GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons.

Developmental and epileptic encephalopathy (DEE) represents a group of neurodevelopmental disorders characterized by infantile-onset intractable seizures and unfavorable prognosis of psychomotor development. To date, hundreds of genes have been linked to the onset of DEE. GNAO1 is a DEE-associated gene encoding the alpha-O1 subunit of guanine nucleotide-binding protein (GαO ). Despite the increasing number of reported children with GNAO1 encephalopathy, the molecular mechanisms underlying their neurodevelopmental phenotypes remain elusive. We herein present that co-immunoprecipitation and mass spectrometry analyses identified another DEE-associated protein, SPTAN1, as an interacting partner of GαO . Silencing of endogenous Gnao1 attenuated the neurite outgrowth and calcium-dependent signaling. Inactivation of GNAO1 in human-induced pluripotent stem cells gave rise to anomalous brain organoids that only weakly expressed SPTAN1 and Ankyrin-G. Furthermore, GNAO1-deficient organoids failed to conduct synchronized firing to adjacent neurons. These data indicate that GαO and other DEE-associated proteins organize the cytoskeletal remodeling and functional polarity of neurons in the developing brain.

Sustained endocrine profiles of a girl with WAGR syndrome.

BACKGROUND: Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome is a rare genetic disorder caused by heterozygous deletions of WT1 and PAX6 at chromosome 11p13. Deletion of BDNF is known eto be associated with hyperphagia and obesity in both humans and animal models; however, neuroendocrine and epigenetic profiles of individuals with WAGR syndrome remain to be determined. CASE PRESENTATION: We report a 5-year-old girl with the typical phenotype of WAGR syndrome. She showed profound delays in physical growth, motor and cognitive development without signs of obesity. Array comparative genome hybridization (CGH) revealed that she carried a 14.4 Mb deletion at 11p14.3p12, encompassing the WT1, PAX6 and BDNF genes. She experienced recurrent hypoglycemic episodes at 5 years of age. Insulin tolerance and hormonal loading tests showed normal hypothalamic responses to the hypoglycemic condition and other stimulations. Methylation analysis for freshly prepared DNA from peripheral lymphocytes using the pyro-sequencing-based system showed normal patterns of methylation at known imprinting control regions. CONCLUSIONS: Children with WAGR syndrome may manifest profound delay in postnatal growth through unknown mechanisms. Epigenetic factors and growth-associated genes in WAGR syndrome remain to be characterized.

A childhood-onset intestinal toxemia botulism during chemotherapy for relapsed acute leukemia.

BACKGROUND: Botulism is a potentially fatal infection characterized by progressive muscle weakness, bulbar paralysis, constipation and other autonomic dysfunctions. A recent report suggested that cancer chemotherapy might increase the risk for the intestinal toxemia botulism in both adults and children. CASE PRESENTATION: We report a 5-year-old boy, who developed general muscle weakness, constipation, ptosis and mydriasis during the third induction therapy for relapsed acute myeloid leukemia. He had recent histories of multiple antibiotic therapy for bacteremia and intake of well water at home. Repeated bacterial cultures identified Clostridium botulinum producing botulinum neurotoxin A. Botulinum toxin A was isolated from his stools at 17, 21, and 23 days after the onset. Symptoms were self-limiting, and were fully recovered without anti-botulinum toxin globulin therapy. CONCLUSION: This is the second report of a pediatric case with cancer chemotherapy-associated intestinal toxemia botulism. Our case provides further evidence that the immunocompromised status due to anti-cancer treatments increases the risk for the development of botulism at all ages in childhood.

High mobility group box 1 enhances hyperthermia-induced seizures and secondary epilepsy associated with prolonged hyperthermia-induced seizures in developing rats.

Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1's role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14-15-day-old male rats were divided into four groups: high-dose HMGB1 (100 µg), moderate-dose (10 µg), low-dose (1 µg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10-11-day-old rats were divided into four groups: pHS + HMGB1 (10 µg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS.

De Novo Truncating Mutation of TRIM8 Causes Early-Onset Epileptic Encephalopathy.

BACKGROUND: Early-onset epileptic encephalopathy (EOEE) is a heterogeneous group of neurodevelopmental disorders characterised by infantile-onset intractable epilepsy and unfavourable developmental outcomes. Hundreds of mutations have been reported to cause EOEE; however, little is known about the clinical features of individuals with rare variants. CASE REPORT AND METHODS: We present a 10-year-old boy with severe developmental delay. He started experiencing recurrent focal seizures at 2 months old. Serial electroencephalograms persistently detected epileptiform discharges from the left hemisphere. Whole-exome sequencing and array-comparative genome hybridization were performed to search for de novo variations. Two-week-old C57Bl/6 mice were used for immunofluorescence studies. RESULTS: This case had a paternally inherited, 0.2-Mb duplication at chromosome 22q11.22. The whole-exome sequencing identified a de novo truncating mutation of tripartite motif containing 8 (TRIM8) (NM_030912:c.1099_1100insG:p.C367fs), one of the epileptic encephalopathy-associated genes. We verified that the murine homologues of these genes are expressed in the postnatal mouse brain. CONCLUSION: This is the second case of EOEE caused by a de novo truncating mutation of TRIM8. Further studies are required to determine the functional roles of TRIM8 in the postnatal development of the human brain and its functional relationships with other EOEE-associated genes.

De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis.

BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder that manifests recurrent attacks of hemiplegia, oculogyric, and choreoathetotic involuntary movements. De novo mutations in ATP1A3 cause three types of neurological diseases: AHC; rapid-onset dystonia-Parkinsonism (RDP); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndromes. It remains to be determined whether or not a rare mutation in ATP1A3 may cause atypical phenotypes. CASE PRESENTATION: A 7-year-old boy presented with recurrent symptoms of generalized paralysis since 1 year and 5 months of age. Hypotonia, dystonia, and choreoathetosis persisted with exacerbation under febrile conditions, but no cerebellar ataxia had ever evolved in 6 years. Whole-exome sequencing (WES) was performed to determine his genetic background, and mutations were validated by the Sanger method. Crude protein extracts were prepared from the cultured cells, and expression of the wild-type or mutant ATP1A3 proteins were analyzed by Western blotting. WES identified a de novo pathogenic mutation in ATP1A3 (c.2266C > T:p.R756C) for this patient. A literature overview of two reported cases with p.R756C and p.R756H mutations showed both overlapping and distinct phenotypes when compared with those of the present case. The expression of the mutant form (R756C) of ATP1A3 did not differ markedly from that of the wild-type and D801N proteins. CONCLUSIONS: This study confirmed that p.R756C mutation of ATP1A3 cause atypical forms of AHC-associated disorders. The wide spectra of neurological phenotypes in AHC are linked to as-yet-unknown deficits in the functions of mutant ATP1A3.

Strategy in short-term memory for pictures in childhood: a near-infrared spectroscopy study.

In Baddeley's working memory model, verbalizable visual material such as pictures are recoded into a phonological form and then rehearsed, while auditory material is rehearsed directly. The recoding and rehearsal processes are mediated by articulatory control process in the left ventrolateral prefrontal cortex (VLPFC). Developmentally, the phonological strategy for serially-presented visual material emerges around 7 years of age, while that for auditory material is consistently present by 4 years of age. However, the strategy change may actually be correlated with memory ability as this usually increases with age. To investigate the relationship between the strategy for pictures and memory ability, we monitored the left VLPFC activation in 5 to 11 year-old children during free recall of visually- or auditorily-presented familiar objects using event-related near-infrared spectroscopy. We hypothesized that the phonological strategy of rehearsal and recoding for visual material would provoke greater activation than only rehearsal for auditory material in the left VLPFC. Therefore, we presumed that the activation difference for visual material compared with auditory material in the left VLPFC may represent the tendency to use a phonological strategy. We found that the activation difference in the left VLPFC showed a significant positive correlation with memory ability but not with age, suggesting that children with high memory ability make more use of phonological strategy for pictures. The present study provides functional evidence that the strategy in short-term memory for pictures shifts gradually from non-phonological to phonological as memory ability increases in childhood.

Parental age and child growth and development: child health check-up data.

BACKGROUND: The aim of the present study was to determine whether parental age has any influence on child health. METHODS: Well-baby check-up data at 1 month and at 12 months of age were used. The trends of parental age in association with growth measurements, incidence of physical and developmental abnormalities, occurrence of low birthweight, and maternal history of spontaneous abortion were analyzed. RESULTS: Associations between increasing paternal age and incidence of psychomotor developmental delay at 12 months, increasing paternal and maternal age and increasing birthweight, and increasing parental age and higher incidence of history of spontaneous abortion were found. The incidence of low-birthweight infants was significantly decreased with increasing paternal age. CONCLUSIONS: Not only increasing maternal age but also increasing paternal age have influences on child development and growth in the general population.

Age-related morphological differences in the spike-and-wave complexes of absence epilepsy.

OBJECTIVE: Absence epilepsy shows age-related clinical features, as is observed in childhood and juvenile absence epilepsy. Electroencephalogram (EEG) is characterized by bursts of 3 Hz spike-and-wave complex (SWC). We noticed a morphological variation of the slow-wave component of SWCs between patients. This study investigated whether the waveform of SWC might be associated with the child's age of this epilepsy. METHODS: Digitally-recorded EEGs under medication-free conditions were collected from 25 children who received the diagnosis of childhood or juvenile absence epilepsy. The morphology of slow wave in SWC in the frontal midline region was quantitatively compared between younger and older children using a cluster-based permutation test. RESULTS: At <7 years of age (2.9-6.5 years of age, n = 6), the electrical potential of the descending slope in the slow wave was positively correlated with age whereas this correlation was not observed in patients of ≥7 years of age (7.1-12.9 years, n = 19). A cluster-based permutation test confirmed the results-among the entire slow wave period (0-285 msec), the period of the descending slope (195-260 msec) showed significantly lower potential in patients of <7 years of age in comparison to patients of ≥7 years of age (sum of t-values: 46.57, p-value: 0.011). CONCLUSIONS: The current study demonstrated an age-dependent morphological difference in the slow-wave components of SWCs in EEGs of patients with pediatric absence epilepsy. This finding may provide a clue to understanding the age-related clinical manifestations of this epilepsy.

Assessment of Pediatric Admissions for Kawasaki Disease or Infectious Disease During the COVID-19 State of Emergency in Japan.

Importance: The development of Kawasaki disease (KD) has been suggested to be associated with droplet- or contact-transmitted infection; however, its triggers and transmission modes remain to be determined. Under an epidemic of SARS-CoV-2, the COVID-19 state of emergency in Japan served as a nationwide social experiment to investigate the impact of quarantine or isolation on the incidence of KD. Objective: To assess the role of droplet or contact transmission in the etiopathogenesis of KD. Design, Setting, and Participants: This multicenter, longitudinal, cross-sectional study was conducted from 2015 to 2020 at Fukuoka Children's Hospital and 5 adjacent general hospitals. The number of admissions for KD and infectious diseases were analyzed. Participants were pediatric patients admitted to the participating hospitals for KD or infectious diseases. Exposures: Quarantine and isolation owing to the COVID-19 state of emergency. Main Outcomes and Measures: The primary end points were the ratios of patients with KD to patients with respiratory tract or gastrointestinal infections admitted from April to May in 2015 to 2019 and 2020. A Poisson regression model was used to analyze them. Results: The study participants included 1649 patients with KD (median [interquartile range] age, 25 [13-43] months; 901 boys [54.6%]) and 15 586 patients with infectious disease (data on age and sex were not available for these patients). The number of admissions for KD showed no significant change between April and May in 2015 to 2019 vs the same months in 2020 (mean [SD], 24.8 [5.6] vs 18.0 [4.0] admissions per month; 27.4% decrease; adjusted incidence rate ratio [aIRR], 0.73; 95% CI, 0.48-1.10; P = .12). However, the number of admissions for droplet-transmitted or contact-transmitted respiratory tract infections (mean [SD], 157.6 [14.4] vs 39.0 [15.0] admissions per month; 75.3% decrease; aIRR, 0.25; 95% CI, 0.17-0.35; P < .001) and gastrointestinal infections (mean [SD], 43.8 [12.9] vs 6.0 [2.0] admissions per month; 86.3% decrease; aIRR, 0.14; 95% CI, 0.04-0.43; P < .001) showed significant decreases between April and May in 2015 to 2019 vs the same months in 2020 (total, 12 254 infections). Thus, the ratio of KD to droplet- or contact-transmitted respiratory tract and gastrointestinal infections incidence in April and May 2020 was significantly increased (ratio, 0.40 vs 0.12; χ21 = 22.76; P < .001). Conclusions and Relevance: In this study, the significantly increased incidence of KD compared with respiratory tract and gastrointestinal infections during the COVID-19 state of emergency suggests that contact or droplet transmission is not a major route for KD development and that KD may be associated with airborne infections in most cases.

Neurodevelopmental Outcomes of High-Risk Preterm Infants: A Prospective Study in Japan.

OBJECTIVES: To determine the neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs, birth weight <1,500 g) after 9 years of follow-up. METHODS: This study prospectively recruited 224 VLBWIs born from 2003 to 2009 in Kyushu University Hospital, Japan. Comorbidities of neurocognitive impairment, epilepsy, and autism spectrum disorder or attention-deficit hyperactivity disorder (ASD/ADHD) were assessed at age 3, 6, and 9 years. RESULTS: Neurodevelopmental profiles were obtained from 185 (83%), 150 (67%), and 119 (53%) participants at age 3, 6, and 9 years, respectively. At age 9 years, 25 (21%) VLBWIs showed intelligence quotient (IQ) <70, 11 (9%) developed epilepsy, and 14 (12%) had a diagnosis of ASD/ADHD. The prevalence of epilepsy was higher in children with an IQ <70 at age 9 years than in those with an IQ ≥70 (44% vs 0%). In contrast, ASD/ADHD appeared at similar frequencies in children with an IQ <70 (16%) and ≥70 (11%). Perinatal complications and severe brain lesions on MRI were considered common perinatal risks for developmental delay and epilepsy but not for ASD/ADHD. Male sex was identified as a unique risk factor for ASD/ADHD. CONCLUSION: These data suggest that VLBWIs showed a higher prevalence of developmental delay, epilepsy, and ASD/ADHD at age 9 years than the general population. Distinct mechanisms might be involved in the pathogenic process of ASD/ADHD from those of developmental delay and epilepsy.

PD1 as a common candidate susceptibility gene of subacute sclerosing panencephalitis.

Although the exact pathogenesis of subacute sclerosing panencephalitis (SSPE) remains to be determined, our previous data suggested a genetic contribution to the host susceptibility to SSPE. During chronic viral infection, virus-specific cytotoxic T lymphocytes display poor effector functions. Since co-inhibitory molecules are involved in the suppression of T lymphocytes, we investigated whether single nucleotide polymorphisms (SNPs) of genes encoding co-inhibitory molecules contributed to a susceptibility to SSPE. Association studies on a total of 20 SNPs in 8 genes (CTLA4, CD80, CD86, PD1, PDL1, PDL2, BTLA and HVEM) and subsequent haplotype analysis of 4 SNPs in the PD1 genes were performed in Japanese and Filipino SSPE patients and controls. Then, we investigated a functional difference in promoter activity of two haplotypes and compared the expression levels of PD1 between SSPE and controls. The frequency of GCG(C) haplotype of PD1 containing -606G allele was significantly higher in SSPE patients than in controls both in Japanese and in Filipinos. The promoter activity was significantly higher in the construct with -606G allele than in that with -606A allele. The expression levels of PD1 were significantly higher in SSPE patients than in the controls. Our results suggested that the PD1 gene contributed to a genetic susceptibility to SSPE.

De novo p.G696S mutation in COL4A1 causes intracranial calcification and late-onset cerebral hemorrhage: A case report and review of the literature.

BACKGROUND: The collagen type IV alpha 1 chain (COL4A1) is an essential component of the basement membrane in small vessels. Pathogenic variants in COL4A1 cause perinatal cerebral hemorrhages in an autosomal-dominant fashion. However, little is known about the long-term outcomes of patients with mildly affecting COL4A1 mutations. CASE REPORT: We report a 17-year-old boy, who presented with recurrent intracranial hemorrhages in the periventricular white matter. He had been followed-up as a child with cerebral palsy bearing intracranial calcifications, developmental delay and epilepsy. Screening tests in infancy provided negative results for intrauterine infections. Severe motor and cognitive deficits persisted after admission. Carbazochrome was introduced on day 19 of admission, which appeared to prevent extension and reactivation of cerebral hemorrhages for over 6 months after discharge. RESULTS: Targeted sequencing of NOTCH3 and TREX1 excluded causal mutations in these genes. The whole-exome sequencing revealed that he carried a de novo mutation in COL4A1 (p.Gly696Ser). An overview of the literature for 345 cases with COL4A1 mutations supported evidence that p.Gly696Ser is associated with the unique phenotype of late-onset hemorrhage among patients with COL4A1-associated cerebral angiopathy. CONCLUSIONS: This case first demonstrates that infants with COL4A1-associated leukoencephalopathy and calcifications have a risk for developing the rupture of small vessels in the cerebral white matter after 10 years of age.

Interleukin-10 is associated with resistance to febrile seizures: genetic association and experimental animal studies.

PURPOSE: Febrile seizures (FS) are the most common form of childhood convulsions. Many reports have shown that a proinflammatory cytokine, interleukin-1 (IL-1) beta, may have a facilitatory effect on the development of FS. We have previously shown that the IL1B -511C/T single nucleotide polymorphism (SNP) is associated with simple FS of sporadic occurrence. The balance between pro- and antiinflammatory cytokines influences the regulation of infections and could, therefore, play a role in the pathogenesis of FS. Here, to determine whether pro- and antiinflammatory cytokine genes are responsible for the susceptibility to FS, we have performed an association study on functional SNPs of cytokine genes in FS patients and controls. METHODS: The promoter SNPs of four inflammatory cytokine genes (IL6 -572C/G, IL8 -251A/T, IL10 -592A/C and TNFA -1037C/T) were examined in 249 patients with FS (186 simple and 63 complex FS) and 225 controls. Because the IL10 -592 SNP showed a positive association with FS, two additional SNPs (IL10 -1082A/G and -819T/C) were subjected to haplotype analysis. Furthermore, we examined the in vivo role of IL-10 in hyperthermia-induced seizures using immature animal models. RESULTS: The frequencies of the IL10 -592C allele and -1082A/-819C/-592C haplotype were significantly decreased in FS as compared with in controls (p = 0.014 and 0.013, respectively). The seizure threshold temperature in the IL-10-administered rats was significantly higher than that in the saline-treated control ones (p = 0.027). CONCLUSIONS: The present study suggests that IL-10 is genetically associated with FS and, contrary to IL-1beta, confers resistance to FS.

Interleukin-1beta enhances susceptibility to hyperthermia-induced seizures in developing rats.

Cytokines have been shown to influence susceptibility to febrile seizures and epilepsy. In this study, the role of interleukin-1beta (IL-1beta) was examined in developing rats. IL-1beta and interleukin-1 receptor antagonist (IL-1ra) were administered to developing rats, and seizures were induced by moist warm air. Twenty male Lewis rats (21-23 days old) were divided into two groups (IL-1beta and saline control groups) and two holes were made in the skull for EEG electrodes. We applied human recombinant IL-1beta intra-nasally 1h before seizures induced by moist warm air. The brain temperature at the appearance of seizure discharges on EEG, and the latency time from the hyperthermia onset until the appearance of seizure discharges on EEG were measured. And the same study using IL-1ra was performed. The median brain temperature for the IL-1beta group, 42.6 degrees C (range: 41.8-43.0), was significantly lower than that for the control, 42.9 (42.3-43.4) (P=0.043). The brain temperature for the IL-1ra group, 43.3 (42.8-43.7), was significantly higher than that for the control, 42.9 (42.2-43.5) (P=0.011), and the latency time for the IL-1ra group, 398s (270-561), was significantly longer than that for the control, 325 (252-462) (P=0.035). These results demonstrate that IL-1beta promotes hyperthermia-induced seizures in developing rats.

Decision-making dilemmas of paediatricians: a qualitative study in Japan.

OBJECTIVE: To delineate the critical decision-making processes that paediatricians apply when treating children with life-threatening conditions and the psychosocial experience of paediatricians involved in such care. DESIGN: We conducted semistructured, individual face-to-face interviews for each participant from 2014 to 2015. The content of each interview was subjected to a comprehensive qualitative analysis. The categories of dilemma were extracted from a second-round content analysis. PARTICIPANTS: Participants were board-certified paediatricians with sufficient experience in making decisions in relation to children with severe illnesses or disabilities. We repeated purposive sampling and analyses until we reached saturation of the category data. RESULTS: We performed interviews with 15 paediatricians. They each reported both unique and overlapping categories of dilemmas that they encountered when making critical decisions. The dilemmas included five types of causal elements: (1) paediatricians' convictions; (2) the quest for the best interests of patients; (3) the quest for medically appropriate plans; (4) confronting parents and families and (5) socioenvironmental issues. Dilemmas occurred and developed as conflicting interactions among these five elements. We further categorised these five elements into three principal domains: the decision-maker (decider); consensus making among families, colleagues and society (process) and the consequential output of the decision (consequence). CONCLUSIONS: This is the first qualitative study to demonstrate the framework of paediatricians' decision-making processes and the complex structures of dilemmas they face. Our data indicate the necessity of establishing and implementing an effective support system for paediatricians, such as structured professional education and arguments for creating social consensus that assist them to reach the best plan for the management of severely ill children.

Early Intervention With Adrenocorticotropin for Acute Encephalopathy-Associated Epileptic Spasms: Report of Two Cases.

PURPOSE: Acute encephalopathy with biphasic seizures and reduced diffusion (AESD) is a leading cause of childhood-onset encephalopathy in Japan. Children with AESD frequently develop intractable epilepsy, whereas their treatment options remain to be determined. METHOD: We present 2 unrelated girls, who developed AESD at 25 months (case 1) and 12 months of age (case 2). Both cases underwent intensive cares from the first day of illness, whereas severe neurological impairments were left on discharge. They showed repeated signs of epileptic spasms at 2 months (case 1) and 8 months (case 2) after the onset of AESD. Video-monitoring electroencephalograms (EEG) detected the recurrent attacks accompanying slow-wave bursts and transient suppressions of the precedent epileptiform discharges, as typically observed in epileptic spasms. RESULTS: Intramuscular injection of adrenocorticotropic hormone (ACTH, 0.0125 mg/kg/d) was introduced within 1 month from the onset of epileptic spasms and continued for 2 weeks. The ACTH treatment disrupted the paroxysmal activity in EEG, and it has relieved these patients from epileptic seizures for more than 1 year. CONCLUSION: This report illustrates the potential efficacy of ACTH for a group of children with epileptic spasms after AESD.

An acute encephalopathy with reduced diffusion in BRAF-associated cardio-facio-cutaneous syndrome.

BACKGROUND: Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder characterized by cardiovascular anomalies, dysmorphic faces, ectodermal abnormalities and developmental delays. Mutations in BRAF and other RAS-MAPK pathway-associated genes are commonly identified in patients with CFCS. While this molecular pathway is known to be associated with neuro-inflammatory conditions, only one case with CFCS has been reported thus far to develop acute encephalopathy in childhood. CASE REPORT: A 3-year-old boy with dysmorphic features and mild psychomotor delay developed acute encephalopathy. After a 45-min long, generalized seizure, the magnetic resonance imaging revealed that the restricted diffusion signals spread to the bilateral subcortical white matters on day 1 of illness. Despite the 14 days of intensive care, the acute symptoms of encephalopathy left him intractable epilepsy and severe neurocognitive impairments. The whole-exome sequencing analysis identified a de novo heterozygous mutation of BRAF (NM_004333:p.Thr241Met) in this case. CONCLUSION: The present case suggests that the hyperactive condition of ERK signals might augment the development of acute encephalopathy and post-encephalopathic epilepsy in childhood.

Association of toll-like receptor 3 gene polymorphism with subacute sclerosing panencephalitis.

Innate immunity plays an important role in measles virus (MV) infection. MV-derived double-stranded RNA is recognized by toll-like receptor 3 (TLR3), retinoic acid-inducible protein I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We investigated whether genes encoding these molecules contributed to the development of subacute sclerosing panencephalitis (SSPE) in Japanese individuals. Four single nucleotide polymorphisms (SNPs) of the three genes (TLR3 rs3775291:Leu412Phe, RIG1 rs277729 and rs9695310, and MDA5 rs4664463) were assessed in 40 SSPE patients and 84 controls. Because the TLR3 SNP showed a positive association with SSPE, three additional SNPs were subjected to haplotype analysis. The frequency of 412Phe allele of TLR3 rs3775291 in SSPE patients was significantly higher than that in controls (P=.03). In haplotype analysis of four SNPs in the TLR3 gene, the frequency of -7C/IVS3+71C/Phe412/c.1377C haplotype was significantly increased in SSPE patients (P=.006, odds ration [OR]: 2.2). TLR3 gene may confer host genetic susceptibility to SSPE in Japanese individuals.

A rightward saccade to an unexpected stimulus as a marker for lateralised visuospatial attention.

The human brain is lateralised to the right for visuospatial attention, particularly when reorienting attention to unexpected stimuli. However, the developmental characteristics of lateralisation remain unclear. To address this question, we devised a saccade task applicable for both adults and children. To assess the utility of this system, we investigated the correlation between line bisection test performance and the saccade task for 54 healthy adult volunteers. Participants followed a visual target that jumped 10 times, alternating between two fixed positions across the midline with a constant pace. In both the rightward and leftward directions, saccadic reaction time (RT) to the target jump decreased and reached a plateau from the first to the tenth jumps. Furthermore, we obtained the time required for reorienting in the contralateral hemisphere using the corrected value of the first RT. We found that longer corrected RTs in the rightward saccade were associated with greater deviation to the left in the line bisection task. This correlation was not observed for leftward saccades. Thus, corrected RTs in rightward saccades reflected the strength of individual hemispheric lateralisation. In conclusion, the rightward saccade task provides a suitable marker for lateralised visuospatial attention, and for investigating the development of lateralisation.