[Factors influencing the occurrence of small for gestational age at different degrees]. / ä¸åŒç¨‹åº¦å°äºŽèƒŽé¾„å„¿å‘ç”Ÿçš„å½±å“å› ç´ åˆ†æž.

OBJECTIVES: To investigate the factors influencing the occurrence of small for gestational age (SGA) at different degrees and provide a basis for early identification of severe SGA cases. METHODS: Neonatal and maternal prenatal information were retrospectively collected from January 2018 to December 2022 at Peking University People's Hospital. The neonates were divided into three groups: severe SGA group (birth weight below the 3rd percentile for gestational age and sex), mild SGA group (birth weight ≥3rd percentile and <10th percentile), and non-SGA group (birth weight ≥10th percentile). An ordered multinomial logistic regression model was used to analyze the factors influencing the occurrence of SGA at different degrees. RESULTS: A total of 14 821 neonates were included, including 258 cases (1.74%) in the severe SGA group, 902 cases (6.09%) in the mild SGA group, and 13 661 cases (92.17%) in the non-SGA group. The proportions of preterm births and stillbirths were higher in the severe SGA group compared to the mild SGA and non-SGA groups (P<0.0125). The proportion of neonatal asphyxia was higher in both the severe SGA and mild SGA groups compared to the non-SGA group (P<0.0125). Ordered multinomial logistic regression analysis showed that maternal pre-pregnancy underweight (OR=1.838), maternal pre-pregnancy obesity (OR=3.024), in vitro fertilization-embryo transfer (OR=2.649), preeclampsia (OR=1.743), connective tissue disease during pregnancy (OR=1.795), nuchal cord (OR=1.213), oligohydramnios (OR=1.848), and intrauterine growth restriction (OR=27.691) were all associated with a higher risk of severe SGA (P<0.05). Maternal parity as a multipara (OR=0.457) was associated with a lower likelihood of severe SGA (P<0.05). CONCLUSIONS: Maternal pre-pregnancy underweight, maternal pre-pregnancy obesity, in vitro fertilization-embryo transfer, preeclampsia, connective tissue disease during pregnancy, oligohydramnios, nuchal cord, and intrauterine growth restriction are closely related to the occurrence of more severe SGA. Maternal parity as a multipara acts as a protective factor against the occurrence of severe SGA.

Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods.

BACKGROUND: Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported. RESULTS: Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR. CONCLUSIONS: Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.

POLR3-related leukodystrophy caused by biallelic POLR3A and 1C pathogenic variants: a single-center experience.

Objectives: This study aimed to investigate the clinical, radiological, and genetic features of POLR3-related leukodystrophy caused by mutations in POLR3A or POLR1C. Methods: Fourteen Chinese patients with POLR3-related leukodystrophy were enrolled in this cross-sectional observational study. The clinical manifestations, brain MRI and genetic tests of the patients were evaluated. Results: Thirteen patients had biallelic variants in POLR3A (92.9%), and one had biallelic variants in POLR1C (7.1%). The median age at disease onset was 9 months. A total of 85.7% of the patients presented with motor delay, abnormal gait, and intelligence disability in the first 2 years of life. Intellectual disability can be categorized based on its severity. It varied from mild (which involves difficulty concentrating) to very severe (with no smiling or laughing or never being able to speak since birth). Short stature was observed in all patients, and delayed dentition was observed in 64.3% of them. Furthermore, three out of 14 patients had myopia. Hypomyelination was invariably present in all patients, whereas myelination of the basal ganglia was preserved in only six out of 14 patients. All the mutations were compound heterozygous and included missense (n = 25), deletion (n = 1), and splice site variants (n = 2). A total of 78.6% of the patients with POLR3A were identified as carrying the c.1771-6C>G variant or the c.1771-7C>G variant. Conclusion: The phenotypic diversity of POLR3-HLD associated with pathogenic variants ranges from mild to very severe for neurological and non-neurological symptoms. Most patients presented symptoms in the first 2 years of life. The c.1771-6C>G or c.1771-7C>G variant is the most frequent mutation site in POLR3A in Chinese individuals.

Glucocorticoid use and varying doses on the long-term outcomes of offspring born to patients with systemic lupus erythematosus.

This study aims to assess the impact of non-fluorinated glucocorticoid use and varying doses on the long-term physical, neurological, and social-emotional development outcomes of offspring born to patients with systemic lupus erythematosus (SLE). The goal is to provide guidance on the appropriate dosage of glucocorticoids during pregnancy in SLE patients. We conducted a follow-up study on the offspring of SLE patients who had pregnancies and were admitted to our obstetrics department between January 1, 2016, and September 30, 2021. Patients who received immunosuppressants and dexamethasone were excluded from the study. The SLE patients were categorized into three groups based on their glucocorticoid use during pregnancy: hormone-free group, ≤ 10 mg/day group, and > 10 mg/day group (equivalent to prednisone). Most patients in the three groups were used hydroxychloroquine during pregnancy. We assessed the physical development status, including weight, height (length), and other relevant factors in three groups. Additionally, we utilized the Age and Stages Questionnaires, Third Edition (ASQ-3) to evaluate the development of communication, gross motor, fine motor, problem-solving, and personal-social. The social-emotional development status was assessed using the Age and Stages Questionnaires: Social-Emotional (ASQ: SE). We standardized the weight, height (length), body mass index, and ASQ-3 domain scores of children of different ages and genders into Z-scores for comparison. The results of this study demonstrated no statistically significant differences in the long-term physical development, neurological development, and social-emotional development outcomes of the offspring of SLE patients in three groups. However, while not reaching statistical significance, it was found that the offspring of the > 10 mg/day group had lower height (length) Z-scores and communication Z-scores compared to the other groups.   Conclusion: The use of non-fluorinated glucocorticoids during pregnancy and varying doses did not have a significant impact on the long-term physical, neurological, and social-emotional development outcomes of offspring born to SLE patients. However, the offspring of SLE patients treated with glucocorticoids > 10 mg/day during pregnancy may be necessary to strengthen the monitoring of height (length) and communication skills in the long term. What is Known: • Fetal exposure to glucocorticoids can have implications for the development of multiple systems and may persist after birth, potentially increasing the risk of neurological abnormalities and other diseases. • There is limited research on the long-term development of offspring born to SLE patients, especially the patients treated with glucocorticoids. What is New: • The use of non-fluorinated glucocorticoids during pregnancy and varying doses did not have a significant impact on the long-term outcomes of offspring born to SLE patients. • The offspring of SLE patients treated with glucocorticoids >10 mg/day during pregnancy may be necessary to strengthen the monitoring of height (length) and communication skills in the long term.

[Association of pregnancy factors with cow's milk protein allergy in infants].

OBJECTIVE: To preliminarily explore the association of pregnancy factors with cow's milk protein allergy in infants. METHODS: This study was based on data from a subcohort of a study called genetic susceptibility to cow's milk allergy in Chinese children, including infants born in Peking University People's Hospital between March 1, 2020, and December 31, 2020. The infants were divided into a cow's milk protein allergy (CMPA) group and a control group according to whether they had developed cow's milk protein allergy at the age of 1 year. We retrospectively collected the clinical data of infants and their mothers before and during pregnancy, and analyzed the association of multiple factors during pregnancy with cow's milk protein allergy in infants. RESULTS: A total of 278 infants were enrolled in this study, including 52 infants with CMPA and 226 infants without CMPA. Among them, there were 143 boys and 135 girls. The proportion of male infants in the CMPA group (69.2%) was higher than that in the control group (47.3%), and the difference was statistically significant (P=0.004). There were no significant differences in the distribution of birth weight, gestational age at birth, low-birth-weight infants, premature, umbilical cord entangle neck, and neonatal asphyxia between the CMPA group and the control group (P>0.05). The proportion of mothers complicated with autoimmune diseases, anemia or antibiotics exposure during pregnancy in the CMPA group was higher than that in the control group, and there were statistical differences between the two groups (P < 0.05). There was no significant difference in the distribution of other pregnancy complications between the two groups (P>0.05), such as eclampsia/preeclampsia, chronic hypertension/gestational hypertension, diabetes/gestational diabetes, thyroid diseases, and so on. There was no significant difference in the overall distribution of some blood routine indexes during pregnancy between the CMPA group and the control group (P>0.05). Multivariate Logistic regression analysis showed that male infant, mothers complicated with autoimmune diseases or anemia, antibiotic exposure during pregnancy were independent risk factors for cow's milk protein allergy. CONCLUSION: Male infant, mothers complicated with autoimmune diseases or anemia, antibiotic exposure during pregnancy were independent risk factors for cow's milk protein allergy.

Genotype and phenotype correlation of PHACTR1-related neurological disorders.

BACKGROUND: PHACTR1 (phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. This study aimed to expand the genotype and phenotype of patients with de novo variants in PHACTR1 and analyse the impact of variants on protein-protein interaction. METHODS: We identified seven patients with PHACTR1 variants by trio-based whole-exome sequencing. Additional two subjects were ascertained from two centres through GeneMatcher. The genotype-phenotype correlation was determined, and AlphaFold-Multimer was used to predict protein-protein interactions and interfaces. RESULTS: Eight individuals carried missense variants and one had CNV in the PHACTR1. Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients with missense variants of PHACTR1. They could present with other types of seizures and often exhibit drug-resistant epilepsy with a poor prognosis. One patient with CNV displayed a developmental encephalopathy phenotype. Using AlphaFold-Multimer, our findings indicate that PHACTR1 and G-actin-binding sequences overlap with PPP1CA at the RPEL3 domain, which suggests possible competition between PPP1CA and G-actin for binding to PHACTR1 through a similar polymerisation interface. In addition, patients carrying missense variants located at the PHACTR1-PPP1CA or PHACTR1-G-actin interfaces consistently exhibit the IESS phenotype. These missense variants are mostly concentrated in the overlapping sequence (RPEL3 domain). CONCLUSIONS: Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to IESS. Moreover, our study confirmed that the variants affect the binding of PHACTR1 to G-actin or PPP1CA, resulting in neurological disorders in patients.

Electroclinical Features and Long-Term Photosensitivity Outcome in Patients With Photoparoxysmal Response With Epilepsy.

BACKGROUND: To investigate electroclinical phenotypes and long-term photosensitivity outcome in a large pediatric cohort of patients with epilepsy with photosensitivity. METHODS: Patients with epilepsy with photosensitivity with four or more years of follow-up were included. Sustained terminal remission (STR) of photosensitivity (≥3.5 years) and seizure control were investigated, as well as the prognostic factors of photosensitivity. Furthermore, a cluster analysis was used to study the different subgroups of photoparoxysmal responses (PPR). RESULTS: We included 190 individuals with a median age at diagnosis of photosensitivity of 93.1 months (interquartile range [IQR] 62.8 to 120 months) and a median follow-up duration of 68.5 months (IQR 51.8 to 84 months). STR of photosensitivity was achieved in 97 (51.1%) patients, and the mean time from age at diagnosis of photosensitivity onset to STR was 16.5 months. Age at the last follow-up (9 to 18 years [P = 0.001]), a history of photoconvulsive response (PCR) (P = 0.009), and posterior epileptiform discharges (EDs) of PPRs (P = 0.05) were significantly associated with a lower chance of entering STR according to a Cox proportional hazards model. The subgroup of generalized epilepsy syndrome exhibited 46.2% of eye closure sensitivity and 47.7% of PCR. The rates of focal epilepsy syndrome (cluster 1), generalized epilepsy syndrome (cluster 2), and unclassified epilepsy (cluster 3) were similar and not statistically different in photosensitive outcome (P = 0.527). CONCLUSIONS: Age nine to 18 years, a history of PCR, and posterior EDs of PPRs were the adverse factors affecting photosensitivity, suggesting the effect of age-related brain changes in STR. There was no difference in the prognosis of photosensitivity in different epileptic syndromes.

Astrocyte-derived complement C3 is activated in patients with tuberous sclerosis complex and mediates immune injury: an integrated bioinformatics analysis.

Background: Tuberous sclerosis complex (TSC) is a genetic disorder associated with multiple neurological manifestations. Cortical tubers (CT) are recognized as the hallmark brain lesions of TSC and contribute to neurological and psychiatric symptoms. To understand the molecular mechanism of neuropsychiatric features of TSC, the differentially expressed genes (DEGs) in CT from patients with TSC and those in normal cortex (NC) from participants acting as healthy controls were investigated. Methods: The dataset of GSE16969, which had already been published and described (https://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.2009.00341.x), was downloaded from the Gene Expression Omnibus (GEO), including samples of 4 CT and 4 NC. The R package "limma" was used to screen DEGs in CT and NC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses of the DEGs were conducted using the R package "clusterProfiler". The online software Ingenuity Pathway Analysis (IPA) was used to explore activation/inaction of canonical pathways. The hub gene was selected based on the protein-protein interaction (PPI) network constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and Cytoscape software. Subsequently, the hub genes at messenger (mRNA) and transcriptional levels were tested. We also explored immune cell-type enrichment using the online database xCell, and assessed the correlation between cell types and C3 expression. Then, we verified the source of C3 by constructing TSC2 knockout cells in the U87 astrocyte cell line. The human neuronal cell line SH-SY5Y was used to examine the effects of excessive complement C3 levels. Results: A total of 455 DEGs were identified. A large number of pathways were involved in the immune response process based on the results of GO, KEGG, and IPA. C3 was identified as a hub gene. Complement C3 was also upregulated in the human CT and peripheral blood. Furthermore, based on the enrichment of functions and signaling pathways, complement C3 played a critical role in immune injury in CT of TSC. In the in vitro experiments, we found that excessive complement C3 was derived from TSC2 knockout U87 cells, and there was an increased intracellular reactive oxygen species (ROS) level in SH-SY5Y cells. Conclusions: Complement C3 is activated in patients with TSC and can mediate immune injury.

Case report: An asymptomatic mother with an inborn error of cobalamin metabolism (cblC) detected through high homocysteine levels during prenatal diagnosis.

Background: The most common disorder of the intracellular cobalamin metabolism pathway is the combined methylmalonic acidemia and homocysteinemia, cblC type (cblC). There is a variation in its clinical spectrum ranging from severe neonatal-onset forms that are highly fatal to later-onset forms which are milder. In this study, the first case of an asymptomatic Chinese woman with a defect in congenital cobalamin (cblC type) metabolism at prenatal diagnosis due to elevated homocysteine level is identified. Case presentation: The proband, a male child born to a 29-year-old G1P0 mother, admitted to local hospital with feeding disorder, intellectual disability, seizures, microcephaly, as well as heterophthalmos. The level of the urine methylmalonic was elevated. Equally found were increased blood propionylcarnitine (C3) and propionylcarnitine/free carnitine ratio (C3/C0) and decreased methionine levels. The plasma total homocysteine level was elevated at 101.04 µmol/L (normal < 15 µmol/L). The clinical diagnosis of combined methylmalonic acidemia and homocysteinemia was supported. Four years later, the mother of the boy married again and came to us for prenatal diagnosis exactly 15 weeks after her last menstrual period. Subsequently, there is an increase in the amniotic fluid methylmalonate. The level of the amniotic fluid total homocysteine was marginally high. A considerably elevated amniotic fluid C3 was equally observed. In addition, there is a respective significant increase in the plasma and urine total homocysteine at 31.96 and 39.35 µmol/L. After the sequencing of MMACHC genes, it is found that the boy, a proband carried a homozygous mutation of the MMACHC at c.658_660delAAG. While the boy's mother, she carries two mutations in MMACHC: c.658_660delAAG and c.617G>A. The fetus is a carrier of the MMACHC gene. Following the administration of routine treatment, the mother remained symptom-free in the course of pregnancy, and she gave birth to a healthy boy. Conclusion: Variable and nonspecific symptoms characterized the cblC type of methylmalonic acidemia combined with homocysteinemia. Both biochemical assays and mutation analysis are recommended as crucial complementary techniques.

Additions to the knowledge of the genus Parancistrocerus Bequaert, 1925 from China (Hymenoptera: Vespidae: Eumeninae).

In this paper, three new species, namely Parancistrocerus fragilitergus sp. n. from Guangxi (China), P. elatitergus sp. n. from Sichuan (China), and P. extentitergus sp. n. from Chongqing and Guizhou (China) are described and illustrated in detail. In addition, P. irritatus Giordani Soika, 1972, P. jaferpaloti Girish Kumar & Carpenter, 2016, and P. sulcatus Giordani Soika, 1994 are newly recorded from China. An updated key to the Chinese species of the genus Parancistrocerus is provided.

The ketogenic diet for Dravet syndrome: A multicenter retrospective study.

OBJECTIVE: The ketogenic diet (KD) is one of the main treatments for drug-resistant epilepsy. However, there have been few multicenter reports on the use of the KD for the treatment of Dravet syndrome (DS). The aim of this study was to analyze the efficacy and safety of this approach based on a large number of multicenter cases. METHODS: This was a retrospective, multicenter cohort study from 14 centers in China. All patients were treated with the KD. We compared the effects of KD intervention time, age, and other factors. RESULTS: From March 2014 to March 2020, we treated 114 patients with DS with the KD. The male-to-female ratio was 67:47. The KD median initiation age was 3 y and 4 mo, and the median number of antiseizure medications (ASMs) was 2.4. KD therapy was the first choice for three patients. Exactly 10.5% of the patients started KD therapy after failure of the first ASM therapy, with 35.1% after failure of the second, 44.7% after the third, and 7% after the fourth or more. After KD therapy for 1, 3, 6, and 12 mo, the seizure-free rates were 14%, 32.5%, 30.7%, and 19.3%, respectively; KD efficacy (≥50% reduction in seizure frequency) were 57.9%, 76.3%, 59.6%, and 43%, respectively; the retention rates were 97.4%, 93%, 71.9%, and 46.5%, respectively; and the rates of adverse events were 25.2%, 19.9%, 11%, and 5.7%, respectively. CONCLUSIONS: Real-world, multicenter data analysis showed that the KD is effective for patients with DS and has a low incidence of side effects.

[Factors affecting phenotypes in the patients with MMACHC gene c.609G>A homozygous variant cblC type methylmalonic acidemia combined with homocysteinuria].

OBJECTIVE: To investigate the factors affecting phenotypes in the patients of methylmalonic acidemia combined with homocysteinemia cblC type with MMACHC c.609G>A homologous variant. METHODS: A retrospective study on the clinical manifestations, complications, treatment, and outcome in 164 patients of cblC type with MMACHC c.609G>A homologous variant was conducted. The patients were diagnosed by biochemical and genetic analysis from January 1998 to December 2020. RESULTS: Among the 164 patients, 2 cases were prenatally diagnosed and began treatment after birth. They are 3 and 12 years old with normal physical and mental development. Twenty-one cases were diagnosed by newborn screening. Among them, 15 cases had with normal development. They were treated from the age of two weeks at the asymptomatic period. Six cases began treatment aged 1 to 3 months after onset. Their development was delayed. One hundred and forty-one cases were clinically diagnosed. Their onset age ranges from a few minutes after birth to 6 years old. 110 cases had early-onset (78.0%). 31 cases had late-onset (22.0%). Five of them died. 24 patients lost to follow-up. Of the 141 clinically diagnosed patients, 130 (92.2%) with psychomotor retardation, 69 (48.9%) with epilepsy, 39 (27.7%) with anemia, 30 (21.3%) had visual impairment, 27 (19.1%) had hydrocephalus, 26 (18.4%) had feeding difficulties, 7 (5.0%) with liver damage, and 5 (3.5%) with metabolic syndrome. The frequency of hydrocephalus and seizures was significantly higher in the early-onset group. The urinary methylmalonic acid increased significantly in the patients with epilepsy. During the long-term follow-up, the level of plasma total homocysteine in the seizure-uncontrolled group was significantly higher than that in the seizure-controlled group, the difference had a statistical significance (P<0.05). CONCLUSION: Most of the patients with MMACHC c.609G>A homozygous variant had early-onset disease, with a high mortality and disability rate. If not treated in time, it will lead to neurological damage, resulting in epilepsy, mental retardation, hydrocephalus, and multiple organ damage. Pre-symptomatic diagnosis and treatment are crucial to prevent irreversible neurological damage. Neonatal screening and prenatal diagnosis are important to improve the outcome of the patients.

Plasma apelin and vascular endothelial growth factor levels in preterm infants: relationship to neonatal respiratory distress syndrome.

AIM: The study aimed to determine the association between cord plasma levels of apelin and vascular endothelial growth factor (VEGF) with respiratory distress syndrome (RDS) in preterm infants. METHODS: This case-control study included 120 preterm infants admitted to the neonatal intensive care unit of our hospital between January 2019 and January 2020. The infants were divided into RDS (n = 60) and non-RDS groups (n = 60). The cord plasma apelin and VEGF levels, perinatal characteristics, and neonatal complications were compared between the two groups. RESULTS: The plasma apelin levels in the RDS group were significantly higher than in the non-RDS group (158.9 ± 24.8 vs. 125.2 ± 18.2 pg/mL, respectively), whereas VEGF levels in the non-RDS group were significantly higher than in the RDS group (187.4 ± 28.5 vs. 245.1 ± 44.8 pg/mL, respectively) (both p < .001). Infants with more severe RDS had higher plasma apelin levels and lower plasma VEGF levels. In the receiver operating characteristic curve analysis for the prediction of RDS, a cutoff of 148.4 pg/mL for apelin level yielded a sensitivity of 63.3% and a specificity of 95.0%, whereas a cutoff of 214.2 pg/mL for VEGF level showed a sensitivity of 86.7% and a specificity of 75.0%. Apelin levels were negatively correlated with VEGF levels in infants with RDS (r = 0.84, p < .001). CONCLUSION: Differences in cord plasma apelin and VEGF levels may aid in the early diagnosis and treatment of RDS in preterm infants.

Genetic susceptibility to cow's milk allergy in Chinese children.

BACKGROUND AND OBJECTIVES: Cow's milk allergy (CMA) is the most common food allergy in young children. Previous studies have reported that single-nucleotide polymorphisms (SNPs) are associated with CMA. The extent to which SNPs contribute to the occurrence of CMA is unknown. The purpose of this study was to investigate the independent relevance of genetic predisposition to CMA in Chinese children. METHODS AND STUDY DESIGN: 200 infants with CMA and 799 healthy controls aged 0-12 months were included. Five previously identified genetic variants (rs17616434, rs2069772, rs1800896, rs855791 and rs20541) were genotyped. Logistic regression was used to analyze the genetic associations or their interactions with a family history of allergy on CMA. RESULTS: Among the five SNPs, only IL10 rs1800896 was significantly associated with CMA (odds ratio (OR) 1.60, p=0.042). Each 1-risk allele increase in the genetic risk score (GRS) was suggestively associated with an 11% higher risk of CMA (1.11: 0.99-1.27, p=0.069) and a 45% increased risk of CMA in the GRS high-risk group compared to the GRS low-risk group (1.45: 1.02-2.06, p=0.037). Furthermore, parental allergy also increased the risk of CMA among children (1.87: 1.46-2.39, p<0.001). Importantly, parental allergy exacerbated the genetic effect on the risk of CMA. CONCLUSIONS: The rs1800896 variant in the IL-10 gene is associated with CMA in Chinese children. In addition, the GRS had an interaction with parental history of allergy, implying that genetic risk for CMA was exacerbated among those with parental history of allergy.

Comparing amniotic fluid mass spectrometry assays and amniocyte gene analyses for the prenatal diagnosis of methylmalonic aciduria.

BACKGROUND: Methylmalonic aciduria (MMA), a rare inherited disorder, is the most common organic aciduria in China, and prenatal diagnosis has contributed to its prevention. However, the prenatal diagnosis of MMA using cultured amniocytes or chorionic villi to detect gene mutations is exclusively applicable to families with a definite genetic diagnosis. To evaluate the reliability of mass spectrometry assays for the prenatal diagnosis of MMA, we conducted a retrospective study of our 10 years' experience. MATERIALS AND METHODS: This retrospective compare study reviewed the medical records for maternal and fetuses data for 287 mothers with a family history of MMA from June 2010 to December 2020. Methylmalonate and propionylcarnitine in cell-free amniotic fluid were measured using a stable isotope dilution method (GC/MS) and MS/MS-based method (LC/MS/MS). Total homocysteine (tHcy) was measured by fluorescence polarization immunoassay. Depending on the presence of disease-causing gene mutations in probands, gene studies on amniocytes from 222 pregnant women were performed. RESULTS: For 222 fetuses of the families with definite genetic diagnosis, gene analyses were performed using cultured amniocytes. 52 fetuses were affected by MMA, whereas 170 were "unaffected". For GC/MS and LC/MS/MS, the specificity was 96.5% and 95.9%, sensitivity was 71.2% and 84.6%, respectively. The positive and negative predictive values were 86.0% and 91.6% and 86.3% and 95.3%, respectively. Propionylcarnitine/butyrylcarnitine ratio showed the highest accuracy and could thus serve as a sensitive indicator to identify those at a risk for MMA. When GC/MS and LC/MS/MS were performed in parallel, the specificity was 92.5% and sensitivity was 95.6%. When evaluating tHcy, the positive and negative predictive values were 95.0% and 96.1%, respectively. In 65 fetuses without family genetic diagnosis, 11 were finally confirmed to have MMA and 54 were "unaffected" by amniotic fluid biochemical assays. The 54 children showed normal urine organic acids and healthy development after birth. CONCLUSIONS: Amniotic fluid biochemical assays using GC/MS and LC/MS/MS in parallel increased the accuracy of prenatal diagnosis of MMA. Propionylcarnitine is a more reliable marker than methylmalonic acid in amniotic fluid. Further, tHcy is recommended for the prenatal diagnosis of combined MMA and homocysteinemia.

Hemophagocytic Lymphohistiocytosis Secondary to Juvenile Myelomonocytic Leukemia: A Case Report and Review of the Literature.

RATIONALE: Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic disorder, which is more rarely accompanied by monosomy 5 or deletion of the long arm of chromosome 5q (-5/5q-) or monosomy 5 (5q-/-5), and hemophagocytic lymphohistiocytosis (HLH) is a rare, uncontrolled hyperinflammation condition, which is more rarely secondary to JMML. Up to now, only a few cases of JMML with -5/5q- and HLH secondary to JMML were described. Here we described an extremely rare case of HLH second to JMML with 5q-. PATIENT CONCERNS: The patient had multiple cafe-au-lait-spots at birth and was found that NF1 gene mutation was positive. At his 6 years old, he developed hepatosplenomegaly, anemia, thrombocytopenia, monocyte count 4.12×109/L in peripheral blood, 13% blasts in peripheral blood, and 11% blasts in bone marrow, without BCR/ABL rearrangement, combining with positive NF1 gene mutation, he was diagnosed as JMML. In the bone marrow, there was chromosomal abnormalities with -5/5q-. In the treatment, HLH occurred. DIAGNOSES: The patient was diagnosed as secondary HLH to JMML. INTERVENTIONS: The patient received the chemotherapy treatment of the improved diffuse alveolar hemorrhage protocol, and meanwhile, he prepared for hematopoietic stem cell transplantation. Then on the basis of anti-infection, symptomatic and supportive therapy, he was commenced the treatment according to the HLH-2004 protocol. OUTCOMES: He had a partial response, manifesting that his fever resolved, but the blood coagulation function did not improve, and the severe thrombocytopenia remained. Then, the parents refused the continual treatment, and the child died of intracranial hemorrhage 3 months after the diagnosis of JMML. LESSONS: JMML and HLH were relatively easy to diagnose based on clinical and laboratory results. Due to the low incidence of JMML with -5/5q- and HLH secondary to JMML, no clinical practice guidelines for the treatment of the disease have been established yet. The clinical data of a case of HLH secondary to JMML with 5q- were analyzed, and relevant studies were studied.

Altered gut microbiota correlates with cognitive impairment in Chinese children with Down's syndrome.

Down's syndrome (DS), a common chromosomal disease caused by chromosome 21 trisomy, is the main cause of cognitive impairment in children worldwide. Emerging evidence suggests that the microbiota-gut-brain axis plays a potential role in cognitive impairment. However, data regarding gut microbiota alterations in DS patients remain scarce, especially data from children with DS. This case-control study was conducted to explore the gut microbiota composition in Chinese DS children. Additionally, the potential association between gut microbiota and cognitive function in DS was evaluated. Microbiota communities in the feces of 15 DS subjects and 15 matched controls were investigated using high-throughput Illumina Miseq sequencing targeting the V3-V4 region of 16S rRNA gene. The relationships between gut microbiota composition and DS cognitive function scores were analyzed. The structure and richness of the gut microbiota differed between DS patients and healthy controls. The abundance of Acidaminococcaceae was decreased in DS patients. Moreover, the Kyoto Encyclopedia of Genes and Genomes analysis showed increased modules related to peptidases and pyrimidine metabolism. Overall, we confirmed that gut microbiota alterations occurred in Chinese patients with DS. Additionally, the fecal microbiota was closely related to DS cognitive impairment. Larger cohorts are needed to confirm these findings and to clarify the mechanisms involved. Elucidating these novel findings in the field of microbiota-gut-brain axis will provide a promising strategy for future studies of DS cognitive impairment.

Correlation among gut microbiota, fecal metabolites and autism-like behavior in an adolescent valproic acid-induced rat autism model.

This study aims to understand the relationship between fecal metabolites and gut microbiota in an adolescent valproic acid-induced rat autism model (VPA-exposed offspring). We analyzed the fecal samples of VPA-exposed offspring using 16S rRNA gene sequencing and untargeted metabolomics. Autism-like behavior was evaluated by a three-chamber sociability test and a self-grooming test. Based on these data, we analyzed the association among fecal metabolites, gut microbiota and autism-like behavior. Behavioral tests showed that VPA-exposed offspring displayed typical autism-like behavior. Forty-nine named differential fecal metabolites and 14 enriched KEGG pathways were identified between the VPA and control groups. Five fecal metabolites may be used as characteristic metabolites. The richness and diversity of gut microbiota did not differ between the two groups, while the overall composition of gut microbiota was significantly different. Candidatus_Saccharimonas, Desulfovibrio, [Eubacterium]_xylanophilum_group and Ruminococcus_2 were the characteristic genera of VPA-exposed offspring. Correlation analysis revealed a tight relationship among gut microbiota, fecal metabolites and autistic behavior in VPA-exposed offspring. This study illustrates that specific alterations in gut microbiota and fecal metabolites may be regarded as characteristics of VPA-exposed offspring. The characteristic gut microbiota and fecal metabolites as well as their relationship may play a crucial role in autism-like behavior caused by prenatal exposure to VPA.

Case Report: A Case of Epileptic Disorder Associated With a Novel CNTN2 Frameshift Variant in Homozygosity due to Maternal Uniparental Disomy.

Background: Contactin 2, encoded by CNTN2 on chromosome 1q32.1, is a neural-specific glycoprotein and plays important roles in neurodevelopment. A deleterious homozygous variant in the CNTN2 gene was previously reported to cause autosomal recessive cortical myoclonic tremor and epilepsy. Since then, there has been no further report confirming the association of CNTN2 and epilepsy. Here, we reported one new case, who presented with epilepsy, carrying a novel homozygous frameshift variant in CNTN2. The clinical and genetic features of the patient were reviewed. Case presentation: The male patient presented with preschool age-of-onset neurodevelopmental impairment and focal seizures of temporal origin, and responded to valproate. A trio-whole exome sequencing revealed a novel homozygous frameshift variant in CNTN2 (c.2873_c.2874delCT, p.Thr958Thrfs). The patient's mother was a heterozygous carrier while his father was wild-type; they were both unaffected and non-consanguineous. Further study revealed that maternal uniparental disomy (1q32.1) unmasked the heterozygous variant of CNTN2 in the proband. Conclusions: This case enhanced the gene-disease relationship between CNTN2 and epilepsy, which will help to further understand this emerging disorder.