[Electroencephalogram characteristics of 26 children with febrile infection-related epilepsy syndrome]. / 26ä¾‹å„¿ç«¥å‘çƒ­æ„ŸæŸ“ç›¸å ³æ€§ç™«ç—«ç»¼åˆå¾çš„è„‘ç”µå›¾åˆ†æž.

OBJECTIVES: To investigate the electroencephalogram (EEG) characteristics and progression of febrile infection-related epilepsy syndrome (FIRES) in children, aiming to enhance diagnosis and treatment approaches. METHODS: A retrospective analysis was conducted on 26 children with FIRES between May 2017 and December 2021. RESULTS: All 26 children (100%) presented with fever at the onset, followed by frequent convulsions that rapidly progressed into convulsive status. Ventilator support was required for 22 cases (85%). During the acute phase, EEG features demonstrated the disappearance of background activity and physiological sleep cycles in all children. Diffuse slow waves and multifocal slow spike slow waves were observed as abnormal waves during the interictal period. A characteristic pattern of focal low amplitude fast wave initiation was detected in all children during seizure episodes. In the chronic phase, the background EEG activity gradually recovered, and the presence of abnormal waves was relatively limited. The characteristic pattern of focal slow wave rhythm initiation was evident during seizure episodes. Additionally, extreme δ brushes were observed in four cases (15%). CONCLUSIONS: These findings suggest that EEG manifestations in children with FIRES exhibit distinctive patterns during the acute and chronic stages, providing significant value for early diagnosis and clinical staging. Extreme δ brushes may be one of the distinctive markers of children with FIRES.

[Clinical effect of tacrolimus in the treatment of myasthenia gravis in children].

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus in the treatment of children with myasthenia gravis (MG). METHODS: A total of 28 children with MG were treated with tacrolimus. MG-Activities of Daily Living (MG-ADL) scale was used to assess clinical outcome and safety after 1, 3, 6, 9, and 12 months of treatment. RESULTS: After tacrolimus treatment, the MG-ADL score at 1, 3, 6, 9 and 12 months was lower than that at baseline (P<0.05), and the MG-ADL score showed a gradually decreasing trend. The response rates to tacrolimus treatment at 1, 3, 6, 9, and 12 months were 59%, 81%, 84%, 88%, and 88% respectively. At 6, 9, 12, and 18 months of treatment, 4, 13, 14, and 15 children respectively were withdrawn from prednisone. No recurrence was observed during treatment. Major adverse reactions/events were asymptomatic reduction in blood magnesium in 5 children and positive urine occult blood in 1 child, which turned negative without special treatment, and tacrolimus was not stopped due to such adverse reactions/events. One child was withdrawn from tacrolimus due to recurrent vomiting. According to CYP3A5 genotypes, all of the patients were divided into two groups: slow metabolic type (n=19) and non-slow metabolic type (fast metabolic type + intermediate type; n=9). The non-slow metabolism group received a higher dose of tacrolimus, but had a lower trough concentration of tacrolimus than the slow metabolism group (P<0.05). The slow metabolism group had a higher response rates to tacrolimus treatment than the non-slow metabolism group (P<0.05). CONCLUSIONS: Tacrolimus appears to be effective and safe in the treatment of children with MG and is thus an option for immunosuppressive therapy. CYP3A5 genotyping has a certain guiding significance for determining the dosage of tacrolimus.

Acute autonomic neuropathy with severe gastrointestinal symptoms in children: a case series.

BACKGROUND: Acute autonomic neuropathy (AAN) is rare disorder with anecdotal report, especially for childhood onset patients. Misdiagnosis or delays in treatment can always be found in clinical practice. We conducted this study to give a description of the manifestations and treatment of AAN in children and therefore help clinicians to make the accurate diagnosis early so that the prognosis of the patients can be improved. METHODS: A systematic record from 3 clinical centers was used to identify 11 subject, 3 males and 8 females, with clinical diagnosed AAN. RESULT: The age ranged from 2 years and 4 months to 14 years and 6 months (mean, 9 ± 3.6 years old) and the course from onset to diagnosis ranged from 7 days to 8 months. All children shared prominent initial symptoms, 7 with frequent vomiting and 4 with motor dysfunctions. The condition of 9 patients improved after treatment of IVIg and intravenous glucocorticoid. CONCLUSION: The clinical manifestations of AAN are diverse, generalized, and non-specific. Gastrointestinal disorders were the most common initial symptoms. Symptoms of gastrointestinal system and abnormal secretion of glands were severe and more common than other symptoms. The mechanism of AAN remains unknown. Although IVIg and intravenous glucocorticoid can be used in clinical practice, there is still no treatment recommendation and further study is needed.

Screening for differentially expressed genes in endophytic fungus strain 39 during co-culture with herbal extract of its host Dioscorea nipponica Makino.

Strain 39 is an endophytic fungus which was isolated from Dioscorea nipponica Makino (DNM). After Strain 39 co-cultured with ethanol extract of DNM rhizomes for several days, the content of saponins in this culture mixture would be obviously increased. To analyze the mechanism of this microbial transformation, we used the differential display reverse transcription polymerase chain reaction (DDRT-PCR) method to compare the transcriptomes between Strain 39 cultured in normal PD medium and in PD medium which added ethanol extract of DNM rhizomes. We amplified 29 DDRT-PCR bands using 12 primer combinations of three anchored primers and five random primers, and six bands were re-amplified. Analysis of real-time PCR and sequence alignment showed that three clones were up-regulated in sample group: squalene epoxidase, squalene synthase, and catalase, one clone was expressed only in sample group. The possible roles and origins of the above genes were discussed, and the molecular mechanism of Strain 39 biotransformation was speculated. This study is the first report of the molecular biotransformation mechanism of saponins production by endophytic fungus of DNM.

Retrospective analysis of the effectiveness of first-line antiepileptic drugs for generalized onset and unclassified epileptic seizures in Chinese children.

BACKGROUND AND PURPOSE: Based on the time until treatment failure, we retrospectively analyzed 389 children to compare the long-term effectiveness of first-line antiepileptic drugs (AEDs) in children with generalized onset or unclassified epileptic seizures. METHODS: Analyses were based on time until treatment failure and time until remission. RESULTS: In terms of time until treatment failure, the failure rates of topiramate and carbamazepine were higher than that of sodium valproate (p < 0.05). For time until 1-year remission, sodium valproate was found to be significantly better than either topiramate or carbamazepine (p < 0.05). For the subgroup with generalized onset epilepsy, sodium valproate was much better than either topiramate or carbamazepine (p < 0.05). No significant differences were found between topiramate and carbamazepine (p = 0.319). For unclassified epileptic seizures, no significant differences were found among the three AEDs. CONCLUSION: Sodium valproate should be the drug of choice for patients with children with generalized onset, and no significant differences were found among the three AEDs in unclassified epileptic seizures.

Neurologic Manifestations as Initial Clinical Presentation of Familial Hemophagocytic Lymphohistiocytosis Type2 Due to PRF1 Mutation in Chinese Pediatric Patients.

Familial hemophagocytic lymphohistiocytosis Type 2 (FHL2) associated central nervous system (CNS) involvement is less understood in children, especially when considering neurologic manifestations as part of the initial presentation. We conducted a retrospective review of the clinical manifestations and genetic abnormality of four Han Chinese children with FHL2 who were patients at the neurology department of Beijing Children's Hospital from November 2015 to October 2018. These four patients initially manifested CNS symptoms in their disease presentation, and all four patients were misdiagnosed as having ademyelinating disease, such as acute disseminated encephalomyelitis and multiple sclerosis. Given these misdiagnoses, it is important that general physicians and pediatricians maintain awareness of the possibility of FHL2 as a differential diagnosis. These four cases included neurologic manifestations including seizures, ataxia, spasticity, gait disorder, and coma. Bilateral abnormal signals in the cerebrum, including in white matter, gray matter, and junctions were discovered. Enhanced magnetic resonance imaging (MRI) in these patients showed spot or ring enhancement and/or hemorrhage. These patients all possessed a compound heterozygote mutation PRF1 gene. Whole exome sequencing analysis revealed seven different mutations (three novel mutations) spread over the PRF1 gene and a heterozygous missense mutation c.1349C > T [p.T450M] that was present in two patients. Three novel mutations, c.634T > C[p.Y212H], c.1083_1094del[p.361_364del], and c.1306G > T [p.D436Y], were discovered and through in silico analysis were discovered to be deleterious. Neurologic manifestations were the initial symptoms of FHL2 in these patients in addition to the expected leukopenia and hepatosplenomegaly. Whole exome sequencing of PRF1 for patients with similar presentations would facilitate prompt and accurate diagnosis and treatment.

Clinical phenotypes, genotypes and treatment in Chinese dystonia patients with KMT2B variants.

BACKGROUND: KMT2B-related dystonia is a recently discovered hereditary dystonia that mostly occurs in childhood. This dystonia usually progresses to generalized dystonia with cervical, cranial, pharynx and larynx involvement. Our study summarizes genotype-phenotype features and deep brain stimulation (DBS) efficacy observed with KMT2B-related dystonia patients in China. METHODS: We identified 20 patients with KMT2B variations from dystonia samples with a gene panel and whole exome sequencing. Genetic, clinical and treatment analyses of these patients with KMT2B mutations were further conducted. RESULTS: We summarized the genotype and phenotypic characteristics of KMT2B-related patients in China, including 16 sporadic patients and 3 pedigrees (including 4 patients). Thirty-five percent (7/20) of patients had been published previously. The age of onset was between 1 month and 24 years (average 6.90 ± 5.72 years). Sixty-five percent (13/20) of patients had onset from lower limbs. Upper limbs or larynx accounted for 15% (3/20) and 20% (4/20) of patients, respectively. In the same family, male patients tended to have more severe symptoms than female patients. Carriers of KMT2B variants may present with nonmotor symptoms without dystonia. Abnormal endocrine metabolism could also be seen in our patients, including advanced bone age that had never been reported previously. Nine of our patients underwent DBS surgery. The mean follow-up time was 4.9 (range 1.3-16) months after DBS, and perceptible improvement of clinical symptoms were observed. CONCLUSIONS: The genotypic and phenotypic spectra of Chinese KMT2B-related dystonia patients were further expanded. DBS surgery might be the preferred option for severe KMT2B-related dystonia patients till now.

Next-Generation Sequencing Analysis Reveals Novel Pathogenic Variants in Four Chinese Siblings With Late-Infantile Neuronal Ceroid Lipofuscinosis.

Neuronal Ceroid Lipofuscinoses (NCLs) are progressive degenerative diseases mainly affect brain and retina. They are characterized by accumulation of autofluorescent storage material, mitochondrial ATPase subunit C, or sphingolipid activator proteins A and D in lysosomes of most cells. Heterogenous storage material in NCLs is not completely disease-specific. Most of CLN proteins and their natural substrates are not well-characterized. Studies have suggested variants of Late-Infantile NCLs (LINCLs) include the major type CLN2 and minor types CLN5, CLN6, CLN7, and CLN8. Therefore, combination of clinical and molecular analysis has become a more effective diagnosis method. We studied 4 late-infantile NCL siblings characterized by seizures, ataxia as early symptoms, followed by progressive regression in intelligence and behavior, but mutations are located in different genes. Symptoms and progression of 4 types of LINCLs are compared. Pathology of LINCLs is also discussed. We performed Nest-Generation Sequencing on these phenotypically similar families. Three novel variants c.1551+1insTGAT in TPP1, c.244G>T in CLN6, c.554-5A>G in MFSD8 were identified. Potential outcome of the mutations in structure and function of proteins are studied. In addition, we observed some common and unique clinical features of Chinese LINCL patient as compared with those of Western patients, which greatly improved our understanding of the LINCLs.

The improvement of bioactive secondary metabolites accumulation in Rumex gmelini Turcz through co-culture with endophytic fungi.

Aspergillus sp., Fusarium sp., and Ramularia sp. were endophytic fungi isolated from Rumex gmelini Turcz (RGT), all of these three strains could produce some similar bioactive secondary metabolites of their host. However the ability to produce active components degraded significantly after cultured these fungi alone for a long time, and were difficult to recover. In order to obtain more bioactive secondary metabolites, the co-culture of tissue culture seedlings of RGT and its endophytic fungi were established respectively, and RGT seedling was selected as producer. Among these fungi, Aspergillus sp. showed the most significant enhancement on bioactive components accumulation in RGT seedlings. When inoculated Aspergillus sp. spores into media of RGT seedlings that had taken root for 20d, and made spore concentration in co-culture medium was 1×104mL-1, after co-cultured for 12d, the yield of chrysophaein, resveratrol, chrysophanol, emodin and physcion were 3.52-, 3.70-, 3.60-, 4.25-, 3.85-fold of the control group. The extreme value of musizin yield was 0.289mg, which was not detected in the control groups. The results indicated that co-culture with endophytic fungi could significantly enhance bioactive secondary metabolites production of RGT seedlings.

Phenotype-Driven Virtual Panel Is an Effective Method to Analyze WES Data of Neurological Disease.

Objective: Whole Exome Sequencing (WES) is an effective diagnostic method for complicated and multi-system involved rare diseases. However, annotation and analysis of the WES result, especially for single case analysis still remain a challenge. Here, we introduce a method called phenotype-driven designing "virtual panel" to simplify the procedure and assess the diagnostic rate of this method. Methods: WES was performed in samples of 30 patients, core phenotypes of probands were then extracted and inputted into an in-house software, "Mingjian" to calculate and generate associated gene list of a virtual panel. Mingjian is a self-updating genetic disease computer supportive diagnostic system that based on the databases of HPO, OMIM, HGMD. The virtual panel that generated by Mingjian system was then used to filter and annotate candidate mutations. Sanger sequencing and co-segregation analysis among the family were then used to confirm the filtered mutants. Result: We first used phenotype-driven designing "virtual panel" to analyze the WES data of a patient whose core phenotypes are ataxia, seizures, esotropia, puberty and gonadal disorders, and global developmental delay. Two mutations, c.430T > C and c.640G > C in PMM2 were identified by this method. This result was also confirmed by Sanger sequencing among the family. The same analysing method was then used in the annotation of WES data of other 29 neurological rare disease patients. The diagnostic rate was 65.52%, which is significantly higher than the diagnostic rate before. Conclusion: Phenotype-driven designing virtual panel could achieve low-cost individualized analysis. This method may decrease the time-cost of annotation, increase the diagnostic efficiency and the diagnostic rate.

The improvement of bioactive secondary metabolites accumulation in Rumex gmelini Turcz through co-culture with endophytic fungi

Abstract Aspergillus sp., Fusarium sp., and Ramularia sp. were endophytic fungi isolated from Rumex gmelini Turcz (RGT), all of these three strains could produce some similar bioactive secondary metabolites of their host. However the ability to produce active components degraded significantly after cultured these fungi alone for a long time, and were difficult to recover. In order to obtain more bioactive secondary metabolites, the co-culture of tissue culture seedlings of RGT and its endophytic fungi were established respectively, and RGT seedling was selected as producer. Among these fungi, Aspergillus sp. showed the most significant enhancement on bioactive components accumulation in RGT seedlings. When inoculated Aspergillus sp. spores into media of RGT seedlings that had taken root for 20 d, and made spore concentration in co-culture medium was 1 × 104 mL-1, after co-cultured for 12 d, the yield of chrysophaein, resveratrol, chrysophanol, emodin and physcion were 3.52-, 3.70-, 3.60-, 4.25-, 3.85-fold of the control group. The extreme value of musizin yield was 0.289 mg, which was not detected in the control groups. The results indicated that co-culture with endophytic fungi could significantly enhance bioactive secondary metabolites production of RGT seedlings.

[Anti-N-methyl-D-aspartate receptor encephalitis in seven children].

OBJECTIVE: To study the clinical and laboratory features and diagnosis of the patient with anti-N-methyl-D-aspartate receptor(NMDAR)encephalitis in children. METHOD: The data of clinical feature, laboratory findings, and radiological manifestation were reviewed and analyzed. RESULT: Of the 7 patients, 4 were female and 3 were male. The age of onset was from 6.6 to 15.5 years (average 9.5 years). The onset of 4 cases started with convulsion. Six cases had seizures which was difficult to control by antiepileptic drugs. All patients had psychiatric symptoms and speech disorder. Six cases had different levels of decreased consciousness and dyskinesias. 6 cases had autonomic nerve instability, and 7 cases developed sleep disorders. The results of MRI examination were normal in all patients. The EEG of most patients showed focal or diffuse slow waves. Six cases had oligoclonal bands. All cases were confirmed to have the disease by detection of anti-NMDA receptor antibodies. No tumor was detected in any of the patients. All patients received immunotherapy. CONCLUSION: Anti-NMDAR encephalitis is a severe but treatable disorder that frequently affects children and adolescents. Pediatric patients had clinical manifestations similar to those of adult patients. But children have a lower incidence of tumors and hypoventilation also occurs less frequently in children. Most of children had a good prognosis.

[Follow-up study on the clinical characteristics and treatment effect of the different types of Guillain-Barré syndrome in children].

OBJECTIVE: To study the clinical characteristics and effects of immunoglobulin treatment in children with the different types of Guillain-Barré syndrome (GBS). METHOD: Data of 108 patients hospitalized for GBS were retrospectively analyzed; 75 cases in this group were given acute high dose of gamma globulin (IVIG) 400 mg/(kg·d) intravenously for 5 d. Clinical and electrophysiological data and information on treatment and recovery of the children were collected during the follow-up and were analyzed. RESULT: According to the clinical and electrophysiologic findings, 32 patients manifested acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 34 had acute motor axonal neuropathy (AMAN), 3 had acute motor and sensory axonal neuropathy (AMSAN), 4 were inexcitable, 2 were unclassified. The clinical progress of the AMAN was faster than the AIDP group. Except for sensory nerve involvement, there was no significant difference in the clinical feature and severity. The mean time of the muscle strength began to recover was (5.59±3.63) days in the AIDP group and (7.21±4.68) days in the AMAN group after IVIG treatment. The time of the AIDP group was shorter than the AMAN group, but the difference was not statistically significant (t=-1.5702, P>0.05). The mean time of the muscle strength increased one grade was (8.88±4.39) days in the AIDP group and (12.67±8.35) days in the AMAN group. The difference was statistically significant (t=-2.3689, P<0.05). No patients in this group died. Follow-up data showed that the complete recovery time was not significantly different (t=0.2041, P>0.05). CONCLUSION: The clinical progress of the AMAN was faster than the AIDP group. Besides sensory nerve involvement, there was no significant difference in the clinical feature and severity. The AIDP group's clinical recovery was faster than AMAN's after the immunoglobulin treatment. The two groups were not significantly different in long-term prognosis.

[Clinical characteristics and diagnosis of acute pandysautonomia in childhood].

OBJECTIVE: To summarize the clinical characteristics of acute pandysautonomia in childhood, to gain better understanding of the diagnosis and differential diagnosis. METHODS: The clinical data of 6 children with acute pandysautonomia were analyzed and followed-up. All the 6 patients had routine blood and cerebrospinal fluid (CSF), electrocardiography (ECG), electromyography (EMG), cranial magnetic resonance imaging (MRI) and autonomic nerve function tests (head upright tilt test, dermatography test, and thermal/sympathetic sweat response). Other laboratory examinations such as immunologic markers of CSF, electroencephalography (EEG), spinal cord MRI and somatosensory evoked potential (SEP) were also performed in some patients. RESULTS: Of the 6 patients, 1 was male, and 5 were female. The age of onset was from 2.3 to 14.5 years (average 8.2 years). The initial symptoms were gastrointestinal dysfunction in 3 patients and somatic motor dysfunction as their initial symptoms, one had irritability in 1 case, pain in 1 and dysphagia in 1, respectively. Autonomic nerve signs and symptoms: (1) Skin and mucosa are rough and dry, there was no or little perspiration, alacrimia or little tear in all patients. (2) Vision problem appeared in 1 patient, blepharoptosis in 3 patients, pupillary abnormality existed in all patients. (3) Gastrointestinal symptoms were present in all patients. Vomiting and constipation were present in 4 patients, diarrhea and constipation were alternatively present in 1 patient, abdominal distention and abdominal pain were present in 2 patients. (4) Cardiovascular system manifestations included postural dizziness or syncope in 3 patients, tightness and palpitation in 2 patients. (5) Urinary dysfunction was present in 4 patients. In addition, mild to moderate somatic motor dysfunction was present in 5 patients, sensory dysfunction in 3 patients. Autonomic nerve function tests were abnormal in all patients. Laboratory findings included serum IgM antibody to herpes simplex virus and antistreptolysin "O" (ASO) test were positive respectively in 1 patient. The immunological markers in CSF were abnormal in 3 patients and the protein level in CSF was slightly elevated in 3 patients. Cranial MRI was slightly abnormal in 4 patients. ECG was slightly abnormal in all patients. EMG was abnormal in 5 patients. SEP was abnormal in 3 patients. Five patients received IVIG therapy. Five patients were followed-up. One patient died, one lost to follow up and one had slight improvement. Significant improvement was seen in 2 patients. CONCLUSION: Acute pandysautonomia in children usually had non-specific symptoms and could affect multiple organs. Heterotropia, cardiovascular dysfunction and gastrointestinal dysfunction were commonly seen in these patients. In acute pandysautonomia patients, IVIG seemed to be effective and the prognosis was poor in severe cases.

Effectiveness of the first antiepileptic drug in the treatment of pediatric epilepsy.

Most previous studies on the effectiveness of the first antiepileptic drug have dealt with adults. The present retrospective study of 520 patients was designed to investigate the interaction among efficacy, tolerability, and overall effectiveness of the first antiepileptic drug in children with newly diagnosed epilepsy. A total of 344 patients became seizure-free with the first prescribed antiepileptic drug. A lower proportion of patients with symptomatic epilepsy (60.3%) or cryptogenic epilepsy (61.5%) became seizure-free, compared with patients with idiopathic epilepsy (73.8%), and more patients with symptomatic or cryptogenic epilepsy changed their treatments owing to intolerable side effects. Most patients (95.6%) received sodium valproate (n = 234), topiramate (n = 143), or carbamazepine (n = 120). The majority of seizure-free patients required only a moderate daily dose. Patients who took carbamazepine (16.7%) or topiramate (11.9%) had a higher incidence of adverse events, necessitating a change of treatment, compared with patients treated with valproate (4.3%), and fewer of them became seizure-free. Overall, 66.2% of the patients became seizure-free with the first-ever antiepileptic drug, and most of them at a moderate dose. Moreover, tolerability was as important as efficacy in determining overall effectiveness.

[Diagnosis of childhood narcolepsy and significance of HLA in its diagnosis].

OBJECTIVE: Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, and features of rapid eye movement (REM) sleep, such as cataplexy, sleep paralysis and hypnagogic hallucinations. The present study aimed to investigate the diagnostic basis of childhood narcolepsy and possible role of HLA Class II alleles in the onset of this disease. METHODS: The clinical data of 40 narcoleptic children were analyzed. All patients received Multiple Sleep Latency Test (MSLT) and they were analyzed in combination with clinical features. Polymerase chain reaction/sequence specific primers (PCR/SSP) methods were used to detect the HLA-DRB1 and DQB1 alleles. RESULTS: Narcolepsy was diagnosed in 40 children. The age range was 3 to 14 years (mean 8.5 +/- 2.5 years), 29 were male and 11 female. Their mean course of disease was 6.5 months, 14 patients (30%) were less than 3 months old, 21 patients (52%) were less than 6 months old. All the patients had excessive daytime sleepiness, cataplexy appeared in 37 cases, hypnagogic hallucination in 22 and sleep paralysis in 6. Mean sleep latency on MSLT was less than 5 min, the average number of sleep-onset rapid eye movement (SOREM) was 4.33 +/- 0.26 episodes (2-5 episodes), the latency of SOREM episodes were 4.0 +/- 1.8 min (0.25-4.9 min). Thirty-five patients were DRB1 1501 and DQB1 0602 positive (Pc < 0.01), 2 were DRB1 1502 and DQB1 0601 positive, while 3 were DRB1 15 and DQB1 6 negative. CONCLUSIONS: Some pediatric patients with narcolepsy were different from adult patients in that the pediatric cases had a sudden onset and shorter disease course. Diagnosis of this disease was based on the clinical manifestations, MSLT and absence of any medical or psychiatric disorder that could account for the symptoms. The authors demonstrated that DRB1 1501 and DQB1 0602 were susceptibility genes for narcolepsy and those who were DRB1 15 negative could not be excluded.