[A family with early onset myopathy caused by MEGF10 gene defect and literature review].

Objective: To summarize the genetic and clinical phenotypic characteristics of patients with early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) caused by multiple epidermal growth factor 10 (MEGF10) gene defect. Methods: The clinical data of 3 infants in 1 family with EMARDD caused by MEGF10 gene defect diagnosed in the Department of Neonatology, Xiamen Children's Hospital in April 2022 were analyzed retrospectively. Using "multiple epidermal growth factor 10" "myopathy" or "MEGF10" "myopathy" as the key words, and searching the relevant literature reports of CNKI, Wanfang Database and PubMed Database from the establishment of the database to September 2022. Combined with this family, the main clinical information and genotype characteristics of EMARDD patients caused by MEGF10 gene defect were summarized. Results: The proband, male, first infant of monozygotic twins, was admitted to hospital 7 days after birth "due to intermittent cyanosis with weak sucking". The infant had dysphagia accompanied with cyanosis of lips during feeding and crying after birth. Physical examination on admission revealed reduced muscle tone of the extremities, flexion of the second to fifth fingers of both hands with limited passive extension of proximal interphalangeal joints, and limited abduction of both hips. He was diagnosed as dysphagia of newborn, congenital dactyly. After admission, he was given limb and oral rehabilitation training, breathing gradually became stable and oral feeding fully allowed, and discharged along with improvement. The younger brother of the proband was admitted to the hospital at the same time, and his clinical manifestations, diagnosis and treatment process were the same as those of the proband. The elder brother of the proband died at the age of 8 months due to the delayed growth and development, severe malnutrition, hypotonia, single palmoclal crease and weak crying. A whole exon sequencing of the family was done, and found that the 3 children were all compound heterozygous variations at the same site of MEGF10 gene, with 2 splicing variants (c.218+1G>A, c.2362+1G>A), which came from the father and mother respectively, and the new variation was consistent with the autosomal recessive inheritance model. Three children were finally diagnosed as EMARDD caused by MEGF10 gene defect. There are 0 Chinese literature and 18 English literature that met the search conditions. Totally 17 families including 28 patients were reported. There were 31 EMARDD patients including 3 infants from this family. Among them, there were 13 males and 18 females. The reported age of onset ranged from 0 to 61 years. Except for 5 patients with incomplete clinical data, 26 patients were included in the analysis of phenotypic and genotypic characteristics. The clinical features were mainly dyspnea (25 cases), scoliosis (22 cases), feeding difficulties (21 cases), myasthenia (20 cases), and other features including areflexia (16 cases) and cleft palate or high palatal arch(15 cases). Muscle biopsy showed non-specific changes, with histological characteristics ranging from slight muscle fiber size variation to minicores change which was seen in all 5 patients with at least 1 missense mutation of allele. In addition, the adult onset was found in patients with at least 1 missense variant of MEGF10 gene. Conclusions: MEGF10 gene defect related EMARDD can occur in the neonatal period, and the main clinical features are muscle weakness, breathing and feeding difficulties. Patients with myopathy who have at least 1 missense mutation and muscle biopsy indicating minicores change may be relatively mild.

[Clinical analysis of 15 patients with epileptic spasms and focal seizures as a single ictal event in neonatal period].

Objective: To investigate the phenomenon of epileptic spasms (ES) and focal seizures (FS) in a single ictal event (FS-ES phenomenon) and to study the etiology, manifestations, and prognosis of this phenomenon. Methods: The data of the 15 neonates who had ES and FS in a single ictal event, according to video-electroencephalography (VEEG) recording in Department of Neonatology of Children's Hospital of Fudan University during the period of January 2018 to December 2019, was analyzed retrospectively. Results: Of the 15 neonates, 7 were male and 8 were female. Gestational age was 39 (32-42) weeks. Birth weight was 3 100 (1 825-3 850) g. The initial onset age of convulsions was 2 (1-10) days. The age of the first discovery of FS-ES phenomenon was 25 (14-32) days. The age of seizure-free was 7(1-27) months. All of the initial seizure types were FS. The FS-ES phenomenon of 15 patients started with FS. The FS-ES phenomenon manifested in 2 forms: FS followed by ES (12 cases), ES appeared during an FS without interrupting FS (2 cases). In 1 neonate the spasm occurred in both forms. The etiology included genetic factors (9 cases), intracranial infection (1 case), abnormal brain tissue structure (2 cases), and etiology was unknown in 3 cases. All the neonates had a poor prognosis except one. Conclusions: The FS-ES phenomenon in the neonatal period starts with FS. There are various etiologies. Etiologies of most patients are genetic factors. Most of the patients have a poor prognosis.

[Genetic etiology of newborn deaths].

Objective: To explore the genetic etiologies of newborn deaths. Methods: A total of 98 newborns who were recruited to the Neonatal Genome Project of the Children's Hospital of Fudan University and died in the hospital from January 2018 to August 2020 were enrolled in this study. The genetic information and the interventions based on the genetic findings were retrospectively analyzed. T-test, Mann-Whitney U test, Chi square test and Fisher's exact probability test were used to compare the demographic features and clinical characteristics between the patients with or without a genetic finding. Results: Among 98 newborns (55 males and 43 females), there were 63 preterm and 35 term infants, with a gestational age of (33±5) weeks, a birth weight of (2 107±975) g and the age at death of 12 (2,34) days. Sixteen (16%)patients were identified with genetic variants, including 11 with single nucleotide variants, 4 with copy number variants and 1 with both single nucleotide variant and copy number variant. The detected single nucleotide variants were spanning 12 genes, among which 3 were multiple disorders-related, 2 metabolic disorder-related, 2 hematological disorder-related, 2 respiratory disorder-related, 2 cardiovascular disorder-related and 1 skeletal disorder-related. The patients with a positive genetic finding had significant differences in the birth weight ((2 605±940) vs. (2 009±957) g, t=2.283, P=0.025), the gestational age ((36±5) vs. (33±5) weeks, t=2.131, P=0.036), the age at death ((37 (5, 69) vs. 11 (2, 29) days, Ζ=-2.245, P=0.025) and the history of asphyxia at birth (1/16 vs. 46% (38/82), P=0.002)when compared to those without a genetic finding. In addition, the genetic etiology rates of patients who were born term or with a birth weight ≥ 2 000 g were significantly higher than those who were born preterm (29% (10/35) vs. 10% (6/63), P=0.022) or with a birth weight<2 000 g (25% (13/51) vs. 7% (3/46), χ2=5.016,P=0.025), respectively. Six cases were medically actionable based on the genetic findings and the treatments included special diet, applying specific medicine, hematopoietic stem cell transplantation and lung transplantation. Conclusions: Genetic etiologies are not rare in newborn deaths and mainly associated with metabolic disorder, multi-system disorders, hematological disorder, respiratory disorder, cardiovascular disorder and skeletal disorder. Some findings are medically actionable, based on which the specific treatments could be scheduled timely. A genetic etiology should be investigated in newborn deaths especially in those who are term birth or with a birth weight ≥2 000 g or without a history of asphyxia at birth.

[Genotype and phenotype analysis of neonates with neonatal encephalopathy complicated with perinatal hypoxic event].

Objective: To explore the underlying genetic causes of neonatal encephalopathy complicated with perinatal asphyxia. Methods: From the neonates recruited to the Neonatal Genome Project of Children's Hospital of Fudan University between January 2016 and January 2019, 113 neonates with neonatal encephalopathy and acute peripartum or intrapartum event or Apgar score ≤7 were enrolled in this study. The clinical data, laboratory results, the findings of electroencephalograph and magnetic resonance imaging or head ultrasound, and the genetic information were retrospectively analyzed. Results: Of the 133 neonates with neonatal encephalopathy and acute peripartum or intrapartum event or Apgar score ≤7 scores, 77 (57.9%) were males, 56 (42.1%) were female, 56 (42.1%) were delivered via cesarean section, and 77(57.9%) were born by vaginal delivery. Among these cases, 68 (51.1%) were diagnosed of hypoxic ischemic encephalopathy, 25 (18.8%) had intracranial hemorrhage, 20 (15%) were related to genetic diseases, and 5 (3.8%) had sepsis without central nervous infection. A total of 20 cases with positive results by next-generation sequencing test were identified, including 19 cases with pathogenic variations and 1 case with variation of uncertain significance. These 20 cases included 4 cases with congenital myopathy (2 cases of MTM1 gene pathogenic variants, 1 case of ACTA1 and 1 case of RYR1 gene pathogenic variants), 4 cases with genetic syndrome (2 cases of CHD7 gene pathogenic variants, 1 case of PTN11 gene pathogenic variant, and 1 case of NSDHL gene pathogenic variant), 3 cases with metabolic disorders (1 case of OTC gene pathogenic variant, 1 case of MTHFR gene pathogenic variant, and 1 case of ALDH7A1 gene pathogenic variant), 2 cases with epileptic encephalopathy (1 case of KCNT1 and 1 case of PACS2 gene pathogenic variants), 1 case with congenital central hypoventilation syndrome (PHOX2B gene pathogenic variant) and 6 cases with copy-number pathogenic variations. Among these 20 cases, 8(40.0%) neonates were presented with persistent hypotonia, 7(35.0%) neonates with seizures, and 5(25.0%) neonates with congenital malformation. Genetic counseling and further follow-up were performed or suggested for these 20 cases; 4 neonates were deceased, 10 neonates underwent palliative care, and 6 neonates were improved after supportive care and their further follow-up plan were performed in clinics. Conclusions: Genetic diseases are not rare in neonates with neonatal encephalopathy complicated with perinatal hypoxia event. The common causes in these neonates include congenital myopathy, metabolic disorders, genetic syndrome, and epilepsy encephalopathy.

[Genetic screening in early diagnosis of neonatal WAS gene-related disorders].

Objective: To explore the clinical value of genetic screening for early identification of WAS gene-related disorders in newborns. Methods: This was a retrospective study. Neonatal Genome Project from Children's Hospital of Fudan University collected 5 800 high-risk newborns in the neonatal intensive care unit to study the patients' genetic causes using high-throughput sequencing from January 2016 to December 2017. Eleven newborns (all were boys) with pathogenic or likely pathogenic variants in WAS gene were enrolled. Data of clinical characteristics,gene variants and genotype-phenotype correlation were collected and summarized. Results: Eleven patients included 5 cases with Wiskott-Aldrich syndrome (WAS) and 6 cases with X-linked thrombocytopenia (XLT).Two patients with WAS developed clinical manifestations in the early neonatal period,and 3 patients in 5-8 weeks after birth. Three neonates with XLT were hospitalized for other diseases in the first place.Their platelet count was found to be reduced after admission to hospital, and diagnosis was made after genetic testing. Eleven pathogenic or likely pathogenic variants in WAS gene were identified. Among them, 7 were first reported in this study, including 2 frame shift variants c.138delG and c.388_390del, 4 splicing variants c.1453+1G>A,c.734+1G>C,c.135G>A and c.1453+3G>C, and 1 missense variant c.1118C>T. The other 4 reported variants were c.777+1G>A,c.107_108delTT, c.436delC and c.1509_*3delAGTG. Conclusions: The clinical features of WAS gene-related disorders in neonatal period lack specificity. Genetic screening in newborns plays an important role in the early diagnosis of diseases and provides providing evidence for the early intervention.

[Effect of red blood cell transfusion on the oxygenation of mesenteric tissue in premature infants].

Objective: To investigate the effect of red blood cell transfusion on the oxygenation of mesenteric tissue in premature infants. Methods: In this prospective cohort study, preterm infants with gestational age <37 weeks who were treated with red blood cell transfusions were enrolled from June 2017 to March 2018 in Department of Neonatology, Children's Hospital of Fudan University. The infants were categorized into feeding intolerance group and feeding tolerance group according to the feeding intolerance standard. Near-infrared spectroscopy was applied to continuously monitor intestinal oxygen saturation from 2 h before red blood cell transfusion to 48 h after red blood cell transfusion. Intergroup differences of basic conditions were analyzed with t test, Mann-Whitney U test and χ(2) test. Mixed linear model was used to compare intragroup and intergroup differences in intestinal oxygen saturation over time. Results: A total of 73 cases with gestational age <37 weeks were enrolled, of whom 41 were males and 32 were females, with mean gestational age of (30±4)weeks and mean birth weight of (1 543±688)g; there were 33 cases in feeding intolerance group and 42 cases in feeding tolerance group. The average intestinal oxygen saturations at 2 h before blood transfusion, during blood transfusion, 2, 6, 12, 24, and 48 h after transfusion were 0.50±0.07, 0.52±0.07, 0.52±0.08, 0.51±0.08, 0.51±0.07, 0.51±0.08, and 0.51±0.07 respectively in feeding intolerance group and were 0.51±0.04, 0.55±0.04, 0.57±0.05, 0.57±0.04, 0.56±0.04, 0.56±0.04, and 0.56±0.05 respectively in feeding tolerance group. Compared with 2 h before transfusion, intestinal oxygen saturation were increased during transfusion in both group (feeding intolerance group t=4.992, P=0.000; feeding tolerance group t=9.615, P=0.000), however this effect lasted until 48 h after transfusion in feeding tolerance group (t=5.519, 12.409, 10.033, 9.133, 7.983, all P=0.000). Additionally, the increasement of intestinal oxygen saturation over time were lower in feeding intolerance group(F=8.876, P=0.000). Besides, the level of intestinal oxygen saturation was positively correlated with postmenstrual age (PMA)(F=4.863, P=0.031). In infants with PMA<30 weeks, particularly in feeding intolerance group, the level of intestinal oxygen saturation significantly decreased at 2 h after transfusion (t=23.063, P=0.002). Conclusions: Feeding status and PMA may play a role in development of transfusion-associated necrotizing enterocolitis. Red blood cell transfusion may increase the risk for mesenteric ischemia and is more likely to cause necrotizing enterocolitis in preterm infants with PMA <30 weeks as well as feeding intolerance. Clinical Trail: Children's Hospital of Fudan University, NCT02544100.

[Longitudinal observation on the control of intestinal helminthiasis].

OBJECTIVE: To search suitable measure for rapid control intestinal helminthiasis and long-term strengthen efficacy. METHODS: The treatment was taken in egg-positive population of intestinal helminthiasis in 1986-1988. The treatment was carried out only in the selected population in 1989-1992. No measure was taken in 1993-2000. RESULTS: (1) The prevalence rate of hookworm, Ascaris and Trichuris decreased to 3.2%, 37.3% and 3.5% respectively after administration of albendazole twice a year for 3 years. (2) The prevalence rate of hookworm continued to decrease to 0.5% after treatment on selected population. (3) The prevalence rate and the intensity of hookworm has been less than 1% and 10/LPG for 8 years. No hookworm larvae had been isolated from the soil. CONCLUSION: The hookworm transmission was effectively controlled in the study site.

In vivo boron-11 MRI and MRS using (B24H22S2)4- in the rat.

In vivo boron-11 magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were performed on a rat that had been infused with a potential boron neutron capture therapy agent, Na4B24H22S2, using methods for detecting nuclei with a short T2 relaxation time. MRI and MRS were also performed on a euthanized rat that had been similarly infused in vivo. Boron-11 spectral intensities decreased in the living rat over a 25-h period. The results demonstrate the capability of MRI and MRS to noninvasively monitor the distribution and excretion of boron agents in vivo.