Search

Abstract Hydraulic actuated quadruped robots have bright application prospects and significant research values in unmanned area investigation, disaster rescue and other scenarios, due to the advantages of high payload and high power to weight ratio. Among these fields, inevitable collision of robots may occur when contact with unknown objects, step on empty objects, or collapse, all of which have an impact on the working hydraulic system. To overcome the unknown external disturbances, this paper proposes an active disturbance rejection control (ADRC) strategy of double vane hydraulic rotary actuators for the hip joints of the quadruped robots. Considering the order of the valve-controlled actuator model, a three-stage tracking differentiator, a four-stage extended state observer, and a state error feedback controller are designed relatively, and the extended state observer is adopted to observe and compensate the uncertainty of external load torque of the system. The effectiveness of the ADRC method is verified in simulation environment and a single joint experimental platform. Moreover, the impact experiments of the limb leg unit are carried out after introducing the proposed ADRC strategy into hip joint, the limb leg unit of quadruped robots presents better impact resistance ability.

BackgroundTRIM8-related neuro-renal syndrome (NRS), caused by pathogenic variants of the TRIM8 gene, is characterized by epilepsy, developmental delay (DD) and renal disorders. The severity of the neurological effects as well as the presence of renal disorders is variable among patients. Here, we report three additional patients with clinical features compatible with NRS and summarize the association between the variants’ loci and phenotype of TIRM8-related NRS.MethodsA retrospective analysis was conducted for three Chinese children with NRS due to TRIM8 variants identified through whole-exome sequencing (WES). Previous reports of patients with TRIM8-related NRS were reviewed systematically. Demographic and clinical data were collected from these patientsResultsTwo de novoTRIM8 truncating variants in three NRS patients were identified in our study, including c.1327_c.1328delCCinsTG (p. Arg443*) and c.1375C>T (p.Gln459*). Our three patients all exhibited drug-resistant epilepsy and early-onset DD, and two of whom developed electrical status epilepticus during sleep (ESES). Brain magnetic resonance imaging (MRI) showed periventricular leukomalacia in one patient and normal in the other two. All three patients demonstrated nephrotic range proteinuria (NRP) or nephrotic syndrome (NS) with normal renal function during follow-up. There was a total of 27 patients with TRIM8-related NRS have been identified to date. The most common clinical features are renal diseases (89%), DD (89%), followed by epilepsy (78%). 67% of patients eventually progressed to end-stage renal disease (ESRD). Focal seizure was the most frequent seizure type (57%). 52% of patients presented drug-resistant epilepsy. 64% of patients exhibited non-specific brain MRI abnormalities. Brain atrophy was the most common change (50%). Two patients with TRIM8 variants closer to the N-terminal had neurological diseases without renal damage. Five patients with TRIM8 variants closer to the C-terminal had no severe neurological diseases. Seven patients had Gln459* variant which is the most common variant (7/27, 25.9%). The severity of the renal and neurological damage of the seven patients was variable.ConclusionThis study expands the number of individuals with confirmed NRS due to pathogenic variants in TRIM8. Neurological and renal phenotype with the same variant locus differed in their severity. Further research is needed to explore the relationship between genotype and phenotype of TRIM8 variants.

Epilepsy is a common neurological disorder that affects approximately 10.5 million children worldwide. Approximately 33% of affected patients exhibit resistance to all available antiseizure medications, but the underlying mechanisms are unknown and there is no effective treatment. Increasing evidence has shown that an abnormal gut microbiota may be associated with epilepsy. The gut microbiota can influence the function of the brain through multiple pathways, including the neuroendocrine, neuroimmune, and autonomic nervous systems. This review discusses the interactions between the central nervous system and the gastrointestinal tract (the brain–gut axis) and the role of the gut microbiota in the pathogenesis of epilepsy. However, the exact gut microbiota involved in epileptogenesis is unknown, and no consistent results have been obtained based on current research. Moreover, the target that should be further explored to identify a novel antiseizure drug is unclear. The role of the gut microbiota in epilepsy will most likely be uncovered with the development of genomics technology.

Abstract Continuous cultivation of faba beans often results in a high occurrence of Fusarium wilt. Nevertheless, this issue can be successfully managed through wheat‐faba bean intercropping. Our objective is to elucidate the function of non‐host wheat in combating faba bean Fusarium wilt. We assessed the impact of wheat on the development of faba bean Fusarium wilt through field and pot experiments, and examined and identified the compounds in the root exudates of wheat. The influence of wheat root exudates on Fusarium commun mycelial growth and spore multiplication was investigated through indoor culture experiments. Wheat‐faba bean intercropping significantly reduced the occurrence of Fusarium wilt in field trials. Root separation experiments in pots indicated that wheat root exudates might play a vital role in this outcome. The exogenous addition of wheat root exudates to faba bean grown alone notably decreased the occurrence and severity of Fusarium wilt. Furthermore, the exogenous addition of wheat root exudates effectively hindered the growth and reproduction of Fusarium commun's mycelium. And, wheat root exudates contained six compounds with relatively high concentrations, including salicylic acid, p‐hydroxybenzoic acid, tartaric acid, malic acid, glutamic acid, and threonine, all of which inhibited the growth and spore formation of Fusarium commun. In a wheat‐faba bean intercropping system, these six compounds found in the root exudate of non‐host wheat can help control Fusarium wilt in faba bean by inhibiting the mycelial growth and sporulation of Fusarium commun.

ObjectivesThis study aimed to investigate the clinical, radiological, and genetic features of POLR3-related leukodystrophy caused by mutations in POLR3A or POLR1C.MethodsFourteen Chinese patients with POLR3-related leukodystrophy were enrolled in this cross-sectional observational study. The clinical manifestations, brain MRI and genetic tests of the patients were evaluated.ResultsThirteen patients had biallelic variants in POLR3A (92.9%), and one had biallelic variants in POLR1C (7.1%). The median age at disease onset was 9 months. A total of 85.7% of the patients presented with motor delay, abnormal gait, and intelligence disability in the first 2 years of life. Intellectual disability can be categorized based on its severity. It varied from mild (which involves difficulty concentrating) to very severe (with no smiling or laughing or never being able to speak since birth). Short stature was observed in all patients, and delayed dentition was observed in 64.3% of them. Furthermore, three out of 14 patients had myopia. Hypomyelination was invariably present in all patients, whereas myelination of the basal ganglia was preserved in only six out of 14 patients. All the mutations were compound heterozygous and included missense (n = 25), deletion (n = 1), and splice site variants (n = 2). A total of 78.6% of the patients with POLR3A were identified as carrying the c.1771-6C>G variant or the c.1771-7C>G variant.ConclusionThe phenotypic diversity of POLR3-HLD associated with pathogenic variants ranges from mild to very severe for neurological and non-neurological symptoms. Most patients presented symptoms in the first 2 years of life. The c.1771-6C>G or c.1771-7C>G variant is the most frequent mutation site in POLR3A in Chinese individuals.

Abstract This systematic review and meta‐analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library were systematically searched. All the relevant randomized controlled trials (RCTs) and observational studies (OSs) of VGB for IESS were included and analyzed separately. The primary outcome was the cessation of epileptic spasms (ES). Five RCTs and nine OSs compared the efficacy of VGB vs hormonal monotherapy for IESS. Meta‐analysis of the five RCTs showed that hormonal monotherapy was significantly better than VGB monotherapy (OR = 0.37, 95% CI = 0.20‐0.67) for patients with new‐onset IESS. Meta‐analysis of the nine OSs agrees with the result from RCTs (OR = 0.61, 95% CI = 0.43‐0.85). VGB was more effective in patients with TSC than in those with other etiologies (five OSs, OR = 5.59, 95% CI = 2.17‐14.41). There was no significant difference in the efficiency of VGB combined with hormonal therapy vs hormonal monotherapy for IESS (two RCTs, OR = 0.75, 95% CI = 0.09‐6.45). Hormonal monotherapy is better than VGB monotherapy for non‐TSC‐associated IESS. But for patients with IESS due to TSC, VGB is the first choice. VGB combined with hormone therapy does not definitely increase ES control rates compared with that of hormonal monotherapy.

Structural rearrangements of chromosome 4p gives rise to a group of rare genomic disorders that mainly result in two different clinical entities: Wolf-Hirschhorn syndrome (WHS) and partial 4p trisomy. The severity of the phenotype depends on the size of the deletion or locus duplication. Here, we present two unrelated individuals with a copy number variation of chromosome 4p. Inverted duplication deletions (inv dup-del) in 4p are particularly rare. Case 1 describes a 15-year-old girl with a 1.055 Mb deletion of terminal 4p, distal to the recognized critical region of WHS, and a large duplication of 9.6 Mb in size from 4p16.3 to p16.1. She had postnatal development delay, intellectual disability (especially pronounced in speech), seizure/electroencephalogram anomalies, and facial dysmorphic features. This unusual chromosomal imbalance resulted in the WHS phenotype rather than the 4p trisomy syndrome phenotype. Case 2 describes a 21-month-old boy with a 1.386 Mb terminal 4p deletion who presented with slight developmental delay, borderline intellectual disability, and seizures. Combined with previous reported cases of 4 pter del-dup or pure 4p terminal deletions, our observations suggest that terminal chromosome 4p deletion is more pathogenic than the concomitant partial 4p duplication, and some regions of the 4p terminal may have regulatory effects on the remaining region of 4p. About nine cases have been reported thus far to date, and our study delineates further genotype-phenotype correlations about terminal 4p duplication-deletions for predicting disease prognosis and patient counseling.

Abstract Background Landau-Kleffner syndrome (LKS) is an acquired aphasia and electroencephalogram (EEG) abnormalities mainly in temporoparietal areas. SLC26A4 mutations can cause hearing loss associated with enlarged vestibular aqueduct (EVA). Case presentations We report a case of LKS in a 5-year-old boy with non-syndromic EVA due to homozygous mutations of c.919-2A>G (IVS7-2A>G) in SLC26A4. He had normal language development before 2 years old. At the age of 2.5 years, he was admitted to the hospital due to remarkable language delay, and diagnosed with hearing loss with EVA. The seizures started at 4.4 years of age and EEG recording showed electrical status epilepticus during sleep (ESES) with a posterior-temporal predominance. He received cochlear implantation in the right ear at 4.7 years of age, which improved his hearing and language skills. The nocturnal focal motor seizures recurred at 4.9 years of age. Then a remarkable inability to respond to calls and reduction in spontaneous speech were noticed. He was treated with methylprednisolone at 5 years old, which controlled the seizures, suppressed ESES, and remarkably improved the language ability. The absence of seizures maintained until the last follow-up at 5.3 years of age, with further improvements in EEG recording and language ability. Conclusions The co-existence of LKS and hearing loss caused by SLC26A4 mutations increases the difficulty of LKS diagnosis, especially in the presence of hearing loss and impaired language skills. EEG discharges predominantly in temporoparietal areas, the occurrence of ESES, and language improvement after antiepileptic medications are potential indicators for LKS diagnosis.

ObjectivesTo investigate neonatal electroencephalography (EEG) background activity and electrographic seizures in patients in the pediatric intensive care unit (PICU) who underwent bedside video-electroencephalography (vEEG) monitoring.MethodsA total of 232 pediatric patients admitted or transferred to PICU that underwent vEEG monitoring were retrospectively enrolled in this study, and electrographic status epilepticus was observed after vEEG monitoring.ResultsThe median age was 1.56 years [95% confidence interval (CI) = 1.12–2.44]. Electrographic seizures occurred in 88 patients (37.9%), out of which 36 cases (40.9%) had electrographic status epilepticus. Prior epileptic encephalopathy diagnosis [odds ratio (OR) = 6.57, 95% CI = 1.91–22.59, p = 0.003], interictal epileptiform discharges (OR = 46.82, 95%CI = 5.31–412.86, p = 0.0005), slow disorganized EEG background (OR = 11.92, 95%CI = 1.31–108.71, p = 0.028), and burst-suppression EEG background (OR = 23.64, 95%CI = 1.71–327.57, p = 0.018) were the risk factors for electrographic seizures' occurrence. Of the 232 patients, the condition of 179 (77.2%) patients improved and they were discharged, 34 cases (14.7%) were withdrawn, and 18 cases (7.8%) died. The in-hospital death rate was 47.6% (10 in 21 cases) in patients with attenuated/featureless, compared to 0/23 with normal EEG background.ConclusionsElectrographic status epilepticus occurs in more than one-third of patients with electrographic seizures. vEEG is an efficient method to determine electrographic seizures in children. Abnormal EEG background activity is associated with both electrographic seizures' occurrence and unfavorable in-hospital outcomes.

ObjectiveTo analyze the genotypes and phenotypes of mosaic male patients with PCDH19-related epilepsy (PCDH19-RE) and explore the correlation between genotype, variant allele frequency (VAF), and phenotypic severity.MethodsClinical data and peripheral blood samples of 11 male mosaic patients were collected and analyzed in our study. The VAF of the PCDH19 gene from peripheral blood was quantified using amplicon-based deep sequencing. Additional 20 mosaic male patients with PCDH19-RE were collected from the published literature, with 10 patients whose VAFs of the PCDH19 gene were available for analytic purposes.ResultsIn our cohort of 11 patients, 10 variants were identified, and four were novel. The VAF of the PCDH19 gene from peripheral blood ranged from 27 to 90%. The median seizure onset age was 6 months (range: 4–9 months). Clinical manifestations included cluster seizures (100%), fever sensitivity (73%), focal seizures (91%), developmental delay/intellectual disability (DD/ID, 82%), and autistic features (45%). Thirty-one mosaic male patients collected from our cohort and the literature developed seizures mostly (87%) within one year of age. Variant types included missense variants (42%), truncating variants (52%), splice variants (3%), and whole PCDH19 deletion (3%). Among 21 patients with a definite VAF from our cohort and the literature, nine had a low VAF ( ≤ 50%) and 12 had a high VAF (> 50%). Seventy-five percent of variants from the high VAF group were missense, whereas 89% of those from the low VAF group were truncations. The median seizure onset age was 6 months in the low VAF group and 9 months in the high VAF group (p = 0.018). Forty-four percent (4/9) of patients from the low VAF group achieved seizure-free for ≥1 year, whereas none of the 12 patients from the high VAF group did (p = 0.021). DD/ID was present in 83% (10/12) of the high VAF group and 56% (5/9) of the low VAF group (p = 0.331).ConclusionThe predominant variant types were truncating and missense variants. Missense variants tended to have higher VAFs. Patients with a high VAF were more likely to have a more severe epileptic phenotype. Our findings shed light on the phenotypic implications of VAF in mosaic males with PCDH19-RE.

Abstract To analyze the relationship between the characteristics of burst suppression (BS) pattern and different etiologies in epilepsy. Patients with a BS pattern who were younger than 6 months old were screened from our electroencephalogram (EEG) database. The synchronized and symmetric BS patterns under different etiologies in epilepsy were analyzed. A total of 32 patients had a BS pattern on EEG. The etiologies included genetic disorders (37.5%), cortical malformations (28.1%), inborn errors of metabolism (12.5%), and unknown (21.9%). Twenty-five patients were diagnosed with Ohtahara syndrome, one as early myoclonic encephalopathy, and one as epilepsy of infancy with migrating focal seizure. Five cases could not be classified into any epileptic syndrome. Asynchronous BS pattern was identified in 18 cases, of which 13 (72%) patients had genetic and/or metabolic etiologies. Synchronous BS pattern was identified in 14 cases, of which 8 (57%) patients had structural etiologies. Twenty-three patients had symmetric BS patterns, of which 15 (65%) patients had genetic etiologies. Nine patients had asymmetric BS patterns, of which 8 (89%) patients had structural etiologies. Patients with genetic epilepsies tended to have asynchronous and symmetric BS patterns, whereas those with structural epilepsies were more likely to have synchronous and asymmetric BS patterns.

ObjectiveTo determine the contribution of genetic etiologies in epilepsy with photosensitivity.MethodsA total of 35 epileptic patients with genetic photosensitivity from January 2019 to May 2021 were analyzed.ResultsPathogenic variants were identified in 35 patients, including SCN1A(7) CHD2(6), TPP1(3), SYNGAP1(3), GABRA1(2), GABRG2(1), KCTD7(1), MFSD8(1), KCNC1(1) GBA(1), CACNA1A(1), KCNMA1(1), FLNA(1), SZT2(1), SLC2A1(1), 5q33.2-34del(1), and mitochondrial variants(3). The predominant epileptic syndrome was progressive myoclonus epilepsy (PME) and Dravet syndrome, while the most common seizure type in both spontaneous seizures and photoconvulsive response (PCR) was myoclonic seizures. The abnormal EEG background and brain MRI were mainly seen in the PME patients. In PME, initial low-frequencies (1–6 Hz) photosensitivity was observed in 70% (7/10) of patients. Among the other patients, 12 patients (48.0%, 12/25) had photosensitivity at initial low -frequencies and 12 patients (48.0%, 12/25) had photosensitivity at initial middle frequencies (6–20 Hz). At the 1-year follow-up, 77.7% (21/27) still remained photosensitive.ConclusionThe most common genes for epilepsy with genetic photosensitivity are SCN1A and CHD2, and the most common syndromes are PME and Dravet syndrome. MFSD8, KCNMA1, SZT2, FLNA, and SLC2A1 variants might be candidate genes for photosensitivity. PPRs at initial low-frequencies may be a marker of PME, and the most typical feature of genetic photosensitivity may be low- or middle- frequencies induced PPRs. Photosensitivity in epilepsy with genetic photosensitivity may be difficult to disappear in a short period of time.

ObjectiveThis study aimed to delineate the detailed characteristics of startle-induced epileptic spasms (ES) and explore the brain regions where startle-induced ES originated.MethodsAmong 581 patients with ES registered in our database, 30 were diagnosed with startle-induced ES according to video-electroencephalogram (EEG) and seizure semiology and were included in this study. Patients' clinical characteristics and ictal high-frequency oscillations (HFOs) were analyzed.ResultsMean age at the onset of startle-induced ES was 28.1 months. Half of the patients had structural etiology, two of whom were diagnosed with co-existing structural and genetic etiologies. The focal neuroimaging abnormalities were predominant in the frontal cortex (9/15, 60.0%). Fifteen patients (50%) had prominent interictal epileptiform discharges in the frontal and anterior temporal. Ictal HFOs counts of the startle-induced ES in the anterior region were significantly higher than those in the posterior regions (p < 0.05). Five patients (16.7%) became seizure-free ≥6 months, and ten (33.3%) showed startle-induced ES cessation ≥6 months. All patients except one had mild to severe psychomotor developmental delay after the onset of seizures.ConclusionPatients with startle-induced ES typically had brain lesions and showed drug-resistant. The neuroimaging and EEG findings, including ictal HFOs, support that startle-induced ES often originates from the frontal cortex.

ObjectiveTo analyze the clinical features, treatment, and prognosis of patients with vitamin B6-responsive infantile spasms (IS).MethodsThe clinical features, genetics, and follow-up data of 30 patients were collected and analyzed.ResultsThe age of epileptic spasms (ES) onset was from 3 months to 12 months. They all received high doses of vitamin B6 at different times after the onset of ES, ranging from 1 day to 5 months. ES were controlled within 11 days in 93% (28/30) patients, and as late as 1 month and 2 months in the other two patients. In the course of treatment, 28 patients were seizure-free all the time, and seizures of other two patients recurred due to withdrawal of vitamin B6. The available follow-up EEG results of 28 patients were normal in 26 cases, and 81% (21/26) had suppressed epileptic discharges within 6 months. Of the 26 cases with normal follow up EEG, 4 had developmental delay and 22 had normal development. The time for EEG to return to normal in 22 patients with normal development ranged from 14 days to 2 years (mean = 111.5 days; median = 52.5 days). The time for EEG to return to normal in the other 4 patients with development delay ranged from 4 months to 2 years (mean = 375 days; median = 330 days). To the last follow-up, seizures were controlled well in 29 surviving patients, and 21 patients were able to deactivate from all medications without seizures recurrence. Sixteen patients showed varying degrees of developmental delay after onset. After seizure control, the psychomotor development was delayed in 7 patients (one died) until the last follow-up. Genetic analysis did not show any meaningful results.ConclusionAn observation period of 1–2 weeks is essential to identify patients with vitamin B6-responsive IS. The treatment time could be extended according to the treatment response and EEG changes. It might take a longer time for EEG to return to normal and to stop taking drugs in patients with persistent or unimproved developmental delay. Neurodevelopmental outcomes and prognosis of vitamin B6-responsive IS were relatively favorable.

Objective: To analyze the clinical feature, treatment, and prognosis of epileptic spasms (ES) in vitamin B6–dependent epilepsy, including patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 mutation, pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency, and PLPBP deficiency.Methods: We analyzed data from a cohort of 54 cases with PDE, 13 cases with PNPO deficiency, and 2 cases with PLPBP deficiency and looked for the presentation of ES among them.Results: A total of 11 patients with the seizure presentation of ES have been collected. Among them, four patients carried mutations in ALDH7A1, six carried mutations in PNPO, and the remaining one carried mutation in PLPBP. The analysis of this cohort identified nine cases presenting as infantile spasms distributed in the three diseases and two cases presenting as Ohtahara syndrome diagnosed with PDE and PNPO deficiency, respectively. In the PDE and PLPBP deficiency groups, seizures were controlled by pyridoxine monotherapy, and the remaining one had refractory seizures due to secondary brain atrophy. In the groups with PNPO deficiency, one patient showed seizure-free when treated by PLP combined with valproic acid, three still had infrequent seizures treated by PLP monotherapy or pyridoxine or PLP combined with other antiseizure medications, and two died. In two cases presenting as Ohtahara syndrome, after regular treatment, one showed seizure-free, the others showed a marked decrease in seizure frequency, and they both showed an improvement in EEG.Significance: ES might be a common form of seizures in PNPO deficiency, and EEG presented as hypsarrhythmia or a burst suppression pattern. It is difficult for pyridoxine to control frequent seizures caused by secondary brain injury. In our PNPO deficiency cohort, patients with infantile spasms did not respond better to PLP than pyridoxine. Timely and correct treatment could prevent the transformation of the child’s disease from Ohtahara syndrome and infantile spasms to subsequent epileptic encephalopathy or refractory epilepsy.

ObjectiveThis study aimed to obtain a comprehensive understanding of the genetic and phenotypic aspects of GABRG2-related epilepsy and its prognosis and to explore the potential prospects for personalized medicine.MethodsThrough a multicenter collaboration in China, we analyzed the genotype-phenotype correlation and antiseizure medication (ASM) of patients with GABRG2-related epilepsy. The three-dimensional protein structure of the GABRG2 variant was modeled to predict the effect of GABRG2 missense variants using PyMOL 2.3 software.ResultsIn 35 patients with GABRG2 variants, 22 variants were de novo, and 18 variants were novel. The seizure onset age was ranged from 2 days after birth to 34 months (median age: 9 months). The seizure onset age was less than 1 year old in 22 patients (22/35, 62.9%). Seizure types included focal seizures (68.6%), generalized tonic-clonic seizures (60%), myoclonic seizures (14.3%), and absence seizures (11.4%). Other clinical features included fever-sensitive seizures (91.4%), cluster seizures (57.1%), and developmental delay (45.7%). Neuroimaging was abnormal in 2 patients, including dysplasia of the frontotemporal cortex and delayed myelination of white matter. Twelve patients were diagnosed with febrile seizures plus, eleven with epilepsy and developmental delay, two with Dravet syndrome, two with developmental and epileptic encephalopathy, two with focal epilepsy, two with febrile seizures, and four with unclassified epilepsy. The proportions of patients with missense variants in the extracellular region and the transmembrane region exhibiting developmental delay were 40% and 63.2%, respectively. The last follow-up age ranged from 11 months to 17 years. Seizures were controlled in 71.4% of patients, and 92% of their seizures were controlled by valproate and/or levetiracetam.ConclusionThe clinical features of GABRG2-related epilepsy included seizure onset, usually in infancy, and seizures were fever-sensitive. More than half of the patients had cluster seizures. Phenotypes of GABRG2-related epilepsy were ranged from mild febrile seizures to severe epileptic encephalopathies. Most patients with GABRG2 variants who experienced seizures had a good prognosis. Valproate and levetiracetam were effective treatments for most patients.

ObjectiveThe aim of this study was to analyze the phenotypic spectrum, treatment, and prognosis of 72 Chinese children with SCN2A variants.MethodsThe SCN2A variants were detected by next-generation sequencing. All patients were followed up at a pediatric neurology clinic in our hospital or by telephone.ResultsIn 72 patients with SCN2A variants, the seizure onset age ranged from the first day of life to 2 years and 6 months. The epilepsy phenotypes included febrile seizures (plus) (n = 2), benign (familial) infantile epilepsy (n = 9), benign familial neonatal-infantile epilepsy (n = 3), benign neonatal epilepsy (n = 1), West syndrome (n = 16), Ohtahara syndrome (n = 15), epilepsy of infancy with migrating focal seizures (n = 2), Dravet syndrome (n = 1), early infantile epileptic encephalopathy (n = 15), and unclassifiable developmental and epileptic encephalopathy (n = 8). Approximately 79.2% (57/72) patients had varying degrees of developmental delay. All patients had abnormal MRI findings with developmental delay. 91.7% (55/60) patients with de novo SCN2A variants had development delay, while only 16.7% (2/12) patients with inherited SCN2A variants had abnormal development. 83.9% (26/31) SCN2A variants that were located in transmembrane regions of the protein were detected in patients with development delay. Approximately 69.2% (9/13) SCN2A variants detected in patients with normal development were located in the non-transmembrane regions. Approximately 54.2% (39/72) patients were seizure-free at a median age of 8 months. Oxcarbazepine has been used by 38 patients, and seizure-free was observed in 11 of them (11/38, 28.9%), while 6 patients had seizure worsening by oxcarbazepine. All 3 patients used oxcarbazepine and with seizure onset age > 1 year presented seizure exacerbation after taking oxcarbazepine. Valproate has been used by 53 patients, seizure-free was observed in 22.6% (12/53) of them.ConclusionThe phenotypic spectrum of SCN2A-related epilepsy was broad, ranging from benign epilepsy in neonate and infancy to severe epileptic encephalopathy. Oxcarbazepine and valproate were the most effective drugs in epilepsy patients with SCN2A variants. Sodium channel blockers often worsen seizures in patients with seizure onset beyond 1 year of age. Abnormal brain MRI findings and de novo variations were often related to poor prognosis. Most SCN2A variants located in transmembrane regions were related to patients with developmental delay.

Abstract Background Progressive myoclonic epilepsy (PME) is a group of neurodegenerative diseases with genetic heterogeneity and phenotypic similarities, and many cases remain unknown of the genetic causes. This study is aim to summarize the clinical features and study the genetic causes of PME patients. Methods Sanger sequencing of the target gene, Next Generation Sequencing (NGS) panels of epilepsy, trio-based Whole Exome Sequencing (WES) and detection of cytosine-adenine-guanine (CAG) repeat number were used to investigate the genetic causes of PME patients. Results Thirty-eight children with PME whose seizure onset age ranged from 3 months to 12 years were collected from February 2012 to November 2019 in three hospitals in Beijing, China. The seizure types included myoclonic seizures (n = 38), focal seizures (n = 19), generalized tonic-clonie seizure (GTCS) (n = 13), absence seizures (n = 4), atonic seizures (n = 3), epileptic spasms (n = 2) and tonic seizures (n = 1). Twenty-seven cases were sporadic and 11 had family members affected. Established PME-related genes were identified in 30 out of 38 (78.9%) patients who had either recessively inherited or de novo heterozygous mutations. Among these 30 cases, there were 12 cases (31.6%) of neuronal ceroid lipofuscinoses (the causing gene contains TPP1, PPT1, CLN5, CLN6 and MFSD8), two cases of sialidosis (the causing gene is NEU1), two cases of neuronopathic Gaucher disease (the causing gene is GBA), one case of spinal muscular atrophy-progressive myoclonic epilepsy (the causing gene is ASAH1), four cases of KCNC1 mutation-related PME, four cases of KCTD7 mutation-related PME, two cases of TBC1D24 mutation-related PME, one case of GOSR2 related PME, and two of dentatorubral-pallidoluysian atrophy (the causing gene is ATN1). In total, 13 PME genes were identified in our cohort. The etiology was not clear in eight patients. Conclusion PME is a group of clinically and genetically heterogeneous diseases. Genetic diagnosis was clear in 78.9% of PME patients. Various of genetic testing methods could increase the rate of genetic diagnosis. Neuronal ceroid lipofuscinoses (NCL) is the most common etiology of PME in children. Nearly one third PME children were diagnosed with NCL. GOSR2 related PME was in our cohort in Asia for the first time.

Abstract Studies in animal models of epilepsy and pre-surgical patients have unanimously found a strong correlation between high-frequency oscillations (HFOs, > 80 Hz) and the epileptogenic zone, suggesting that HFOs can be a potential biomarker of epileptogenicity and epileptogenesis. This consensus includes the definition and standard detection techniques of HFOs, the localizing value of pathological HFOs for epileptic foci, and different ways to distinguish physiological from epileptic HFOs. The latest clinical applications of HFOs in epilepsy and the related findings are also discussed. HFOs will advance our understanding of the pathophysiology of epilepsy.

Abstract Objective To summarize and extend the phenotypic characterization of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome, and to discuss genotype-phenotype correlations. Methods Collecting clinical information of 17 patients with pathogenic variants in PIGN, PIGA, and PIGT. Genetic studies were performed on all patients. Results There were 7 patients with 15 PIGN mutations (one patient carrying 3 mutations), 8 patients with 8 PIGA mutations, and 2 patients with 5 PIGT mutations (one patient carrying 3 mutations). All patients had epilepsy and developmental delay, with 71% of them showed hypotonia. And among these patients’ various seizure types, the focal seizure was the most common one. Eighty-two percent patients showed a significant relationship between seizures and fever. Serum ALP was elevated in one patient with PIGN mutations and in two patients with PIGA mutations. Brain MRI showed enlarged subarachnoid space in 56% of patients. Some other different characteristics had also been found in our patients: First, atypical absence seizures presented in three patients with PIGN mutations; Second, diffuse slow waves mixed with focal or multifocal discharges of interictal EEG in 88% cases with PIGA-deficient; Third, phenotypes of seven out of eight patients with PIGA mutations were difficult to be classified as severe or less severe group; Last, mild neurological symptoms and developmental status rather than severe conditions occurred in one patient with PIGT mutations. Conclusion With epilepsy, developmental delay, and/or hypotonia as common features, the knowledge of MCAHS in terms of phenotype and genotype has been expanded. In cases with PIGN-deficient, we expanded the types of atypical absence seizures, and described one patient with elevated serum ALP. Focal seizures with diffuse slow waves mixed with focal or multifocal discharges on EEG rather than infantile spasms with hypsarrhythmia, which as previously reported were often seen in our patients with PIGA mutations. The classifications of phenotypes caused by PIGA mutations should be more continuous than discrete. The mild phenotype of one patient with PIGT mutations expanded the clinical presentation of MCAHS3.

Objective: The DYNC1H1 gene is related to a variety of diseases, including spinal muscular atrophy with lower extremity–predominant 1, Charcot–Marie–Tooth disease type 2O, and mental retardation, autosomal dominant13 (MRD13). Some patients with DYNC1H1 variant also had epilepsy. This study aimed to detect DYNC1H1 variants in Chinese patients with infantile spasms (ISs).Methods: We reviewed clinical information, video electroencephalogram (V-EEG), and neuroimaging of a newly identified cohort of five patients with de novo DYNC1H1gene variants.Results: Five patients with four DYNC1H1variants from four families were included. All patients had epileptic spasms (ESs), the median age at seizure onset was 7.5 months (range from 5 months to 2 years 7 months), and the interictal V-EEG results were hypsarrhythmia. Four of five patients had brain magnetic resonance imaging (MRI) abnormalities. Four de novo DYNC1H1 variants were identified, including two novel variants (p.N1117K, p.M3405L) and two reported variants (p.R1962C, p.F1093S). As for the variant site, two variants are located in the tail domain, one variant is located in the motor domain, and one variant is located in the stalk domain. All patients had tried more than five kinds of antiepileptic drugs. One patient has been controlled well by vigabatrin (VGB) for 4 years, and another patient by VGB and steroids for 1.5 years. The other three patients still had frequent ESs. All patients had severe intellectual disability and development delays.Significance: IS was one of the phenotypes of DYNC1H1 variants. Most patients had non-specific brain MRI abnormality. Two of four DYNC1H1 variants were novel, expanding the variant spectrum. The IS phenotype was related to the variant's domains of DYNC1H1 variant sites. All patients were drug-refractory and showed development delays.

Background: Contactin 2, encoded by CNTN2 on chromosome 1q32.1, is a neural-specific glycoprotein and plays important roles in neurodevelopment. A deleterious homozygous variant in the CNTN2 gene was previously reported to cause autosomal recessive cortical myoclonic tremor and epilepsy. Since then, there has been no further report confirming the association of CNTN2 and epilepsy. Here, we reported one new case, who presented with epilepsy, carrying a novel homozygous frameshift variant in CNTN2. The clinical and genetic features of the patient were reviewed.Case presentation: The male patient presented with preschool age-of-onset neurodevelopmental impairment and focal seizures of temporal origin, and responded to valproate. A trio-whole exome sequencing revealed a novel homozygous frameshift variant in CNTN2 (c.2873_c.2874delCT, p.Thr958Thrfs). The patient’s mother was a heterozygous carrier while his father was wild-type; they were both unaffected and non-consanguineous. Further study revealed that maternal uniparental disomy (1q32.1) unmasked the heterozygous variant of CNTN2 in the proband.Conclusions: This case enhanced the gene–disease relationship between CNTN2 and epilepsy, which will help to further understand this emerging disorder.

The study aimed to review the clinical, radiological, and pathological findings and electroencephalogram (EEG) of pediatric epilepsy patients with temporal onset focal seizures induced by intermittent photic stimulation (IPS). Four patients with temporal onset photosensitivity focal seizures were analyzed. Three (75%) of the four patients were female. The average age of seizure-onset was 4.4 years. The interictal EEG showed both generalized and focal spike and waves in one patient and focal or multifocal spike and waves alone in three patients. Photoparoxysmal response (PPR) was evoked in all patients and showed generalized discharges (patients 2–4), both generalized and posterior discharges (patient 1). Both generalized and focal discharges could coexist in interictal discharges and PPR. The sensitive frequencies of PPR and photoconvulsive response (PCR) were 12–30 and 10–16 Hz, respectively, which were close to the occipital rhythm. In all patients, the onset of PCR was recorded, namely, the left anterior and mesial temporal lobe (TL), the left posterior TL, and the whole left TL, which showed two forms: the seizure of two patients was the onset of slow waves in the temporal area without spreading generalized discharges (patients 1 and 4), and the other one was fast rhythmic activities in the temporal area, spreading to the occipital area or gradually evolving into the generalized discharges (patients 2 and 3). During follow-up, except for patient 3 who had occasional seizures, the seizures of the remaining patients were under control. Temporal onset focal seizures could be induced by IPS. Temporal onset photosensitivity seizures were mostly easy to control with antiseizure drugs.

Objective:KCNT2 gene mutations had been described to cause developmental and epileptic encephalopathies (DEEs). In this study, we presented the detailed clinical features and genetic analysis of two unrelated patients carrying two de novo variants in KCNT2 and reviewed eight different cases available in publications.Methods: Likely pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Results: Our two unrelated patients were diagnosed with Ohtahara syndrome followed by infantile spasms (IS) and possibly the epilepsy of infancy with migrating focal seizures (EIMFS), respectively. They both manifested dysmorphic features with hirsute arms, thick hair, prominent eyebrows, long and thick eyelashes, a broad nasal tip, and short and smooth philtrum. In the eight patients reported previously, two was diagnosed with IS carrying a ‘change-of-function' mutation and a gain-of-function mutation, respectively, two with EIMFS-like carrying a gain-of-function mutation and a loss-of-function mutation, respectively, one with EIMFS carrying a loss-of-function mutation, three with DEE without functional analysis. Among them, two patients with gain-of-function mutations both exhibited dysmorphic features and presented epilepsy phenotype, which was similar to our patients.Conclusion: Overall, the most common phenotypes associated with KCNT2 mutation were IS and EIMFS. Epilepsy phenotype associated with gain- and loss-of-function mutations could overlap. Additional KCNT2 cases will help to make genotype-phenotype correlations clearer.

Epilepsy is one of the most common neurological disorders generally characterized by sudden and recurrent unprovoked seizures, which is commonly diagnosed through visual inspection of electroencephalography (EEG) signals. However, since EEG signals are highly complex, nonlinear and nonstationary in nature, both visual inspection and the existing computed aid detection approaches fail to capture the intrinsic dynamics of seizure events, leading to unsatisfactory detection performance. Therefore, an accurate computer-aided automatic epileptic seizure diagnosis system is valuable and urgently needed in clinical application. In this study, we propose an automatic classification method using nonlinear dynamics features and nonlinear classifiers for determining whether the EEG signals are in interictal or ictal activities, respectively. The main novelty of this paper is that investigating the performance of discernable entropy-based nonlinear dynamics features used for automatic diagnosis of an epileptic seizure. First, the discrete wavelet transform is applied to obtain de-noised and sub-band signals. Second, the nonlinear dynamics features are extracted based on information entropy theory. Subsequently, one-way analysis of variance and forward sequential feature selection technique are employed to identify the most explainable features for seizure detection. Then the selected features are fed to six different classifiers, namely, least square-support vector machine (LS-SVM), K-nearest neighbors, logistic regression, linear discriminant analysis, Naive Bayes classifier, and random forest, for automatic diagnosis of the epileptic seizure. Finally, a public EEG dataset from Bonn University, Germany, is utilized to investigate the performance of the proposed method. The experimental results show that the LS-SVM yields the optimal performance with an accuracy of 99.50%, a sensitivity of 100.00%, and a specificity of 99.40%. Our proposed method shows great potential for real-time diagnosis of the epileptic seizures, which can be deployed in hospitals to assist clinicians in accurate diagnosis of seizures.

This study aimed to analyze the genotypes and phenotypes of GNAO1 variants in a Chinese cohort. Seven male and four female patients with GNAO1 variants were enrolled, including siblings of brothers. Ten different GNAO1 variants (nine missense and one splicing site) were identified, among which six were novel. All the variants were confirmed to be de novo in peripheral blood DNA. Eight (73%, 8/11) patients had epilepsy; the seizure onset age ranged from 6 h after birth to 4 months (median age, 2.5 months). Focal seizures were observed in all eight patients, epileptic spasms occurred in six (75%, 6/8), tonic spasm in four (50%, 4/8), tonic seizures in two, atypical absence in one, and generalized tonic–clonic seizures in one. Seven patients had multiple seizure types. Eight (73%, 8/11) patients had movement disorders, seven of them having only dystonia, and one having dystonia with choreoathetosis. Varying degrees of developmental delay (DD) were present in all 11 patients. The phenotypes were diagnosed as early infantile epileptic encephalopathy (EIEE) in two (18%) patients, which were further diagnosed as West syndrome. Movement disorders (MD) with developmental delay were diagnosed in two (18%) brothers. EIEE and MD were overlapped in six (55%) patients, among which two were diagnosed with West syndrome, one with Ohtahara syndrome, and the other three with non-specific EIEE. One (9%) patient was diagnosed as DD alone. The onset age of GNAO1-related disorders was early infancy. The phenotypic spectrum of GNAO1 included EIEE, MD with DD, and DD alone.

ObjectiveTo describe the clinical characteristics of 12 patients from six families with pyridoxine-dependent epilepsy (PDE) carrying ALDH7A1 mutations, and analyze the impact of early diagnosis and treatment, as well as possible genotype–phenotype relationship.MethodsClinical and genetics data of 12 patients were collected.ResultsFamily 1–3 presented with symptoms in the neonatal period, while family 4-6 presented during early infancy. In the same family, the age of onset was similar. The focal motor seizure appeared in all patients. The affected identical twins from family 4 were diagnosed with infantile spasms. Mutation analysis identified nine different ALDH7A1 mutations among six families. The neurodevelopment of siblings in family 1 was mild delay and normal separately due to the minor difference of delayed diagnosis time. Siblings in family 2 showed severely delayed and normal development respectively due to the significant difference of a delayed diagnosis for 4 years. In family 5, although the difference of the delayed diagnosis time is up to 7 years, the nearly normal psychomotor development in both patients might be due to infrequent seizures before the delayed diagnosis. A severe phenotype exhibited in family 3, 4, and 6. The survived affected patients presented with severe developmental delay or refractory seizures and their twins or older sisters presented a similar clinical history and died in the early days of life. Mutation analysis showed D511N and IVS11 + 1G > A in family 3, V188A and exon1 deletion in family 4, and Y354C and exon 8–13 deletion in family 6.ConclusionPatients from the same family often have the same phenotype, including onset age and seizure type. Early treatment with pyridoxine and infrequent seizures showed positive relationship with prognosis. The deletion of exon 1 and exon 8–13 might be associated with the severe phenotype.

BackgroundRecently, the electroencephalogram pattern of electrical status epilepticus during sleep (ESES) had been reported in some genetic disorders, and most of them were noted with developmental and epileptic encephalopathy (DEE) or epileptic encephalopathy (EE). This study aimed to determine the genetic etiologies and clinical characteristics of ESES in DEE/EE.MethodsWe performed a cohort study in cases of DEE or EE with ESES. Tio-based genetic testing was performed in 74 cases and was analyzed to identify underlying variants.ResultsPathogenic or likely pathogenic variants were identified in 17/74 cases, including KCNQ2 (n = 6), KCNA2 (n = 5), GRIN2A (n = 3), SLC9A6 (n = 1), HIVEP2 (n = 1), and RARS2 (n = 1). Eleven were boys. The median age at seizure onset was 6 months. ESES occurred at the mean age of 2.0 ± 1.2 years, predominant in the Rolandic region in 14 years. Twelve of 17 cases had the first stage of different epilepsy preceding ESES: 2/12 were diagnosed as Ohtahara syndrome, 2/12 were diagnosed as infantile spasms, 3/12 were diagnosed as DEE, and 5/12 were diagnosed as EE without the epileptic syndrome.ConclusionMonogenic variants explained over 20% of DEE/EE with ESES. ESES could be an age-related feature in genetic disorders and occurred after the first stage of different epilepsy. Both age-related factors and genetic etiology were suggested to play a role in the occurrence of ESES in genetic DEE/EE.

Objective: To establish and broaden the phenotypic spectrum of secretory carrier membrane protein (SCAMP5) associated with epilepsy and neurodevelopmental delay.Methods: A Chinese patient was identified at the First Hospital of Peking University, and the three unrelated patients were recruited from two different countries (Italy and United States) through GeneMatcher. SCAMP5 pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Result: The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk. All four unrelated patients were found to have the same heterozygous pathogenic SCAMP5 de novo variant (p. Gly180Trp).Conclusion: Epilepsy, severe developmental delay, abnormal neurological exam findings, with or without ASD or variably dysmorphic features and were common in patients with SCAMP5 variant. The onset time and type of seizure varied greatly. The EEG and brain MRI findings were not consistent, but diverse and nonspecific. The motor ability of patients with heterozygous SCAMP5 variant might have a regressive course; language development was more severely affected.

Mutations in KCNA2 gene, encoding for the voltage-gated K+ channel Kv1.2, has been reported to be associated with epilepsy disorders. This channel is mainly expressed in the central nervous system and plays an important role in neuronal excitability and neurotransmitter release. Herein, we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells of an eight-year-old girl with epileptic encephalopathy and electrical status epilepticus during sleep carrying a mutation (c.1214C > T, p.Pro405Leu) in KCNA2. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro.

KCNA2 gene mutations were described to cause a new molecular entity within the developmental and epileptic or epileptic encephalopathies. Here, we firstly reported a patient with an unusual mosaicism for KCNA2, presenting two distinct mosaic missense mutations at the same loci. Clinical trio-based whole-exome sequencing using next-generation sequencing (NGS) revealed two novel mutations in KCNA2: c.1225A > T [p.(Ile409Phe)] and c.1225A > C [p.(Ile409Leu)]. Both missense mutations were in mosaic status and Sanger sequencing confirmed them as de novo. The affected 5-year-old girl presented as seizures with fever sensitivity, and mild cognitive and behavioral disorders. EEG showed focal centrotemporal epileptiform discharges accompanied by nocturnal focal seizures at the age of slightly older than 5 years, more likely carrying a loss-of-function mutation of KCNA2-related phenotype. Further NGS with a mean coverage of 6950 × showed 26% (mosaic mutation reads/total reads) of the c.1225A > T mutation and 23% of the c.1225A > C mutation. The sum of their allele fractions was close to 50%, approximately equal to a heterozygous variant. The patient had no seizures for 8 months on combination of levetiracetam (18.75 mg/kg/d) and valproate (20 mg/kg/d) till the last follow-up at the age of 5 years and 11 months. Our findings highlighted the two mosaic mutations responsible for the pathogenesis of KCNA2-related encephalopathy. The patient expanded the mutational spectrum of KCNA2-related encephalopathy and provided new insight into the complex genetic disorder.

Purpose: To evaluate the effects of a single oral dose of pyridoxine on lysine metabolites including α-aminoadipic semialdehyde (a-AASA), piperideine-6-carboxylate (P6C), the sum of AASA and P6C (AASA-P6C), pipecolic acid (PA), and α-aminoadipic acid (α-AAA) in PDE patients.Methods: The lysine metabolites of 15 patients with molecularly confirmed PDE were detected before and 4 h after taking a single oral dose of pyridoxine, respectively, using liquid chromatography-mass spectrometry (LC-MS/MS) method. Five types of samples were freshly prepared, including plasma, serum, dried blood spots (DBS), urine, and dried urine spots (DUS).Results: All the patients had been treated with long-term oral pyridoxine for several months to years, with doses of 30–360 mg/d. The concentrations of a-AASA, P6C, AASA-P6C, PA, and a-AAA before and after taking a single oral dose of pyridoxine for the same analyte detected in the same type of sample varied among patients. The mean concentrations increased in almost all the metabolites after taking an oral dose of pyridoxine, with or without statistical significance. Whereas, the metabolites concentrations might increase or decrease among different patients, or in different samples of the same patient, without a regular tendency. There was no statistical correlation between the concentrations before and after taking pyridoxine in the same type of sample for most metabolites.Conclusions: No obvious relationship between the metabolite levels or concentration differences and the age, pyridoxine dose (a single oral dose and long-term maintenance dose), duration of treatment, or neurodevelopmental phenotype was found at present study. The large individual differences among patients, probably affected by various genotypes, leading to quite different effects of pyridoxine on the change degree of metabolites concentrations. Our study suggested that long-term pyridoxine treatment could control seizures rather than getting toxic lysine metabolites such as a-AASA and P6C back to normal. In the future, more therapies should be focused to alleviate the metabolites accumulation and further improve the prognosis of PDE.

Biomaterials are complex composites with hierarchical structure and multi-function. The mechanical properties of biomaterials are often outstanding, especially considering their weak constituents. After evolving for millions of years to adapt to water surroundings, the diving beetles Cybister japonicus possess a pair of relatively large flattened hind legs which are optimized for sliding and rowing functions for swimming. In this paper, the morphology and microstructures of the hind leg biomaterial of Cybister japonicus are observed by scanning electron microscope (SEM). The nano-mechanical properties of the hind leg cuticle are measured with a nano-indentation system and the bending fracture stress is investigated by employing a multi-functional mechanical properties testing machine. The results of this study provide an appropriate biological pattern for the structural design of novel advanced lightweight composites with high specific strength.

Based on the non-Fourier heat conduction wave model, the thermal wave scattering near the opening in the platinum–rhodium glass fiber leaky plate structure is studied by using complex function method and conformal mapping method, and the general solution of the thermal wave scattering problem is given. The boundary condition of the open surface is adiabatic. The influence of the geometrical and physical parameters of the leaky plate on the temperature distribution in the plate is analyzed, and the numerical results of the temperature concentration are given. This study can provide theoretical basis and reference data for the design and optimization of the opening structure of platinum–rhodium glass fiber leaky plate.

Hypomyelinating disorders are a group of clinically and genetically heterogeneous diseases characterized by neurological deterioration with hypomyelination visible on brain MRI scans. This study was aimed to clarify the clinical and genetic features of HMDs in Chinese population.119 patients with hypomyelinating disorders in Chinese population were enrolled and evaluated based on their history, clinical manifestation, laboratory examinations, series of brain MRI with follow-up, genetic etiological tests including chromosomal analysis, multiplex ligation probe amplification, Sanger sequencing, targeted enrichment-based next-generation sequencing and whole exome sequencing.Clinical and genetic features of hypomyelinating disorders were revealed. Nine different hypomyelinating disorders were identified in 119 patients: Pelizaeus-Merzbacher disease (94, 79%), Pelizaeus-Merzbacher-like disease (10, 8%), hypomyelination with atrophy of the basal ganglia and cerebellum (3, 3%), GM1 gangliosidosis (5, 4%), GM2 gangliosidosis (3, 3%), trichothiodystrophy (1, 1%), Pol III-related leukodystrophy (1, 1%), hypomyelinating leukodystrophy type 9 (1, 1%), and chromosome 18q deletion syndrome (1, 1%). Of the sample, 94% (112/119) of the patients were genetically diagnosed, including 111 with mutations distributing across 9 genes including PLP1, GJC2, TUBB4A, GLB1, HEXA, HEXB, ERCC2, POLR3A, and RARS and 1 with mosaic chromosomal change of 46, XX,del(18)(q21.3)/46,XX,r(18)(p11.32q21.3)/45,XX,-18. Eighteen novel mutations were discovered. Mutations in POLR3A and RARS were first identified in Chinese patients with Pol III-related leukodystrophy and hypomyelinating leukodystrophy, respectively.This is the first report on clinical and genetic features of hypomyelinating disorders with a large sample of patients in Chinese population, identifying 18 novel mutations especially mutations in POLR3A and RARS in Chinese patients, expanding clinical and genetic spectrums of hypomyelinating disorders.

Objective. Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA) that leads to severe physiologic and developmental problems. Our study is aimed at elucidating the clinical and genetic characteristics of Chinese MLD patients. Methods. Clinical data of 21 MLD patients was collected. All coding exons of ARSA and their flanking intronic sequences were amplified by polymerase chain reaction and subjected to direct sequencing. Results. All 21 patients were diagnosed with MLD clinically and genetically, out of which 17 patients were late infantile and 4 were juvenile types. A total of 34 ARSA mutations, including 28 novel mutations (22 missense, 1 splicing, 1 nonsense, 3 small insertions, and 1 small deletion mutation) and 6 known mutations (5 missense and 1 small insertion mutation), were identified. Prenatal diagnosis was performed for four pedigrees. One fetus was a patient, two fetuses were carriers, and two were wild type. Conclusions. The present study discovered 28 novel ARSA mutations and widely expanded the mutation spectrum of ARSA. Four successful prenatal diagnoses provided critical information for MLD families.

Botnets are a common and serious threat to the Internet. The search for the infected nodes of a P2P botnet is affected by the number of commonly connected nodes, with a lower detection accuracy rate for cases with fewer commonly connected nodes. However, this paper calculates the Mahalanobis distance—which can express correlations between data—between indirectly connected nodes through traffic with commonly connected nodes, and establishes a relationship evaluation model among nodes. An iterative algorithm is used to obtain the correlation coefficient between the nodes, and the threshold is set to detect P2P botnets. The experimental results show that this method can effectively detect P2P botnets with an accuracy of >85% when the correlation coefficient is high, even in cases with fewer commonly connected nodes.

A DDoS (Distributed Denial of Service) attack makes use of a botnet to launch attacks and cause node congestion of wireless sensor networks, which is a common and serious threat. Due to the various kinds of features required in a Peer-to-Peer (P2P) botnet for DDoS attack detection via current machine learning methods and the failure to effectively detect encrypted botnets, this paper extracts the data packet size and the symmetric intervals in flow according to the concept of graphic symmetry. Combined with flow information entropy and session features, the frequency domain features can be sorted so as to obtain features with better correlations, which solves the problem of multiple types of features required for detection. Information entropy corresponding to the flow size can distinguish an encrypted botnet. This method is implemented through machine learning techniques. Experimental results show that the proposed method can detect the P2P botnet for DDoS attack and the detection accuracy is higher than that of traditional feature detection.

To improve the low acceptance ratio and revenue to cost ratio caused by the poor match between the virtual nodes and the physical nodes in the existing virtual network embedding (VNE) algorithms, we established a multi-objective optimization integer linear programming model for the VNE problem, and proposed a novel two-stage virtual network embedding algorithm based on topology potential (VNE-TP). In the node embedding stage, the field theory once used for data clustering was introduced and a node embedding function designed to find the optimal physical node. In the link embedding stage, both the available bandwidth and hops of the candidate paths were considered, and a path embedding function designed to find the optimal path. Extensive simulation results show that the proposed algorithm outperforms other existing algorithms in terms of acceptance ratio and revenue to cost ratio.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that causes seizures in neonates and infants. Mutations of the ALDH7A1 gene are now recognized as the molecular basis PDE and help to define this disease. Three Chinese children with PDE were clinically analyzed, followed by treatment and examination of the ALDH7A1 mutations. The seizures of the 3 patients were all resistant to multiple anticonvulsants (2 to 7 types). For case 1, onset of seizures was at the age of 2 months. His seizures were well controlled by intravenous pyridoxine for several days at the age of 3 months 20 days and recurred at intervals of 13, 14 and 38 days after pyridoxine withdrawn for 3 times. At the age of 7 months, symptoms of PDE appeared and uninterrupted oral pyridoxine started. For case 2, her seizures occurred at 8 days after birth. After administration of multiple antiepileptic drugs observed ineffective, high-dose pyridoxine continuous therapy was taken at the age of 10 months and the significant treatment effect induced a diagnostic PDE. Seizure onset in case 3 was at the first day of birth. He experienced inadvertently pyridoxine therapy several times (first time at 2 days after birth) and achieved good therapeutic effect, which was confirmed by physicians until 4 months 10 days. The treatment process in our 3 patients suggested that pyridoxine should be early and purposefully used in patients with early onset seizures. ALDH7A1 gene mutation analysis revealed compound heterozygous mutations in each case: heterozygous c.410G>A (p.G137E) and IVS11+1G>A in case 1, heterozygous c.952G>C (p.A318P) and heterozygous c.965C>T (p.A322V) in case 2, and heterozygous c.902A>T (p.N301I) and IVS11+1G>A in case 3. Only p.N301I was reported previously, all other mutations were novel. This is the first time to report cases of Chinese patients diagnosed with PDE by molecular genetic analysis.

Background electroencephalography (EEG), recorded with scalp electrodes, in children with electrical status epilepticus during slow-wave sleep (ESES) syndrome and control subjects has been analyzed. We considered 10 ESES patients, all right-handed and aged 3–9 years. The 10 control individuals had the same characteristics of the ESES ones but presented a normal EEG. Recordings were undertaken in the awake and relaxed states with their eyes open. The complexity of background EEG was evaluated using the permutation entropy (PE) and sample entropy (SampEn) in combination with the ANOVA test. It can be seen that the entropy measures of EEG are significantly different between the ESES patients and normal control subjects. Then, a classification framework based on entropy measures and adaptive neuro-fuzzy inference system (ANFIS) classifier is proposed to distinguish ESES and normal EEG signals. The results are promising and a classification accuracy of about 89% is achieved.

Background PHACTR1 (phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. This study aimed to expand the genotype and phenotype of patients with de novo variants in PHACTR1 and analyse the impact of variants on protein-protein interaction. Methods We identified seven patients with PHACTR1 variants by trio-based whole-exome sequencing. Additional two subjects were ascertained from two centres through GeneMatcher. The genotype-phenotype correlation was determined, and AlphaFold-Multimer was used to predict protein-protein interactions and interfaces. Results Eight individuals carried missense variants and one had CNV in the PHACTR1. Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients with missense variants of PHACTR1. They could present with other types of seizures and often exhibit drug-resistant epilepsy with a poor prognosis. One patient with CNV displayed a developmental encephalopathy phenotype. Using AlphaFold-Multimer, our findings indicate that PHACTR1 and G-actin-binding sequences overlap with PPP1CA at the RPEL3 domain, which suggests possible competition between PPP1CA and G-actin for binding to PHACTR1 through a similar polymerisation interface. In addition, patients carrying missense variants located at the PHACTR1-PPP1CA or PHACTR1-G-actin interfaces consistently exhibit the IESS phenotype. These missense variants are mostly concentrated in the overlapping sequence (RPEL3 domain). Conclusions Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to IESS. Moreover, our study confirmed that the variants affect the binding of PHACTR1 to G-actin or PPP1CA, resulting in neurological disorders in patients. [ABSTRACT FROM AUTHOR]