Autism spectrum disorder is a neurodevelopmental condition typified by difficulties in social interactions, repetitive and restricted behaviour and heightened anxiety. Increasing evidence suggests that oxidative stress and neuroinflammatory processes are crucial in the development of these behavioural abnormalities. Ertugliflozin, a sodium-glucose cotransporter-2 inhibitor approved by the FDA for treating type 2 diabetes mellitus, has also been reported to exert antioxidant and anti-inflammatory effects. BTBR T + Itpr3tf/J (BTBR) mice are widely used as a preclinical model of autism spectrum disorder, as they show core autism-like behavioural features. The present study investigated whether ertugliflozin could ameliorate autism spectrum disorder-like behaviour in BTBR mice and explored the associated mechanisms. It was found that ertugliflozin treatment significantly improved social interaction while reducing repetitive behaviours and anxiety-like responses compared with untreated BTBR mice. Ertugliflozin (20 mg/kg/day), administered orally, reduced neuronal loss in the CA1 region of the hippocampus and the prefrontal cortex. In addition, ertugliflozin reduced oxidative stress, as demonstrated by decreased malondialdehyde levels, restoration of glutathione content and improved activities of superoxide dismutase and catalase. A significant suppression of inflammatory cytokines accompanied these biochemical improvements. Furthermore, ertugliflozin significantly inhibited microglial activation in BTBR mice. Collectively, the findings indicate that ertugliflozin alleviates autism spectrum disorder-like behavioural deficits in BTBR mouse models, at least in part, by reducing oxidative stress and neuroinflammation. This study highlights ertugliflozin as a potential therapeutic candidate for the management of autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including impairments in social behavior and communication. The impaired excitatory and inhibitory signals have been implicated in the pathophysiology of social behavior deficits. Altered calretinin (CR)-containing GABAergic interneurons have been observed in ASD, but their roles and underlying mechanisms remain unveiled. Here, using valproic acid (VPA)-exposed mice for CR-Cre and R26::LS-tdTomato (Ai14) model of ASD, we prove that a decreased number of CR interneurons in the mPFC of an animal model for ASD. Double-staining experiments demonstrated the decreased number of CR interneurons stained for c-Fos. Also, reduction in GCaMP7s fluorescence intensity was elicited in sociability and social novelty preference using in vivo fiber photometry, manifesting VPA-induced suppression of CR-positive cell activation. Additionally, we observed the abnormalities of dendrites in CR interneurons including lower dendritic arbors, decreased dendrite complexity, and spine density, paralleled by abnormal development of spine morphology. Intriguingly, the electrophysiological recordings of tdTomato-labeled interneurons revealed that exposure to VPA depressed intrinsic neuronal excitability by decreasing spontaneous and evoked action potential frequencies. These changes were concomitant with impairments of glutamatergic and GABAergic synaptic transmission of CR interneurons. Strikingly, chemogenetic silencing of mPFC CR-expressing interneurons induced social interaction deficits in mice. These sociability impairments can be rescued by optogenetic activation of CR activity in VPA-exposed mice. Our study indicates that prenatal exposure to VPA induced reduced activities, abnormalities in morphological development, and decreased intrinsic excitability as well as accompanying impaired synaptic transmission of CR interneurons. Our findings provide strong evidence for the notion that the CR interneurons has a critical role in the regulation of social behavior in mice and manifest that CR interneurons dysfunction may be implicated in social impairments in ASD.

To summarize the clinical characteristics of a cohort of nine Chinese children with GNAO1 encephalopathy and analyze their genotypes. A retrospective study was conducted on nine children diagnosed with GNAO1 encephalopathy at the Neurology Department of two children’s hospitals between January 2019 and December 2022. Their clinical manifestations, genetic test results, cranial imaging, electroencephalography and treatment were summarized. Their prognosis was followed up. All nine patients presented with moderate-to-severe psychomotor developmental delay and dystonia. Six patients exhibited neonatal or infantile-onset epilepsy, manifesting as generalized tonic-clonic seizure, myoclonic seizure, epileptic spasms, and were diagnosed with developmental and epileptic encephalopathy 17 (DEE 17). Two patients presented with choreoathetosis in infancy without epileptic seizure and were diagnosed with the neurodevelopmental disorder with involuntary movements (NEDIM). One patient presented with choreoathetosis at two years of age and developed focal seizures at six years of age, representing an intermediate phenotype. During a follow-up period of 0.8–3.5 years, one child died due to infection. The remaining eight continued to exhibit psychomotor retardation. Pathogenic or likely pathogenic de novo heterozygous missense variants in GNAO1 were identified in all nine cases. Among these, the variants c.17G > T (p.Ser6Ile), c.119G > C (p.Gly40Ala), and c.748 C > T (p.Leu250Phe) are novel. In conclusion, we analyzed the clinical characteristics and genetic variants of a cohort of nine Chinese children with GNAO1 variants and identified three novel GNAO1 variants. Our study expanded the spectrum of genotypes and phenotypes in GNOA1-associated encephalopathy.

Dysfunction in social interactions is a core symptom of autism spectrum disorder (ASD). Nevertheless, the neural mechanisms underlying social deficits in ASD are poorly understood. By integrating electrophysiological, in vivo fiber photometry, viral-mediated tracing, optogenetic and pharmacological stimulation, we show reduced intrinsic excitability and hypoactivity of SOM interneurons in medial prefrontal cortex (mPFC) in Magel2-deficient mice, an established ASD model, were required to social defects. Chemogenetic inhibition of mPFC SOM-containing interneurons resulted in reduced social interaction in wild-type Magel2 mice. These sociability deficits can be rescued by optogenetic activation by excitability of SOM in the mPFC and mPFCSOM-LS inhibitory pathway in Magel 2 knockout mice. These results demonstrate the hypoactivity for SOM action in the mPFC in social impairments, and suggest targeting this mechanism that may prove therapeutically beneficial for mitigating social behavioral disturbances observed in ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including deficits in social interaction, repetitive and stereotyped behaviors, along with higher levels of anxiety and cognitive impairments. Previous studies demonstrate pronounced reduced density of calretinin (CR)-expressing GABAergic interneurons in both ASD patients and animal models. The object of the current study was to determine the role of CR in ASD-relevant behavioral aberrations. Herein, the mRNA and protein levels of CR in the prefrontal cortex (PFC) of mouse model of ASD based on prenatal exposure to valproic acid (VPA) were determined by qRT-PCR and Western blot analysis, respectively. Moreover, the behavioral abnormalities in naive mice with CR deficiency mediated by recombinant adeno-associated virus (rAAV) were evaluated in a comprehensive testing battery including social interaction, marble burying, self-grooming, open-field, elevated plus maze and novel object recognition tests. Furthermore, the action potential changes caused by CR deficiency were examined in neurons within the PFC in naive mouse. The results show that the mRNA and protein levels of PFC CR of VPA-induced mouse ASD model were reduced. Concomitantly, mice with CR knockdown displayed ASD-like behavioral aberrations, such as social impairments, elevated stereotypes, anxiety and memory defects. Intriguingly, patch-clamp recordings revealed that CR knockdown provoked decreased neuronal excitability by increasing action potential discharge frequencies together with decreased action potential threshold and rheobase. Our findings support a notion that CR knockdown might contribute to ASD-like phenotypes, with the pathogenesis most likely stemming from increased neuronal excitability.

CSNK2B deficiency underlies the pathogenesis of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS). In this study, we present four cases of pediatric seizures caused by de novo variants in CSNK2B, with the aim to reinforce the clinical and variant data pertaining to early genetic factors associated with epilepsy. Trio whole exome sequencing were used to detect variants in the proband and her family members, and bioinformatics annotation was performed for the variant. Sanger sequencing and CSNK2B cDNA sequencing were employed to ascertain the carrier status of additional family members and evaluate the potential impact of variants on splicing. All four cases presented with epilepsy as the initial manifestation, accompanied by global developmental delay, particularly in language and motor developmental delay. Cases 1, 3 and 4 exhibited full-scale tonic-clonic seizures, while case 2 displayed myoclonic and typical absence seizures. Furthermore, case 2 demonstrated delayed growth and development compared to age-matched peers. No abnormality was detected in the head magnetic resonance imaging (MRI). Genetic analysis revealed novel heterozygous variants in the CSNK2B gene in all four cases, including c.175 + 1G > A, c.73-2A > G, c.291 + 1G > A and c.481delA. In case 2, reverse transcription analysis of CSNK2B mRNA revealed the retention of the 3’ end sequence of Intron 2 and deletion of the 5’ end sequence of Exon 3. In treatment, four case received a combination of one to three types of antiseizure medication and rehabilitation training individually. Case 1 continued to experience seizures to varying degrees, while cases 2–4 demonstrated effective seizure control. Overall motor and intellectual development improved in all four cases, however, there was slow recovery in language function. This study elucidates the molecular etiology of epilepsy in four cases with POBINDS and expands the mutational spectrum of pathogenic variants in the CSNK2B, highlighting their impact on splicing. The highly genetic heterogeneous phenotype of POBINDS relies on the detection of pathogenic variants in CSNK2B. Conventional antiseizure medication effectively control seizures, while rehabilitation treatment can significantly improve intelligence and motor function to varying degrees; however, language recovery tends to be relatively slow.

IntroductionActivating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) has been implicated in the pathogenesis of neurodevelopmental disorders and neuromuscular diseases (MIM: 620700). This paper analyzes the clinical manifestations of three patients with developmental delay caused by ASCC3 genetic variation. Additionally, we discuss the previously reported clinical features of these patients along with our own findings, thereby enhancing our understanding of these genetic disorders and providing valuable insights into diagnosis, treatment, and potential interventions for affected individuals.MethodsIn this study, we utilized trio-whole-exome sequencing (Trio-WES) and trio-copy number variations sequencing (Trio-CNV-seq) to analyze three unique families diagnosed with developmental delay caused by variation in ASCC3. Additionally, we retrospectively examined eleven previously reported ASCC3 genetic variations exhibiting similar clinical features.ResultsProband I (family 1) and Proband III (family 3) exhibited global developmental delays, characterized by intellectual disability, motor impairment, language retardation, lower muscle strength, and reduced muscle tone in their extremities. Proband II (family 2) presented poor response and dysphagia during feeding within 7 days after birth, clinical examination displayed short limbs, long trunk proportions, and clenched fists frequently observed alongside high muscle tone in his limbs -all indicative signs of developmental delay. Trio-WES revealed compound heterozygous variants in ASCC3 inherited from their parents. Proband I carried c. [489 dup]; [1897C>T], proband II carried c. [2314C>T]; [5002T>A], and proband III carried c. [5113G>T]; [718delG] variations, respectively.ConclusionThis study present the first report of Chinese children carrying compound heterozygous genetic variants in ASCC3 with LOF variants, elucidating the relationship between these variants and various aspects of intellectual disability. This novel finding expands the existing spectrum of ASCC3 variations.

OBJECTIVE:To explore the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Spastic paraplegia type 5A (SPG5A).METHODS:A pedigree suspected for Hereditary spastic paraplegia (HSP) at Henan Children's Hospital on August 15 2022 was selected as the study subject. Clinical data of the pedigree was collected. Peripheral blood samples were collected from members of the pedigree. Following extraction of genomic DNA, trio-WGS was carried out, and candidate variant was verified by Sanger sequencing.RESULTS:The child, a 1-year-old boy, had presented with microcephaly, hairy face and dorsal side of distal extremities and trunk, intellectual and motor development delay, increased muscle tone of lower limbs, hyperreflexes of bilateral knee tendons, and positive pathological signs. His parents and sister both had normal phenotypes. Trio-WGS revealed that the child has harbored a homozygous c.1250G>A (p.Arg417His) variant of the CYP7B1 gene, for which his mother was heterozygous, the father and sister were of the wild type. The variant was determined to have originated from maternal uniparental disomy (UPD). The result of Sanger sequencing was in keeping with the that of trio-WGS. SPG5A due to maternal UPD of chromosome 8 was unreported previously.CONCLUSION:The child was diagnosed with SPG5A, a complex type of HSP, for which the homozygous c.1250G>A variant of the CYP7B1 gene derived from maternal UPD may be accountable.

Autism spectrum disorder (ASD) is associated with a range of abnormalities characterized by deficits in socialization, communication, repetitive behaviors, and restricted interests. We have recently shown that neuronal nitric oxide synthase (nNOS) expression was decreased in the basolateral amygdala (BLA) of mice after postnatal valproic acid exposure. Neuronal activity-regulated pentraxin (Narp) could contribute to the regulation of the GluA4 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) subunits which are predominantly expressed in interneurons. However, the specific role of nNOS re-expression on excitatory neurotransmitter with relevance to ASD core symptoms in VPA-treated animals remains to be elucidated. Herein, nNOS overexpression using a lentiviral vector and L-arginine-activating PI3K-Akt-mTOR signaling can restore nNOS expression in the BLA induced by VPA. Restoration of nNOS expression in these mice was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, stereotyped/repetitive behaviors, and anxiety-like traits. Most strikingly, re-expression of nNOS upregulated surface expression of Narp and GluA4 in nNOS-positive interneuron as shown by immunoprecipitation and Western blotting. Whole-cell patch-clamp recordings demonstrated that restoration of nNOS had a significant enhancing effect on AMPA receptor-mediated excitatory glutamatergic synaptic neurotransmission, which was inhibited by disturbing the interaction between Narp and GluA4 in acutely dissociated BLA slices. Overall, these data offer a scientific basis for the additional study of nNOS re-expression as a promising therapeutic target by correcting AMPA receptor-mediated synaptic function in ASD and related neurodevelopmental disorders.

We report a case of a Chinese girl who presented with multiple seizure types of epilepsy, followed by motor and intellectual regression, vision impairment, and cerebral and cerebellar atrophy. She carries an unreported compound heterozygous variant of the ASAH1 gene and is diagnosed with spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA-PME), a disorder in which ceramide accumulation in lysosomes due to a decrease in acid ceramidase activity. This case suggests attention to this rare class of deceases involving both the central and peripheral nervous systems.

PurposeAnalyze the relationship between changes in the proportion of X-chromosome deletions and clinical manifestations in children with Turner syndrome (TS).MethodsX-chromosome number abnormalities in 8,635 children with growth retardation were identified using fluorescence in situ hybridization (FISH). Meanwhile, the relationship between the proportion of X-chromosome deletions and the clinical manifestations of TS, such as face and body phenotype, cardiovascular, renal, and other comorbidities in children with TS was analyzed.ResultsA total of 389 children had X-chromosome number abnormalities, with an average age at diagnosis of 9.2 years. There was a significant increase in diagnoses around the ages of 3 and 7 years and highest number of diagnoses at 10 years of age. 130 with XO (complete loss of an X-chromosome), 205 with XO/XX, 8 with XO/XXX, 23 with XO/XX/XXX, 19 with XO/XY, and 4 with XO/XY/XYY. Body and facial phenotypes increased with higher mosaicism proportions, with a relatively high correlation shown with Pearson correlation analysis (r = 0.26, p = 1.7e-06). The incidence of congenital heart malformations was 25.56%, mainly involving a bicuspid aortic valve, and were more common in patients who had complete loss of an X-chromosome. However, this relationship was not present for renal disease (p = 0.26), central nervous system, thyroid, or liver disease.ConclusionThe mosaicism (XO/XX) is the most common karyotype of TS in screened cases. The phenotypes in children with TS may increase with the proportion of X-chromosome deletions, but the renal disease and comorbidities did not show the same characteristics.

The inflammatory process mediated by nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain comprising 3 (NLRP3) inflammasome plays a predominant role in the neurological dysfunction following traumatic brain injury (TBI). SB332235, a highly selective antagonist of chemokine receptor 2 (CXCR2), has been demonstrated to exhibit anti-inflammatory properties and improve neurological outcomes in the central nervous system. We aimed to determine the neuroprotective effects of SB332235 in the acute phase after TBI in mice and to elucidate its underlying mechanisms. Male C57BL/6J animals were exposed to a controlled cortical impact, then received 4 doses of SB332235, with the first dose administered at 30 min after TBI, followed by additional doses at 6, 24, and 30 h. Neurological defects were assessed by the modified neurological severity score, while the motor function was evaluated using the beam balance and open field tests. Cognitive performance was evaluated using the novel object recognition test. Brain tissues were collected for pathological, Western blot, and immunohistochemical analyses. The results showed that SB332235 significantly ameliorated TBI-induced deficits, including motor and cognitive impairments. SB332235 administration suppressed expression of both CXCL1 and CXCR2 in TBI. Moreover, SB332235 substantially mitigated the augmented expression levels and activation of the NLRP3 inflammasome within the peri-contusional cortex induced by TBI. This was accompanied by the blocking of subsequent production of pro-inflammatory cytokines. Additionally, SB332235 hindered microglial activity induced by TBI. These findings confirmed the neuroprotective effects of SB332235 against TBI, and the involved mechanisms were in part due to the suppression of NLRP3 inflammasome activity. This study suggests that SB332235 may act as an anti-inflammatory agent to improve functional outcomes in brain injury when applied clinically.

Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental disorders, characterized by social interaction deficit, stereotyped or repetitive behaviors. Apart from these core symptoms, a great number of individuals with ASD exhibit higher levels of anxiety and memory deficits. Previous studies demonstrate pronounced decrease of γ-aminobutyric acid B1 receptor (GABAB1R) protein level of frontal lobe in both ASD patients and animal models. The aim of the present study was to determine the role of GABAB1R in ASD-related behavioral aberrations. Herein, the protein and mRNA levels of GABAB1R in the prefrontal cortex (PFC) of sodium valproic acid (VPA)-induced mouse ASD model were determined by Western blot and qRT-PCR analysis, respectively. Moreover, the behavioral abnormalities in naive mice with GABAB1R knockdown mediated by recombinant adeno-associated virus (rAAV) were assessed in a comprehensive test battery consisted of social interaction, marble burying, self-grooming, open-field, Y-maze and novel object recognition tests. Furthermore, the action potential changes induced by GABAB1R deficiency were examined in neurons within the PFC of mouse. The results show that the mRNA and protein levels of GABAB1R in the PFC of prenatal VPA-induced mouse ASD model were decreased. Concomitantly, naive mice with GABAB1R knockdown exhibited ASD-like behaviors, such as impaired social interaction and communication, elevated stereotypes, anxiety and memory deficits. Patch-clamp recordings also revealed that GABAB1R knockdown provoked enhanced neuronal excitability by increasing action potential discharge frequencies. Overall, these findings support a notion that GABAB1R deficiency might contribute to ASD-like phenotypes, with the pathogenesis most likely resulting from enhanced neuronal excitability. SUBHEADINGS: GABAB1 Knockdown Induces Behavioral Aberrations with ASD.

Objective:To investigate the clinical and genetic characteristics of proline-rich transmenbrane protein 2 (PRRT2) gene mutations in 19 children.Methods:The clinical and pedigree data of 19 children with PRRT2 gene mutations admitted to our hospital between January 2018 and July 2021 were retrospectively analyzed for characteristics of the mutation and clinical phenotypes.Results:A total of 19 probands from 19 families had heterozygous mutations in the PRRT2 gene. Among the probands, 13 were males and 6 were females. A total of 17 children had one parent carrying the same mutation, while 2 others had de-novo mutations. The patterns of seizure included focal seizures or focal seizures followed by generalized seizures, and generalized seizures. Among them, 15 had base duplication mutations (c.649dupC, p.Arg217Profs*8), 2 had base deletion mutations (c.649delC, p.Arg217Glufs*12), 1 had 2 disease-causing gene mutations (PRRT2, c.649dupC, p.Arg217Profs*8, and SPAST gene c.349C>T p.Arg117*), and 1 had a nonsense mutation (c.46G>T, p.Glu16*) which was novel and previously unreported. Thirteen children were diagnosed with benign familial infantile epilepsy (BFIE), 2 with paroxysmal kinesigenic dyskinesia (PKD), 2 with benign infantile epilepsy (BIE), and 2 with infantile convulsions with paroxysmal choreoathetosis (ICCA) .Conclusion:The PRRT2 gene mutations are genetic culprits of BFIE, PKD, BIE and ICCA. Of these, c.649dupC is a hotspot mutation, and c.46G>T is a previously unreported pathogenic mutation.

ObjectiveThis study presents the clinical phenotypes and genetic analysis of seven patients with benign familial infantile epilepsy (BFIE) diagnosed by whole-exome sequencing. MethodsThe clinical data of seven children with BFIE diagnosed at the Department of Neurology, Children's Hospital Affiliated to Zhengzhou University between December 2017 and April 2022 were retrospectively analyzed. Whole-exome sequencing was used to identify the genetic causes, and the variants were verified by Sanger sequencing in other family members. ResultsThe seven patients with BFIE included two males and five females ranging in age between 3 and 7 months old. The main clinical phenotype of the seven affected children was the presence of focal or generalized tonic-clonic seizures, which was well controlled by anti-seizure medication. Cases 1 and 5 exhibited predominantly generalized tonic-clonic seizures accompanied by focal seizures while cases 2, 3, and 7 displayed generalized tonic-clonic seizures, and cases 4 and 6 had focal seizures. The grandmother and father of cases 2, 6, and 7 had histories of seizures. However, there was no family history of seizures in the remaining cases. Case 1 carried a de novo frameshift variant c.397delG (p.E133Nfs*43) in the proline-rich transmembrane protein 2 (PRRT2) gene while case 2 had a nonsense variant c.46G > T (p.Glu16*) inherited from the father, and cases 3-7 carried a heterozygous frameshift variant c.649dup (p.R217Pfs*8) in the same gene. In cases 3 and 4, the frameshift variant was de novo, while in cases 5-7, the variant was paternally inherited. The c.397delG (p.E133Nfs*43) variant is previously unreported. ConclusionThis study demonstrated the effectiveness of whole-exome sequencing in the diagnosis of BFIE. Moreover, our findings revealed a novel pathogenic variant c.397delG (p.E133Nfs*43) in the PRRT2 gene that causes BFIE, expanding the mutation spectrum of PRRT2.

The in�ammatory process mediated by nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain comprising 3 (NLRP3) in�ammasome plays a predominant role in the neurological dysfunction following traumatic brain injury (TBI). SB332235, a highly selective antagonist of chemokine receptor 2 (CXCR2), has been demonstrated to exhibit anti-inammatory properties and improve neurological outcomes in the central nervous system. We aimed to determine the neuroprotective effects of SB332235 in the acute phase after TBI in mice and to elucidate its underlying mechanisms. Male C57BL/6J animals were exposed to a controlled cortical impact, then received 4 doses of SB332235, with the �rst dose administered 30 min after TBI, followed by additional doses at 6, 24, and 30 hours. Neurological defects were assessed by the modi�ed neurological severity score, while the motor function was evaluated using the beam balance and open �eld tests. Cognitive performance was evaluated using the novel object recognition test. Brain tissues were collected for pathological, Western blot, and immunohistochemical analyses. The results showed that SB332235 signi�cantly ameliorated TBI-induced de�cits, including motor and cognitive impairments. Moreover, SB332235 substantially mitigated the augmented expression levels and activation of the NLRP3 in�ammasome within the peri-contusional cortex induced by TBI. This was accompanied by the blocking of subsequent production of pro-inammatory cytokines. Additionally, SB332235 hindered microglial activity induced by TBI. These �ndings con�rmed the neuroprotective effects of SB332235 against TBI, and the involved mechanisms were in part due to the suppression of NLRP3 in�ammasome activity. This study suggests that SB332235 may act as an anti-inammatory agent to improve functional outcomes in brain injury when applied clinically.

Objective:To summarize the clinical phenotype and genetic characteristics of biallelic variation in HPDL leading to neurodevelopmental disorders with progressive spasticity and cerebral white matter abnormalities. Methods:The clinical and genetic data of 3 cases with neurodevelopmental disorders confirmed in the Department of Neurology of the Affiliated Children′s Hospital of Zhengzhou University from February 2018 to June 2022 were analyzed. The second-generation sequencing method was used to sequence the HPDL gene and the first-generation Sanger sequencing was used to verify the family members, and the characteristics of gene variants were summarized, and the 3 cases were treateds and followed-up. Results:Among the 3 children with neurodevelopmental disorders, 2 were females and 1 was male, and the age of onset was 25 days to 11 years of birth. In the clinical phenotypes, cases 1 and 2 were children with Leigh-like syndrome with infancy onset, with recurrent seizures, intelligent backwardness, language and motor delay, lactic acid increase, acidosis. Cranial magnetic resonance plain scan suggested deepening of the sulcus in the bilateral cerebral hemisphere, abnormal symmetrical signals in the basal ganglia, dorsal thalamus, cerebral peduncles and brainstem, expansion of the supratentorial ventricle, and thinning of the corpus callosum. And cranial magnetic resonance spectroscopy suggested visible lactate peaks in the measurement area of bilateral putamen lesions. Case 3 presented with spastic paraplegia, early motor retardation, and late spastic gait. The plain skull magnetic resonance imaging scan showed no abnormalities. In the 3 cases, the whole exon genome sequencing showed the heterozygous variant c.26_.28delGCC(p.Cys9_His10delinsTyr) and the parent missense heterozygous variant c.788C>T(p.Thr263Met), the paternal truncated variant c.1051C>T(p.Gln351 *) and the parent frameshift variant c.995de1C(p.Thr332Mfs * 9), the parent missense variant c.781C>G (p.Leu261Val) and the parent truncated variant c.721C>T (p.Gln241 *). The c.26_28delGCC(p.Cys9_His10delinsTyr) was an unreported site mutation. No abnormalities were found in chromosomal copy number variation and mitochondria-related genes. Cases 1 and 2 were treated with anti-seizure drugs and cocktail, and the seizure was under effective control; case 3 was treated with comprehensive treatment and rehabilitation function training, and exercise and intelligence were improved. Conclusions:The clinical phenotype of the biallelic variant in HPDL was Leigh-like syndrome and hereditary spastic paraplegia, characterized by compound heterozygous variant, including whole code, missense, frameshift, and truncated variants. Biallelic variation in HPDL was found to be the genetic etiology of the 3 probands.

本人很荣幸被聘请为中国临床案例成果数据库(以下简称"案例库")学术委员会罕见病学组委员,并参加了2021年4月25日在北京召开的罕见病学组成立会,与中华医学会杂志社魏均民社长、案例库编辑部李静主任及全国其他罕见病专家共同探讨数据库的建设方案,并提出拙见.

OBJECTIVETo analyze the clinical phenotype and genetic variant of a child with Snijders Blok-Campeau syndrome (SBCS).METHODSA child who was diagnosed with SBCS in June 2017 at Henan Children's Hospital was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected and the extraction of genomic DNA, which was subjected to trio-whole exome sequencing (trio-WES) and genome copy number variation (CNV) analysis. Candidate variant was verified by Sanger sequencing of his pedigree members.RESULTSThe main clinical manifestations of the child have included language delay, intellectual impairment and motor development delay, which were accompanied with facial dysmorphisms (broad forehead, inverted triangular face, sparse eyebrows, widely spaced eyes, narrow palpebral fissures, broad nose bridge, midface hypoplasia, thin upper lip, pointed jaw, low-set ears and posteriorly rotated ears). Trio-WES and Sanger sequencing revealed that the child has harbored a heterozygous splicing variant of the CHD3 gene, namely c.4073-2A>G, for which both of his parents were of wild-type. No pathogenic variant was identified by CNV testing.CONCLUSIONThe c.4073-2A>G splicing variant of the CHD3 gene probably underlay the SBCS in this patient.

目的 观察癫痫患儿规范应用抗癫痫发作药物(antiseizure medications,ASMs)或联合糖皮质激素治疗后低纤维蛋白原血症发生情况及严重程度,探讨抗癫痫治疗后发生低纤维蛋白原血症的因素和治疗结局.方法 33例应用ASMs或联合糖皮质激素规范治疗后发生低纤维蛋白原血症的癫痫患儿,确诊低纤维蛋白原血症后给予人纤维蛋白原、必要时降低丙戊酸钠药物剂量等治疗.记录癫痫发作类型、综合征类型、病因、治疗后发生低纤维蛋白原血症的中位时间、发生低纤维蛋白原血症时的治疗方案;于抗癫痫治疗前、诊断低纤维蛋白原血症时、低纤维蛋白原血症治疗次日及治疗后1个月检测纤维蛋白原(fibrinogen,Fib)、凝血酶原时间、凝血酶时间、活化部分凝血活酶时间、纤维蛋白降解产物、D-二聚体、中性粒细胞计数、白细胞计数、血红蛋白、血小板计数.随访至2022年8月,观察患儿低纤维蛋白原血症复发情况.结果 33例发作类型为痉挛发作24例,强直-阵挛发作6例,强直痉挛发作2例,肌阵挛发作1例;婴儿癫痫性痉挛综合征21例;病因不明14例,结构性病因13例,遗传性病因6例;1例因不易止血发现且合并轻度肝功能损伤,余32例在随访期间常规检测血常规、凝血功能时发现.诊断低纤维蛋白原血症时,33例中32例应用丙戊酸钠,其中26例(含21例婴儿癫痫性痉挛综合征)应用糖皮质激素联合丙戊酸钠等ASMs,1例应用糖皮质激素联合左乙拉西坦、托吡酯及氯硝西泮,6例未应用糖皮质激素(5例应用丙戊酸钠联合其他ASMs,1例单用丙戊酸钠).诊断低纤维蛋白原血症时Fib水平[0.930(0.850,0.980)g/L]低于抗癫痫治疗前[2.460(2.140,2.675)g/L](Z=-5.013,P＜0.001),凝血酶时间[(20.676±1.756)s]长于抗癫痫治疗前[(18.284±1.605)s](t=7.478,P＜0.001),活化部分凝血活酶时间[(34.803±5.446)s]短于抗癫痫治疗前[(40.447±5.402)s](t=-6.030,P＜0.001).31例诊断低纤维蛋白原血症时Fib水平＜1.0 g/L,静脉滴注人纤维蛋白原,30例应用丙戊酸钠者同时口服左卡尼汀,次日低纤维蛋白原血症纠正;2例诊断低纤维蛋白原血症时Fib水平为1.0 g/L,口服左卡尼汀并降低丙戊酸钠剂量后低纤维蛋白原血症得到纠正.33例低纤维蛋白原血症治疗次日Fib水平[1.950(1.515,2.490)g/L]高于诊断低纤维蛋白原血症时(P＜0.05),凝血酶原时间[(12.564±1.140)s]、凝血酶时间[(17.491±1.515)s]均短于诊断低纤维蛋白原血症时[(13.752±1.591)、(20.676±1.756)s](P＜0.05);低纤维蛋白原血症治疗1个月Fib水平[1.550(1.390,1.659)g/L]高于诊断低纤维蛋白原血症时(P＜0.05),凝血酶时间[(17.680±1.465)s]短于诊断低纤维蛋白原血症时(P＜0.05),活化部分凝血活酶时间[(37.601±5.728)s]长于诊断低纤维蛋白原血症时(P＜0.05).中位随访32.75(24.90,43.88)个月,1例间隔2个月再次发生低纤维蛋白原血症,再次静脉滴注人纤维蛋白原并降低丙戊酸钠剂量后纠正,余患儿未再发生低纤维蛋白原血症.结论 应用丙戊酸钠或联合糖皮质激素治疗、发作类型为婴儿癫痫性痉挛综合征的癫痫患儿易发生低纤维蛋白原血症,临床应注意监测癫痫患儿凝血功能,发现低纤维蛋白原血症后及时处理,减少相关出血并发症.