Split intein converting peptide protein interaction into electrochemically assisted metal ion catalytic signal in the prenatal screening of pediatric epilepsy.

Dravet syndrome is a rare form of epilepsy starting from infancy that can plaque the affected individuals all though his/her life with repeated seizures, and this condition is currently without a complete cure. So prenatal screening of molecular markers of this condition is urgently needed to help couples conceiving new lives to steer clear of this potential danger. And such an assay should ideally be of low cost and could be completed in a point-of-care fashion. This work reports an attempt to construct such an assay using simple peptides in the place of conventional biosensing macro-molecules such as antibodies and enzymes. Specifically, a marker protein of this syndrome can bring the two pieces of a self-splitting peptide "intein" together, which in turn facilitate the formation of metal ion coordination site, recruiting cupric ion to generate catalytically amplified signal readout. Using this method, disease marker protein Nav of this syndrome can be quantitatively detected directly in amniotic fluid samples, and samples associated with potential risk factors such as family history of this syndrome shows statistically evident decrease of this marker protein. These results may promise future application of the proposed method in clinical practice to reduce the social burden of Dravet syndrome by reducing its actual incident rate.

Epileptic seizures as an initial symptom for Sturge­Weber syndrome type III: A report of two cases.

Sturge-Weber syndrome (SWS) type III, a rare neurocutaneous disorder, presents diagnostic challenges due to its variable clinical manifestations. The present study focuses on enhancing the understanding of this syndrome by conducting a detailed analysis of two pediatric cases and providing a comprehensive review of the existing literature. The cases, managed at the Children's Hospital Affiliated to Shandong University (Jinan, China), highlight the diverse clinical presentations and successful management strategies for SWS type III. In the first case, a 4-year-old male patient exhibited paroxysmal hemiplegia, epileptic seizures and cerebral angiographic findings indicative of left pia mater and venous malformation. The second case involved a 2.5-year-old male patient presenting with recurrent seizures and angiographic findings on the right side. Both cases underscore the importance of considering epileptic seizures, acquired and transient hemiplegia and cognitive impairments in the diagnosis of SWS type III. The present study provides insights into the effective use of both pharmacological and surgical interventions, drawing from the positive outcomes observed in these cases. The findings emphasize the need for heightened awareness and a meticulous approach in diagnosing and treating SWS type III, contributing to the better management and prognosis of this condition.

Clinical phenotype and genotype of NPRL2-related epilepsy: Four cases reports and literature review.

BACKGROUND: NPRL2-related epilepsy, caused by pathogenic germline variants of the NPRL2 gene, is a newly discovered childhood epilepsy linked to enhanced mTORC1 signalling. However, the phenotype and genotype of NPRL2 variants are still poorly understood. Here, we summarize the association between the phenotype and genotype of NPRL2-related epilepsy. METHODS: A retrospective analysis was conducted for four Chinese children with epilepsy due to likely pathogenic NPRL2 variants identified through whole-exome sequencing (WES). Previous reports of patients with NPRL2-related epilepsy were reviewed systematically. RESULTS: One of our patients presented focal epilepsy involving the central region, which should be distinguished from self-limited epilepsy with centrotemporal spikes (SeLECTS). The four novel likely pathogenic NPRL2 variants consisted of two nonsense variants, one frameshift variant, and one copy number variant (CNV). Bioinformatics analysis revealed the two nonsense variants to be highly conserved and cause alterations in protein structure. Including our four cases, a total of 33 patients with NPRL2-related epilepsy have been identified to date. The most common presentation is focal epilepsy (70%), including sleep-related hypermotor epilepsy (SHE), temporal lobe epilepsy (TLE), and frontal lobe epilepsy (FLE). Infantile epileptic spasms syndrome (IESS) is also a notable feature of NPRL2-related epilepsy. Malformations of cortical development (MCD, 8/20), especially focal cortical dysplasia (FCD, 6/20), are common neuroimaging abnormalities. Two-thirds of the NPRL2 variants reported are loss of function (LoF) (14/21). Among these mutations, c.100C>T (p.Arg34*) and c.314T>C (p.Leu105Pro) have been detected in two families (likely due to a founder effect). CONCLUSION: NPRL2-related epilepsy shows high phenotypic and genotypic heterogeneity. Our study expands the genotype spectrum of NPRL2-related epilepsy, and the phenotype of focal epilepsy involving the central region should be clearly distinguished with SeLECTS, with reference value for clinical diagnosis.

Vagus nerve stimulation for treating developmental and epileptic encephalopathy in young children.

Objective: To investigate the clinical variables that might predict the outcome of developmental and epileptic encephalopathy (DEE) after vagus nerve stimulation (VNS) therapy and identify the risk factors for poor long-term outcome. Patients and methods: We retrospectively studied 32 consecutive children with drug-resistant DEE who had undergone VNS surgery from April 2019 to July 2021, which were not suitable for corpus callosotomy. In spite of combining valproic acid, levetiracetam, lamotrigine, topiramate, etc. (standard anti-seizure medicine available in China) it has not been possible to effectively reduce seizures in the population we investigate (Cannabidiol and brivaracetam were not available in China). A responder was defined as a frequency reduction decrease > 50%. Seizure freedom was defined as freedom from seizures for at least 6 months. Sex, electroencephalograph (EEG) group, neurodevelopment, time lag, gene mutation, magnetic resonance imaging (MRI), and epilepsy syndrome were analyzed with Fisher's exact test, The age at onset and age at VNS therapy were analyzed with Kruskal-Wallis test, statistical significance was defined as p < 0.05. And used the effect size to correction. Results: Among the 32 patients, the median age at VNS implantation was 4.7 years (range: 1-12 years). At the most recent follow-up, five children (15.6%) were seizure-free and 22 (68.8%) were responders. Univariate analysis demonstrated that the responders were significantly associated with mild development delay/intellectual disability (p = 0.044; phi coefficient = 0.357) and a multifocal EEG pattern (p = 0.022; phi coefficient = -0.405). Kaplan-Meier survival analyses demonstrated that a multifocal EEG pattern (p = 0.049) and DEE without epileptic spasm (ES) (p = 0.012) were statistically significant (p = 0.030). Multivariate analysis demonstrated that DEE with ES had significant predictive value for poor long-term outcome (p = 0.014, hazard ratio = 5.433, confidence interval = 1.402-21.058). Conclusions: Our study suggested that VNS was a generally effective adjunct treatment for DEE. Although the predictive factors for VNS efficacy remain unclear, it should be emphasized that patients with ES are not suitable candidates for epilepsy surgery. Further investigations are needed to validate the present results.

[Analysis of CNNM2 gene variant in a child with Hypomagnesemia, seizures, and mental retardation syndrome].

OBJECTIVE: To explore the genetic etiology of a child with Hypomagnesemia, epilepsy and mental retardation syndrome (HSMR). METHODS: A child who was admitted to the Children's Hospital of Shandong University on July 9, 2021 due to repeated convulsions for 2 months was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his pedigree members were collected for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 1-year-and-7-month-old male, had presented with epilepsy and global developmental delay. Serological testing revealed that he has low serum magnesium. Genetic testing showed that the child has harbored a heterozygous c.1448delT (p.Val483GlyfsTer29) variant of the CNNM2 gene, which was de novo in origin. The variant has caused substitution of the Valine at position 483 by Glycine and formation of a termination codon after 29 amino acids at downstream. As predicted by Swiss-Model online software, the variant may alter the protein structure, resulting in a truncation. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1448delT (p.Val483GlyfsTer29) was predicted as a pathogenic variant (PVS1+PS2+PM2_Supporting+PP4). CONCLUSION: The heterozygous c.1448delT variant of the CNNM2 gene probably underlay the HSMR in this child. Above finding has enriched the phenotype-genotype spectrum of the CNNM2 gene.

Effectiveness and tolerability of perampanel monotherapy in children with newly diagnosed focal epilepsy.

Objective: To examine the clinical effectiveness and tolerability of perampanel (PER) as initial monotherapy in pediatric patients with newly diagnosed focal epilepsy. Methods: A retrospective analysis was conducted on 62 children with newly diagnosed focal epilepsy who were treated with PER at the Epilepsy Center of Jinan Children's Hospital from July 2021 to July 2022. The treatment status, prognosis, and adverse reactions were followed up for a minimum of 6 months after the initiation of PER monotherapy. The effectiveness of the patients was estimated by the PER effective rate at 3-, 6-, and 12-month follow-up evaluations and adverse reactions were also recorded. The effective rates of PER in different etiologies and epilepsy syndromes were also statistically analyzed. Results: The effective rates of PER treatment at the different time points of evaluation were 88.7% (3 months), 79.1% (6 months), and 80.4% (12 months). With PER treatment, seizure freedom varied over time, with 61.3%, 71.0%, and 71.7% of patients at the 3-, 6-, and 12-month follow-ups, respectively. Among the etiologies of epilepsy, the effective rates of genetic etiology, structural etiology, and unknown etiology were generally above 50% at the 3-, 6-, and 12-month follow-ups. Among the epilepsy syndromes, the categories with higher treatment efficacy were self-limiting epilepsy with centrotemporal spikes (SeLECTs), self-limited epilepsy with autonomic seizures (SeLEAS), and childhood occipital visual epilepsy (COVE), with an effective rate of above 80%. Adverse events were documented in 22 patients (35.5%), but they were mild and tolerable. The most common adverse events comprised irritability, drowsiness, dizziness, and increased appetite. Conclusion: PER has favorable effectiveness and tolerability as initial monotherapy for children with newly diagnosed focal epilepsy, which could be a potential option for long-term medication in the treatment of focal epilepsy in children. The current study provided potential evidence for PER as initial monotherapy in children with focal epilepsy in clinical practice.

Long-Term Outcome of Adrenocorticotropic Hormone Therapy in Children With New-Onset Infantile Spasms.

BACKGROUND: To investigate for pretreatment clinical variables to predict the outcome of new-onset epileptic spasms after adrenocorticotropic hormone (ACTH) therapy and to identify risk factors for poor long-term outcome. METHODS: We retrospectively studied 129 consecutive patients with infantile spasms syndrome (ISS). These patients received ACTH with antiseizure medication therapy for the first time and were regularly followed up for more than six months at our hospital. The response to treatment was assessed after two weeks of ACTH injection. Kaplan-Meier survival analysis and the multivariate Cox proportional hazard regression model were used. RESULTS: Among the 129 patients, 61 (47.3%) had a good response after two weeks of ACTH treatment. At the time of the latest follow-up, 71 (55%) patients were seizure-free (International League Against Epilepsy class1). The univariate analysis revealed that normal neurodevelopment (P = 0.018), time lag of less than one month (P = 0.026), no hypsarrhythmia on EEG (P = 0.004), and serum calcium level ≥2.50 mmol/L (P = 0.035) were significantly associated with a good response. Only a good response to ACTH therapy was significantly associated with a positive long-term outcome. The Kaplan-Meier survival analysis showed that serum calcium level ≧2.50 mmol/L was significantly associated with a positive long-term outcome (P = 0.030). Multivariate analysis confirmed that no response to ACTH therapy was an independent variable that predicted long-term seizure recurrence (P < 0.001, hazard ratio = 4.602, confidence interval = 2.252 to 9.406). CONCLUSIONS: A good response to ACTH therapy had a significant predictive value for long-term seizure outcomes. Calcium may play an important role in the treatment of ISS with ACTH.

Safety and Tolerability of COVID-19 Vaccine in Children With Epilepsy: A Prospective, Multicenter Study.

BACKGROUND: We designed this study to investigate the effects of the coronavirus disease 2019 (COVID-19) vaccine on epileptic seizures, as well as its adverse effects, in children with epilepsy (<18 years). METHODS: This anonymous questionnaire study involved a multicenter prospective survey of outpatients and inpatients with epilepsy (＜18 years) registered in epilepsy clinics in eight hospitals in six cities of Shandong Province. RESULTS: A total of 224 children with epilepsy were included in the study. Fifty of them experienced general adverse events after vaccination. The most common local adverse events were pain or tenderness at the injection site. The most common systemic adverse effects were muscle soreness and headache. No severe adverse events were reported. There were no significant differences in the number of antiseizure medications (P = 0.459), gender (P = 0.336), etiology (P = 0.449), age (P = 0.499), duration of disease (P = 0.546), or seizure type (P = 0.475) between the patients with and without general adverse events. We found that the risk of seizure after vaccination was decreased in children who were seizure free for more than six months before vaccination. There was no significant difference in the number of seizures during the first month before vaccination, the first month after the first dose, and the first month after the second dose (P = 0.091). CONCLUSION: The benefits of vaccination against COVID-19 outweighed the risks of seizures/relapses and severe adverse events after vaccination for children with epilepsy.

Phenotype and genotype analyses of Chinese patients with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations.

Background: Autosomal dominant mental retardation type 5 (MRD5), a rare neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), developmental delay (DD), and epilepsy predominantly, is caused by a heterozygous mutation in the SYNGAP1 gene. SYNGAP1 mutations have been rarely reported in the Chinese population. Here, we present an investigation of SYNGAP1 mutations in a clinical cohort with ID and DD in Shandong, a northern province in China, to further explore the genotype and phenotype correlations. Methods: A retrospective study was conducted on 10 children with SYNGAP1 mutations presenting ID, DD, and epilepsy who were diagnosed between January 2014 and May 2022. Clinical data and genetic tests were collected. Treatment and regular follow-ups were carried out to pay close attention to the prognosis of the patients. Results: We described 10 unrelated affected individuals with SYNGAP1 mutations, displaying ID, DD, epilepsy, or seizures. All mutations of SYNGAP1 in the 10 patients were de novo, except patient 3 whose father was unavailable, including five nonsense mutations, two frameshift mutations, two splicing mutations, and one codon deletion. Among these mutations, five were novel and the other five were previously reported. Significantly, all patients with epilepsy were sensitive to anti-seizure drugs, especially sodium valproate. Furthermore, rehabilitation training seemed to exert a more improved effect on motor development than language development for the patients. Conclusion The 10 patients carrying SYNGAP1 mutations were diagnosed as MRD5. Five novel genetic mutations were found, which expanded the mutational spectrum of the SYNGAP1 gene. The identification of these mutations in this study helps explore the relationship between genotypes and phenotypes and contributes to genetic counseling and therapeutic intervention for patients with MRD5.

Effect of inactivated COVID-19 vaccines on seizure frequency in patients with epilepsy: A multicenter, prospective study.

Objectives: Several COVID-19 vaccines list "uncontrolled epilepsy" as a contraindication for vaccination. This consequently restricts vaccination against COVID-19 in patients with epilepsy (PWE). However, there is no strong evidence that COVID-19 vaccination can exacerbate conditions in PWE. This study aims to determine the impact of COVID-19 vaccination on PWE. Methods: PWE were prospectively recruited from 25 epilepsy centers. We recorded the seizure frequency at three time periods (one month before the first vaccination and one month after the first and second vaccinations). A generalized linear mixed-effects model (GLMM) was used for analysis, and the adjusted incidence rate ratio (AIRR) with 95% CI was presented and interpreted accordingly. Results: Overall, 859 PWE were included in the analysis. Thirty-one (3.6%) and 35 (4.1%) patients were found to have increased seizure frequency after the two doses, respectively. Age had an interaction with time. The seizure frequency in adults decreased by 81% after the first dose (AIRR=0.19, 95% CI:0.11-0.34) and 85% after the second dose (AIRR=0.16, 95% CI:0.08-0.30). In juveniles (<18), it was 25% (AIRR=0.75, 95% CI:0.42-1.34) and 51% (AIRR=0.49, 95% CI:0.25-0.95), respectively. Interval between the last seizure before vaccination and the first dose of vaccination (ILSFV) had a significant effect on seizure frequency after vaccination. Seizure frequency in PWE with hereditary epilepsy after vaccination was significantly higher than that in PWE with unknown etiology (AIRR=1.95, 95% CI: 1.17-3.24). Two hundred and seventeen (25.3%) patients experienced non-epileptic but not serious adverse reactions. Discussion: The inactivated COVID-19 vaccine does not significantly increase seizure frequency in PWE. The limitations of vaccination in PWE should focus on aspects other than control status. Juvenile PWE should be of greater concern after vaccination because they have lower safety. Finally, PWE should not reduce the dosage of anti-seizure medication during the peri-vaccination period.

The EEG Features of Four Cases of Subacute Sclerosing Panencephalitis in North China : SSPE EEG Features.

Objective. To analyze the EEG features of four subacute sclerosing panencephalitis cases in North China. Methods. We retrospectively analyzed the EEG features in four patients with subacute sclerosing panencephalitis and 12 patients in control group from North China. Results. The periodic long-interval diffuse discharges were found in all of the four cases with subacute sclerosing panencephalitis. The morphology and component of periodic complexes were varied in different patients and different wakefulness states. Some EEG parameter settings help to identify periodic long-interval diffuse discharges including the slowed sweep speed, decreased sensitivity and reduced number of montages. In each patient with subacute sclerosing panencephalitis, the periodic long-interval diffuse discharges associated with two types of brief episodes (1:1) during awake period were found and none of the patients in the control group had this EEG pattern. The score system based on the periodic discharges and brief episodes also shows that all the patients with SSPE reached score 5 while none of the patients in the control group has a score greater than 3, which suggests that this EEG pattern may have diagnostic value. Conclusions. In subacute sclerosing panencephalitis, the morphology and component of periodic long-interval diffuse discharges were varied in different patients and different wakefulness states. Specific EEG parameter settings help to identify periodic long-interval diffuse discharges. Periodic long-interval diffuse discharges associated with two types of brief episodes (1:1) during awake period may strongly suggest the diagnosis of subacute sclerosing panencephalitis.

Generation of an induced pluripotent stem cell line (SDQLCHi044-A) from a patient with autosomal dominant mental retardation type 5 harboring heterozygous mutation in SYNGAP1 gene.

Autosomal dominant mental retardation type 5 (MRD5) is a rare neurodevelopmental disorder caused by mutations in the SYNGAP1 gene. Here, we established an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells (PBMCs) of a 30-month-old boy carrying a heterozygous mutation (c.2059C > T) in the SYNGAP1 gene. The iPSCs exhibited a normal karyotype, expressed pluripotency markers, and displayed differentiation potential in vitro.

Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy.

Objective: The LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit ß1/ß2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been reported to be associated with human diseases. Among LAMAs encoding the laminin α subunit, LAMA1-4 have also been reported to be associated with human disease. In this study, we investigated the association between LAMA5 and epilepsy. Methods: Trios-based whole-exome sequencing was performed in a cohort of 118 infants suffering from focal seizures with or without spasms. Protein modeling was used to assess the damaging effects of variations. The LAMAs expression was analyzed with data from the GTEX and VarCards databases. Results: Six pairs of compound heterozygous missense variants in LAMA5 were identified in six unrelated patients. All affected individuals suffered from focal seizures with mild developmental delay, and three patients presented also spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than in controls. The recessive burden analysis showed that recessive LAMA5 variants identified in this cohort were significantly more than the expected number in the East Asian population. Protein modeling showed that at least one variant in each pair of biallelic variants affected hydrogen bonds with surrounding amino acids. Among the biallelic variants in cases with only focal seizures, two variants of each pair were located in different structural domains or domains/links, whereas in the cases with spasms, the biallelic variants were constituted by two variants in the identical functional domains or both with hydrogen bond changes. Conclusion: Recessive LAMA5 variants were potentially associated with infant epilepsy. The establishment of the association between LAMA5 and epilepsy will facilitate the genetic diagnosis and management in patients with infant epilepsy.

SQNN: a spike-wave index quantification neural network with a pre-labeling algorithm for epileptiform activity identification and quantification in children.

Objective.Electrical status epilepticus during slow sleep (ESES) is a phenomenon identified by strong activation of epileptiform activity in the electroencephalogram (EEG) during sleep. For children disturbed by ESES, spike-wave index (SWI) is defined to quantify the epileptiform activity in the EEG during sleep. Accurate SWI quantification is important for clinical diagnosis and prognosis. To quantify SWI automatically, a deep learning method is proposed in this paper.Approach.Firstly, a pre-labeling algorithm (PreLA) composed of the adaptive wavelet enhanced decomposition and a slow-wave discrimination rule is designed to efficiently label the EEG signal. It enables the collection of large-scale EEG dataset with fine-grained labels. Then, an SWI quantification neural network (SQNN) is constructed to accurately classify each sample point as normal or abnormal and to identify the abnormal events. SWI can be calculated automatically based on the total duration of abnormalities and the length of the signal.Main results.Experiments on two datasets demonstrate that the PreLA is effective and robust for labeling the EEG data and the SQNN accurately and reliably quantifies SWI without using any thresholds. The average estimation error of SWI is 3.12%, indicating that our method is more accurate and robust than experts and previous related works. The processing speed of SQNN is 100 times faster than that of experts.Significance.Deep learning provides a novel approach to automatic SWI quantification and PreLA provides an easy way to label the EEG data with ESES syndromes. The results of the experiments indicate that the proposed method has a high potential for clinical diagnosis and prognosis of epilepsy in children.

SQNN: A Spike-wave index Quantification Neural Network with a pre-labeling algorithm for epileptiform activity identification and quantification in children.

OBJECTIVE: Electrical status epilepticus during slow sleep (ESES) is a phenomenon identified by strong activation of epileptiform activity in the electroencephalogram (EEG) during sleep. For children disturbed by ESES, spike-wave index (SWI) is defined to quantify the epileptiform activity in the EEG during sleep. Accurate SWI quantification is important for clinical diagnosis and prognosis. To quantify SWI automatically, a deep learning method is proposed in this paper. APPROACH: Firstly, a pre-labeling algorithm (PreLA) composed of the adaptive wavelet enhanced decomposition and a slow-wave discrimination rule is designed to efficiently label the EEG signal. It enables the collection of large-scale EEG dataset with fine-grained labels. Then, an SWI Quantification Neural Network (SQNN) is constructed to accurately classify each sample point as normal or abnormal and to identify the abnormal events. SWI can be calculated automatically based on the total duration of abnormalities and the length of the signal. MAIN RESULTS: Experiments on two datasets demonstrate that the PreLA is effective and robust for labeling the EEG data and the SQNN accurately and reliably quantifies SWI without using any thresholds. The average estimation error of SWI is 3.12%, indicating that our method is more accurate and robust than experts and previous related works. The processing speed of SQNN is 100 times faster than that of experts. SIGNIFICANCE: Deep learning provides a novel approach to automatic SWI quantification and PreLA provides an easy way to label the EEG data with ESES syndromes. The results of the experiments indicate that the proposed method has a high potential for clinical diagnosis and prognosis of epilepsy in children.

[Clinical and genetic analysis of a patient with Angelman syndrome due to a frameshift variant of UBE3A gene].

OBJECTIVE: To explore the genetic basis for a Chinese boy featuring developmental delay and epilepsy. METHODS: Clinical data of the patient was collected. Genomic DNA of the patient and his parents was extracted and subjected to high-throughput sequencing. Pathogenicity of the variant was predicted and validated. RESULTS: Sequencing results showed that the patient has carried a de novo c.1470delA (p.V491Ffs*6) variant of the UBE3A gene, which was predicted to be pathogenic. CONCLUSION: The frameshift variant c.1470delA (p.V491Ffs*6) probably underlay the disorders in this child.

[A case with autosomal dominant mental retardation type 5 due to de novo SYNGAP1 variant].

OBJECTIVE: To investigate the clinical and genetic features of a Chinese girl featuring mental retardation, intellectual disability, language development delay and epilepsy. METHODS: G-banded chromosomal karyotyping was carried out for the child. Genomic DNA of the patient and her parents was extracted and subjected to high-throughput sequencing. The results were analyzed with bioinformatic tools and validated by Sanger sequencing. RESULTS: The karyotype of the child was ascertained as 46,XX. Sequencing result showed that she has carried a de novo heterozygous c.1861C>T (p.R621X) variant of the SYNGAP1 gene. CONCLUSION: The nonsense variant c.1861C>T (p.R621X) of the SYNGAP1 gene probably underlies the disease in this child. Above result has enabled genetic diagnosis and counseling for her family.

[Application of apparent diffusion coefficient in children aged 2-12 years with intellectual disability/global developmental delay who have normal conventional brain MRI findings].

OBJECTIVE: To study the value of fast spin-echo diffusion weighted imaging (TSE-DWI) apparent diffusion coefficient (ADC) in children aged 2-12 years with intellectual disability (ID)/global developmental delay (GDD) who have normal conventional brain MRI findings. METHODS: A total of 578 children with normal conventional brain MRI findings who met the diagnostic criteria for ID/GDD and 375 normal children were enrolled. Their imaging and clinical data were collected. All children underwent scanning with brain TSE-DWI sequence and routine sequence. ADC values of each brain region were compared between normal children with different ages, as well as between children with different degrees of ID/GDD in each age group. The influence of Adaptive Behavior Assessment System-II (ABAS-II) score on ADC values of each brain region was analyzed. RESULTS: For the normal children, the ADC values of the frontal and temporal white matter, the corpus callosum, the inner capsule, the centrum semiovale, the cerebellar dentate nucleus, the optic radiation, the thalamus, the lenticular nucleus, and the caudate nucleus gradually decreased with age (P<0.05). ADC values of the deep white matter, the shallow white matter, the deep gray matter nuclei, and the shallow gray matter increased with the increase in the degree of ID/GDD in the ID/GDD children aged 4-6 years (P<0.05). In the children with ID/GDD, the ADC values of the deep white matter, the shallow white matter, and the deep gray matter nuclei decreased with age (P<0.05). The ADC values of the children with ID/GDD decreased with the increase in ABAS-II score (P<0.05). CONCLUSIONS: ADC can reflect the subtle structural changes of brain regions in children with ID/GDD who have normal conventional brain MRI findings. It may be associated with social adaptation. It can provide an objective basis for the quantitative diagnosis of ID/GDD in children.

[Analysis of DOCK6 gene mutation in a child affected with Adams-Oliver syndrome type 2].

OBJECTIVE: To detect pathogenic mutation of DOCK6 gene in a patient with convulsive seizure and refractory epilepsy. METHODS: CytoScan HD-Array and next generation sequencing were used to detect the potential mutation in the patient. RESULTS: The proband has carried compound heterozygous mutations of c.188C>T (p.Arg63Gln) and c.5374C>T (p.Glu1792Lys) of the DOCK6 gene, which were respectively inherited from his mother and father. Neither mutation was reported previously. Bioinformatic analysis indicated that the two amino acids are highly conserved. Based on the ACMG guidelines, the c.188C>T mutation was predicted to be likely pathogenic, while the c.5374C>T mutation was of uncertain significance. CONCLUSION: The compound heterozygous mutations of c.188C>T (p.Arg63Gln) and c.5374C>T (p.Glu1792Lys) of the DOCK6 gene probably underlie the disease in this patient.