NEXMIF mutations in intellectual disability and epilepsy: A report of 2 cases and literature review / 中南大学学报(医学版)

More than 100 genes located on the X chromosome have been found to be associated with X-linked intellectual disability (XLID) to date, and NEXMIF is a pathogenic gene for XLID. In addition to intellectual disability, patients with NEXMIF gene mutation can also have other neurological symptoms, such as epilepsy, abnormal behavior, and hypotonia, as well as abnormalities of other systems. Two children with intellectual disability and epilepsy caused by NEXMIF gene mutation were treated in the Department of Pediatrics, Xiangya Hospital, Central South University from March 8, 2017 to June 20, 2020. Patient 1, a 7 years and 8 months old girl, visited our department because of the delayed psychomotor development. Physical examination revealed strabismus (right eye), hyperactivity, and loss of concentration. Intelligence test showed a developmental quotient of 43.6. Electroencephalogram showed abnormal discharge, and cranial imaging appeared normal. Whole exome sequencing revealed a de novo heterozygous mutation, c.2189delC (p.S730Lfs*17) in the NEXMIF gene (NM_001008537). During the follow-up period, the patient developed epileptic seizures, mainly manifested as generalized and absent seizures. She took the medicine of levetiracetam and lamotrigine, and the seizures were under control. Patient 2, a 6-months old boy, visited our department due to developmental regression and seizures. He showed poor reactions to light and sound, and was not able to raise head without aid. Hypotonia was also noticed. The electroencephalogram showed intermittent hyperarrhythmia, and spasms were monitored. He was given topiramate and adrenocorticotrophic hormone (ACTH). Whole exome sequencing detected a de novo c.592C>T (Q198X) mutation in NEXMIF gene. During the follow-up period, the seizures were reduced with vigabatrin. He had no obvious progress in the psychomotor development, and presented strabismus. There were 91 cases reported abroad, 1 case reported in China, and 2 patients were included in this study. A total of 85 variants in NEXMIF gene were found, involving 83 variants reported in PubMed and HGMD, and the 2 new variants presented in our patients. The patients with variants in NEXMIF gene all had mild to severe intellectual disability. Behavioral abnormalities, epilepsy, hypotonia, and other neurological symptoms are frequently presented. The phenotype of male partially overlaps with that of female. Male patients often have more severe intellectual disability, impaired language, and autistic features, while female patients often have refractory epilepsy. Most of the variants reported so far were loss-of-function resulted in the reduced protein expression of NEXMIF. The degree of NEXMIF loss appears to correlate with the severity of the phenotype.

Application of ventricular shunt for children with post-infective hydrocephalus / 中南大学学报(医学版)

To investigate the effects of ventricular shunt placement in children with post-infective hydrocephalus.
 Methods: A total of 24 cases of post-infectious hydrocephalus, who received ventricular shunt, were enrolled. Age, gender, disease progression, clinical manifestation, laboratory data, treatment, prognosis, complication, and sequela for each patient were retrospectively reviewed.
 Results: Of the 24 cases, 8 had a full recovery, 11 had slight sequela, 2 had severe sequela, 1 was in vegetative state, and 2 died because of bacterial meningitis and tubercular meningitis. Epilepsy, mental impairment, visual and hearing damage were the main sequelae.
 Conclusion: Ventricular shunt is the preferred treatment in children with post-infective hydrocephalus, which shows positive clinical efficacy and can improve the long-term prognosis of such patients.

ORAI1 variation induced combined immunodeficiency: a case report and literature review / 中华儿科杂志

Objective@#To summarize the clinical manifestations and gene variations of combined immunodeficiency caused by ORAI1 variation with a case report and literature review.@*Methods@#The clinical data of the patient who was diagnosed with ORAI1 variation caused combined immunodeficiency in the Department of Pediatrics in Xiangya Hospital of Central South University in February 2018 were extracted and analyzed. The literature till August 2018 was searched with key words of 'ORAI1', and 'immunodeficiency' in both English and Chinese in the database of China national knowledge infrast ructure (CNKI), Wanfang and Pubmed.@*Results@#The patient was a 15 months old girl with acute onset of bilateral ptosis after upper respiratory tract infection, which was rapidly progressed to systemic myasthenia and accompanied with recurrent respiratory tract infection during the treatment. The patient poorly to responded immunomodulatory therapy and anti-infection therapy. Laboratory tests demonstrated decreased complement C3 and NK cell (CD3-CD56+), increased anti-thyroglobulin, thyroid peroxidase antibody and B lymphocyte (CD3-CD19+), and slightly increased anti-acetylcholine receptor antibody. Genetic analysis showed the homozygous variation of ORAI1 gene exon l c.12 G>T (p.E4D), with heterozygostty of both parents. There were only 4 papers reporting this disease in the literature review. A total of 7 patients with ORAI1 gene variation were reported, including 3 homozygous variations, 2 heterozygous variations and 2 complex heterozygous variations. The clinical manifestations included early onset recurrent infection, congenital hypotonia, elevated serum IgA and IgM, decreased NK cells, and family history of hereditary diseases. Four of the 7 reported cases died of pulmonary infection and sepsis, and the other 3 survived with low muscular tone and poor self-care ability.@*Conclusions@#The most common clinical manifestations of ORAI1 variation caused combined immunodeficiency are recurrent infection and congenital hypotonia. Myasthenia induced recurrent respiratory tract infection is an important factor of poor prognosis in severe patients. There is a lack of effective treatment for this disease, and the prognosis is poor.

Immunotherapy and prognosis of autoimmune encephalitis / 中华实用儿科临床杂志

Autoimmune encephalitis(AE) is one of the most rapidly developing research fields in pediatric neurology.Previous studies have indicated that delayed-use or non-use of immunotherapy will lead to poor prognosis.Therefore, this article summarizes the current opinion of immunotherapy and prognostic factors for AE in order to provide treatment guidance for clinicians.

Diagnosis and treatment of 12 cases of febrile infection-related epilepsy syndrome / 中国医师杂志

Objective@#To investigate the clinical features, diagnosis and treatment of febrile infection-related epilepsy syndrome (FIRES).@*Methods@#The clinical data of 12 children with FIRES admitted to Xiangya Hospital of Central South University from 2015 to 2018 were retrospectively analyzed. The basic information, clinical manifestations, electroencephalogram, imaging examination, treatment and prognosis were analyzed.@*Results@#Of the 12 patients, 7 were male and 5 were female. The age of onset was (7.0±3.7)years (1.3 year to 13 years). The average hospitalization time (34-86 days, median 52 days). Twelve patients were healthy before the disease, and had fever before convulsion. The interval between fever and seizure was (3.5±1.7)days (1-7 days). The status epilepticus and consciousness deficit were the main clinical manifestations. The electrogram of 8 patients showed status epilepticus when admitted. 12 patients had disturbance of consciousness; the acute episodes were focal seizures (100%, 12/12) and generalized tonic-clonic seizures (41.7%, 5/12). All patients used 3-5 antiepileptic drugs (median 4), all treated with hormones and gamma globulin. 4 patients with ketogenic diet (KD) were treated within 2 weeks of onset, and the average duration from onset to electroencephalogram (EEG) improvement was (19.2±5.0)days. In 8 patients who did not use KD within 2 weeks of onset, the average duration from onset to EEG improvement was (29.9±9.6)days.@*Conclusions@#FIRES is more common in normal children with school age. The main manifestation is refractory status epilepticus in the days after acute fever, focal episodes of seizures, anti-epileptic drug resistance. Early initiation of KD produces a favorable prognosis.

Diagnosis and treatment of 12 cases of febrile infection-related epilepsy syndrome / 中国医师杂志

Objective To investigate the clinical features,diagnosis and treatment of febrile infection-related epilepsy syndrome (FIRES).Methods The clinical data of 12 children with FIRES admitted to Xiangya Hospital of Central South University from 2015 to 2018 were retrospectively analyzed.The basic information,clinical manifestations,electroencephalogram,imaging examination,treatment and prognosis were analyzed.Results Of the 12 patients,7 were male and 5 were female.The age of onset was (7.0 ± 3.7)years (1.3 year to 13 years).The average hospitalization time (34-86 days,median 52 days).Twelve patients were healthy before the disease,and had fever before convulsion.The interval between fever and seizure was (3.5 ± 1.7) days (1-7 days).The status epilepticus and consciousness deficit were the main clinical manifestations.The electrogram of 8 patients showed status epilepticus when admitted.12 patients had disturbance of consciousness;the acute episodes were focal seizures (100％,12/12) and generalized tonic-clonic seizures (41.7％,5/12).All patients used 3-5 antiepileptic drugs (median 4),all treated with hormones and gamma globulin.4 patients with ketogenic diet (KD) were treated within 2 weeks of onset,and the average duration from onset to electroencephalogram (EEG) improvement was (19.2 ± 5.0)days.In 8 patients who did not use KD within 2 weeks of onset,the average duration from onset to EEG improvement was (29.9 ± 9.6) days.Conclusions FIRES is more common in normal children with school age.The main manifestation is refractory status epilepticus in the days after acute fever,focal episodes of seizures,anti-epileptic drug resistance.Early initiation of KD produces a favorable prognosis.

Treatment strategies for congenital heart disease in infants with severe pneumonia / 中南大学学报(医学版)

To observe the results of different treatment of congenital heart disease (CHD) complicated with severe pneumonia in infants.
 Methods: A total of 27 infants with CHD and severe pneumonia were admitted to the Department of Pediatrics, Xiangya Hospital from January 2014 to December 2014, of whom 18 were male and 9 were female. The average age was 2.0-19.0(5.9±4.3) months, with an average body weight of 3.3-10.0 (5.8±1.8) kg. Infants were treated with a strategy of complete control of the lung infection before surgery (internal medicine group). From January 2015 to December 2015, 29 infants with same condition were admitted, of whom 15 were males and 14 females. The average age was 2.0-27.0 (6.1±3.9) months, with an average body weight of 3.1-8.0 (4.8±1.0) kg. Infants were treated with a strategy of combined treatment (combined treatment group), in which early surgical treatment were performed after a short time antibiotics and supportive treatment.
 Results: One nosocomial death in internal medicine group, with an average hospital stay for 3-26 (11±6) d. Further surgeries were performed in 5 patients after discharge with no surgical death. The mean preoperative hospital stay in combined treatment group was 1-21 (10±6) d. The mean total hospital stay for combined treatment group was 14-48 (24±9) d and the mean postoperative hospital stay was 6-35 (14±7) d. One patient died soon after surgery in combined treatment group. Thirty-day follow-up found that no other patient died in combined treatment group, and 6 patients died in internal medicine group. The 30-day mortality was 3.4% in combined treatment group and 22.2% in internal medicine group (P<0.01).
 Conclusion: Infant congenital heart disease complicated with severe pneumonia requires early surgical treatment, which contributed to the control of pulmonary infection and reduce mortality.

Clinical analysis of 51 children with seizure secondary to tuberous sclerosis / 中国医师杂志

Objective To analyze the clinical characteristics and treatment of children with tuberous sclerosis (TSC) complicated with epilepsy,so as to improve the level of diagnosis and treatment and improve the prognosis of children with TSC.Methods The clinical data of TSC children complicated with epilepsy diagnosed and followed up in Xiangya Hospital of Central South University were collected and analyzed retrospectively.Results Of the 51 children,49 (96.1％) had their first visit because of epileptic seizures.Their electroencephalogram (EEG) showed epileptiform discharges during the epileptic period.The therapeutic effect of vigabatrin on TSC patients with spastic seizures was significantly different from that of antiepileptic drugs alone or in combination.Conclusions Epileptic seizure is the most common reason for first visit and seizure control will affect the prognosis of children to a large extent.Vigabatrin had remarkable effect on TSC patients with spasm seizure,and rapamycin has broad prospects in the treatment of children with TSC.

Recurrent fever, bulging fontanelle and elevated white blood cell / 中华实用儿科临床杂志

This patient presented with fever,seizure and bulging fontanelle when he was 6-month-old.According to the investigations,white blood cell (WBC),erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) increased significantly,and Streptococcus Pneumonia grew in both blood and cerebrospinal fluid (CSF).He responded to standard antibiotic treatment poorly even it lasted long enough.At the same time,the inflammation seemed to be over-activated,the WBC level was still elevated,high fever continued.Thus they thought of primary immunodeficiency and sent blood sample for gene panel testing (Sanger sequencing) but got negative result.At last,they added steroid together with anti-tuberculosis drug therapy,his temperature as well as the intracranial pressure became better ever since.At the age of 1 year and 1 month,he got another Streptococcus Pneumonia meningitis,while he was still on anti-tuberculosis drug therapy and tapering off steroid.At this time,he presented with coarse hair,hypohidrosis and delayed eruption of teeth,which strongly indicated Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID).NEMO is the most common gene responsible for EDA-ID and locates on X chromosome.It has a pseudogene named IKBKGP which locates downstream of NEMO.IKBKGP and NEMO share 3-10 exons with the homology of 99.8％,which makes it difficult to find out most real mutations within NEMO with Sanger sequencing.Then they performed PCR with the primer starting upstream of the shared exons.Finally,they found out the pathogenic mutation [c.505G ＞ C(p.A169P)] of NEMO,which has been reported.This finding led us to make the right diagnosis as well as the proper treatment and the prognosis for this patient.

Clinical features and treatment of epilepsy with myoclonic-atonic seizures in children / 中华实用儿科临床杂志

Objective To summarize the clinical features,treatment and prognosis of epilepsy with myoclonic-atonic seizures (MAE),in order to provide the data for treatment choice.Methods The clinical data of 7 cases diagnosed as MAE between June 2014 and February 2017 from Department of Pediatrics,Xiangya Hospital of Central South University,were obtained and analyzed.The clinical data included gender,onset age,seizure types,electroencephalography (EEG) pattern,brain magnetic resonance imaging (MRI),genetic testing,treatments,outcome,and so on.Results In 7 cases,5 cases were male and 2 cases were female.Ages of onset were 16 months to 52 months.All patients had myoclonic-atonic and myoclonic seizures.Background EEG activity showed diffuse slow delta waves in all patients.The EEG recordings showed 1.5-3.5 Hz generalized spike-and-wave and polyspike-and-wave in all cases.Chromosome testing,copy number variations (CNVs) and exome-sequencing studies (trios) were performed in 3 cases,in which 1 case was found normal,1 case had mutation for CLN6 (c.434A ＞T) and 1 case had mutation for SLC6A1 (c.714 + 1G ＞ A) were found.Six cases were seizure-free.Seizures were controlled by combination of antiepileptic drugs (AEDs) in 2 cases.The seizures of 2 cases were controlled by adrenocorticotropic hormone (ACTH) and AEDs.The seizures of 2 cases were controlled by ketogenic diet (KD) and AEDs,and 1 case experienced a seizure reduction.Seven patients showed better EEG findings after treatment.Cognitive decline was observed in all cases.Conclusion Diagnosis of MAE relies on the clinical manifestations of epileptic seizures,EEG findings,as well as neurological manifestation.Genetic factors have been considered to play an important role in the etiology of MAE.Combination of Valproate and other AEDs is effective in drug treatment.KD and ACTH have been shown to have superior efficacy compared with traditional medical treatment.

The clinical characteristics and molecular genetics of infantile neuroaxonal dystrophy: The current research progress / 中国医师杂志

Infantile neuroaxonal dystrophy (INAD) is a rare autosome-recessive disease characterized by progressive motor and cognitive regression.The PLA2G6 gene is its causative gene,which encodes calcium-independent phospholipase A2 enzyme (iPLA2-VIA).The diagnosis of INAD is difficult because of its clinical heterogeneity,and the rate of misdiagnosis is high.The purpose of this study is to describe the clinical characteristics,molecular genetics,treatment and prognosis of INAD to improve the acknowledgement of INAD in medical workers and to help make an early diagnosis of INAD.

Morphology and differentially expressed proteins in hippocampus of mesial temporal lobe epilepsy model of immature rats induced by pilocarpine / 中南大学学报(医学版)

OBJECTIVE@#To examine the changes of morphology and differentially expressed proteins in hippocampus at the latent stage of chronic mesial temporal lobe epilepsy (MTLE) in immature rats, and to explore the global mechanism of chronic MTLE at a new point.@*METHODS@#MTLE models of immature rats were induced by lithium-pilocarpine. The rats were divided into 2 groups randomly: a control group (n=20) and an MTLE model group (n=20). At the latent stage, nissl and Timm staining were performed to evaluate the cell loss and mossy fiber sprouting. The differentially expressed proteins were separated by 2-dimensional polyacrylamide gel electrophoresis (2-DE) combined with matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF-MS) technology. Western blot was used to determine the differentially expression levels of partial proteins.@*RESULTS@#Neuron loss and abnormal mossy fiber sprouting were obviously observed in the hippocampus in the MTLE model group; 2-DE patterns of hippocampus of the MTLE model group in latent stage and the control group were established. Thirty-one differential proteins were identified by MALDI-TOF-MS, which were categorized into several groups by biological functions: synaptic and neurotransmitter release related proteins, cytoskeletal proteins, cell junctions proteins, energy metabolism and mitochondrial proteins, biological enzymes, cellular structure related proteins, signal regulating molecular and others. The expression levels of partial proteins determined by Western blot were similar to the changes of proteomics.@*CONCLUSION@#The differentially expressed proteins of synapse-related proteins such as dynamin-1, neurogranin and ubiquitin, which cause the synapse reorganization and mossy fiber terminal sprouting related to the formation of abnormal excitatory network, probably play critic roles in the mechanism of MTLE.

Clinical characteristics of osteopetrosis in 4 children / 中南大学学报(医学版)

Four boys (2 months to 8 years old) were diagnosed with autosomal recessive form of osteopetrosis. Symptoms manifested in the first few months of life in 3 patients, and there was family history in 1. Primary symptoms included anemia, thrombocytopenia, hepatosplenomegaly, failure to thrive, recurrent infectious history and macrocephaly. The typical radiological images on plain radiogram were diffuse sclerosis, bone modelling defects at the metaphyses of long bones, "bone-in-bone" appearance, and "sandwich" vertebrae. Bone marrow biopsy showed markedly reduced platelets. Osteopetrosis refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. Diffuse sclerosis leads to crowding of the bone marrow, resulting in anemia and extramedullary hemopoiesis. Hematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and offers the best chance of longer-term survival.

Diagnosis and emergency treatment of increased intracraniai pressure in children / 中国小儿急救医学

Increased intracranial pressure is one of the most severe complications with significant mortality in children,so early diagnosis and treatment of this disorder is critical to save the patient's life.This article reviews etiologies,pathophysiology,and general principles of diagnosis and management of increased intracranial pressure.Based on primary diseases and clinical presentations,the goal of therapeutic strategy is to decrease intracranial pressure,avoid neurologic sequelae,and improve the outcome in patients.

Molecular mechanism for change in permeability in brain microvascular endothelial cells induced by LPS / 中南大学学报(医学版)

Objective To investigate the molecular mechanism for change in permeability in brain microvascular endothelial cells (bEnd.3) induced by lipopolysaccharide (LPS). Methods Monolayers of bEnd.3 were exposed to LPS,in the presence or absence of exoenzyme C3 transferase. We monitored the monolayer barrier integrity by transendothelial electrical resistance assay (TEER),activity of RhoA by pull down assay,NF-κB by luciferase reporter assay,and F-actin dynamic structure by Rhodamine-phalloidin staining. Results Incubation of monolayers with LPS caused substantial barrier hyperpermeability. Under the had been treated for 3 and 12 h with LPS (P＜0.05). Such effects could be inhibited partly by pretreatment of RhoA inhibitor exoenzyme C3 transferase. LPS activated RhoA and NF-κB at 0.5 h. The C3 transferase could significantly reverse the NF-κB activation (P＜0.05). The F-actin rearrangments displayed in a time-dependent manner and occurred originally after the stimulation of LPS for 3 h,which could be diluted by the pretreatment of C3 transferase as well. Conclusion LPS induces the disruption of F-actin cytoskeleton and brain microvascular endothelial barrier integrity,in part,through RhoA and NF-κB activation. The mechanism underlying this pathophysiological effect of RhoA is to influence the disruption of the F-actin cytoskeleton by regulating NF-κB activites.