Metabolomics of cerebrospinal fluid reveals prognostic biomarkers in pediatric status epilepticus.

AIMS: Status epilepticus (SE) is the most common neurological emergency in pediatric patients. This study aimed to screen for prognostic biomarkers of SE in the cerebrospinal fluid (CSF) using metabolomics. METHODS: Ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) was conducted to identify prognostic biomarkers in CSF metabolomics by comparing the poor outcome group (N = 13) with the good outcome group (N = 15) of children with SE. Differentially expressed metabolites were identified using Mann-Whitney U test corrected by Benjamini-Hochberg and partial least squares discriminant analysis (PLS-DA). RESULTS: The PLS-DA model identified and validated significant metabolic differences between the poor and good outcome groups of children with SE (PLS-DA with R2 Y = 0.992 and Q2 = 0.798). A total of 49 prognosis-related metabolites were identified. Of these metabolites, 20 including glutamyl-glutamine, 3-iodothyronamine, and L-fucose had an area under the curve (AUC) ≥ 80% in prognostic prediction of SE. The logistic regression model combining glutamyl-glutamine and 3-iodothyronamine produced an AUC value of 0.976, with a sensitivity of 0.863 and specificity of 0.956. Pathway analysis revealed that dysregulation of the citrate cycle (TCA) and arginine biosynthesis may contribute to poor SE prognosis. CONCLUSIONS: This study highlighted the prognosis-related metabolomic disturbances in the CSF of children with SE and identified potential prognostic biomarkers. A prognostic prediction model combining glutamyl-glutamine and 3-iodothyronamine with high predictive value was established.

Cortical and subcortical morphological alteration in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder with serious seizures. We aim to explore the brain morphometry of patients with AS and figure out whether the seizure is associated with brain development. METHODS: Seventy-three patients and 26 healthy controls (HC) underwent high-resolution structural brain MRI. Group differences between the HC group and the AS group and also between AS patients with seizure (AS-Se) and age-matched AS patients with non-seizure (AS-NSe) were compared. The voxel-based and surface-based morphometry analyses were used in our study. Gray matter volume, cortical thickness (CTH), and local gyrification index (LGI) were assessed to analyze the cortical and subcortical structure alteration in the AS brain. RESULTS: Firstly, compared with the HC group, children with AS were found to have a significant decrease in gray matter volume in the subcortical nucleus, cortical, and cerebellum. However, the gray matter volume of AS patients in the inferior precuneus was significantly increased. Secondly, patients with AS had significantly increased LGI in the whole brain as compared with HC. Thirdly, the comparison of AS-Se and the AS-NSe groups revealed a significant decrease in caudate volume in the AS-Se group. Lastly, we further selected the caudate and the precuneus as ROIs for volumetric analysis, the AS group showed significantly increased LGI in the precuneus and reduced CTH in the right precuneus. Between the AS-Se and the AS-NSe groups, the AS-Se group exhibited significantly lower density in the caudate, while only the CTH in the left precuneus showed a significant difference. CONCLUSIONS: These results revealed cortical and subcortical morphological alterations in patients with AS, including globally the decreased brain volume in the subcortical nucleus, the increased gray matter volume of precuneus, and the whole-brain increase of LGI and reduction of CTH. The abnormal brain pattern was more serious in patients with seizures, suggesting that the occurrence of seizures may be related to abnormal brain changes.

Disrupted Topological Organization of White Matter Network in Angelman Syndrome.

BACKGROUND: Angelman syndrome (AS) is a genetic disorder that affects neurodevelopment. The investigation of changes in the brain white matter network, which would contribute to a better understanding of the pathogenesis of AS brain, was lacking. PURPOSE: To investigate both local and global alterations of white matter in patients with AS. STUDY TYPE: Prospective. SUBJECTS: A total of 29 AS patients (6.6 ± 1.4 years, 15 [52%] females) and 19 age-matched healthy controls (HC) (7.0 ± 1.5 years, 10 [53%] females). FIELD STRENGTH/SEQUENCE: A 3-T, three-dimensional (3D) T1-weighted imaging by using gradient-echo-based sequence, single shell diffusion tensor imaging by using spin-echo-based echo-planar imaging. ASSESSMENT: Network metrics including global efficiency (Eg ), local efficiency (Eloc ), small world coefficient (Swc), rich-club coefficient (Φ), and nodal degree (ND) were estimated from diffusion MR (dMR) data. Connections among highly connected (hub) regions and less connected (peripheral) regions were also assessed. Correlation between the topological parameters and age for each group was also calculated to assess the development of the brain. STATISTICAL TESTS: Linear regression model, permutation test. P values estimated from the regression model for each brain region were adjusted by false discovery rate (FDR) correction. RESULTS: AS patients showed significantly lower Eg and higher swc compared to HC. Φn significantly increased at higher k-levels in AS patients. In addition, the connections among hub regions and peripheral regions were significantly interrupted in AS patients. DATA CONCLUSION: The AS brain showed diminished connectivity, reflected by reduced network efficiency compared to HC. Compared to densely connected regions, less connected regions were more vulnerable in AS. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

High genetic burden in 163 Chinese children with status epilepticus.

PURPOSE: This study aimed to investigate the genetic aetiology in Chinese children diagnosed with status epilepticus (SE). METHODS: Next-generation sequencing, copy number variation (CNV) analysis, and other genetic testing methods were conducted for children with SE lacking an identifiable non-genetic aetiology. Furthermore, the phenotype and molecular data of patients with SE were retrospectively analysed. RESULTS: Among children with SE lacking an identifiable non-genetic aetiology, 73 out of 163 children (44.8 %) were found to have causative variants associated with SE including 66 monogenic mutations in 22 genes and 7 CNVs. Based on the American College of Medical Genetics and Genomics scoring system, the monogenic variants included 64 pathogenic/likely pathogenic and 2 uncertain significance variants. SCN1A gene mutations (n = 32) were the most common cause, followed by TSC2 (n = 5), CACNA1A (n = 5), SCN2A (n = 4), SCN9A (n = 2) and DEPDC5 (n = 2) gene mutations. Sixteen mutations were identified in single genes. Furthermore, 51 (77.3 %) monogenic mutations were de novo. Age at SE onset < 1 year (odds ratio [OR] = 2.70, 95 % confidence interval [CI]: 1.25-5.83, p = 0.012) and co-morbidity of intellectual disability (OR = 3.36, 95 %CI: 1.61-6.99, p = 0.001) were independently associated with pathogenic genetic variants. CONCLUSION: This study identified genetic aetiology in 44.8 % of patients with SE, which indicates a high burden of genetic aetiology among children with SE in China. Our findings highlight the importance for genetic testing of children with SE that lacks an identifiable non-genetic aetiology.

The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.

There is still no comprehensive description of the general population regarding clinical features and genetic etiology for co-occurring epilepsy and autism spectrum disorder (ASD) in Chinese children. This study was a retrospective study of children diagnosed with epilepsy and ASD from January 1st, 2015, to May 1st, 2018, at the Children's Hospital of Fudan University. A total of 117 patients met the inclusion criteria, and 103 subjects were eligible. Among them, 88 underwent genetic testing, and 47 children (53.4%) were identified as having pathogenic or likely pathogenic variants: 39 had single gene mutations (83.0%, 39/47), and eight had copy number variants (17.0%, 8/47), with SCN1A (14.9%, 7/47) and MECP2 (10.6%, 5/47) gene mutations being the most common. Mutations in other genes encoding voltage-gated ion channels including SCN2A, CACNA1A, CACNA1H, CACNA1D, and KCNQ2 were also common, but the number of individual cases for each gene was small. Epilepsy syndrome and epilepsy-associated syndrome were more common (P = 0.014), and higher rates of poly-therapy (P = 0.01) were used in the positive genetic test group than in the negative group. There were no statistically significant differences in drug-refractory epilepsy, ASD severity, or intellectual disability between the positive genetic test group and the negative genetic group. These data strongly indicate the need for ASD screening in children with epilepsy with voltage-gated ion channel gene variants for better diagnosis and early intervention.

[Autism spectrum disorder-like symptoms in the population with intellectual disability aged 6 to 18 years].

OBJECTIVE: To investigate the incidence of autism spectrum disorder (ASD)-like symptoms in the population with intellectual disability (ID). METHODS: The students with ASD or ID, aged 6-18 years, who studied in a special school in Shanghai from January to June, 2017, as well as the typically developing (TD) population of the same age, who studied in a general school in Shanghai during the same period, were enrolled. Social Responsiveness Scale (SRS) was completed by their parents or other guardians, and the ASD-like symptoms were evaluated. RESULTS: A total of 69 subjects with ASD, 74 subjects with ID and 177 TD subjects were enrolled. The ID group had a significantly higher SRS-positive rate than the TD group (47.3% vs 1.7%; P<0.001) and a significantly lower SRS-positive rate than the ASD group (47.3% vs 87.0%; P<0.001). The total score of SRS was 114±26 in the ASD group, 80±24 in the ID group and 38±19 in the TD group. The ID group had a significantly higher total score of SRS than the TD group (P<0.05), and the score on the subscale of social cognition showed the most significant difference between the two groups (Cohen's d=2.00). There were no significant differences in the total score of SRS and the scores on each subscale of SRS between the mild-to-moderate ID and severe-to-extremely severe ID groups (P>0.05), and there was no significant correlation between SRS score and IQ (P>0.05). CONCLUSIONS: The ID population aged 6-18 years has more ASD-like symptoms than the general population, and ASD screening and intervention should be performed for the ID population as early as possible.

Performance of the Autism Spectrum Rating Scale and Social Responsiveness Scale in Identifying Autism Spectrum Disorder Among Cases of Intellectual Disability.

The Autism Spectrum Rating Scale (ASRS) and the Social Responsiveness Scale (SRS) have been widely used for screening autism spectrum disorder (ASD) in the general population during epidemiological studies, but studies of individuals with intellectual disability (ID) are quite limited. Therefore, we recruited the parents/caregivers of 204 ASD cases, 71 ID cases aged 6-18 years from special education schools, and 402 typically developing (TD) children in the same age span from a community-based population to complete the ASRS and SRS. The results showed that the ID group scored significantly lower on total and subscale scores than the ASD group on both scales (P < 0.05) but higher than TD children (P < 0.05). Receiver operating characteristic analyses demonstrated a similar fair performance in discriminating ASD from ID with the ASRS (area under the curve (AUC) = 0.709, sensitivity = 77.0%, specificity = 52.1%, positive predictive value (PPV) = 82.2%) and the SRS (AUC = 0.742, sensitivity = 59.8%, specificity = 77.5%, PPV = 88.4%). The results showed that individuals with ID had clear autistic traits and discriminating ASD from ID cases was quite challenging, while assessment tools such as ASRS and SRS, help to some degree.