Search

Hereditary hemorrhagic telangiectasia (HHT) is characterized by telangiectasias in multiple organs. We experienced an infant with cerebral hemorrhaging and suspected HHT based on his family history of HHT. Computed tomography angiography confirmed a cerebral arteriovenous fistula. The onset of cerebral arteriovenous fistulas associated with HHT is relatively early, and the incidence of bleeding is relatively common. When HHT is suspected based on a family history, early imaging screening is recommended to improve the neurological prognosis, even in asymptomatic cases. (Received April 7, 2020; Accepted May 7, 2020; Published August 1, 2020).

Background: Elucidating developmental changes in the symptoms of autism spectrum disorder (ASD) is important to support individuals with ASD. However, no report has clarified the developmental changes in attention to social information for a broad age range. The aim of this study was to investigate the developmental changes in attention to social information from early childhood to adolescence in individuals with ASD and typically developed (TD) children., Methods: We recruited children with ASD (n = 83) and TD participants (n = 307) between 2 and 18 years of age. Using the all-in-one-eye-tracking system, Gazefinder, we measured the percentage fixation time allocated to areas of interest (AoIs) depicted in movies (the eyes and mouth in movies of a human face with/without mouth motion, upright and inverted biological motion in movies showing these stimuli simultaneously, people and geometry in preference paradigm movies showing these stimuli simultaneously, and objects with/without finger-pointing in a movie showing a woman pointing toward an object). We conducted a three-way analysis of variance, 2 (diagnosis: ASD and TD) by 2 (sex: male and female) by 3 (age group: 0-5, 6-11, and 12-18 years) and locally weighted the scatterplot smoothing (LOESS) regression curve on each AoI., Results: In the face stimuli, the percentage fixation time to the eye region for the TD group increased with age, whereas the one for the ASD group did not. In the ASD group, the LOESS curves of the gaze ratios at the eye region increased up to approximately 10 years of age and thereafter tended to decrease. For the percentage fixation time to the people region in the preference paradigm, the ASD group gazed more briefly at people than did the TD group., Limitations: It is possible that due to the cross-sectional design, the degree of severity and of social interest might have differed according to the subjects' age., Conclusions: There may be qualitative differences in abnormal eye contact in ASD between individuals in early childhood and those older than 10 years.

Rationale: Although percutaneous endoscopic gastrojejunostomy (PEG-J) tubes are believed to reduce the side effect of aspiration, cautious catheter management is required. Intussusception is a serious complication of these tubes., Patient Concerns: A 7-year-old boy bedridden with hypoxic encephalopathy owing to drowning at the age of 1 year was admitted our hospital with urinary retention for 1 month. At the age of 4 years, a PEG-J tube was inserted. Concomitant with hyperaldosteronemia, an intestinal intussusception from the duodenum to the jejunum was observed via computed tomography (CT). The patient's condition worsened dramatically; gastrointestinal perforation was suspected, and laparotomy was performed., Diagnosis: Jejuno-jejunal intussusception., Interventions: Open surgery was performed to release the intussusception. By assessing the reduced intestinal tract, the intussusception starting from a 50 cm portion from the Treitz ligament had been extended to 100 cm from the Treitz ligament. The oral side jejunum was dilated. No evidence of intestinal perforation or strangulated ileus was observed, and the intussusception was manually remediable., Outcomes: Preoperative CT examination showed intussusception from the duodenum to the jejunum. Laparotomy showed intussusception on the anal side of the Treitz ligament. With regard to the CT findings associated with the progression of intussusception to the duodenal site, as a result of the telescope phenomenon extending to the duodenum due to the relaxation of the Treitz ligament through repeated intussusception, it was considered that CT examination revealed intussusception extending from the jejunum to the duodenum of oral side. After 3 postoperative weeks, the patient was finally able to return home., Lessons: If the ileus is observed during the insertion of a PEG-J, clinicians should consider the possibility of intussusception even in the duodenum.

Rationale: Helicobacter pylori infection causes atrophic gastritis in childhood, but atrophic gastritis due to H pylori infection is extremely rare in infancy. The relationship between H pylori infection and chronic diarrhea without protein leakage remains controversial., Patient Concerns: An 8-month-old male infant presented to our hospital with severe watery diarrhea, erythema, and failure to thrive from approximately 1 month after birth. Blood, stool, esophagogastroduodenoscopy, total colonoscopy, and H pylori urease analysis results were positive, thereby suggesting atrophic gastritis., Diagnoses: Atrophic gastritis and chronic diarrhea due to H pylori infection., Interventions: We performed H pylori eradication therapy using triple therapy with vonoprazan (6 mg/kg), amoxicillin (300 mg/d), and clarithromycin (120 mg/kg) for 7 days., Outcomes: From approximately 1 week after the H pylori eradication therapy, the frequency of defecation had decreased, stool shape had improved, and body weight had gradually increased., Lessons: H pylori infection can cause atrophic gastritis and chronic diarrhea even in infancy. Early eradication therapy for H pylori infection may be useful for prevention of gastric cancer and improvement in growth disorders.

Background: To present the strategies and preliminary findings of the first 3 years after implementing a Helicobacter pylori screening and eradication program to prevent gastric cancer in Saga Prefecture., Methods: A screening and treatment program to eradicate H. pylori from third-grade junior high students was started in Saga Prefecture in 2016, using local governmental grants. Screening was with urinary anti-H. pylori antibody tests, followed by H. pylori stool antigen tests for students who were antibody positive. Those positive on both tests underwent H. pylori eradication by triple therapy based on a potassium-competitive acid blocker., Results: From 2016 to 2018, the participation rate was 83.1% and the H. pylori infection rate was 3.1% (660/21,042). The participation rates were higher in 2017 (85.4%) and 2018 (85.9%) compared with 2016 (78.5%) (P < 0.0001), and the infection rate also decreased in a time-dependent manner (2016: 3.6%, 2017: 3.3%, 2018: 2.5%, P = 0.0001). In total, 501 students positive for H. pylori received eradication therapy (85.1% success) and adverse events occurred in 20 of these (4.0%). However, no serious complications occurred., Conclusions: The H. pylori screening and eradication project for school students in Saga Prefecture has started successfully and we have seen both a steady increase in the participation rate and a steady decrease in the infection rate, without major safety concerns.

Coenzyme Q10 deficiency causing gastrointestinal symptoms has not been reported. At least 15 genes are involved in CoQ10 biosynthesis, and one of the genes is AarF domain-containing kinase 4 (ADCK4). This case report first showed a patient who presented with Crohn's disease (CD) combined with ADCK4 glomerulopathy (ADCK4-GN). After approximately 2 years of infliximab treatment for CD, this patient has remained in clinical remission with no adverse effects. Moreover, two important findings were obtained: first, individuals with ADCK4-GN may present with complications, such as CD, which is a gastrointestinal disease, and infliximab may be effective for CD associated with ADCK4-GN. Second, infliximab may also be effective and safe for individuals with CD who are undergoing peritoneal dialysis. Thus, the results of the present study may be used in managing patients with such condition, and as a result, better clinical outcomes will be obtained.

Rationale: Eosinophilic esophagitis (EoE) is an inflammatory disease diagnosed based on clinical symptoms and pathological findings. EoE is treated with proton pump inhibitors (PPIs), topical steroids, and elimination diet-reintroduction therapy. After remission is achieved with the elimination diet, foods can be reintroduced sequentially to identify specific food triggers; however, this reintroduction method was not previously standardized., Patient Concerns: A 12-year-old girl presented to our hospital with a 3-year history of epigastric pain. Esophagogastroduodenoscopy revealed linear furrows, esophageal rings, white exudates, and pallor throughout the esophagus. Histopathological findings revealed eosinophilic infiltration >15 eos/hpf on esophageal biopsy. There were no obvious abnormal findings in the stomach and duodenum., Diagnoses: EoE INTERVENTIONS AND OUTCOMES:: Because PPI was ineffective, we proposed a 6-food-group elimination diet (SFGED) and reintroduction therapy for EoE, which was initially planned out over a 6-week interval. However, a 5-day interval of SFGED and reintroduction therapy was performed instead. The treatment was effective and causative food antigens (egg and nuts) were identified. Since her symptoms recovered following short-term treatment, the nutritional impact was minimized, as was the duration of her hospitalization. Consequently, the patient's quality of life was well-preserved., Lessons: SFGED and reintroduction therapy for EoE may be effective even for short-term treatments involving 5-day intervals.

Background: Enterovirus D68 (EV-D68) has been reported to have caused severe bronchial asthma attacks and hospitalization epidemics in Japan in September 2015., Objective: To investigate the prevalence of β 2 -agonist inhalation in a pediatric emergency center during a period of increased hospitalization for bronchial asthma, which was suggested to be associated with EV-D68., Methods: We investigated the prevalence of β 2 -agonist inhalation in a pediatric emergency center in Saga city, Japan, from April 2013 to October 2015, and also clarified the trends in bronchial asthma hospitalization in the same area during that time., Results: The prevalence of β 2 -agonist inhalation in the pediatric emergency center, September 2015 was highest when EV-D68 became widespread. The monthly average for β 2 -agonist inhalation during the study period was 91 cases, but the count in September 2015 was 255 cases. Hospitalized cases of bronchial asthma in September 2015 were increased for age ≥3 years and not increased for age <3 years, but the prevalence of β 2 -agonist inhalation at the pediatric emergency center was increased even under the age of 3 years., Conclusion: During the epidemic period for EV-D68, cases requiring β 2 -agonist inhalation were increased. The EV-D68 epidemic may be related to not only severe cases requiring hospitalization, but also exacerbation of relatively mild symptoms of bronchial asthma.

Background and Objective: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive infantile-onset disorder characterized by cataracts, cerebellar ataxia, and progressive myopathy caused by mutation of SIL1. In mice, a defect in SIL1 causes endoplasmic reticulum (ER) chaperone dysfunction, leading to unfolded protein accumulation and increased ER stress. However, ER stress and the unfolded protein response (UPR) have not been investigated in MSS patient-derived cells., Methods: Lymphoblastoid cell lines (LCLs) were established from four MSS patients. Spontaneous and tunicamycin-induced ER stress and the UPR were investigated in MSS-LCLs. Expression of UPR markers was analyzed by western blotting. ER stress-induced apoptosis was analyzed by flow cytometry. The cytoprotective effects of ER stress modulators were also examined., Results: MSS-LCLs exhibited increased spontaneous ER stress and were highly susceptible to ER stress-induced apoptosis. The inositol-requiring protein 1α (IRE1α)-X-box-binding protein 1 (XBP1) pathway was mainly upregulated in MSS-LCLs. Tauroursodeoxycholic acid (TUDCA) attenuated ER stress-induced apoptosis., Conclusion: MSS patient-derived cells exhibit increased ER stress, an activated UPR, and susceptibility to ER stress-induced death. TUDCA reduces ER stress-induced death of MSS patient-derived cells. The potential of TUDCA as a therapeutic agent for MSS could be explored further in preclinical studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to determine the frequency of central nervous system comorbidities in children with neurofibromatosis type 1 (NF1)., Methods: We performed a nationwide survey to investigate neurological comorbidities in 3-15-year-old children with NF1 in Japan by sending questionnaires to pediatricians and pediatric neurologists. A secondary questionnaire was sent to the parents of identified NF1 patients to assess neurological comorbidities including headache, attention deficit-hyperactivity disorder (ADHD) Rating Scale (RS), and the Social Responsiveness Scale 2., Results: The primary survey identified 760 NF1 patients, and the parents of 565 patients were sent the secondary questionnaire. The parental response rate was 25.7% (145; 63 girls, 81 boys, one unspecified). Among the patients, 42.9% (55/128; 35 girls, 20 boys) were reported to exhibit intellectual problems. On the ADHD-RS, 40.2% (47/117) of NF1 patients aged 6-15 had ADHD (RS score >93rd percentile), with a rate of 47.7% in boys and 30.8% in girls. Furthermore, 20.2% of patients had suspected autism spectrum disorder (29/143; 10 girls, 19 boys), with Social Responsiveness Scale score ≥76. Headache was reported by 49.6% (61/123) of children over 5 years old, and 25.2% (31/123; 10 girls, 21 boys) reported migraine. Other neurological comorbidities included 20 cases of epilepsy (13.8%), 11 cases of optic nerve glioma (7.6%), five cases of brain tumor (3.4%), six cases of cerebrovascular disease (4.1%), and two cases of hydrocephalus (1.4%)., Conclusion: Intellectual problems, ADHD, autism spectrum disorder, and migraine are major neurological comorbidities in NF1., (© 2017 Japan Pediatric Society.)

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that shows a characteristic progeria phenotype. We conducted a questionnaire survey of 1173 tertiary hospitals in Japan and reviewed the academic reports, to identify the characteristics of Asian patients with classical HGPS. As a result, four Japanese patients were identified; this was estimated to account for approximately two-third of the prevalence in Japan. Three Asian patients who had definitively been diagnosed with classical HGPS were identified in the literature; in total, the clinical characteristics of seven patients were evaluated. Most of the clinical phenotypes of Asian patients were essentially similar to those of patients of other ethnicities, such as sclerodermatous skin, growth failure, loss of scalp hair or severe complications of cardiovascular and cerebral ischemic disease. In conclusion, to circumvent or minimalize severe vascular complication, an early diagnosis, careful observation and, promisingly, new intervention with farnesylation inhibitors may improve the prognosis of classical HGPS patients.

Hemophilic pseudotumor is a rare complication, even in patients with severe hemophilia. Herein we report on a case of hemophilic pseudotumor in a patient with mild hemophilia A and allergic rhinitis, initially suspected to be a nasal tumor. The pseudotumor was cured by supplementation with recombinant factor VIII concentrates, and medication for allergic rhinitis. Pseudotumor should always be considered in hemophiliac patients, even in those with only mild deficiency of coagulation factors., (© 2017 Japan Pediatric Society.)

This study was conducted to evaluate the attenuating potential of 2-hydroxypropyl-β-cyclodextrin (HPBCD) against Niemann-Pick Type C (NPC) disease, as well as the physical and chemical properties, particularly the cholesterol-solubilizing ability, in an NPC disease model in vitro. As parameters of NPC abnormalities, intracellular free and esterified cholesterol levels and lysosome volume were measured in Npc1 null Chinese hamster ovary cells. HPBCD showed dose-dependent effects against dysfunctional intracellular cholesterol trafficking, such as the accumulation and shortage of free and esterified cholesterols, respectively, in Npc1 null cells. However, the effectiveness was gradually offset by exposure to ≥8mM HPBCD. The same effect was also observed for increasing lysosome volume in Npc1 null cells. The degree of substitution of the hydroxypropyl group had little influence on the attenuating effects of HPBCD against the NPC abnormalities, at least in the range between 2.8 and 7.4. Next, we compared the effects of other hydroxyalkylated β-cyclodextrin derivatives with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-β-cyclodextrin (HEBCD) and 2-hydroxybutyl-β-cyclodextrin (HBBCD). The cholesterol solubilizing potential, attenuating effects against NPC abnormalities and cytotoxicity induction were HBBCD≫HPBCD>HEBCD, HBBCD=HPBCD>HEBCD and HBBCD≫HPBCD=HEBCD, respectively. HPBCD may be superior in terms of safety and efficacy in Npc1 null cells compared with HEBCD and HBBCD. The results of this study will provide a rationale for the optimization of HPBCD therapy for NPC disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations., Methods: In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively., Results: We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously., Significance: Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Purpose: Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation defects have been reported in Beckwith-Wiedemann syndrome patients with epimutations; however, limited numbers of DMRs have been analyzed. The susceptibility of DMRs to aberrant methylation, alteration of gene expression due to aberrant methylation, and causative factors for multiple methylation defects remain undetermined., Methods: Comprehensive methylation analysis with two quantitative methods, matrix-assisted laser desorption/ionization mass spectrometry and bisulfite pyrosequencing, was conducted across 29 DMRs in 54 Beckwith-Wiedemann syndrome patients with epimutations. Allelic expressions of three genes with aberrant methylation were analyzed. All DMRs with aberrant methylation were sequenced., Results: Thirty-four percent of KvDMR1-loss of methylation patients and 30% of H19DMR-gain of methylation patients showed multiple methylation defects. Maternally methylated DMRs were susceptible to aberrant hypomethylation in KvDMR1-loss of methylation patients. Biallelic expression of the genes was associated with aberrant methylation. Cis-acting pathological variations were not found in any aberrantly methylated DMR., Conclusion: Maternally methylated DMRs may be vulnerable to DNA demethylation during the preimplantation stage, when hypomethylation of KvDMR1 occurs, and aberrant methylation of DMRs affects imprinted gene expression. Cis-acting variations of the DMRs are not involved in the multiple methylation defects.

Niemann-Pick Type C disease (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Previously, we reported that intravenous administration of 2-hydroxypropyl-β-cyclodextrin (HPB-CD) in two patients with NPC had only partial and transient beneficial effects on neurological function. The most likely reason for HPB-CD not significantly improving the neurological deficits of NPC is its inability to cross the blood-brain barrier. Herein, we describe the effects of intrathecal HPB-CD in an eight-year-old patient with a perinatal onset of NPC, administered initially at a dose of 10 mg/kg every other week and increased up to 10 mg/kg twice a week. Clinically, the patient maintained residual neurological functions for two years, at which time nuclear magnetic resonance spectroscopy showed a decreased choline to creatine ratio and increased N-acetylaspartate to creatine ratio, and positron emission tomography revealed increased standardized uptake values. Total-tau in the cerebrospinal fluid (CSF) was also decreased after two years. No adverse effects were observed over the course of treatment. The CSF concentrations of HPB-CD during the distribution phase after the injections were comparable with those at which HPB-CD could normalize cellular cholesterol abnormality in vitro. Further studies are necessary to elucidate the mechanisms of action of HPB-CD in NPC, and to determine the optimal dose and intervals of HPB-CD injection.

Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann-Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD in Npc1 -deficient mice. When treated with HPBCD (20,000 mg/kg, subcutaneously), over half of the wild-type ( Npc1 +/+ ) or Npc1 +/- mice died by 72 h after the injection. In contrast, all of the Npc1 -/- mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the HPBCD treatment in Npc1 +/+ or Npc1 +/- mice. However, these pathophysiological changes were significantly alleviated in Npc1 -/- mice. In addition, in vitro analysis showed that the Npc1 gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that the NPC1 genotype exacerbates the cytotoxicity of HPBCD and Npc1 -/- mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared with Npc1 +/+ or Npc1 +/- mice. We suggest that the Npc1 genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells.

We describe a 15-day-old newborn girl who was fed with formula milk that was accidentally diluted with sake (Japanese wine prepared from fermented rice). The clinical features were flushed skin, tachycardia and low blood pressure indicating circulatory failure, somnolence and metabolic acidosis without hypoglycemia. The serum ethanol concentration was 43.0 mg/dL at 3 h after intake. The patient recovered under intravenous fluid replacement without complications. Follow-up examinations at 1, 2, 3, 6 and 12 months confirmed normal psychomotor development., (© 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.)

Acute encephalopathy with biphasic seizures and late reduced diffusion was recently established clinicoradiologically as an encephalopathy syndrome. The outcome of this encephalopathy is characterized by a low mortality rate and high incidence of neurologic sequelae. Although the exact pathogenesis of this encephalopathy is uncertain, excitotoxic injury with delayed neuronal death is proposed. On the basis of this hypothesis, we tried a combination therapy of N-methyl-D-aspartate receptor antagonist, dextromethorphan, and apoptosis inhibitor, cyclosporine A, in four patients with acute encephalopathy with biphasic seizures and late reduced diffusion. All patients recovered except for hyperactivity in one patient. Furthermore, an additional four patients with near-miss encephalopathy, who showed mild disturbance of consciousness at 24 hours after prolonged febrile seizures associated with exanthem subitum, recovered without secondary seizures by the early administration of dextromethorphan. The combination regimen of dextromethorphan and cyclosporine A could be effective for the treatment and prevention of acute encephalopathy with biphasic seizures and late reduced diffusion., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Niemann-Pick Type C disease (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Currently, there are no effective treatments for NPC, although miglustat has shown some effectiveness in stabilizing neurological status in juvenile-onset NPC patients. Recent studies have demonstrated the efficacy of hydroxypropyl-β-cyclodextrin (HPB-CD) in NPC mice. Herein, we describe the effects of HPB-CD in two patients with NPC. The two patients received HPB-CD infusions twice (Patient 2) or thrice (Patient 1) weekly, starting with a dose of 80 mg/kg per dose that was increased gradually to 2g/kg per dose (Patient 2) or 2.5 g/kg per dose (Patient 1). Although HPB-CD did not improve the neurological deficits in either patient, it was partially effective in improving hepatosplenomegaly and central nervous system dysfunction, especially during the first 6 months of treatment. No adverse effects were observed over the course of treatment, although Patient 1 exhibited transient cloudiness of the lungs with fever after 2 years. For more effective treatment of NPC patients with HPB-CD, it is necessary to improve drug delivery into the central nervous system., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) has a close relationship with epilepsy. A previous study showed complex partial seizures (CPS) to be the most frequent type of epileptic seizures in cases of ASD. Patients with childhood-onset CPS were retrospectively studied to investigate the prevalence of ASD and to characterize the association between CPS and ASD. The study cohort comprised 86 patients with CPS manifesting at 1 to 9 years of age. Symptomatic CPS and Panayiotopoulos syndrome were excluded. Patients with ASD (ASD group) were compared with those without ASD (non-ASD group). Of the 86 patients with childhood-onset CPS, 36 (42%) also had ASD. This ASD group was predominantly male (68.6%), with higher rates of intellectual disability (69%), and reported frequent seizures (60% had monthly or more frequent seizures). CPS without secondary generalization were more common in the ASD group (69%) than in the non-ASD group (36%), as were frontal paroxysms on EEG (54.5% vs 30%, respectively). In the non-ASD group, 82% of cases had been seizure free for 2 or more years, in comparison to 50% in the ASD group. ASD is frequently associated with childhood-onset CPS. Male gender, cognitive deficits, frequent seizures, and frontal paroxysms are risk factors for the association of ASD with CPS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

An association has long been suspected between febrile seizures and interleukin-1beta, the most potent endogenous pyrogen. Interleukin-1beta production increases after double-stranded RNA stimulation in leukocytes of febrile seizure patients. To elucidate the genetics of the immune response, the gene expression pattern after double-stranded RNA stimulation was investigated using DNA microarray. Compared with the control group, expression of the genes ACCN4 (sodium channel), KCNC3 (potassium channel), GABRE (gamma-aminobutyric acid receptor epsilon subunit), RIPK2 (receptor interacting protein kinase-2), TLR4 (toll-like receptor-4), IL26 (interleukin-26), and TNF (tumor necrosis factor), and CASP1 (caspase-1) was increased in the febrile seizure group (P < 0.01). Because RIPK2 and CASP1 are associated with interleukin-1beta production, increased expression might cause increased interleukin-1beta production in the febrile seizure patients. The induced expression of several ion channel genes by double-stranded RNA may affect neuronal excitability which leads to seizure susceptibility during infection.

This study examined the possibility that children with and without a history of febrile seizures might mount different immune responses to double-stranded ribonucleic acid, which is a common viral factor that induces host cell immune responses, and is recognized by Toll-like receptor 3. The production of interleukin-1beta and interferon-alpha from double-stranded ribonucleic acid-stimulated leukocytes was examined in 27 children (age 3.6+/-0.3 years) with a history of febrile seizures and in 18 children (age 3.4+/-0.2 years) without a history of febrile seizures. Significantly (P=0.0007) increased interleukin-1beta production was observed in children with a history of febrile seizures, compared with control subjects. When patients with a single prior episode of febrile seizures (n=9) and those with multiple prior episodes of febrile seizures (n=18) were compared, a significant difference in interleukin-1beta production was not observed. Genotyping of interleukin-1beta(-511), Toll-like receptor 3, Toll-IL-1 receptor domain-containing adapter inducing interferon-beta, and interleukin-1 receptor antagonist polymorphisms revealed no significant differences in allelic distribution among febrile seizure patients and control subjects. Interleukin-1beta production was not significantly influenced by genotype. Viral infection results in increased interleukin-1beta production in febrile seizure patients, and this may play a role in febrile seizures.

Purpose: Severe myoclonic epilepsy in infancy (SMEI) is a distinct epilepsy syndrome. Patients with borderline SMEI (SMEB) are a subgroup with clinical features similar to those of core SMEI but are not necessarily consistent with the accepted diagnostic criteria for core SMEI. The aim of this study was to delineate the genetic correlation between core SMEI and SMEB and to estimate the frequency of mutations in both phenotypes., Methods: We examined 96 healthy volunteers and 58 unrelated individuals whose clinical features were consistent with either core SMEI (n = 31) or SMEB (n = 27). We screened for genetic abnormalities within exons and their flanking introns of the genes encoding major subunits of the Na+ channels (SCN1A, SCN2A, SCN1B, and SCN2B) by using a direct sequencing method., Results: In both core SMEI and SMEB, various mutations of SCN1A including nonsense and missense mutations were identified, whereas no mutations of SCN2A, SCN1B, and SCN2B were found within the regions examined. All mutations were heterozygous and not found in 192 control chromosomes. Mutations were identified in 26 (44.8%) of the 58 individuals and were more frequent (p < 0.05) in core SMEI (19 of 31) than in SMEB (seven of 27), as assessed by the continuity-adjusted chi2 test. Mutations resulting in a molecular truncation were found only in core SMEI. Among the mutations, two missense mutations were found in both core SMEI and SMEB., Conclusions: Our findings confirm that SMEB is part of the SMEI spectrum and may expand the recognition of SMEI and suggest other responsible or modifying genes.

Prostaglandin H synthase (PHS) is a key enzyme in the synthesis of prostaglandins (PGs). Recently, enhanced expression of PHS-2 in brain tumors and the correlation between the PHS-2 level and the histopathological grade of glioma has been reported. Furthermore, in vitro inhibition of glioma cell growth by a specific PHS-2 inhibitor, NS398, has been demonstrated. It has also been shown that prostaglandin E2 (PGE2) contributes to colon carcinogenesis by binding to the prostaglandin E receptor subtype EP1. We therefore evaluated the effects of NS398 and two EP1 antagonists, SC51089 and AH6809, on glioma cell lines. To evaluate mechanisms of NS398's action, two glioma cell lines, a PHS-2-positive cell line (KMG4) and a PHS-2-deficient cell line (A 172), were used. NS398 inhibited both the anchorage-dependent and -independent growth of glioma cell lines regardless of PHS-2 expression, suggesting that some PHS-2-independent mechanisms underlie the antineoplastic effect of NS398. However, the antineoplastic effect was attenuated by the addition of PGE2, which is one of the main products of PHS, suggesting the predominant mechanism is PHS-dependent. The EP1 antagonists, SC51089 and AH6809, inhibited the growth of glioma cell lines in vitro. Furthermore, NS398 or SC51089 slowed tumor growth in vivo, which was assessed using KMG4 tumor xenografts on SCID mice. PHS-2 inhibitors and EP1 antagonists might be useful in the prevention and/or treatment of glioma.

We report two unrelated cases of Costello syndrome, presenting with poor postnatal growth, mild mental retardation, poor feeding, curly hair, coarse characteristic face, loose skin, hypotonia, and cardiac involvement. Nasal papilloma and acanthosis nigricans were the most characteristic features of this syndrome. Both cases had atrial fibrilation from infancy to early childhood. One patient had hypertonia in the lower extremities and pes equinovarus, while the other had hypotonia and pes planovalgus.