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Among the approximately 20 million patients with drug-resistant epilepsy (DRE) worldwide, the vast majority can benefit from surgery to minimize seizure reduction and neurological impairment. Precise preoperative localization of epileptogenic zone (EZ) and complete resection of the lesions can influence the postoperative prognosis. However, precise localization of EZ is difficult, and the structural and functional alterations in the brain caused by DRE vary by etiology. Neuroimaging has emerged as an approach to identify the seizure-inducing structural and functional changes in the brain, and magnetic resonance imaging (MRI) and positron emission tomography (PET) have become routine noninvasive imaging tools for preoperative evaluation of DRE in many epilepsy treatment centers. Multimodal neuroimaging offers unique advantages in detecting EZ, especially in improving the detection rate of patients with negative MRI or PET findings. This approach can characterize the brain imaging characteristics of patients with DRE caused by different etiologies, serving as a bridge between clinical and pathological findings and providing a basis for individualized clinical treatment plans. In addition to the integration of multimodal imaging modalities and the development of special scanning sequences and image post-processing techniques for early and precise localization of EZ, the application of deep machine learning for extracting image features and deep learning-based artificial intelligence have gradually improved diagnostic efficiency and accuracy. These improvements can provide clinical assistance for precisely outlining the scope of EZ and indicating the relationship between EZ and functional brain areas, thereby enabling standardized and precise surgery and ensuring good prognosis. However, most existing studies have limitations imposed by factors such as their small sample sizes or hypothesis-based study designs. Therefore, we believe that the application of neuroimaging and post-processing techniques in DRE requires further development and that more efficient and accurate imaging techniques are urgently needed in clinical practice. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.
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Purpose: Sjögren-Larsson syndrome is a rare, autosomal, recessive neurocutaneous disorder caused by mutations in the ALDH3A2 gene, which encodes the fatty aldehyde dehydrogenase enzyme. Deficiency in fatty aldehyde dehydrogenase results in an abnormal accumulation of toxic fatty aldehydes in the brain and skin, which cause spasticity, intellectual disability, ichthyosis, and other clinical manifestations. We present the clinical features and mutation analyses of a case of SLS.Materials and Methods: The family history and clinical data of the patient were collected. Genomic DNA was extracted from peripheral blood samples of the patient and her parents, and next-generation sequencing was performed. The candidate mutation sites that required further validation were then sequenced by Sanger sequencing. Bioinformatics software PSIPRED and RaptorX were used to predict the secondary and tertiary structures of proteins.Results: The patient, a five-year-old girl with complaints of cough for three days and intermittent convulsions for seven hours, was admitted to the hospital. Other clinical manifestations included spastic paraplegia, mental retardation, tooth defects, and ichthyosis. Brain magnetic resonance imaging showed periventricular leukomalacia. Genetic screening revealed compound heterozygous mutations in the ALDH3A2 gene: a frameshift mutation c.779delA (p.K260Rfs*6) and a missense mutation c.1157A > G (p.N386S). Neither of the ALDH3A2 alleles in the compound heterozygote patient were able to generate normal fatty aldehyde dehydrogenase, which were likely responsible for her phenotype of Sjögren-Larsson syndrome.Conclusion: The compound heterozygous mutations found in the ALDH3A2 gene support the diagnosis of Sjögren-Larsson syndrome in the patient and expand the genotype spectrum of the gene.
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Aldehído Oxidorreductasas/genética , Síndrome de Sjögren-Larsson/diagnóstico , Síndrome de Sjögren-Larsson/genética , Preescolar , Femenino , Mutación del Sistema de Lectura , Humanos , Mutación Missense , Linaje , Síndrome de Sjögren-Larsson/fisiopatologíaRESUMEN
BACKGROUND: Post-stroke epilepsy is a common and easily overlooked complication of acute cerebrovascular disease. Long-term seizures can seriously affect the prognosis and quality of life of patients. Electroencephalogram (EEG) is the simplest way to diagnose epilepsy, and plays an important role in predicting seizures and guiding medication. AIM: To explore the EEG characteristics of patients with post-stroke epilepsy and improve the detection rate of inter-seizure epileptiform discharges. METHODS: From January 2017 to June 2020, 10 patients with post-stroke epilepsy in our hospital were included. The clinical, imaging, and EEG characteristics were collected. The stroke location, seizure type, and ictal and interictal EEG manifestations of the patients with post-stroke epilepsy were then retrospectively analyzed. RESULTS: In all 10 patients, epileptiform waves occurred in the side opposite to the stroke lesion during the interictal stage; these manifested as sharp wave, sharp-wave complex, or spike discharges in the anterior head lead of the side opposite to the lesion. CONCLUSION: In EEG, epileptiform waves can occur in the side opposite to the stroke lesion in patients with post-stroke epilepsy.
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Tubulin plays an essential role in cortical development, and TUBA1A encodes a major neuronal α-tubulin. Neonatal mutations in TUBA1A are associated with severe brain malformations, and approximately 70% of patients with reported cases of TUBA1A mutations exhibit lissencephaly. We report the case of a 1-year-old boy with the TUBA1A nascent mutation c.1204C >T, p.Arg402Cys, resulting in lissencephaly, developmental delay, and seizures, with a brain MRI showing normal cortical formation in the bilateral frontal lobes, smooth temporo-parieto-occipital gyri and shallow sulcus. This case has not been described in any previous report; thus, the present case provides new insights into the broad disease phenotype and diagnosis associated with TUBA1A mutations. In addition, we have summarized the gene mutation sites, neuroradiological findings, and clinical details of cases previously described in the literature and discussed the differences that exist between individual cases of TUBA1A mutations through a longitudinal comparative analysis of similar cases. The complexity of the disease is revealed, and the importance of confirming the genetic diagnosis from the beginning of the disease is emphasized, which can effectively shorten the diagnostic delay and help clinicians provide genetic and therapeutic counseling.
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Essential tremor (ET) and Parkinson's disease (PD) are common chronic movement disorders that can cause a substantial degree of disability. However, the etiology underlying these two conditions remains poorly understood. In the present study, Whole-exome sequencing of peripheral blood samples from the proband and Sanger sequencing of the other 18 family members, and pedigree analysis of four generations of 29 individuals with both ET and PD in a nonconsanguineous Chinese family were performed. Specifically, family members who had available medical information, including historical documentation and physical examination records, were included. A novel c.1909A>T (p.Ser637Cys) missense mutation was identified in the eukaryotic translation initiation factor 4γ1 (EIF4G1) gene as the candidate likely responsible for both conditions. In total, 9 family members exhibited tremor of the bilateral upper limbs and/or head starting from ages of ≥40 years, 3 of whom began showing evidence of PD in their 70s. Eukaryotic initiation factor 4 (eIF4)G1, a component of the translation initiation complex eIF4F, serves as a scaffold protein that interacts with many initiation factors and then binds to the 40S ribosomal subunit. The EIF4G1 (p.Ser637Cys) might inhibit the recruitment of the mRNA to the ribosome. In conclusion, the results from the present study suggested that EIF4G1 may be responsible for the hereditary PD with 'antecedent ET' reported in the family assessed.
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OBJECTIVE: When magnetic resonance imaging (MRI) fails to detect an underlying epileptogenic lesion, the odds of a good outcome after epilepsy surgery are significantly lower (20%-65% compared with 60%-90% if a lesion is detected). We investigated the possible effects of introducing hybrid 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI into the decision algorithm for patients with lesioned and nonlesioned drug-resistant epilepsy. METHODS: Three databases were searched from January 1990 to October 2022. We registered the protocol with International Platform of Registered Systematic Review and Meta-analysis Protocols. Studies in which 18F-FDG PET/MRI was conducted with ≥12 months of postsurgical follow-up in patients with refractory epilepsy. Random-effects meta-analysis was used to calculate the proportion of patients with good outcomes. Metaregression was used to investigate sources of heterogeneity. RESULTS: We identified 8105 studies, of which 23 (1292 patients in total) were included. The overall good postoperative outcome rate was 71% (95% confidence interval 63.6-74.9). Good outcome was associated with the location of the refractory epileptic lesion (temporal lobe or extratemporal; risk ratio 1.27 [95% confidence interval 1.01-1.52], P = 0.009); Length of postoperative follow-up ≥40 months included in the same study accounted for 0.6% of the observed heterogeneity. CONCLUSIONS: Seventy-one percent of patients with refractory epilepsy and 18F-FDG PET/MRI epileptogenic lesion features had a good outcome of epilepsy after surgery. Our findings can be incorporated into routine preoperative consultations and emphasize the importance of the complete resection of the temporal lobe epileptogenic zone for 18F-FDG PET/MRI detection when safe and feasible.
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Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Epilepsia , Humanos , Fluorodesoxiglucosa F18 , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/cirugía , Electroencefalografía/métodos , Convulsiones , Tomografía de Emisión de Positrones/métodos , Epilepsia/diagnóstico por imagen , Epilepsia/cirugía , Epilepsia/patología , Imagen por Resonancia Magnética , Epilepsia del Lóbulo Temporal/cirugíaRESUMEN
Hereditary spastic paraplegia (HSP) comprises a group of hereditary and neurodegenerative diseases that are characterized by axonal degeneration or demyelination of bilateral corticospinal tracts in the spinal cord; affected patients exhibit progressive spasticity and weakness in the lower limbs. The most common manifestation of HSP is spastic paraplegia type 4 (SPG4), which is caused by mutations in the spastin (SPAST) gene. The present study reports the clinical characteristics of affected individuals and sequencing analysis of a mutation that caused SPG4 in a family. All affected family members exhibited spasticity and weakness of the lower limbs and, notably, only male members of the family were affected. Wholeexome sequencing revealed that all affected individuals had a novel c.1785C>A (p. Ser595Arg) missense mutation in SPAST. Bioinformatics analysis revealed changes in both secondary and tertiary structures of the mutated protein. The novel missense mutation in SPAST supported the diagnosis of SPG4 in this family and expands the spectrum of pathogenic mutations that cause SPG4. Analysis of SPAST sequences revealed that most pathogenic mutations occurred in the AAA domain of the protein, which may have a close relationship with SPG4 pathogenesis.
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Paraplejía Espástica Hereditaria , Humanos , Masculino , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/patología , Mutación Missense , Espastina/genética , MutaciónRESUMEN
BACKGROUND: Spinocerebellar ataxia recessive type 7 (SCAR7) is a rare clinical manifestation beginning in childhood or adolescence. SCAR7 is caused by tripeptidyl peptidase 1 (TPP1) gene mutations, and presents with cerebellar ataxia, pyramidal signs, neurocognitive impairment, deep paresthesia, and cerebellar atrophy. CASE SUMMARY: Here, we describe a 25-year-old female patient in China who presented with increasing difficulty walking, falling easily, shaking limbs, instability holding items, slurred speech, coughing when drinking, palpitations, and frequent hunger and overeating. Magnetic resonance imaging showed cerebellar atrophy. Whole exome sequencing detected two compound heterozygous mutations in the TPP1 gene: c.1468G>A p.Glu490Lys and c.1417G>A p.Gly473Arg. Considering the patient's clinical presentation and genetic test results, we hypothesized that complex heterozygous mutations cause TPP1 enzyme deficiency, which may lead to SCAR7. CONCLUSION: We report the first case of SCAR7 from China. We also identify novel compound heterozygous mutations in the TPP1 gene associated with SCAR7, expanding the range of known disease-causing mutations for SCAR7.
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OBJECTIVES: To investigate the application value of multimodal MRI combined with PET metabolic parameters in detecting temporal lobe epilepsy (TLE) with dual pathology (DP) and the prediction effect of post-surgical outcomes in these patients. METHODS: We retrospectively reviewed 50 patients with TLE-DP who underwent surgery at our hospital between January 2016 and December 2021 and collected the demographics, clinical characteristics, video-electroencephalography (v-EEG), neuroimaging, and surgical data. Seizure outcome data were collected during a regular follow-up of at least 12 months and were graded using Engel scores. Fisher's exact test was used to compare the differences in DP detection rates of various diagnostic modalities. Univariate and multivariate analyses were performed to explore the prognostic factors for predicting seizure outcomes post-surgery. RESULTS: Of the 50 patients, 20 were males. The median age was 30, the median age at first seizure was 14, and the median duration was ten years. Voxel-based morphometry-PET statistical parametric mapping-PET/MRI (VBM-PSPM-PET/MRI) had the highest detection rate, followed by PET/MRI, VBM analysis, and PET-SPM. Regardless of follow-up duration, v-EEG, PET, image post-processing methods, and VBM-PSPM-PET/MRI statistically correlated with seizure outcomes using the log-rank test in the Kaplan-Meier analysis. Multivariate analysis showed that VBM-PSPM-PET/MRI was an independent predictor of TLE-DP (hazard ratio (HR) = 15.674, 95 % CI = 0.002-0.122, P < 0.00 1). CONCLUSIONS: Our study illustrates that VBM-PSPM-PET/MRI has the highest detection value in patients with TLE-DP and can provide independent prognostic information for patients who undergo surgery. This approach has the most substantial potential for the selection of candidates for patients who undergo surgical treatment and for prognostic stratification.
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Epilepsia del Lóbulo Temporal , Masculino , Humanos , Adulto , Femenino , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/cirugía , Estudios Retrospectivos , Convulsiones , Imagen por Resonancia Magnética , Tomografía de Emisión de PositronesRESUMEN
Angelman syndrome (AS) is an autosomal dominant neurodevelopmental genetic disease with maternal imprint, which is associated with the presence of the abnormal chromosome 15q11-q13, and the loss of maternal specific expression of ubiquitin-protein ligase E3A (UBE3A). The expression levels of UBE3A depend on the parental origin and exhibit tissue specificity. In normal brain tissues, the maternal UBE3A gene is actively expressed, whereas the paternal UBE3A gene is not. In total, ~85% of pediatric patients with AS present with epilepsy within their 3rd year of life. This condition is usually difficult to control with medical treatment. An 8-year-old female visited the Affiliated Hospital of Jining Medical University due to frequent epilepsy. Her clinical manifestations included specific facial features, moderate mental retardation and frequent seizures. It was interesting to note that her 15-year-old sister exhibited similar clinical manifestations to those of AS. The results of the electroencephalogram and the imaging examinations were also in line with the characteristics of AS. In order to further clarify the diagnosis, all the suspected genes in her sister and in their parents were sequenced. The multiplex ligation-dependent probe amplification project of the Angel/chubby and copy number variation (CNV) sequencing were assessed concomitantly to identify the pathogenic genes responsible for the development of AS. The latter occurs due to the missense mutation c.1146T>G, which results in asparagine replacement by lysine at position 382 (p.Asn382Lys) in exon 7. This amino acid change affects the normal expression of UBE3A; the mutation is a novel mutation, which, to the best of our knowledge, has not been previously reported. Relevant large fragments of mutations and methylation abnormalities were not found in the associated genes. The data further revealed absence of 25-bp repeat mutations at the shear mutation site of exon 1 of the small nuclear ribonucleoprotein polypeptide N gene in the subjects examined. No suspected CNV was found following analysis.
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BACKGROUND: Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene. It can cause severe neurological impairment and diverse clinical manifestations, including epilepsy. CASE SUMMARY: Here, we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy. Magnetic resonance imaging showed myelin hypoplasia. Electroencephalography findings supported a diagnosis of epilepsy. Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene: The splicing mutation c.154-3C>G and the missense mutation c.71C>T (p. Pro24Leu). Considering the patient's clinical presentation and genetic test results, the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL, which may have led to ADSL deficiency. Finally, the child was diagnosed with ADSL deficiency. CONCLUSION: We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency, thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency. Additionally, we describe epilepsy that occurs in patients with ADSL deficiency.
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Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.
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Temporal lobe epilepsy (TLE) is a severe chronic neurological disease caused by abnormal discharge of neurons in the brain and seriously affect the long-term life quality of patients. Currently, new insights into the pathogenesis of TLE are urgently needed to provide more personalized and effective therapeutic strategies. Accumulating evidence suggests that sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate receptor 2 (S1PR2) signaling pathway plays a pivotal role in central nervous system (CNS) diseases. However, the precise altered expression of SphK1 and S1PR2 in TLE is remaining obscure. Here, we have confirmed the expression of SphK1 and S1PR2 in the pilocarpine-induced epileptic rat hippocampus and report for the first time the expression of SphK1 and S1PR2 in the temporal cortex of TLE patients. We found an increased expression of SphK1 in the brain from both epileptic rats and TLE patients. Conversely, S1PR2 expression level was markedly decreased. We further investigated the localization of SphK1 and S1PR2 in epileptic brains. Our study showed that both SphK1 and S1PR2 co-localized with activated astrocytes and neurons. Surprisingly, we observed different subcellular localization of SphK1 and S1PR2 in epileptic brain specimens. Taken together, our study suggests that the alteration of the SphK1/S1PR2 signaling axis is closely associated with the course of TLE and provides a new target for the treatment of TLE.
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Tuberous sclerosis complex (TSC) is a genetic disease characterized by seizures, mental deficiency, and abnormalities of the skin, brain, kidney, heart, and lungs. TSC is inherited in an autosomal dominant manner and is caused by variations in either the TSC1 or TSC2 gene. TSC-related epilepsy (TRE) is the most prevalent and challenging clinical feature of TSC, and more than half of the patients have refractory epilepsy. In clinical practice, we found several patients of intractable epilepsy caused by TSC1 truncating mutations. To study the changes of protein expression in the brain, three cases of diseased brain tissue with TSC1 truncating mutation resected in intractable epilepsy operations and three cases of control brain tissue resected in craniocerebral trauma operations were collected to perform protein spectrum detection, and then the data-independent acquisition (DIA) workflow was used to analyze differentially expressed proteins. As a result, there were 55 up- and 55 down-regulated proteins found in the damaged brain tissue with TSC1 mutation compared to the control. Further bioinformatics analysis revealed that the differentially expressed proteins were mainly concentrated in the synaptic membrane between the patients with TSC and the control. Additionally, TSC1 truncating mutations may affect the pathway of amino acid metabolism. Our study provides a new idea to explore the brain damage mechanism caused by TSC1 mutations.
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OBJECTIVE: To observe the expressions of sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate receptor 2 (S1PR2) in hippocampus of epileptic rats and to investigate the pathogenesis of SphK1 and S1PR2 in epilepsy. METHODS: One hundred and eight male Sprague-Dawley (SD) rats were randomly divided into control group (n=48) and pilocarpine (PILO) group (n=60). A robust convulsive status epilepticus (SE) was induced in PILO group rats by the application of pilocarpine. Control group rats were injected with respective of physiological saline. Pilocarpine group was randomly divided into 6 subgroups (n=8): acute group (E6 h, E1 d, E3 d), latent group (E7 d) and chronic group (E30 d, E56 d). Each subgroup has 8 control rats and 8 epileptic rats. Hippocampal tissue and brain slices were obtained from control rats and rats subjected to the Li-PILO model of epilepsy at 6 h, 1 d, 3 d,7 d,30 d and 56 d after status epilepticus (SE). Western blot technique was used to determine the expressions of SphK1 and S1PR2 in hippocampus at different point of time after pilocarpine treatment. Immunofluorescence was applied to detect the activation and proliferation of hippocampal astrocytes and the localization of SphK1 and S1PR2 in rat hippocampal astrocytes. RESULTS: Compared with control group, the levels of SphK1 in acute phase (E3 d), latent phase (E7 d) and chronic phase (E30 d, E56 d) were significantly increased while the expressions of S1PR2 were decreased in acute phase (E3 d), latent phase (E7 d) and chronic phase (E30 d, E56 d)(Pï¼0.05 or Pï¼0.01). Immunofluorescence results showed astrocyte activation and proliferation in hippocampus of epileptic (E7 d) rats (Pï¼0.05). Confocal microscopy confirmed the preferential expressions of SphK1 and S1PR2 in epileptic rat(E7 d)hippocampal astrocytes. CONCLUSION: The results indicate that SphK1 and S1PR2 may play an important role in the pathogenesis of epilepsy by regulating the activation and proliferation of hippocampal astrocytes and altering neuronal excitability.
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Epilepsia/enzimología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Receptores de Lisoesfingolípidos/metabolismo , Animales , Astrocitos/enzimología , Epilepsia/fisiopatología , Hipocampo/citología , Hipocampo/enzimología , Masculino , Pilocarpina , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores de Esfingosina-1-FosfatoRESUMEN
Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by mutations in genes that encode subunits of the branchedchain αketoacid dehydrogenase (BCKD) complex. Impairment of the BCKD complex results in an abnormal accumulation of branchedchain amino acids and their corresponding branchedchain keto acids in the blood and cerebrospinal fluid, which are neurovirulent and may become lifethreatening. An 11dayold boy was admitted to the hospital with paroxysmal spasticity of lower extremities. Of note, his 10yearold sister presented similar symptoms during the neonatal period, and her condition was diagnosed as MSUD when she was 1.5 years old. Genetic screening was performed, and the boy and his sister exhibited two novel compound heterozygous mutations in the branched chain keto acid dehydrogenase E1 subunit ß (BCKDHB) gene: A substitution from guanine to adenine in the coding region at position 1,076 (c.1,076G>A) in exon 10 and a deletion of a thymine at position 705 (c.705delT) in exon 6. The missense mutation c.1076G>A results in an amino acid substitution from arginine to lysine at position 359 (p.Arg359Lys), whereas the mutation c.705delT results in the replacement of a cysteine at position 235 with a stop codon (p.Cys235Ter). Neither of the BCKDHB alleles in the compound heterozygote patients is able to generate normal E1ß subunits, resulting in a possible impairment of the activity of the BCKD complex. In the present study, it was hypothesized that the two novel heterozygous mutations in the BCKDHB gene found in the Chinese family may be responsible for the phenotype of the two siblings with MSUD.
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3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/genética , Extremidad Inferior , Enfermedad de la Orina de Jarabe de Arce/genética , Hermanos , Alelos , Sustitución de Aminoácidos , Aminoácidos de Cadena Ramificada , Pueblo Asiatico , Secuencia de Bases , Encefalopatías , Niño , Electroencefalografía/métodos , Exones , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Lactante , Extremidad Inferior/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Enfermedad de la Orina de Jarabe de Arce/diagnóstico por imagen , Mutación Missense , Linaje , FenotipoRESUMEN
The mutation in CNKSR2 leads to a broad spectrum of phenotypic variability and manifests as an X-linked intellectual disability. However, we reported that the male patient in this study not only had intellectual disability but also epileptic seizures. In addition, there were progressive language impairment, attention deficit hyperactivity disorder and autism. Electroencephalograms showed continuous spike-and-wave during sleep. Genetic testing revealed a de novo mutation of the CNKSR2 gene (c.2185C>T, p.Arg729Ter) in the child that was not detected in the parents. Therefore, the child was diagnosed with X-linked epilepsy aphasia syndrome. Deletion of the CNKSR2 gene has been rarely reported in epilepsy aphasia syndrome, but no de novo mutation has been found in this gene. This report not only adds to the spectrum of epilepsy aphasia syndrome but also helps clinicians in diagnosis and genetic counseling.
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Toll-like receptor (TLR) 9, recognizing different ligands, confers distinct features of plasmacytoid dendritic cells (pDCs). Our previous study demonstrated a role for TLR9 in the mechanism of experimental autoimmune neuritis (EAN). In this study, we explored whether suppressive oligodeoxynucleotides (sODN) could induce tolerogenic pDCs via TLR9 and thus promote the recovery of EAN. Effects of different TLR9 ligands, CpG ODN and sODN on P0 180-199 peptide-stimulated pDCs were measured by detecting the expression of co-stimulatory molecules, indoleamine 2,3-dioxygenase (IDO), secretion of Th1- and Th2-type cytokines and the TLR9 signaling pathway. CpG ODN- or sODN-treated pDCs were intravenously injected into the EAN mice and their effects were compared. Our data showed that P0180-199 peptides significantly promoted mRNA expression of co-stimulatory molecules (CD40, CD80 and CD86) in pDCs and induced secretion of Th1-type cytokines. Treatment of CpG ODN aggravated the effects of P0 180-199 peptides on pDCs; however, sODN had the opposite effects and significantly upregulated the IDO expression in pDCs. Further analysis showed that MYD88 is necessary for sODN to modulate the TLR9/NF-κB signaling in pDCs. Finally, the sODN-treated pDCs significantly promoted recovery of the EAN mice. Taken together, sODN could induce tolerogenic pDCs and thus ameliorate the EAN.
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Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Neuritis Autoinmune Experimental/inmunología , Oligodesoxirribonucleótidos/farmacología , Péptidos/farmacología , Animales , Antígeno B7-1/genética , Antígeno B7-2/genética , Antígenos CD40/genética , Células Cultivadas , Islas de CpG/genética , Citocinas/biosíntesis , Citocinas/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/metabolismo , Neuritis Autoinmune Experimental/terapia , ARN Mensajero/genética , Células TH1/inmunología , Células Th2/inmunología , Receptor Toll-Like 9/inmunología , Factor de Transcripción ReIA/metabolismoRESUMEN
Guillain-Barré syndrome (GBS) is a post-infectious autoimmune disease. Dendritic cells (DCs) can recognize the pathogen and modulate the host immune response. Exploring the role of DCs in GBS will help our understanding of the disease development. In this study, we aimed to analyze plasmacytoid and conventional DCs in peripheral blood of patients with GBS at different stages of the disease: acute phase as well as early and late recovery phases. There was a significant increase of plasmacytoid DCs in the acute phase (p=0.03 vs healthy donors). There was a positive correlation between percentage of plasmacytoid DCs and the clinical severity of patients with GBS (r=0.61, p<0.001). Quantitative polymerase chain reaction and flow cytometry confirmed the aberrant plasmacytoid DCs in GBS. Thus, plasmacytoid DCs may participate in the development of GBS.
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Células Dendríticas/inmunología , Síndrome de Guillain-Barré/inmunología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/biosíntesis , Antígenos CD/genética , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Convalecencia , Femenino , Citometría de Flujo , Gangliósidos/inmunología , Síndrome de Guillain-Barré/sangre , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/fisiopatología , Síndrome de Guillain-Barré/terapia , Humanos , Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Persona de Mediana Edad , Conducción Nerviosa , Intercambio Plasmático , Índice de Severidad de la Enfermedad , Receptor Toll-Like 7/biosíntesis , Receptor Toll-Like 7/genética , Receptor Toll-Like 9/biosíntesis , Receptor Toll-Like 9/genética , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: Borneol is the processed item from resin of Dryobalanops aromatica Gaertn. f. It can enhance the activity of antioxidant enzymes in brain tissue and reduce inflammatory response by improving the energy metabolism of ischemic brain regions, and thereby reduces brain tissue damage. The objective of this paper was to study the anti-cerebral ischemia effect of borneol and its mechanism. MATERIALS AND METHODS: The anti-cerebral ischemia effect of borneol was studied by ligation of bilateral common carotid arteries (CCA), and vagus nerves in mice and the acute cerebral ischemia-reperfusion experiment in rats. RESULTS: Compared with the blank and solvent control groups, the borneol low-; medium-; and high-dose groups can significantly prolong the gasping time of mice after decapitation, and extend the survival time of mice after ligation of bilateral CCA, and vagus nerves. CONCLUSION: Compared with the Xueshuantong injection group, the prolongation of survival time of mice after ligation of bilateral CCA, and vagus nerves was more apparent in the high-dose borneol experimental group; each experimental group can significantly reduce the number of leukocyte infiltration, the number of ICAM-1-positive vessels, as well as the number of TNF-α-positive cells. CONCLUSION: Borneol has an anti-cerebral ischemia effect.