Compound Heterozygous Variants in a Surviving Patient With Alkuraya-Kucinskas Syndrome: A New Case Report and a Review of the Literature.

Background: Alkuraya-Kucinskas syndrome is an autosomal recessive disorder characterized by brain abnormalities associated with cerebral parenchymal underdevelopment, arthrogryposis, club foot, and global developmental delay. Most reported cases were cases of premature termination of pregnancies or neonatal deaths. To date, limited studies of nine surviving patients with global developmental delay and intellectual disability have been reported. In this study, we report another surviving patient. Methods: Whole-exome sequencing was utilized for the proband, and variants were filtered, annotated, and classified. Candidate variants were validated by Sanger sequencing of the proband and his family. The literature was reviewed; the prognosis among different regions and the variant type was analyzed. Results: A non-synonymous variant [NM_015312.3: exon29: c.4892C>G (p.Pro1631Arg)] was identified and validated in the patient's father. A frameshift duplication [NM_015312.3: exon62: c.10872dupA (p.Arg3625Lysfs*5)] that caused early translation termination was identified in his mother. The literature was reviewed, variants were classified into three regions of KIAA1109, and their survival status was summarized. Conclusion: We reported another survival proband with Alkuraya-Kucinskas syndrome driven by KIAA1109. Our case expands the genotypic spectrum of Alkuraya-Kucinskas syndrome and explored the relationship between the variant region and survival.

Association between acute disseminated encephalomyelitis and thyroid autoimmunity in children.

BACKGROUND: Abnormal thyroid peroxidase antibody (TPOAb) levels are observed in various autoimmune diseases. However, the relationship between TPOAb and pediatric acute disseminated encephalomyelitis (PADEM) remains unclear. This study aimed to investigate the positive rate of TPOAb and thyroid dysfunction in children with acute disseminated encephalomyelitis (ADEM) and assess the relationship between TPOAb and clinical features of PADEM. METHODS: This retrospective single-center case-control study was conducted from April 2017 to April 2019. We enrolled 23 children with ADEM and 23 age- and sex-matched healthy controls. Based on whether they were positive for TPOAb, the children with ADEM were allocated either to the TPOAb+ or TPOAb- group. The median follow-up time was 12 months (6-30 months). Observers were blinded to the patient groupings. We compared the clinical and imaging characteristics of the two groups. RESULTS: Among the 23 patients with PADEM, 47.8% presented with abnormal TPOAb levels, while there were no TPOAb+ cases in the control group. Among the children with ADEM, there were significantly increased TPOAb positive rates and significantly decreased fT3 levels. TPOAb+ and TPOAb- subgroup analysis revealed significant differences in gait, fever, and total IgG. In the TPOAb+ group, there was a significant decrease in TPOAb levels at 2 weeks after ADEM onset. The follow-up of patients who were TPOAb+ at 3 months after onset showed a gradual decrease in their TPOAb levels back to normal. One patient who presented new nervous system symptoms after over 1 month also showed a simultaneous increase in TPOAb levels. There was a significant negative correlation between Glasgow Coma Scale (GCS) scores and TPOAb levels (p = 0.042, r = -0.892). CONCLUSION: There was a negative correlation of TPOAb levels with GCS scores. Therefore, TPOAb levels could be used for the prognosis of patients with PADEM. We recommend determining thyroid function when assessing patients with PADEM during follow-up.

Isolated subacute combined degeneration in late-onset cobalamin C deficiency in children: Two case reports and literature review.

RATIONALE: Subacute combined degeneration (SCD) is a disease caused by decreased vitamin B12 intake or metabolic disorders. It is more common in the elderly and rarely seen in children. Here, we report 2 pediatric cases of SCD in late-onset cobalamin C (CblC) deficiency. PATIENT CONCERNS: The patients complained of unsteady gait. Their physical examination showed sensory ataxia. Magnetic resonance imaging showed classic manifestations of SCD. The serum vitamin B12 level was normal, but urine methylmalonic acid and serum homocysteine levels were high. DIAGNOSIS: The pathogenic gene was confirmed as MMACHC. The 2 patients each had 2 pathogenic mutations C.482 G>A and C.271dupA and C.365A>T and C.609G>A in this gene. They were diagnosed with combined methylmalonic acidemia and homocysteinemia-CblC subtype. INTERVENTIONS: The patients were treated with methylcobalamin 500 µg intravenous injection daily after being admitted. After the diagnosis, levocarnitine, betaine, and vitamin B12 were added to the treatment. OUTCOMES: Twelve days after treatment, the boy could walk normally, and his tendon reflex and sense of position returned to normal. The abnormal gait seemed to have become permanent in the girl and she walked with her legs raised higher than normal. LESSONS: To the best of our knowledge, this is the first report of 2 cases of isolated SCD in children with late-onset CblC disorder. Doctors should consider that SCD could be an isolated symptom of CblC disorder. The earlier the treatment, the lower the likelihood of sequelae.

Long noncoding RNA GAS5 silencing inhibits the expression of KCNQ3 by sponging miR-135a-5p to prevent the progression of epilepsy.

Epilepsy is one of the most common neurological disorders in humans. Recently, long noncoding RNAs (lncRNAs) have been reported to be important players in neurological diseases. Herein, this study aimed to examine the effect of lncRNA GAS5 on the occurrence of epilepsy in rat and cell models of epileptic seizure. The expression of lncRNA GAS5 was measured in the established rat and cell models. The binding sites between lncRNA GAS5 and miR-135a-5p, as well as those between miR-135a-5p and 3' untranslated region of KCNQ3 were predicted by miRDB and Targetscan, separately, followed by verification using dual-luciferase reporter gene assay. The expression of miR-135a-5p was measured in response to the overexpression of lncRNA GAS5. The mRNA and protein levels of KCNQ3 were examined in response to overexpression of miR-135a-5p. Next, the latency of epilepsy and frequency of epileptic seizures were assessed in rats injected with Lv-shGAS5 and Lv-miR-135a-5p in epileptic seizure model. In the rat and cell models, lncRNA GAS5 was highly expressed when epileptic seizure was induced. The expression of miR-135a-5p was decreased by overexpression of lncRNA GAS5. Meanwhile, the mRNA and protein levels of KCNQ3 were decreased in response to knockdown of miR-135a-5p. After the treatment of Lv-shGAS5 and Lv-miR-135a-5p, the average latent period of epilepsy was prolonged and the frequency of seizures was decreased. The key findings of the present study provide evidence emphasizing that lncRNA GAS5 functions as a competitive endogenous RNA of miR-135a-5p to increase expression of KCNQ3, and lncRNA GAS5 silencing inhibited the occurrence and progression of epilepsy.

Partial least squares based identification of Duchenne muscular dystrophy specific genes.

Large-scale parallel gene expression analysis has provided a greater ease for investigating the underlying mechanisms of Duchenne muscular dystrophy (DMD). Previous studies typically implemented variance/regression analysis, which would be fundamentally flawed when unaccounted sources of variability in the arrays existed. Here we aim to identify genes that contribute to the pathology of DMD using partial least squares (PLS) based analysis. We carried out PLS-based analysis with two datasets downloaded from the Gene Expression Omnibus (GEO) database to identify genes contributing to the pathology of DMD. Except for the genes related to inflammation, muscle regeneration and extracellular matrix (ECM) modeling, we found some genes with high fold change, which have not been identified by previous studies, such as SRPX, GPNMB, SAT1, and LYZ. In addition, downregulation of the fatty acid metabolism pathway was found, which may be related to the progressive muscle wasting process. Our results provide a better understanding for the downstream mechanisms of DMD.

Status of asthma control in children and the effect of parents' knowledge, attitude, and practice (KAP) in China: a multicenter study.

BACKGROUND: Asthma is the most common chronic respiratory disease seriously endangering the health of children. But disease awareness and self-management skills are relatively poor in children; parents play an important role in the control of childhood asthma. OBJECTIVE: To investigate the status of asthma control and severity of asthma in children and to identify impact factors. METHODS: We studied 1 tertiary hospital in each of the 29 provinces. A total of 2,960 parents with children with asthma who visited those hospitals were selected for the knowledge, attitude, and practice (KAP) questionnaire survey, and separated into the controlled asthma group and uncontrolled asthma group according to children's asthma conditions in the past 12 months. Multivariate analysis was carried out based on the answers to 28 tested factors. RESULTS: In the past 12 months, 66.0% of children with asthma had asthma attacks, 26.8% visited an emergency room, and 16.2% were hospitalized. The total cost for asthma was significantly higher in the uncontrolled group than controlled group (χ(2) = 23.14, P < .01). Twelve protective factors of asthma control were founded, such as older age of children, long disease course, high KAP scores of parents, compliance with using nasal steroids, and knowledge of "3 or more times recurrent wheezing suggesting asthma." The risk factors were eczema and family history of asthma. CONCLUSION: Children's asthma is poorly controlled. The cost of asthma is significantly higher in uncontrolled asthma than in controlled. The age of children, course of asthma, personal history of allergy, family history of asthma, parents' education level, and parents' KAP are factors that affect asthma control.

[Changes of body weight and galanin in epileptic children treated with topiramate].

OBJECTIVE: Topiramate is a new broad-spectrum anti-epileptic drug. Decreased body weight and appetite are common side effects of topiramate. The side effect affects the growth and development in children greatly. Little is known about the mechanisms of topiramate-induced weight loss and decreased appetite in children with epilepsy in China and abroad. galanin is one of factors that affect appetite. It is a neuroendocrine peptide and play an important role in the control of appetite and body weight in the mechanism of hormone release. The purpose of this study was to explore the mechanism of topiramate-induced weight loss in children with epilepsy and the relation of weight loss with change of galanin, thereby to provide evidences for improvement of quality of life, compliance to treatment and reduce side effects of growth and development in children with epilepsy. METHODS: Totally 61 patients with especial epilepsy were enrolled into this study and the disease was defined by clinical manifestations and electroencephalography (EEG). Among them 32 cases had generalized seizures and 29 had local seizures. Sixteen normal children were enrolled as control group. The patients' age ranged from 0.5 to 14 (4.76 +/- 4.05) years and the patients were instructed to take 0.5 - 1 mg/kg of topiramate per day, with 0.5 - 1 mg/kg every 3 - 5 d increased to maximum of 3 - 8 mg/kg per day. Patients continued receiving the doses for 4 months. All patients' serum galanin levels and body height and weight and hepatic function were detected before and after antiepileptic drugs treatment. The galanin was detected by using radioimmunoassay. RESULTS: After treatment with topiramate (61 cases) for 4 months, plasma galanin [(22.01 +/- 8.12) pg/ml] declined as compared with baseline [(26.56 +/- 9.35) pg/ml, t = 2.85, P < 0.01] in children with epilepsy. Twenty-two of 61 patients lost weight, their plasma galanin concentration was significantly lower [(26.51 +/- 10.00) pg/ml vs. (20.45 +/- 8.09) pg/ml, t = 2.91, P < 0.01], but there was no significant change in the weight-gained patients (39/61) and control group (n = 16). In children with epilepsy, the mean value of body weight decreased as compared with the pre-treatment values, but the difference was not significant; however, the body-mass index (BMI) was significantly lower than that obtained before treatment (t = 8.628, P < 0.01). Eighteen of 22 patients who lost weight had decreased appetite, but only five of 39 patients who gained weight showed decreased appetite (chi(2) = 28.50, P < 0.001). The mean value of plasma galanin declined after treatment in patients (23 cases) with decreased appetite [(18.35 +/- 7.80) pg/ml vs. (27.28 +/- 6.90) pg/ml, t = 4.84, P < 0.001]; while plasma galanin did not change significantly after treatment in patients (38 cases) without decreased appetite [(24.23 +/- 7.66) pg/ml vs. (26.12 +/- 5.49) pg/ml, t = 1.04, P > 0.05]. CONCLUSION: Topiramate treatment may lower the body weight and reduce appetite in part of children with epilepsy which may be mediated by the reduced plasma galanin level.

[Expression of nuclear factor-kappaB and its inhibitor in alveolar macrophages of patients with neonatal hyaline membrane disease].

OBJECTIVE: Inflammatory reaction and injury in immature lungs are associated with activation of nuclear factor-kappa B (NF-kappaB) to trigger proinflammatory cytokine release, but the mechanism thereof is not fully understood. The present study was conducted to understand possible relationship between expression of NF-kappaB and its inhibitor and severity and outcome of neonates with hyaline membrane disease (HMD). METHODS: Serial samples of bronchoalveolar lavage fluid (BALF) were obtained during mechanical ventilation from 31 preterm infants with HMD. These infants were divided into two groups: survivors group [n = 22, birth weight (1500 +/- 320) g and gestational age (31.2 +/- 1.8) weeks] and nonsurvivors group [birth weight (1340 +/- 280) g, gestational age (30.8 +/- 2.1) weeks]. Nineteen preterm infants [birth weight (1470 +/- 280) g, gestational age (30.6 +/- 1.9) weeks] without respiratory disorders were enrolled as control subjects. Alveolar macrophages (AM) were isolated by differential adherence. AM was cultured and treated with lipopolysaccharide (LPS) for 1 hr. Then, nuclear extracts of AM were analyzed by electrophoretic mobility shift assay (EMSA) for NF-kappaB expression. NF-kappaB inhibitor (IkappaB-alpha protein) in cytoplasmic extracts was detected by using Western blotting and IL-1beta and IL-8 in BALF by enzyme-linked immunosorbent assay (ELISA). RESULTS: NF-kappaB complexes were observed by EMSA, they were characterized by competition with cold oligonucleotide and p65-specific antibodies. The addition of an excess of cold oligonucleotide, corresponding to the NF-kappaB binding site, turned off the signal of the band, showing that the band was specific. An excess of an irrelevant oligonucleotide (corresponding to the SP-1) did not show any effect. The addition of an anti-p65 antibody caused the supershift of the two upper bands. After EMSA, the NF-kappaB complexes were quantified by using a ImageQuant software. NF-kappaB expression in AM at 24 hrs was higher in all the patients with HMD as compared with control subjects (survives/control, 34.1 vs 11.4 RDU, P < 0.01; nonsurvivors/control, 55.2 vs 11.4 RDU, P < 0.01). The NF-kappaB expression in AM at 72 hrs was higher than that in control subjects but not for nonsurvivors (survivors/control, 47.8 vs 25.6 RDU, P < 0.01; nonsurvivors/control, 21.8 vs 25.6, P > 0.05). The NF-kappaB expression in AM from nonsurvivors was depressed at 72 hrs as compared to 24 hrs (21.8 vs 55.2, P < 0.01), whereas the NF-kappaB expression in AM from survivors was still higher at 72 hrs than that at 24 hrs (47.8 vs 34.1, t = 4.43, P < 0.01). CONCLUSION: Altered NF-kappaB activation in AM of BALF of neonates with HMD was observed, and it may be mediated by decreased IkappaB synthesis, increased IkappaB degradation, or both. In HMD nonsurvivors NF-kappaB translocation was hampered upon LPS activation.