A multicenter clinical study on parent-implemented early intervention for children with global developmental delay.

Objective: Early identification and intervention for children with global developmental delay (GDD) can significantly improve their prognosis and reduce the possibility of developing intellectual disability in the future. This study aimed to explore the clinical effectiveness of a parent-implemented early intervention program (PIEIP) for GDD, providing a research basis for the extended application of this intervention strategy in the future. Methods: During the period between September 2019 and August 2020, children aged 3 to 6 months diagnosed with GDD were selected from each research center as the experimental group and the control group. For the experimental group, the PIEIP intervention was conducted for the parent-child pair. Mid-term and end-stage assessments were performed, respectively, at 12 and 24 months of age, and parenting stress surveys were completed. Results: The average age of the enrolled children was 4.56 ± 1.08 months for the experimental group (n = 153) and 4.50 ± 1.04 months for the control group (n = 153). The comparative analysis of the variation in the progress between the two groups by independent t-test showed that, after the experimental intervention, the developmental quotient (DQ) of locomotor, personal-social, and language, as well as the general quotient (GQ) of the Griffiths Mental Development Scale-Chinese (GDS-C), the children in the experimental group demonstrated higher progress than those in the control group (P < 0.05). Furthermore, there was a significant decrease in the mean standard score of dysfunctional interaction, difficult children and the total level of parental stress in the term test for the experimental groups (P < 0.001 for all). Conclusions: PIEIP intervention can significantly improve the developmental outcome and prognosis of children with GDD, especially in the areas of locomotor, personal-social, and language.

Clinical characterization of Lamb-Shaffer syndrome: a case report and literature review.

BACKGROUND: Lamb-Shaffer syndrome (LAMSHF, MIM 616,803) is a rare neurodevelopmental disorder due to haploinsufficiency of SOX5. Furthermore, studies about the clinical features of LAMSHF patients with same allele of c.1477C > T (p. R493*) are very limited. CASE PRESENTATION: We analyzed the phenotypes of one of our cases and two previously reported cases with c.1477C > T (p. R493*), and reviewed the correlating literature. A de novo heterozygous variation c.1477C > T (p. R493*) in SOX5 was identified in a 4 years and 2 months old boy with global development delay by trio-based whole exome sequencing. We compared our case and previously 2 cases reported with recurrent variation, the overlapping clinical features are global developmental delay or intellectual disability, language delay and scoliosis, but their other clinical characteristics are different. CONCLUSIONS: This study suggests that the clinical features of LAMSHF patients with recurrent variations in the SOX5 gene are different. It is suggested that the LAMSHF-related SOX5 gene should be screened and included as one of the candidate genes for neurodevelopmental disorders of unknown etiology.

[Short-term persistent symptoms in preschool children with mild/common coronavirus disease 2019 caused by Omicron variant infection after discharge: a follow-up study]. / Omicronå˜å¼‚æ ªæ„ŸæŸ“çš„è½»åž‹/æ™®é€šåž‹æ–°åž‹å† çŠ¶ç— æ¯’è‚ºç‚Žå­¦é¾„å‰å„¿ç«¥å‡ºé™¢åŽçŸ­æœŸç›¸å ³æŒç»­ç—‡çŠ¶çš„éšè®¿.

OBJECTIVES: To investigate the persistent symptoms in preschool children after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant infection, and to provide a basis for developing follow-up plans after infection and reducing and preventing related symptoms after infection. METHODS: The children, aged 0-5 years, who had Omicron BA.2 infection and were discharged from the pediatric ward of Shanghai Renji Hospital South Branch from April 13 to May 8, 2022, were enrolled as subjects, and related demographic and clinical data were collected. The children were followed up from the time to SARS-CoV-2 clearance for two consecutive tests with an interval of >24 hours till 4-5 weeks after clearance, and telephone follow-up was performed on the primary caregivers to investigate related persistent symptoms. RESULTS: Among the 103 children who met the inclusion criteria, there were 61 boys and 42 girls, with a median age of 18 months. The primary caregivers who had received two or more doses of COVID-19 vaccine accounted for 64.1% (66/103). Fever (98.1%, 101/103) was the most common symptom in these children, followed by cough/expectoration (63.1%, 65/103), gastrointestinal problems (37.9%, 39/103), loss of appetite (30.1%, 31/103), weakness (27.2%, 28/103), and nasal obstruction/runny nose (16.5%, 17/103). The follow-up at 1 month after discharge reported that 44 children (42.7%) had at least one persistent symptom, including respiratory symptoms in 14 children (13.6%) and gastrointestinal problems in 19 children (18.4%). The children whose primary caregivers received two or more doses of COVID-19 vaccine had a significantly shorter time to SARS-CoV-2 clearance than those whose primary caregivers did not receive or only received one dose of COVID-19 vaccine (P<0.05), while there was no significant difference between the two groups in the proportion of children with at least one persistent symptom (P>0.05). CONCLUSIONS: Nearly half of the preschool children may have related persistent symptoms after SARS-CoV-2 Omicron variant infection, mainly gastrointestinal and respiratory symptoms. Most of the symptoms may be mild, and continuous follow-up is needed to observe their outcomes. Vaccination of COVID-19 vaccine for primary caregivers has a certain protective effect on children.

Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons.

Background: Mutations in CHD8, chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated. Methods: We examined the expression of CHD8 in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of CHD8 deficiency. Results: We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin-positive neurons. In the developing mouse brain, expression of Chd8 peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of Chd8 results in reduced axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which recovers by P3 and P7. Conclusion: Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency.

NSDHL-containing duplication at Xq28 in a male patient with autism spectrum disorder: a case report.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which genetics plays a key aetiological role. The gene encoding NAD(P)H steroid dehydrogenase-like protein (NSDHL) is expressed in developing cortical neurons and glia, and its mutation may result in intellectual disability or congenital hemidysplasia. CASE PRESENTATION: An 8-year-old boy presented with a 260-kb NSDHL-containing duplication at Xq28 (151,868,909 - 152,129,300) inherited from his mother. His clinical features included defects in social communication and interaction, restricted interests, attention deficit, impulsive behaviour, minor facial anomalies and serum free fatty acid abnormality. CONCLUSION: This is the first report of an ASD patient with a related NSDHL-containing duplication at Xq28. Further studies and case reports are required for genetic research to demonstrate that duplication as well as mutation can cause neurodevelopmental diseases.

CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors.

Background: Human genetic and genomic studies have supported a strong causal role of SHANK3 deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying SHANK3 deficiency resulting in ASD is not fully understood. Recently, the zebrafish has become an attractive organism to model ASD because of its high efficiency of genetic manipulation and robust behavioral phenotypes. The orthologous gene to human SHANK3 is duplicated in the zebrafish genome and has two homologs, shank3a and shank3b. Previous studies have reported shank3 morphants in zebrafish using the morpholino method. Here, we report the generation and characterization of shank3b mutant zebrafish in larval and adult stages using the CRISPR/Cas9 genome editing technique. Methods: CRISPR/Cas9 was applied to generate a shank3b loss-of-function mutation (shank3b-/- ) in zebrafish. A series of morphological measurements, behavioral tests, and molecular analyses were performed to systematically characterize the behavioral and molecular changes in shank3b mutant zebrafish. Results: shank3b-/- zebrafish exhibited abnormal morphology in early development. They showed reduced locomotor activity both as larvae and adults, reduced social interaction and time spent near conspecifics, and significant repetitive swimming behaviors. Additionally, the levels of both postsynaptic homer1 and presynaptic synaptophysin were significantly reduced in the adult brain of shank3b-deficient zebrafish. Conclusions: We generated the first inheritable shank3b mutant zebrafish model using CRISPR/Cas9 gene editing approach. shank3b-/- zebrafish displayed robust autism-like behaviors and altered levels of the synaptic proteins homer1 and synaptophysin. The versatility of zebrafish as a model for studying neurodevelopment and conducting drug screening will likely have a significant contribution to future studies of human SHANK3 function and ASD.

Alterations in plasma cytokine levels in chinese children with autism spectrum disorder.

Genetic alterations, together with environmental risk factors during infancy and childhood, contribute significantly to the etiology of autism spectrum disorder (ASD), a heterogeneous neurodevelopmental condition characterized by impairments in social interaction and restricted, repetitive behaviors. Mounting evidence points to a critical contribution of immunological risk factors to the development of ASD. By affecting multiple neurodevelopmental processes, immune system dysfunction could act as a point of convergence between genetics and environmental factors in ASD. Previous studies have shown altered cytokine levels in individuals with ASD, but research in Asian populations are limited. Here, we measured the plasma levels of 11 candidate cytokines in ASD and typically developing (TD) children. The cohort included 41 TD children and 87 children with ASD, aged 1-6 years. We found that as compared to the TD group, children with ASD had higher plasma levels of Eotaxin, TGF-ß1 and TNF-α. The increase in TGF-ß1 level was most significant in males, while the increase in Eotaxin was most significant in females. Eotaxin level negatively correlated with the social affect score (SA) in ADOS, while TNF-α level positively correlated with total development quotient (DQ), measured using GMDS. These pilot findings suggest potentially important roles of Eotaxin, TGF-ß1 and TNF-α in ASD in the Chinese population. Autism Res 2018, 11: 989-999. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Alteration of immune system function is an important risk factor for autism spectrum disorder (ASD). Here we found that the levels of cytokines, including Eotaxin, TGF-ß1 and TNF-α, are elevated in Chinese children with ASD, as compared to typically developing children. The change in TGF-ß1 level was most prominent in boys, while that of Eotaxin was more significant in girls. These results provide evidence for changes in cytokine profile in Chinese children with ASD.

Developmental profiling of ASD-related shank3 transcripts and their differential regulation by valproic acid in zebrafish.

SHANK3 is a scaffolding protein that binds to various synaptic proteins at the postsynaptic density (PSD) of excitatory glutamatergic synapses. SHANK3 is not only strongly implicated in autism spectrum disorders (ASD) but also plays a critical role in human Phelan-McDermid syndrome (22q13.3 deletion syndrome). Accumulated experimental evidence demonstrates that the zebrafish model system is useful for studying the functions of ASD-related gene during early development. However, many basic features of shank3 transcript expression in zebrafish remain poorly understood. Here, we investigated temporal, spatial, and isoform-specific expression patterns of shank3 during zebrafish development on the basis of previous researches and the differential effects of each shank3 transcript expression after exposure to valproic acid (VPA), an ASD-associated drug. At first, we observed that both shank3a and shank3b were barely expressed at very early ages (before 24 h post-fertilization (hpf)), whereas their expression levels were increased and mainly enriched in the nervous system after 24 hpf. Secondly, all of the six shank3 transcripts gradually increased during the first 7 hpf and then decreased. Subsequently, they exhibited a second increasing peak between 1 month post-fertilization (mpf) and adulthood. Thirdly, VPA treatment affected the isoform-specific expression of zebrafish shank3. In particular, the mRNA expression levels of those isoforms that contain a SAM domain were significantly increased, whereas the mRNA expression level of those which contained an ANK domain but without a SAM domain was decreased. To conclude, our findings support the molecular diversity of shank3 in zebrafish and provide a molecular framework to understand the isoform-specific function of shank3 in zebrafish.