OBJECTIVE: To explore the clinical phenotype and genetic characteristics of a child with hereditary Spastic paraplegia type 52 (SPG52) due to variant of AP4S1 gene. METHODS: A child diagnosed with SPG52 at the Department of Pediatrics of the First Affiliated Hospital of Anhui Medical University in May 2010 was selected as the study subject. Whole-exome sequencing (WES) was carried out for the child and his parents. Candidate variants were confirmed by Sanger sequencing. Pathogenicity of the candidate variant was interpreted according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). The study protocol was approved by the Ethics Committee of the Hospital (Ethics No.: PJ2024-04-56). RESULTS: The child had presented with global developmental delay from infancy, and featured progressive lower limb spasticity, contractures, talipes equinovarus, and muscle weakness, but with no significant facial dysmorphism. His first febrile seizure occurred before one year of age, followed by several afebrile seizures. The seizures had remitted after 3 to 4 years of antiepileptic therapy, and electroencephalography was normal. However, he had severe intellectual disability, and MRI revealed reduced white matter. WES identified a homozygous AP4S1 c.289C>T (p.Arg97*) variant in the child, for which both of his parents were heterozygous carriers. The variant was rated as pathogenic based on the ACMG guidelines. Literature review has identified 8 publications on SPG52, involving 18 patients from 12 pedigrees. Combined with our case, 14 had carried homozygous variants of the AP4S1 gene, 3 had compound heterozygous variants, and 2 had heterozygous variants, involving 12 distinct variant sites. The cohort included 7 males and 12 females. All patients exhibited progressive lower limb spasticity and weakness as the primary feature, with certain loss of independent ambulation. Most patients had intellectual disability, some had distinctive facial features, though febrile seizures or epilepsy were common. Electroencephalography often showed increased slow-wave activity. Brain MRI frequently demonstrated ventriculomegaly, a thin corpus callosum, and reduced white matter. CONCLUSION The homozygous c.289C>T (p.Arg97*) variant of the AP4S1 gene probably underlay the pathogenesis of SPG52 in this child. Above discovery has expanded the mutational spectrum of AP4S1 and provided valuable insights for the genetic diagnosis, counseling, and clinical management of SPG52.
Humans ; Male ; Spastic Paraplegia, Hereditary/genetics* ; Child, Preschool ; Female ; Exome Sequencing ; Child ; Infant ; Adaptor Protein Complex 4/genetics* ; Phenotype ; Mutation

Objective:To explore the clinical phenotype and genetic characteristics of a child with hereditary Spastic paraplegia type 52 (SPG52) due to variant of AP4S1 gene. Methods:A child diagnosed with SPG52 at the Department of Pediatrics of the First Affiliated Hospital of Anhui Medical University in May 2010 was selected as the study subject. Whole-exome sequencing (WES) was carried out for the child and his parents. Candidate variants were confirmed by Sanger sequencing. Pathogenicity of the candidate variant was interpreted according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). The study protocol was approved by the Ethics Committee of the Hospital (Ethics No.: PJ2024-04-56).Results:The child had presented with global developmental delay from infancy, and featured progressive lower limb spasticity, contractures, talipes equinovarus, and muscle weakness, but with no significant facial dysmorphism. His first febrile seizure occurred before one year of age, followed by several afebrile seizures. The seizures had remitted after 3 to 4 years of antiepileptic therapy, and electroencephalography was normal. However, he had severe intellectual disability, and MRI revealed reduced white matter. WES identified a homozygous AP4S1 c. 289C>T (p.Arg97*) variant in the child, for which both of his parents were heterozygous carriers. The variant was rated as pathogenic based on the ACMG guidelines. Literature review has identified 8 publications on SPG52, involving 18 patients from 12 pedigrees. Combined with our case, 14 had carried homozygous variants of the AP4S1 gene, 3 had compound heterozygous variants, and 2 had heterozygous variants, involving 12 distinct variant sites. The cohort included 7 males and 12 females. All patients exhibited progressive lower limb spasticity and weakness as the primary feature, with certain loss of independent ambulation. Most patients had intellectual disability, some had distinctive facial features, though febrile seizures or epilepsy were common. Electroencephalography often showed increased slow-wave activity. Brain MRI frequently demonstrated ventriculomegaly, a thin corpus callosum, and reduced white matter. Conclusion:The homozygous c. 289C>T (p.Arg97*) variant of the AP4S1 gene probably underlay the pathogenesis of SPG52 in this child. Above discovery has expanded the mutational spectrum of AP4S1 and provided valuable insights for the genetic diagnosis, counseling, and clinical management of SPG52.

Objective:To explore the clinical phenotype and genetic characteristics of a child with hereditary Spastic paraplegia type 52 (SPG52) due to variant of AP4S1 gene. Methods:A child diagnosed with SPG52 at the Department of Pediatrics of the First Affiliated Hospital of Anhui Medical University in May 2010 was selected as the study subject. Whole-exome sequencing (WES) was carried out for the child and his parents. Candidate variants were confirmed by Sanger sequencing. Pathogenicity of the candidate variant was interpreted according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). The study protocol was approved by the Ethics Committee of the Hospital (Ethics No.: PJ2024-04-56).Results:The child had presented with global developmental delay from infancy, and featured progressive lower limb spasticity, contractures, talipes equinovarus, and muscle weakness, but with no significant facial dysmorphism. His first febrile seizure occurred before one year of age, followed by several afebrile seizures. The seizures had remitted after 3 to 4 years of antiepileptic therapy, and electroencephalography was normal. However, he had severe intellectual disability, and MRI revealed reduced white matter. WES identified a homozygous AP4S1 c. 289C>T (p.Arg97*) variant in the child, for which both of his parents were heterozygous carriers. The variant was rated as pathogenic based on the ACMG guidelines. Literature review has identified 8 publications on SPG52, involving 18 patients from 12 pedigrees. Combined with our case, 14 had carried homozygous variants of the AP4S1 gene, 3 had compound heterozygous variants, and 2 had heterozygous variants, involving 12 distinct variant sites. The cohort included 7 males and 12 females. All patients exhibited progressive lower limb spasticity and weakness as the primary feature, with certain loss of independent ambulation. Most patients had intellectual disability, some had distinctive facial features, though febrile seizures or epilepsy were common. Electroencephalography often showed increased slow-wave activity. Brain MRI frequently demonstrated ventriculomegaly, a thin corpus callosum, and reduced white matter. Conclusion:The homozygous c. 289C>T (p.Arg97*) variant of the AP4S1 gene probably underlay the pathogenesis of SPG52 in this child. Above discovery has expanded the mutational spectrum of AP4S1 and provided valuable insights for the genetic diagnosis, counseling, and clinical management of SPG52.

Objective:To observe the clinical efficacy of mouse nerve growth factor (mNGF) combined with rehabilitation on children with global developmental delay(GDD).Methods:It was a prospective multicenter clinical randomized controlled trial (RCT) involving 120 children with GDD admitted to 5 hospitals in China from May 2020 to January 2022.They were randomly divided into mNGF group and conventional rehabilitation group using block randomization method.All children were managed by standardized rehabilitation after recruitment, and those in the mNGF group were additionally given mNGF injections.All subjects were surveyed using the Gesell Development Diagnosis Schedules(GDDS) at baseline, 90 days and 120 days after treatment, and their developmental quotient (DQ) was recorded.Clinical efficacy was analyzed by the paired t-test, rank sum test and Chi- squared test. Results:After 90 days of treatment and the continuous follow-up to 120 days, the increases in the DQ of gross motor (7.520±13.900 vs.0.450±11.459), fine motor (7.800±15.346 vs.1.250±11.581), adaptive behavior (7.730±13.428 vs.2.100±12.022) and personal-social behavior (6.780±11.651 vs.1.780±10.120) than baseline were significantly higher in mNGF group than those of conventional rehabilitation group (all P<0.05). Serious adverse events and important drug-related medical events were not reported. Conclusions:mNGF combined with rehabilitation effectively enhances the development levels of gross motor, fine motor, adaptive behavior and personal-social behavior, and continuously improves the condition of GDD in children with a high safety.

Objective:To establish Sprague-Dawley (SD) rat models of cognitive impairment through repeated stimulation of lipopolysaccharide (LPS) in the early brain development, and to inquire into the effect of " multi-hits" mediated by inflammatory response on the histology and behavior of SD rat models and related molecular mechanisms.Methods:This study adopted a group design for experiments.The " multi-hits" SD rat models were established by intraperitoneal injection of LPS.According to the random number table method, 24 pregnant rats were randomly divided into 4 groups: control group, LPS1 group, LPS2 group and LPS3 group, 6 rats in each group.In the control group, saline was intraperitoneally injected into rats with gestational age of 18 days and 20-day-old neonatal rats.Rats with gestational age of 18 days were intraperitoneally injected with saline in the LPS1 group, 0.05 mg/kg LPS in the LPS2 group, and 0.1 mg/kg LPS in the LPS3 group.The pups in LPS1-3 groups were all injected intraperitoneally with 1 mg/kg LPS at the postnatal age of 20 days.The motor and cognitive function of the pups were evaluated overall by behavioral experiments such as forelimb suspension tests, grid tests and water maze tests.The relative expression of glial fibrillary acidic protein (GFAP), Notch1 and Jagged1 in brain tissue of pups was mainly detected by Western blot (WB) and histological experiments.One-way ANOVA analysis of variance and independent samples t- test were used to compare data among groups and between groups, respectively. Results:(1) Behavioral experiments: compared with the control group, LPS1-3 groups showed progressive decrease in forelimb suspension time [(34.81±5.66) s, (22.47±4.35) s, and (13.20±4.25) s vs.(43.88 ± 4.85) s], and the number of missteps in the grid experiment increased progressively (16.13±2.90, 20.75±3.10, 25.13±4.45 vs.9.00±2.72). The differences were statistically significant ( F=69.77, 35.59, all P<0.001). Both the escape latency and total distance in Morri′s water maze test increased progressively ( P<0.05). (2) WB experiment: the relative expression levels of GFAP, Notch1 and Jagged1 proteins in LPS1-3 groups were significantly higher than that in the control group ( P<0.05). (3) Hematoxylin-eosin (HE) staining and electron microscope pathology: compared with the control group, LPS1-3 groups had more loosely arranged frontal cortices and more obvious cell pyknosis.Under the electron microscope, the cytoplasm was swelling to varying degrees, mitochondrial cristae were broken, and part of the nuclear membrane was damaged. Conclusions:In the " multi-hits" cognitive impairment model, the damage to the brain tissue structure and behavioral changes of pups may be related to the up-regulation of Notch1/Jagged1 pathway mediated by repeated exposure to LPS.

Chinese rehabilitation guidelines for cerebral palsy (2022) mainly refers to the international evidence-based medicine and relevant guidelines for rehabilitation of cerebral palsy in recent five years.On the basis of the Chinese rehabilitation guidelines for cerebral palsy (2015), combined with the medical literature and research achievements published at home and abroad before June 2022, the evidence-based practice guidelines are revised by combining the common opinions of pediatric rehabilitation experts in China.The content includes introduction, overview, the assessment and intervention guideline for infants at high risk of cerebral palsy, evaluation of children with cerebral palsy under ICF-CY framework, rehabilitation treatment, Traditional Chinese Medicine rehabilitation therapy, rehabilitation nursing, rehabilitation approaches and management.This article interprets the guide in combination with the hot spots of cerebral palsy prevention and treatment at home and abroad, in order to help pediatric rehabilitation workers deepen their understanding of the guidelines and better guide the clinical rehabilitation practice.

Objective:To analyze the microdeletion and microduplication characteristics of pathogenic copy number variations (pCNVs) and clinical phenotypes in children with neurodevelopmental disorders, and to clarify the genetic pathogenic cause of children with neurodevelopmental disorders.Methods:Children who were identified as neurodevelopment disorders such as global developmental delay and mental disorder, by next generation sequencing-based whole genomic copy number variation testing from January 2017 to November 2019 at the First Affiliated Hospital of Anhui Medical University were enrolled, and the clinical phenotypes and pCNVs were reviewed analyzed.Results:There were 36 pCNVs in total 31 children, consisting of 24 microdeletion segments (66.67%)and 12 microduplication segments (33.33%), with sizes ranging from 320.00 kb to 93.26 Mb (mean 11.33 Mb). pCNVs frequently occurred in chromosome 15 , chromosome 8 and chromosome X, there were 9 children with 9 pCNVs in chromosome 15(25.00%), 3 children with 5 pCNVs in chromosome 8(13.89%)and 3 children with 4 pCNVs in chromosome X(11.11%) .The mainly clinical manifestations were motor disorder (30 children, 96.77%), mental disorder (22 children, 70.97%), speech development delay(22 children, 70.97% )accompanied by the malformation(11 children, 35.48%), abnormal face(11 children, 35.48%) and epilepsy(8 children, 25.81%), multisystem abnormalities generally exist in one individual.Conclusion:This study demonstrates the clinical utility of whole genome CNVs testing in the genetic diagnosis of children with neurodevelopment disorders.Genetic pathogenesis of children with neurodevelopmental disorders can be revealed by the analysis of pCNVs.

Objective: To compare the efficacy of goal-activity-motor environment (GAME) therapy and neurodevelopmental therapy (NDT) in the early intervention of high-risk infants with cerebral palsy (IHRCP), and to provide scientific evidence-based medical basis for early intervention of IHRCP. Methods: A total of 62 cases of IHRCP were enrolled in the Children′s Neurological Rehabilitation Center of the First Affiliated Hospital of Anhui Medi-cal University from June 2017 to December 2018.They were divided into GAME group (32 cases) and NDT group (30 cases) according to the admission order.Gross Motor Function Scale (GMFM), Fine Motor Function Measure (FMFM) and Gesell Development Scale (GDS) were used for detection and comparison.The differences among the gross motor, the fine motor score and the developmental quotient (DQ) between two groups before treatment, 9 months after treatment and 12 months after treatment, and the normalization rate and the incidence of cerebral palsy between the two groups at 12 months of age were compared. Results: (1) Motor function was as follows: at 9 months[GAME: (32.63±15.83) scores, (30.03±15.88) scores], [NDT: (33.37±15.61) scores, (29.67±12.54) scores] and at 12 months[GAME: (40.56±15.79) scores, (36.31±14.98) scores], [NDT: (40.47±15.50) scores, (36.73±14.58) scores] after treatment, and GMFM and FMFM scores in GAME and NDT groups were significantly higher than those before treatment[GAME: (27.56±14.24) scores, (21.75±11.35) scores], [NDT: (26.93±14.96) scores, (21.30±10.67) scores], and the differences were significant (all P<0.01), but there was no significant difference between the 2 groups (all P> 0.05). (2) DQ had no significant difference in DQ between GAME group(63.59±10.83) and NDT group (61.59±7.96) before treatment (P>0.05). The total DQ at 9 months, 12 months, the total DQ of GAME group (73.67±12.00, 81.59±13.03) was significantly higher than that of NDT group (66.05±9.54, 75.17±1.92) (all P<0.05). Among them, the improvement of GAME in speech (79.84±16.56, 83.19±17.05) at 9 months and 12 months, and adaptive ability(78.63±16.37, 85.78±13.60) were significantly higher than that of NDT group(71.63±13.36, 72.53±12.77), (68.20±14.97, 77.43±12.10), and the differences were significant (all P<0.05). (3) Prognosis was as follows: at 12 months after treatment, 25 cases in GAME group and 23 cases in NDT group developed into normal children, there was no significant difference in the normalization rate between the 2 groups (P>0.05); the incidence of cerebral palsy was present in 6 cases in GAME group and 5 cases in NDT group, and there was no significant difference between the 2 groups (P>0.05). Conclusions GAME therapy and NDT had significant effects on both gross and fine exercise of IHRCP, and the efficacy of the two methods is similar.Both GAME therapy and NDT can equally promote IHRCP development into normal infants and reduce the incidence of cerebral palsy.

Interpretation of The International Statistical Classification of Diseases and Related Health Problems-11 published by World Health Organization(WHO) and The Diagnostic and Statistical Manual of Mental Disorders of Fifth published by American Psychological Association(APA), and reference of literature in recent 10 years.In order to be in agreement with international standards which used to classify the diagnosis of neurodevelopmental disorders in children and to provide a reference for clinical diagnosis.

Cerebral palsy or high risk of cerebral palsy can be diagnosed accurately and early using the clinical signs and symptoms of cerebral palsy,involves neuroimaging,standardized neurological and standardized motor assess-ments before 6 months' corrected age. When the clinical diagnosis is suspected but cannot be made with certainty,re-commend using the interim clinical diagnosis of high risk of cerebral palsy until a diagnosis is confirmed,because infant with cerebral palsy require and benefit from different early interventions. Before 5 months' corrected age,the most pre-dictive tools for detecting risk are term - age magnetic resonance imaging(MRI),the Prechtl Qualitative Assessment of General Movements(GMs),and the Hammersmith Infant Neurological Examination(HINE). After 5 months' corrected age,the most predictive tools for detecting risk are MRI,HINE and the Developmental Assessment of Young Children. Early diagnosis and early intervention can optimize infant motor and cognitive plasticity,prevent secondary complica-tions. Cerebral palsy - specific early intervention maximizes neuroplasticity and minimizes deleterious modifications to muscle and bone growth and development. Early interventions included Goals - Activity - Motor Enrichment,neurode-velopmental treatment(Bobath,Vojta),Conductive Education and Environmental enrichment. Infants with of cerebral palsy who receive early CIMT have better hand function,and infants with any type and topography of cerebral palsy who receive GAME have better motor and cognitive skills than those who receive usual care.