[Advances of research on childhood brain development diseases--from what we know about Rett syndrome].
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Biomedical Research↗
Biomedical subjects
Xi-ru Wu
Publications and source records attributed to Xi-ru Wu.
[Research progress on congenital muscular dystrophy].
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Humans↗
[Protection of interleukin-1 receptor antagonist on epileptiform discharges induced by magnesium-free treatment in developing rat cortical neurons].
OBJECTIVE: To study the protection of IL-1ra in cultured developing neuron injury following Mg(2+)-free-induced epileptiform discharges. METHODS: Rat embryo cortical neurons cultured for 6 d and 17 d were directly exposed to Mg(2+)-free media, or pretreated with IL-1 receptor antagonist or NMDA receptor antagonists before being exposed to Mg(2+)-free media, and then returned to regular media.MTT assay was used to study mitochondrial function injury, laser-scanning confocal microscope to measure [Ca(2+)]i, and real-time RT-PCR to detect gene mRNA expression. RESULTS: (1) MTT conversion rates were higher in neurons pre and co treated with 10 mg/L IL-1ra than those of neurons with only Mg(2+)-free treatment in neurons cultured for 17 d, but not in neurons cultured for 6 d.(2) [Ca(2+)]i was lower in neurons pre and co-treated with 10 mg/L IL-1ra than those of neurons with only Mg(2+)-free treatment, either in neurons cultured for 6 d or in neurons cultured for 17 d, and the effects of IL-1ra on [Ca(2+)]i change were different between neurons cultured for 6 d and neurons cultured for 17 d.(3) Pre and co-treated with 10 mg/L IL-1ra NR1 mRNA expression increase induced by Mg(2+)-free treatment was decreased, either in neurons cultured for 6 d or neurons cultured for 17 d, and this effect showed no difference between neurons cultured for 6 d and 17 d; Pre and co-treated with 10 mg/L IL-1ra NR2A mRNA expression increase induced by Mg(2+)-free treatment in neurons cultured for 17 d was decreased, and NR2A mRNA expression showed no difference between IL-1ra group and age-matched control group, but have no effect on neurons cultured for 6 d; Pre and co-treated with 10 mg/L IL-1ra have NR2B mRNA expression increase induced by Mg(2+)-free treatment was not affected, either in neurons cultured for 6 d or neurons cultured for 17 d. CONCLUSION: Neuroprotection of IL-1Ra in seizure-induced injury is age-dependent. The mech-anism of the neuroprotection of IL-1Ra includes down-regulation of [Ca(2+)]i and others.
Animals↗
[Expression of mythl-CpG-binding protein-2 gene in developing rat brain].
OBJECTIVE: To analyze the expression of mecp2 gene at mRNA and protein;Cerebral cortex level in the cerebral cortex of the normal Wistar rat throughout development. METHODS: We chose the 15th day (E15), 17th day (E17), 19th day (E19) of embryo period, the day of birth (P0), the 7th day (P7), the 14th day (P14), the 28th day (P28) of postnatal period, and adulthood as analyzing time points. The expression of mecp2 gene at mRNA level was analyzed by real-time PCR and Northern blot. The expression of MeCP2 protein was analyzed by Western blot. RESULTS: There was one type of mecp2 mRNA transcript (approximately 10 kb) expressed in the cerebral cortex of the normal Wistar rat. The expression level of mecp2 mRNA varied subtly during the development. There was one type of MeCP2 protein (75 000) expressed in the cerebral cortex of the normal Wistar rat. The expression level of MeCP2 protein remained the lowest on E15, from E19 to adulthood the expression levels of MeCP2 protein increased dramatically compared with that on E15. From P7 to adulthood, the differences of expression between two time points were subtle. CONCLUSION: The expression level of MeCP2 protein increases as the neurons in the cerebral cortex of normal Wistar rat grow mature. This indicates that MeCP2 protein is very important to neuron's maturation, and probably has relationship with maintaining maturation state of neurons.
Animals↗
[X-linked adrenoleukodystrophy ABCD1 gene mutation analysis in China].
OBJECTIVE: To investigate mutations of ABCD1 gene in X- linked adrenoleukodystrophy (ALD) patients in China. METHODS: Polymerase chain reaction and DNA direct sequencing were employed to analyze the 10 exons of ABCD1 gene in 25 ALD patients. RESULTS: Seventeen mutations in different exons (except exons 4, 9 and 10) were identified in 18 of 25 patients. Most of the mutations were missense mutations, including R182P, G266R, H283D, S404P, N509I, R518G, L520Q, Q556R, S606L and R617C, four (H283D, S40 4P, N509I, R518G) of 10 missense mutations were novel. Also identified were 3 nonsense mutations (W132X, W242X, W595X), 1 dinucleotides deletion mutation (1414 del AG) resulting in frameshift, and 1 base pair deletion at splice acceptor site (IVS5-6 del C). Two synonymous mutations (L516L and V349V) appeared simultaneously in 2 unrelated patients, and no other mutations could be found with them in all 10 exons screened. CONCLUSION: There were no hot spot mutations in ABCD1 gene in China. Mutations in gene were found over 70% of patients with ALD in China. The ABCD1 gene mutations identified revealed no obvious correlation between the type of mutation and phenotype.
ATP Binding Cassette Transporter, Subfamily D, Mem↗
[Long-term effect of repeated febrile convulsions on seizure susceptibility in immature rats].
OBJECTIVE: To elucidate the long-term effect of repeated febrile convulsions (FC) on seizure susceptibility in immature rats. METHODS: Warm-water-immersion rat FC model was developed with SD rats 22 days of age, 15 attacks of seizures were induced in the rats every other day, and some of the rats were left un-stimulated for 3 months, then were re-stimulated. Seizure phenomenon was observed, including the latency and the duration of seizures and the temperature of rats. Hippocampal neuron loss and mossy fiber sprouting were detected by thionine staining and Timm staining. RESULTS: After the 15th bath, the latency, the duration of seizures, and the temperature of rats were respectively (4.3 +/- 0.8) min, (5.5 +/- 2.9) min, (42.2 +/- 0.7) degrees C. Three months later, on re-stimulation, in 14 of 19 rats with previous FC experience seizures occurred while in only one of 13 non-FC rats seizure occurred and lasted for 8.5 min. Three months later, the latency, the duration of seizures, and the temperature of rats were respectively (5.4 +/- 0.6) min, (19.3 +/- 5.1) min, and (42.4 +/- 0.4) degrees C (4 rats with status epileptics were not included). The incidence of seizures on re-stimulation in rats of FC group (74%) was significantly higher than that in non-FC group (8%) (chi(2) = 13.50, P < 0.01), and the duration of seizures [(19.3 +/- 5.1) min] was significantly longer than those induced in early life [(5.5 +/- 2.9) min] (t = 10.49, P < 0.01). After the 15th bath, no significant change was demonstrated in rats of different groups. While 3 months later, prominent neuron loss was observed in hippocampal CA(3) region in rats with previous FC experience (P < 0.01). Significant mossy fiber sprouting phenomenon was detected after the 15th bath and 3 months later (P < 0.05). CONCLUSION: Repeated FC in early life enhances long term susceptibility of rats to seizure.
Animals↗
[Clinical feature of Rett syndrome and MeCP2 genotype/phenotype correlation analysis].
OBJECTIVE: Rett syndrome (RTT) is a neurodevelopmental disorder which causes severe mental retardation. This study aimed at elucidating clinical features of 66 Chinese RTT cases diagnosed by The Department of Pediatric Neurology, Peking University First Hospital since 1987, and at analysis of the MeCP2 genotype / phenotype correlation. METHODS: Sixty-six RTT cases were followed up every one to two years to get the information of their clinical manifestations and the response to the L-carnitine treatment which was administered to the patients at a dose of 80-100 mg/(kg d). MeCP2 mutation analysis by PCR and sequencing were performed on 39 cases. RESULTS: In this cohort of cases, the onset of the disease occurred between 3 and 38 months of age, 89% of the cases lost their purposeful hand use at 7 months to six years of age, all the cases had stereotype hand movement which presented at 1 to 5 years of age, 85% of the cases lost language ability at 11 months to eight years of age, 21% of the cases lost the ability of walking at ages of 2 years and 9 months to 15 years. The symptoms/signs such as small head circumference, seizures, breathing irregularities, teeth grinding, scoliosis/ kyphosis were presented in many of the cases. The clinical manifestations were improved in 6 cases after L-carnitine treatment. MeCP2 gene mutation was found in 64% of the cases. Two cases with non-sense mutation C502t (amino acid change R168X) died, two cases with missense mutation C397T (amino acid change R133C) and one case with missense mutation A398T (amino acid change R133H) preserved several words. CONCLUSION: Deceleration of the head growth, loss of acquired purposeful hand use, stereotype hand movement and language deterioration were the main characteristics of RTT. L-carnitine could improve the clinical manifestation of some cases. There are some correlations between MeCP2 genotype and phenotype.
Adolescent↗
[Calcium channels and human genetic diseases].
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Ataxia↗
Case-control study and transmission/disequilibrium tests of the genes encoding GABRA5 and GABRB3 in a Chinese population affected by childhood absence epilepsy.
BACKGROUND: Childhood absence epilepsy (CAE) is one of the most frequently recognized syndromes among the idiopathic generalized epilepsies (IGEs). CAE is considered to be a genetic disease, with a possible polygenic inheritance pattern. The genes responsible for CAE have not been identified yet. The object of this study was to investigate whether or not CAE is associated with the gene encoding the gamma-aminobutyric acid (GABA) type-A receptor subunits alpha5 (GABRA5) and beta3 (GABRB3) in a Chinese population. METHODS: Five microsatellite DNA repeats, 69CA, 85CA, 155CA1, 155CA2, and A55CA1, adjoining chromosome 15q11-q13, were used as genetic markers. Both case-control study and transmission/disequilibrium tests (TDTs), as well as fluorescence-based semi-automated genotyping techniques, were used in 90 CAE patient-mother-father trios and 100 normal controls of Han ethnicity to conduct association analysis. RESULTS: The frequencies of allele 5 of 69CA, alleles 2 and 8 of 85CA, alleles 6 and 7 of 155CA1, allele 2 of 155CA2, and alleles 1 and 11 of A55CA1 were significantly higher in CAE patients than in normal controls. To prevent spurious associations arising from population admixture, we further conducted TDT tests in the 90 CAE trios. The results of TDT analysis further suggested that microsatellite DNA repeats 85CA, 155CA1, and 155CA2 were associated with CAE. CONCLUSIONS: GABA type-A receptor subunit genes GABRA5 and GABRB3 may be either directly involved in the etiology of CAE in the Chinese population or in linkage disequilibrium with disease-predisposing sites.
Adolescent↗
[Association of child absence epilepsy with T-STAR gene].
OBJECTIVE: To investigate the Association of child absence epilepsy with T-STAR gene. METHODS: PCR was conducted on the DNA of peripheral blood white cells from 48 children with child absence epilepsy (CAE), 47 male and 49 female, aged 2.9 approximately 14, of Han nationality in Northern China and 48 healthy children in the same area to amplify the exons of T-STAR gene The PCR products underwent sequencing to identify the possible mutations. RESULTS: No mutation was found in the exons of the T-STAR gene, however, 3 single nucleotide polymorphisms (SNPs) were found. A case-control study was carried out, using SNP1 and SNP2. There was no significant difference in genotype frequency of the 2 SNPs between the CAE group and control group (SNA1: chi(2) = 2.965, df = 1, P = 0.085; SNP2: chi(2) = 2.965, df = 1, P = 0.085). There was no significant difference in allele frequency of the 2 SNPs between the CAE group and control group too (SNA1: chi(2) = 3.185, df = 2, P = 0.203; SNP2: chi(2) = 3.185, df = 2, P = 0.203). CONCLUSION: T-STAR may not be a susceptibility gene for CAE in Chinese populations.
Adolescent↗
[Preliminary analysis of mutations in X-linked adrenoleukodystrophy gene(ABCD1) in Chinese patients].
OBJECTIVE: To detect the mutations in exon 6 of ABCD1 gene encoding adrenoleukodystrophy protein(ALDP) in Chinese X-linked adrenoleukodystrophy (ALD MIM 300100) patients. METHODS: Genomic DNA from 14 unrelated patients and two patients' parents with X-linked ALD was extracted using standard procedures from the peripheral blood leukocytes. Polymerase chain reaction (PCR) and DNA direct sequencing were employed to analyze exon 6 of ABCD1 gene. RESULTS: Three mutations in exon 6 were identified in 3 of 14 patients. One mutation was deleted 1 base pair at splice acceptor-site (1489-6 del C). It was not clear what the effect of this mutation is on the ALD protein, maybe induce splicing error. One missense mutation: T1559A(L520Q). These two patients' mothers were heterozygous. The third patient had a mutation: G1548A (L516 L), which is a known polymorphism. It was not a disease causing mutation, so there should be another mutation in this patient. CONCLUSION: For the first time, mutations in ABCD1 are identified in Chinese ALD patients in the mainland of China. No major gene deletion or rearrangement is detected in exon 6. Despite many mutations having been identified in patients with these clinical phenotypes, the genotype-phenotype correlations have not been clarified, suggesting that other genetic or environmental factors may also be involved in determining phenotypic expression in ALD. Two carriers are also confirmed.
ATP Binding Cassette Transporter, Subfamily D, Mem↗
[Clinical characteristics of alternating hemiplegia of childhood in 13 patients].
OBJECTIVE: To summarize the clinical characteristics of alternating hemiplegia of childhood (AHC). METHODS: The clinical data of 13 children with AHC were analyzed. Cranial MRI, EEG, analysis of serum amino acids and urinary organic acids, measurement of plasma lactate and pyruvate levels were done in all patients. Other laboratory examinations such as magnetic resonance angio-imaging (MRA), digital subtraction arteriography (DSA) and Video-EEG were also performed in some patients. RESULTS: Of the 13 patients, 12 were male, and 1 was female. The age of onset was from 2 days to 55 months (average 13.1 months). The initial symptoms were abnormal ocular movements (AOMs) consisting of ocular deviation, gaze or nystagmus in 2 cases, AOMs and dystonic posturing in 9 cases, hemiplegia in 2 cases. All patients had recurrent alternating hemiplegic episodes. The hemiplegic attacks lasted from a few minutes to 10 days. The occurrence of the attacks ranged from 8 times daily to one time every 2 months. In 10 patients the abnormal eye movements or dystonic posturing, at times, recurred intermittently during the hemiplegic attack. Choreoathetosis was present in 2 cases. Ataxia was present in 1 case; 7 patients also had the episodes of quadriplegia. During the episodes of quadriplegia, dysarthria or aphasia was present in 4 cases, dyspnea and dysphagia was present in 2 cases, respectively. Sleep could relieve both weakness and associated paroxysmal symptoms. Mental retardation was present in 9 cases, seizures in 3 cases. Except for EEG or Video-EEG was abnormal in 3 patients, other laboratory investigations were normal in all patients. Twelve patients received flunarizine therapy. Flunarizine reduced the severity, duration, or frequency of hemiplegic attacks in 8 patients. CONCLUSION: The results suggest that AHC is characterized by frequent episodes of alternating hemiplegia with extrapyramidal symptoms and mental retardation, flunarizine is effective in treating some AHC patients.
Anticonvulsants↗
[Clinical characteristics of X-linked adrenoleukodystrophy].
OBJECTIVE: X-linked adrenoleukodystrophy (ALD) is a genetically determined disorder that involves the nervous system white matter, axons, adrenal cortex and testes. The typical clinical manifestations are progressive psychomotor regression, vision and/or auditory impairment and adrenal insufficiency. The clinical manifestation, biochemical change and genetic counseling work of X-linked ALD were analyzed. METHODS: The clinical features of 29 cases with ALD were summarized and analyzed, including symptoms and signs, measurement of blood very long chain fatty acids (VLCFA), adrenal function, cranial magnetic resonance imaging (MRI) and pedigree investigation. RESULTS: Among these 29 cases, the clinical phenotype could be classified into childhood cerebral (22 cases), adolescent cerebral (4 cases), adrenomyeloneuropathic (1 case), Addison's disease (1 case) and asymptomatic or presymptomatic (1 case) types. Nine of them had positive family history. Pedigree investigation was consistent with typical sex-linked recessive inheritance. There were 45 ALD patients in these 29 pedigrees. The neurological manifestations varied among members of the same family. Nine cases died during follow up. The causes of death were central respiratory failure or other complications of ALD and so on. Laboratory tests demonstrated abnormally high plasma levels of VLCFA in ALD patients; MRI demonstrated symmetric butterfly-like low T(1) and high T(2) signals in the parieto-occipital white matter. The impairment in the splenium of corpus callosum made the bilateral lesion region converge into one. It could progress anteriorly and injure the bilateral posterior limb of internal capsule and the temporal lobe, and could injure the brainstem inferiorly. Following intravenous injection of contrast material, thin stripe of lacelike enhancement could be observed. CONCLUSIONS: The atypical initial symptom of ALD was seizures. The MRI showed abnormal signal in the cerebellar white matter. This disease can influence the normal development of children, this was more pronounced in the childhood cerebral ALD type. It tended to progress rapidly with dementia, vegetative state or death. Since antenatal diagnostic method is available now, emphasis should be made on the antenatal examination in order to make an early diagnosis and abort pregnancy if necessary.
Adolescent↗
[Effects of recurrent audiogenic seizures on hippocampal structure and seizure behavior of P77PMC rats].
OBJECTIVE: To investigate the functional role of hippocampal mossy fiber sprouting in the pathophysiologic mechanism of initiation and propagation of epilepsy. METHODS: The authors examined hippocampal mossy fiber synaptic reorganization and the changes of hippocampal neurons in P77PMC rats at different stages in the course of recurrent seizures using Timm's method of silver sulfide staining and Nissl staining and observed the effects of recurrent audiogenic seizures (AGSs) on seizure behavior of P77PMC rats. RESULTS: Frequent recurrent AGSs could cause neuronal loss in CA(1) region of hippocampus and hippocampal mossy fiber sprouting got into the inner molecular layer of dentate gyrus in P77PMC rats, and could decrease the latency of IV/V grade of AGSs, increase the durations of AGSs. The mean A of CA(1) region of hippocampus in Nissl staining after 50 times of AGSs was 35.3 +/- 0.8, which was markedly lower than that of the control (44.1 +/- 0.5; F = 333.89, P < 0.001). The mean A of the inner molecular layer of dentate gyrus in Timm's staining after 50 times of AGSs was 49.3 +/- 4.6, which was markedly higher than that of the control (26.8 +/- 1.7; F = 76.83, P < 0.001). After 30 and 50 times of AGSs, the latent periods of IV/V grade of AGSs were 12 +/- 8 (t = 3.805; P < 0.02) and 17 +/- 7 (t = 5.927; P < 0.002) seconds shorter than the initial period of stimulation respectively on average, and the durations of AGSs were 19 +/- 18 (t = 2.644; P < 0.05) and 10 +/- 7 (t = 3.780; P < 0.02) seconds longer. CONCLUSION: Hippocampal mossy fiber sprouting and neuronal loss not only presents in limbic seizure, but also in AGS, the seizure can be initiated in brainstem but rapidly generalized;in AGS-prone rats, recurrent AGSs can cause mossy fiber synaptic reorganization and neuronal loss in hippocampus, and can also enhance seizure susceptibility of P77PMC rats. In the course of recurrent AGSs, enhanced seizure susceptibility happened before hippocampal mossy fiber sprouting. Their temporal relationships indicate that the anatomical changes may be preceded by functional changes of elevated excitability in the brain.
Acoustic Stimulation↗
[Cortical neuron injury occurs following recurrent epileptiform discharges induced by magnesium-free treatment in vitro].
OBJECTIVE: To study cortical neuron injury following recurrent epileptiform discharges induced by magnesium-free treatment in vitro. METHODS: Cultured embryo cortical neurons were exposed to magnesium-free media for 3 h, then they were returned to regular media containing normal level magnesium. At different time after Mg(2+)-free treatment, trypan blue staining and determination of LDH activity were used to determine the cell viability, flow cytometry was applied to measure neuronal apoptosis, and MTT assay to study metabolic rate. RESULTS: (1) Neuronal morphology on light microscopy following Mg(2+)-free treatment showed that there were no prominent alterations. (2) At different time (6, 12, 72 h) after Mg(2+)-free treatment, neuronal viability by trypan blue staining and LDH activity showed modest changes compared with time-matched control in different culture days (6, 12, 17 d) (P > 0.05). (3) Cell apoptosis increased mildly at different time after Mg(2+)-free treatment in neurons cultured for different days, but the increase was not significant (P > 0.05). (4) Metabolic rate decreased at 6 h after Mg(2+)-free treatment (P < 0.05) in neurons cultured for 6 d, and was 86.4% of that of the control; while the rate at 24 h in neurons cultured for 12 d and 17 d also decreased (P < 0.05), being 78.7% and 70.9%, respectively, of that of the control. CONCLUSIONS: These findings demonstrated that the injury occurred on cultured cortical neurons caused by magnesium-free-treatment-induced recurrent epileptiform discharges was mainly functional and relatively mature neurons displayed more severe and much later mitochondrial function impairment than immature neurons.
Animals↗