética , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Técnicas de Visualización de Superficie Celular , Encefalitis/genética , Encefalitis/patología , Mapeo Epitopo/métodos , Epítopos/inmunología , Enfermedad de Hashimoto/genética , Enfermedad de Hashimoto/patología , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/patología , Unión Proteica/genética , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/inmunologíaRESUMEN
Inflammation has been associated with cardiovascular diseases and the key point is the generation of reactive oxygen species (ROS). Exercise modulates medullary neurons involved in cardiovascular control. We investigated the effect of chronic exercise training (Tr) in treadmill running on gene expression (GE) of ROS and inflammation in commNTS and RVLM neurons. Male Wistar rats (N = 7/group) were submitted to training in a treadmill running (1 h/day, 5 days/wk/10 wks) or maintained sedentary (Sed). Superoxide dismutase (SOD), catalase (CAT), neuroglobin (Ngb), Cytoglobin (Ctb), NADPH oxidase (Nox), cicloxigenase-2 (Cox-2), and neuronal nitric oxide synthase (NOS1) gene expression were evaluated in commNTS and RVLM neurons by qPCR. In RVLM, Tr rats increased Ngb (1.285 ± 0.03 vs. 0.995 ± 0.06), Cygb (1.18 ± 0.02 vs.0.99 ± 0.06), SOD (1.426 ± 0.108 vs. 1.00 ± 0.08), CAT (1.34 ± 0.09 vs. 1.00 ± 0.08); and decreased Nox (0.55 ± 0.146 vs. 1.001 ± 0.08), Cox-2 (0.335 ± 0.05 vs. 1.245 ± 0.02), NOS1 (0.51 ± 0.08 vs. 1.08 ± 0.209) GE compared to Sed. In commNTS, Tr rats increased SOD (1.384 ± 0.13 vs. 0.897 ± 0.101), CAT GE (1.312 ± 0.126 vs. 0.891 ± 0.106) and decreased Cox-2 (0.052 ± 0.011 vs. 1.06 ± 0.207) and NOS1 (0.1550 ± 0.03559 vs. 1.122 ± 0.26) GE compared to Sed. Therefore, GE of proteins of the inflammatory process reduced while GE of antioxidant proteins increased in the commNTS and RVLM after training, suggesting a decrease in oxidative stress of downstream pathways mediated by nitric oxide.
Asunto(s)
Encefalitis/fisiopatología , Bulbo Raquídeo/fisiopatología , Estrés Oxidativo , Condicionamiento Físico Animal/fisiología , Núcleo Solitario/fisiopatología , Animales , Antioxidantes/metabolismo , Encefalitis/genética , Expresión Génica , Masculino , Bulbo Raquídeo/metabolismo , Estrés Oxidativo/genética , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Conducta Sedentaria , Núcleo Solitario/metabolismoRESUMEN
Alzheimer's disease is a devastating neurodegenerative disorder, with no disease-modifying treatment available yet. There is increasing evidence that neuroinflammation plays a critical role in the pathogenesis of AD. Andrographolide (Andro), a labdane diterpene extracted from the herb Andrographis paniculata, has been reported to exhibit neuroprotective property in central nervous system diseases. However, its effects on Aß and Aß-induced neuroinflammation have not yet been studied. In the present study, we found that Andro administration significantly alleviated cognitive impairments, reduced amyloid-ß deposition, inhibited microglial activation, and decreased the secretion of proinflammatory factors in APP/PS1 mice. Furthermore, transcriptome sequencing analysis revealed that Andro could significantly decrease the expression of Itgax, TLR2, CD14, CCL3, CCL4, TLR1, and C3ar1 in APP/PS1 mice, which was further validated by qRT-PCR. Our results suggest that Andro might be a potential therapeutic drug for AD by regulating neuroinflammation.
Asunto(s)
Antiinflamatorios/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Diterpenos/uso terapéutico , Encefalitis/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Antiinflamatorios/farmacología , Conducta Animal/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Diterpenos/farmacología , Encefalitis/genética , Encefalitis/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratones Transgénicos , Fármacos Neuroprotectores/farmacología , Presenilina-1/genética , Transcriptoma/efectos de los fármacosRESUMEN
RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death. Its downregulation in Parkinson's and Huntington's disease models ameliorates the pathological phenotypes. In the context of Alzheimer's disease (AD), the coding gene for RTP801, DDIT4, is responsive to Aß and modulates its cytotoxicity in vitro. Also, RTP801 mRNA levels are increased in AD patients' lymphocytes. However, the involvement of RTP801 in the pathophysiology of AD has not been yet tested. Here, we demonstrate that RTP801 levels are increased in postmortem hippocampal samples from AD patients. Interestingly, RTP801 protein levels correlated with both Braak and Thal stages of the disease and with GFAP expression. RTP801 levels are also upregulated in hippocampal synaptosomal fractions obtained from murine 5xFAD and rTg4510 mice models of the disease. A local RTP801 knockdown in the 5xFAD hippocampal neurons with shRNA-containing AAV particles ameliorates cognitive deficits in 7-month-old animals. Upon RTP801 silencing in the 5xFAD mice, no major changes were detected in hippocampal synaptic markers or spine density. Importantly, we found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Encefalitis/genética , Trastornos de la Memoria/genética , Factores de Transcripción/fisiología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Animales , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Encefalitis/etiología , Encefalitis/patología , Femenino , Humanos , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Ratones , Ratones Transgénicos , Neuroinmunomodulación/genética , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/patología , Índice de Severidad de la EnfermedadRESUMEN
Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.