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The patient was a 6-year-old girl with clinically isolated syndrome–like anti-myelin oligodendrocyte glycoprotein–associated disease (MOG-AD). Methylprednisolone pulse therapy resolved her cerebral lesion, and her visual acuity and field fully recovered after plasma exchange. This is the first case report presenting the therapeutic course in a child with clinically isolated syndrome–like MOG-AD. [ J Pediatr Ophthalmol Strabismus . 2023;60(2):e11–e15.]

Background Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous neuromuscular disorder characterized by muscle weakness and caused by mutations in more than 35 different genes. This condition should not be overlooked as a subset of patients with CMS are treatable. However, the diagnosis of CMS is often difficult due to the broad variability in disease severity and course. Case report A five-year-old boy without remarkable family history was born with marked general muscle hypotonia and weakness, respiratory insufficiency, anomalies, and multiple joint contractures. Congenital myopathy was suspected based upon type 1 fiber predominance on muscle biopsy. However, he was diagnosed with CMS at age 4 years when his ptosis and ophthalmoplegia were found to be improved by edrophonium chloride and repetitive nerve stimulation showed attenuation of compound muscle action potentials. An exome sequencing identified a compound heterozygous missense variant of c.737C > T (p.A246V) and a novel intronic insertion c.1166 + 4_1166 + 5insAAGCCCACCAC in RAPSN. RT-PCR analysis which showed the skipping of exon 7 in a skeletal muscle sample confirmed that the intronic insertion was pathogenic. His myasthenic symptoms were remarkably improved by pyridostigmine. Conclusion The patient’s diagnosis of CMS was confirmed by exome sequencing, and RT-PCR revealed that the skipping of exon 7 in RAPSN was caused by a novel intronic insertion. The genetic information uncovered in this case should therefore be added to the collection of tools for diagnosing and treating CMS.

Abnormal maternal gestational weight gain (GWG) increases the risk of obstetric-related complications. This investigation examined the impact of GWG on infant neurodevelopmental abnormalities at 12 months of age using the data of a nationwide Japanese cohort study. Questionnaire data were obtained from the ongoing Japan Environment and Children’s Study cohort study. Maternal GWG was subdivided as below, within, or above the reference values of the Institution of Medicine pregnancy weight guidelines. The Ages and Stages Questionnaire, third edition (ASQ-3) is a parent-reported developmental screening instrument for children across five domains: communication, gross motor, fine motor, problem-solving, and personal–social. Multiple logistic regression analysis was employed to identify correlations between GWG and developmental delay defined as ASQ-3 scores of less than two standard deviations below the mean. A total of 30,694 mothers with singleton live births and partners who completed the questionnaire were analyzed. The prevalence of mothers below, within, and above the GWG guidelines was 60.4% (18,527), 32.1% (9850), and 7.5% (2317), respectively. We recorded 10,943 infants (35.7%) who were outliers in at least one ASQ-3 domain. After controlling for covariates, GWG below established guidelines was associated with a significantly higher risk of developmental delay for the communication (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.09–1.34), gross motor (OR 1.14, 95% CI 1.05–1.24), fine motor (OR 1.13, 95% CI 1.04–1.24), problem-solving (OR 1.09, 95% CI 1.01–1.18), and personal–social (OR 1.15, 95% CI 1.07–1.24) domains.Conclusion: This large survey revealed a possible deleterious effect of insufficient maternal GWG on infant neurodevelopment.Trial registration: The Japan Environment and Children’s Study (JECS) was registered in the UMIN Clinical Trials Registry on January 15, 2018 (number UMIN000030786). What is Known:• Inappropriate maternal gestational weight gain may cause obstetric complications and adverse birth outcomes.• Excess maternal weight gain may result in gestational diabetes, hypertension, eclampsia, caesarean delivery, and macrosomia, while insufficient maternal weight gain has been associated with pre-term birth and small for gestational age. What is New:• This study provides important information on a possible adverse effect of insufficient maternal gestational weight gain on offspring neurodevelopment at 12 months of age.• Our findings indicate a need to reconsider the optimal body mass index and gestational weight gain for women desiring pregnancy.

Background The most common causative pathogen of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was reported as HHV-6. Although excitotoxic injury with delayed neuronal death is considered to be a possible pathogenesis of AESD, the detailed pathophysiology remains unclear. Case presentation We present a twelve-month-old girl with AESD due to HHV-6 primary infection. She was successfully treated for AESD including targeted temperature management and the administration of vitamin B1, B6, and L-carnitine. Although the viral load of HHV-6 in her liquor was high (12,000 copies/mL), she fully recovered without antiviral agent use. Discussion There has been no study focusing on the HHV-6 viral load in patients with AESD, and only a few case reports have been published. We reviewed the clinical features and viral load in the liquor of our case and four reported infants with AESD due to HHV-6 primary infection who had real-time PCR tests results. Viral loads in the three patients with a poor prognosis were 31.5, negative, and 3,390 copies/mL, respectively. On the other hand, the copy numbers of HHV-6 DNA in the two patients with no sequelae were 12,000 and 106 copies/mL, respectively, and our case had the highest viral load among the five summarized patients.

Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects.Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated.Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments.A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Background The association between fetal exposure to alcohol and congenital structural disorders remains inconclusive. The present study searched for relationships between maternal alcohol consumption during pregnancy and the risk of congenital malformations. Methods We evaluated the fixed dataset of a large national birth cohort study including 73,595 mothers with a singleton live birth. Information regarding the alcohol consumption of mothers was obtained from self-reported questionnaires. Physicians assessed for 6 major congenital malformations (congenital heart defects [CHDs], male genital abnormalities, limb defects, cleft lip and/or cleft palate [orofacial clefts (OFC)], severe brain abnormalities, and gastrointestinal obstructions) up to 1 month after birth. Multiple logistic regression analysis was performed to identify associations between maternal alcohol consumption during pregnancy and each malformation. Results The prevalence of maternal drinking in early pregnancy and until the second/third trimester was 46.6% and 2.8%, respectively. The onset of CHD was inversely associated with mothers who quit drinking during early pregnancy (OR 0.85, 95% CI 0.74–0.98). There was no remarkable impact of maternal drinking habit status on the other congenital malformations after adjustment for covariates. Conclusions Maternal alcohol consumption during pregnancy, even in early pregnancy, displayed no significant adverse impact on congenital malformations of interest. Impact This large-scale Japanese cohort study revealed that no teratogenic associations were found between maternal retrospective reports of periconceptional alcohol consumption and congenital malformations after adjustment for covariates. This is the first nationwide birth cohort study in Japan to assess the effect of maternal alcohol consumption during pregnancy on major congenital malformations. Our finding indicated that maternal low-to-moderate alcohol consumption during pregnancy, even in early pregnancy, displayed no significant adverse impact on congenital heart defects, male genital abnormalities, limb defects, orofacial clefts, severe brain abnormalities, or gastrointestinal obstructions.

Background Maternal exposure to pesticides during pregnancy may cause oxidative hemolysis leading to neonatal hyperbilirubinemia. This investigation examined for associations between maternal use of pesticides or repellents during pregnancy and neonatal hyperbilirubinemia requiring phototherapy. Methods We used the dataset from the Japan Environment and Children's Study, a large national birth cohort study registered from January 31, 2011 to March 31, 2014. The fixed data of 61,751 live births were used to evaluate the presence of neonatal hyperbilirubinemia and potential confounding factors. We employed multiple logistic regression analysis to identify correlations between the frequency of maternal pesticide or repellent use during pregnancy and clinically relevant neonatal hyperbilirubinemia. Results After controlling for confounding factors, there were significant associations between neonatal hyperbilirubinemia necessitating phototherapy and the frequent use of indoor insecticide spray (OR 1.21, 95% CI 1.05-1.38). For spray- or lotion-type insect repellents, an opposite relationship was observed (more than a few times a week: OR 0.70, 95% CI 0.61-0.81, up to a few times a month: OR 0.84, 95% CI 0.78-0.91). Conclusion The frequent use of indoor insecticide spray during pregnancy showed an increased risk of neonatal hyperbilirubinemia requiring phototherapy, which was absent for spray- or lotion-type insect repellents. Impact The frequent use of indoor insecticide spray during pregnancy showed an increased risk of neonatal hyperbilirubinemia requiring phototherapy, which was absent for spray- or lotion-type insect repellents. This is the first study examining the effects of maternal exposure to pesticides or repellents on clinically relevant neonatal hyperbilirubinemia using a dataset from a nationwide birth cohort study. This large-scale Japanese cohort study revealed that the frequent use of indoor insecticide spray during pregnancy may increase the risk of neonatal hyperbilirubinemia requiring treatment.

Various genetic and environmental influences have been studied for developmental disorders; however, the precise cause remains unknown. This study assessed the impact of maternal serum total cholesterol (TC) level in early pregnancy on early childhood neurodevelopment.The fixed data of 31,797 singleton births from a large national birth cohort study that commenced in 2011 were used to identify developmental disorders as estimated by Ages and Stages Questionnaire, third edition (ASQ-3) scores of less than -2 standard deviations at 12 months of age. Multiple logistic regression analysis was employed to search for correlations between possibility of developmental disorders and maternal TC levels in early pregnancy classified into 4 groups based on quartile (Q1-Q4) values.After controlling for potential confounding factors in 27,836 participants who ultimately underwent multivariate analysis, we observed that elevated TC levels were significantly associated with a higher risk of screen positive status for communication (Q4: adjusted odds ratio [aOR] 1.20, 95% confidence interval [CI] 1.05-1.37) and gross motor (aOR 1.13, 95% CI 1.03-1.25) ASQ-3 domain scores.This large nationwide survey revealed a possible deleterious effect of hypercholesterolemia in early pregnancy on infant neurodevelopment and age-appropriate skill acquisition at 12 months age.

Study design Case report. Objective Describe the clinical and radiological outcomes of a patient with a piezo-type mechanosensitive ion channel component 2 (PIEZO2)-deficient arthrogryposis receiving surgery for severe kyphoscoliosis. Summary of background data Spinal deformity is a characteristic feature of arthrogryposis due to PIEZO2 gene deficiency, for which surgical correction is indicated when the deformity is progressive to avoid neurological deficits and respiratory impairment. However, there exist few reports on the surgical treatment of spinal deformity in PIEZO2-deficient arthrogryposis, and no therapeutic standards have been established. Methods We retrospectively reviewed a case of proximal junctional kyphosis after posterior spinal fusion for severe kyphoscoliosis in PIEZO2-deficient arthrogryposis. Results The patient was a 13-year-old girl with PIEZO2-deficient arthrogryposis who underwent posterior spinal fusion with an all-pedicle screw construct from T2 to L2 for a preoperative main thoracic curve Cobb angle of 78° and thoracic kyphotic angle of 83°. Postoperative Cobb angle of the main thoracic curve and thoracic kyphotic angle were improved at 11° and 34°, respectively. Although revision surgery was required for neurological deficits from proximal junctional kyphosis, she could walk with a crutch and improvements in clinical questionnaire scores were noted at 2 years and 3 months after surgery. Conclusion Based on the present case, posterior spinal fusion represents a good treatment option for severe spinal deformity in PIEZO2-deficient arthrogryposis. Careful consideration of fusion level is needed to prevent proximal junctional kyphosis. Level of evidence 5.

A 2-year-old girl required medical attention for a sudden onset of repetitive tonic-clonic convulsions after ingesting 20-30 ginkgo seeds. Concentrations of the major forms of circulating vitamin B6, pyridoxal-5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid, as well as the known ginkgo seed toxin 4'-O-methylpyridoxine (MPN) were measured in the serum and cerebrospinal fluid (CSF). PLP is an active form of vitamin B6 and necessary for γ-aminobutyric acid (GABA) production. High MPN concentrations were observed in both the serum and CSF. As the PLP to PL ratio was markedly decreased in serum and CSF examinations, we suspected the ratio to be important in GABA production. This case report provides novel information on the metabolism of vitamin B6 in humans as a result of ginkgo seed poisoning.

BackgroundAbnormal gestational weight gain (GWG) increases the risk of obstetric-related complications. This investigation examined the impact of GWG on infant neurodevelopmental abnormalities at 12 months of age using the data of a nationwide Japanese cohort study.MethodsQuestionnaire data were obtained from the ongoing Japan Environment and Children’s Study cohort study. GWG was subdivided as below, within, or above the reference values of the Institution of Medicine pregnancy weight guidelines. The Ages and Stages Questionnaire, third edition (ASQ-3) is a parent-reported developmental screening instrument for children across five domains: communication, gross motor, fine motor, problem solving, and personal-social. Multiple logistic regression analysis was employed to identify correlations between GWG and developmental delay defined as ASQ-3 scores of less than two standard deviations below the mean.ResultsA total of 30,694 mothers with singleton live births and partners who completed the questionnaire were analyzed. The prevalence of mothers below, within, and above the GWG guidelines was 60.4% (18,527), 32.1% (9,850), and 7.5% (2,317), respectively. We recorded 10,943 infants (35.7%) who were outliers in at least one ASQ-3 domain. After controlling for covariates, GWG below established guidelines was associated with a significantly higher risk of developmental delay for the communication (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.09-1.34), gross motor (OR 1.14, 95% CI 1.05-1.24), fine motor (OR 1.13, 95% CI 1.04-1.24), problem solving (OR 1.09, 95% CI 1.01-1.18), and personal-social domains (OR 1.15, 95% CI 1.07-1.24).ConclusionThis large survey revealed a possible deleterious effect of insufficient GWG on infant neurodevelopment.The Japan Environment and Children’s Study (JECS) was registered in the UMIN Clinical Trials Registry on 15 January 2018 (number: UMIN000030786).

Abnormal maternal gestational weight gain (GWG) increases the risk of obstetric-related complications. This investigation examined the impact of GWG on infant neurodevelopmental abnormalities at 12 months of age using the data of a nationwide Japanese cohort study. Questionnaire data were obtained from the ongoing Japan Environment and Children's Study cohort study. Maternal GWG was subdivided as below, within, or above the reference values of the Institution of Medicine pregnancy weight guidelines. The Ages and Stages Questionnaire, third edition (ASQ-3) is a parent-reported developmental screening instrument for children across five domains: communication, gross motor, fine motor, problem-solving, and personal-social. Multiple logistic regression analysis was employed to identify correlations between GWG and developmental delay defined as ASQ-3 scores of less than two standard deviations below the mean. A total of 30,694 mothers with singleton live births and partners who completed the questionnaire were analyzed. The prevalence of mothers below, within, and above the GWG guidelines was 60.4% (18,527), 32.1% (9850), and 7.5% (2317), respectively. We recorded 10,943 infants (35.7%) who were outliers in at least one ASQ-3 domain. After controlling for covariates, GWG below established guidelines was associated with a significantly higher risk of developmental delay for the communication (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.09-1.34), gross motor (OR 1.14, 95% CI 1.05-1.24), fine motor (OR 1.13, 95% CI 1.04-1.24), problem-solving (OR 1.09, 95% CI 1.01-1.18), and personal-social (OR 1.15, 95% CI 1.07-1.24) domains.Conclusion: This large survey revealed a possible deleterious effect of insufficient maternal GWG on infant neurodevelopment.Trial registration: The Japan Environment and Children's Study (JECS) was registered in the UMIN Clinical Trials Registry on January 15, 2018 (number UMIN000030786). What is Known: • Inappropriate maternal gestational weight gain may cause obstetric complications and adverse birth outcomes. • Excess maternal weight gain may result in gestational diabetes, hypertension, eclampsia, caesarean delivery, and macrosomia, while insufficient maternal weight gain has been associated with pre-term birth and small for gestational age. What is New: • This study provides important information on a possible adverse effect of insufficient maternal gestational weight gain on offspring neurodevelopment at 12 months of age. • Our findings indicate a need to reconsider the optimal body mass index and gestational weight gain for women desiring pregnancy.

Objective The aim of this study was to determine the prognostic factors for acute encephalopathy with reduced diffusion (AED) during the acute phase through retrospective case evaluation. Methods The participants included 23 patients with AED. The diagnosis of AED was based on their clinical course and radiological findings. We divided the patients into severe and non-severe groups based on the neurodevelopmental outcome. The severe group included seven patients (median age, 21 months; range, 6–87 months) and the non-severe group included 16 patients (19 months, 9–58 months). Clinical symptoms, laboratory data and electroencephalogram (EEG) findings within 48 h from the initial seizure onset were compared between the two groups to identify neurological outcome predictors. Results The incidence of coma 12–24 h after onset, serum creatinine (Cr) levels within 2 h after onset, maximum aspartate aminotransferase (AST) levels within 24 h after onset, and the rate of electrographic seizures in EEG were significantly higher in the severe group (Coma, 80%; Cr, 0.40 mg/dl, 0.37–0.73; AST, 363 IU/L, 104–662; electrographic seizures, 80%) than the non-severe group (Coma, 0%; Cr, 0.29 mg/dL, 0.19–0.45; AST, 58.5 IU/L, 30–386; electrographic seizures, 0%). Conclusions Coma 12–24 h after onset, elevation of Cr levels within 2 h after onset, elevation of AST levels within 24 h after onset, and non-convulsive status epileptics (NCSE) in comatose patients were early predictors of severe AED. Patients in a coma after a febrile seizure should be checked for NCSE signs in EEG to terminate NCSE without delay.

Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder characterized by branchiogenic anomalies, hearing loss, and renal anomalies. The aim of this study was to reveal the clinical phenotypes and their causative genes in Japanese BOR patients. Patients clinically diagnosed with BOR syndrome were analyzed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA), array-based comparative genomic hybridization (aCGH), and next-generation sequencing (NGS). We identified the causative genes in 38/51 patients from 26/36 families; EYA1 aberrations were identified in 22 families, SALL1 mutations were identified in two families, and SIX1 mutations and a 22q partial tetrasomy were identified in one family each. All patients identified with causative genes suffered from hearing loss. Second branchial arch anomalies, including a cervical fistula or cyst, preauricular pits, and renal anomalies, were frequently identified (>60%) in patients with EYA1 aberrations. Renal hypodysplasia or unknown-cause renal insufficiency was identified in more than half of patients with EYA1 aberrations. Even within the same family, renal phenotypes often varied substantially. In addition to direct sequencing, MLPA and NGS were useful for the genetic analysis of BOR patients.

We present a 3-year-old girl with beta-propeller protein-associated neurodegeneration (BPAN) who had a de novo heterozygous splice-site mutation of c.831-1G>C in WDR45 and developed infantile spasms; her onset age of infantile spasms was relatively late. Her infantile spasms and hypsarrhythmia disappeared promptly by adrenocorticotropic hormone therapy (CORTROSYN®Z, 0.0125mg/kg/day daily for 2weeks intramuscularly), though the administration of pyridoxal phosphate and valproic acid had poor efficacy. BPAN is known to be associated with various types of seizures, but there are few reports on infantile spasms, especially in females. To date, only 5 patients with BPAN have been reported to develop infantile spasms, and our patient is the second case in females. In this report, we showed that female patients with BPAN had milder phenotypic features than males: males developed intractable infantile spasms in early infancy, while females had treatable infantile spasms in late infancy.

We describe the case of a 17-year-old male soccer player with T-wave inversion in precordial leads in resting electrocardiography, which also disclosed sinus bradycardia, early repolarization, and increased QRS voltage. These findings strongly suggested cardiomyopathy. The patient’s T-wave inversion disappeared during only 2 weeks of detraining, and it re-appeared 2 weeks after resumption of intensive training. This sudden change in electrocardiographic parameters over a short period helped in identifying the adolescent as having athlete’s heart.

Exon skipping therapy has recently received attention for its ability to convert the phenotype of lethal Duchenne muscular dystrophy (DMD) to a more benign form, Becker muscular dystrophy (BMD), by correcting the open reading frame. This therapy has mainly focused on a hot-spot (exons 45-55) mutation in the DMD gene. Exon skipping of an entire stretch of exons 45-55 is an approach applicable to 46.9% of DMD patients. However, the resulting phenotype is not yet fully understood. Here we examined the clinical profiles of 24 patients with BMD resulting from deletions starting at exon 45. The Δ45-55 group ranged in age from 2 to 87 years; no mortality was observed, and one patient was ambulatory at 79 years of age. The age at which patients became wheelchair-bound in the Δ45-48 group (18-88 years old) was approximately 50 years. Cardiomyopathy was well controlled by pharmaceuticals in both deletion groups. In contrast, the Δ45-47 and Δ45-49 groups exhibited more severe phenotypes than those with other mutations: the age at which patients in the Δ45-49 group became wheelchair-bound was around 30-40 years. Our study shows that clinical severity differs between each hot-spot deletion.

There have been no large nationwide birth cohort studies examining for the effects of maternal alcohol use during pregnancy on placental abnormality. This study searched for associations between alcohol consumption and the placental abnormalities of placenta previa, placental abruption, and placenta accreta using the fixed dataset of a large national birth cohort study commencing in 2011 that included 80,020 mothers with a singleton pregnancy. The presence of placental abnormalities and potential confounding factors were recorded, and multiple logistic regression analysis was employed to search for correlations between maternal alcohol consumption during pregnancy and placental abnormalities. The overall rate of prenatal drinking until the second/third trimester was 2.7% (2,112). The prevalence of placenta previa, placental abruption, and placenta accreta was 0.58% (467), 0.43% (342), and 0.20% (160), respectively. After controlling for potential confounding factors, maternal alcohol use during pregnancy was significantly associated with the development of placenta accreta (OR 3.10, 95%CI 1.69-5.44). In conclusion, this large nationwide survey revealed an association between maternal drinking during pregnancy and placenta accreta, which may lead to excessive bleeding during delivery.

Objective Clinically mild encephalitis/encephalopathy with a reversible lesion (MERS) is characterized by reversible lesions with transiently-reduced diffusion in the splenium of the corpus callosum on magnetic resonance imaging. Recently, cases of MERS with accompanying acute focal bacterial nephritis (AFBN) have been reported in children. This study aimed to clarify the clinical features of MERS with AFBN. Methods A retrospective study of patients with MERS was conducted at Nagano Children’s Hospital, Japan, from April 2013 to March 2018. The clinical signs and laboratory findings of MERS patients with AFBN (AFBN group) and without AFBN (non-AFBN group) were measured and compared. Results Of 12 patients diagnosed as having MERS, 3 were also found to have AFBN. Seven of the 9 patients without AFBN were associated with infectious agents, including rotavirus and influenza viruses. No patient received steroids or intravenous immunoglobulin therapy, and none displayed neurological sequelae. Serum C-reactive protein (CRP) levels were significantly higher in the AFBN group than in the non-AFBN group (14.7 mg/dL versus 0.8 mg/dL, P = 0.009). AFBN group patients were also significantly older (97 months versus 27 months, P = 0.018) and experienced significantly less frequent seizures (33% versus 100%, P = 0.045). The mean duration of neurological symptoms was significantly longer in the AFBN group than in the non-AFBN group (4 days versus 1.7 days, P = 0.013). Conclusions Pediatric patients with AFBN often present with non-specific findings, such as fever and abdominal pain. Pediatricians should be aware of the possibility of AFBN in the clinical setting of MERS, particularly when the patient exhibits inexplicably high CRP.

PIEZO2 encodes a mechanically activated cation channel, which is abundantly expressed in dorsal root ganglion neuron and sensory endings of proprioceptors required for light touch sensation and proprioception in mice. Biallelic loss-of-function mutations in PIEZO2 (i.e., PIEZO2 deficiency) were recently found to cause an arthrogryposis syndrome. Sixteen patients from eight families have been reported to date. Herein we report a new case, including detailed clinical characteristics and courses as well as comprehensive neurological features. The patient was a 12-year-old girl presenting with congenital multiple contractures, progressive severe scoliosis, prenatal-onset growth impairment, motor developmental delay with hypotonia and myopathy-like muscle pathology, mild facial features, and normal intelligence. Her neurological features included areflexia, impaired proprioception, and decreased senses. Neurophysiological examination revealed decreased amplitude of sensory nerve action potentials, absent H reflex, and prolongation of central conduction times. Clinical exome sequencing revealed a novel homozygous frameshift mutation in PIEZO2 (NM_022068: c.4171_4174delGTCA: p.Val1391Lysfs*39) with no detectable mRNA expression of the gene. PIEZO2 deficiency represents a clinical entity involving characteristic neuromuscular abnormalities and physical features. Next generation sequencing-based comprehensive molecular screening and extensive neurophysiological examination could be valuable for diagnosis of the disorder.

Intellectual disability (ID) is a clinically and genetically heterogeneous developmental brain disorder. The present study describes two male siblings, aged 7 and 1 yr old, with severe ID, spastic quadriplegia, nystagmus, and brain atrophy with acquired microcephaly. We used the exome sequencing to identify the causative gene in the patients and identified a hemizygous missense variant, c.1282T>A (p.W428R), in the p21-activated serine/threonine kinase 3 gene (PAK3), which is associated with X-linked ID. p.W428R is located within the highly conserved kinase domain and was predicted to induce loss of enzymatic function by three mutation prediction tools (SIFT, PolyPhen-2, and MutationTaster). In addition, this variant has not been reported in public databases (as of the middle of December 2018) or in the data from 3275 individuals of the Japanese general population analyzed using high-depth whole-genome sequencing. To date, only 13 point mutations and deletions in PAK3 in ID have been reported. The literature review illustrated a phenotypic spectrum of PAK3 pathogenic variant, and our cases represented the most severe form of the PAK3-associated phenotypes. This is the first report of a PAK3 pathogenic variant in Japanese patients with X-linked ID.

Students’ depressive symptoms might be related to their own risk factors and to their parents’ status. The objective of this cross-sectional study was to examine the relationship of depressive symptoms with lifestyle variables and parents’ psychological and socio-demographic status among Japanese junior high school students. Of 477 students and their parents, 409 (85.7 %) students and 314 (65.8 %) parents participated in the study. Students answered self-reported questionnaire on depressive symptoms, their heights and weights, subjective stress, body dissatisfaction, lifestyles including sleep duration and extracurricular physical activity in school and other physical activity outside the school, and nutritional intake. Parents responded to questionnaire on depressive symptoms and socio-demographic status. The prevalence of depressive symptoms was 24.9 %. Students with depressive symptoms were more likely to have stress. Students in shorter and longer sleep duration groups were more likely to have depressive symptoms. The students with depressive symptoms had smaller amount of energy intake than did those without depressive symptoms. Multiple logistic regression analysis revealed significant relationships between students’ depressive symptoms and some independent variables. Sex, subjective stress, “almost-never”-categorized extracurricular physical activity in school and other physical activity outside the school, and having a parent with depressive symptoms were significantly associated with students’ depressive symptoms. Reducing mental stress and taking care of lifestyles, especially, “almost-everyday”-categorized extracurricular physical activity in school and other physical activity outside the school, may have benefits for students’ mental health, and having a parent with depressive symptoms may be associated with students’ depressive symptoms.

A 2-year-old girl required medical attention for a sudden onset of repetitive tonic-clonic convulsions after ingesting 20-30 ginkgo seeds. Concentrations of the major forms of circulating vitamin B

Congenital cytomegalovirus (cCMV) infection is the most common congenital infection, with the majority of infected newborns having no detectable signs. The aim of this study was to examine the accuracy of our newly developed DBS-based assay as an appropriate mass screening method for cCMV infection.Between May 2011 and October 2016, newborns delivered at six hospitals in Nagano Prefecture, Japan were enrolled prospectively. We employed dried blood spot (DBS)-based assays with real-time quantitative PCR (qPCR).Prior to the clinical study, confirmation analysis was carried out using positive and negative controls. The sensitivity and specificity of this DBS-based qPCR assay for the detection of CMV DNA were 83 and 97%, respectively. During the study period, 9675 newborns were enrolled. The total recovery rate of DBS was 99.92% (9,667/9,675). From our analysis of the 9,667 samples, 47 DBS samples were found positive by the qPCR test (0.48%), and 9620 (99.5%) DBS samples were CMV-negative.The risk of neural disorders associated with cCMV infection is thought likely to increase with CMV viral load in the blood. DBS screening for cCMV may be sufficient in a clinical setting, and offers a realistic and feasible option for universal mass screening.

Objective Myasthenia gravis (MG) is a T-cell dependent and antibody mediated autoimmune disease. Recent studies of adult patients and animal models have shown that regulatory T cells (Tregs) play an important role in the pathogenesis of MG, but little is known about MG in children. This study evaluated the role of peripheral blood Tregs in childhood ocular MG and assessed if Tregs could be an index for estimating immunological status. Patients and methods Clinical data and peripheral lymphocytes were obtained from 13 children with serum AChR antibody-positive ocular type MG and 18 age-matched controls. Committed cells from MG patients were divided into two clinical stages: active ( n = 12) and remission ( n = 11). Tregs and Th17 cells were analyzed by flow cytometric analysis based on CD4 + CD25 + intracellular Foxp3 + and CD4 + intracellular IL-17A + fractions, respectively. Results The percentage of Tregs among peripheral blood CD4 + T cells in active stage, remission stage, and control groups was 3.3 ± 1.3%, 4.8 ± 1.7%, and 5.0 ± 0.6%, respectively. The Treg population was significantly lower in the active stage than in the remission stage and controls. Furthermore, Treg percentage was significantly lower during relapse of myasthenia symptoms. We witnessed no remarkable associations between the percentage of Tregs and immune suppressant dosages. Conclusions A significant reduction in the peripheral Treg population is considered to contribute to the pathophysiology of ocular type childhood MG and may be a marker of immunological state in these patients.

Background Myasthenia gravis is a B cell–mediated autoimmune disorder. The pathophysiology of childhood-onset ocular myasthenia gravis remains unclear. We investigated serum B cell–activating factor levels and other immunological parameters in child patients with ocular myasthenia gravis. Methods Blood samples were obtained from 9 children with ocular myasthenia gravis and 20 age-matched controls. We assayed serum concentrations of B cell–activating factor, anti-acetylcholine receptor antibody titers, 7 types of cytokines (interleukins-2, -4, -6, -10, and -17A; interferon-γ; tumor necrosis factor-α) as well as the percentages of peripheral blood CD4+, CD8+, and CD19+ cells. Results Serum B cell–activating factor levels were significantly higher before immunosuppressive therapy in patients with childhood-onset ocular myasthenia gravis than in controls and decreased after immunosuppressive therapy. A significant positive correlation was observed between serum B cell–activating factor levels and anti-acetylcholine receptor antibody titers in patients with myasthenia gravis. Serum B cell–activating factor concentrations did not correlate with the percentages of CD4+, CD8+, and CD19+ cells or the CD4+/CD8+ ratio. No significant differences were observed in the levels of the 7 different types of cytokines examined, including interleukin-17A, between preimmunosuppressive therapy myasthenia gravis patients and controls. Conclusions Circulating B cell–activating factor may play a key role in the pathophysiology of childhood-onset ocular myasthenia gravis.

Dimethyl fumarate (DMF) is a modifier of the nuclear factor (erythroid-derived 2)-2 (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) pathway. DMF treatment in the effector phase significantly suppressed the development of Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) both clinically and histologically. DMF treatment leads to an enhanced Nrf2 antioxidant response in TMEV-IDD mice. DMF treatment in the effector phase significantly suppressed the level of IL-17A mRNA. DMF is known to inhibit differentiation of T helper 17 (Th17) cells via suppressing NF-κB. Taken together, our data suggest that DMF treatment in the effector phase may suppress TMEV-IDD not only via enhancing the antioxidant response but also via suppressing IL-17A.

Introduction: Mitochondrial dysfunction results in a wide range of organ disorders through diverse genetic abnormalities. We herein present the detailed clinical course of an infant admitted for extensive, rapidly progressing white matter lesions and hypertrophic cardiomyopathy due to a BOLA3 gene mutation. Case: A 6-month-old girl with no remarkable family or past medical history until 1 month prior presented with developmental regression and feeding impairment. Ultrasound cardiography and brain magnetic resonance imaging (MRI) respectively disclosed the presence of hypertrophic cardiomyopathy and symmetrical deep white matter lesions. She was transferred to our hospital at age 6 months. High lactate levels in her cerebrospinal fluid suggested mitochondrial dysfunction. Despite vitamin supplementation therapy followed by a ketogenic diet, the patient began exhibiting clusters of myoclonic seizures and respiratory failure. Brain and spinal cord MRI revealed rapid progression of the white matter lesions. She died at 10 months of age. Fibroblasts obtained pre-mortem displayed low mitochondrial respiratory chain complex I and II activity. A homozygous H96R (c. 287 A > G) mutation was identified in the BOLA3 gene. Discussion: No reported case of a homozygous BOLA3 gene mutation has survived past 1 year of life. BOLA3 appears to play a critical role in the electron transport system and production of iron-sulfur clusters that are related to lipid metabolism and enzyme biosynthesis.

Evidence suggests that cytokines may be one of the major factors influencing cognitive development in those with autism spectrum disorder (ASD). To shed light on the neural and cognitive mechanisms of ASD, we investigated the association between peripheral cytokine levels and cognitive profiles in children with ASD. The serum levels of 10 cytokines (granulocyte macrophage colony-stimulating factor, interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-α) were examined in 14 children with ASD using the Human Ultrasensitive Cytokine Magnetic 10-Plex Panel for the Luminex platform. The Wechsler Intelligence Scale for Children (WISC) was administered to each subject, and the relationships between WISC scores and serum levels of the cytokines were examined. The full-scale intelligence quotient (IQ) was significantly negatively correlated with the levels of IL-6 (Spearman’s rank, p < 0.0001, false discovery rate q < 0.01). The levels of IL-6 and IFN-γ showed significant negative correlations with the verbal comprehension index (p < 0.001, q < 0.01) and working memory index (p < 0.01, q < 0.05), respectively. No other cytokines were significantly correlated with full-scale IQ or with any of the subscale scores of the WISC. The present results suggest negative correlations of IL-6 and IFN-γ levels with cognitive development of children with ASD. Our preliminary findings add to the evidence that cytokines may play a role in the neural development in ASD., Article, JOURNAL OF INTELLIGENCE. 5(2):19 (2017)

Background Cat scratch disease is a common infectious disorder caused by Bartonella henselae that is transmitted primarily by kittens. It typically exhibits a benign and self-limiting course of subacute regional lymphadenopathy and fever lasting two to eight weeks. The most severe complication of cat scratch disease is involvement of the nervous system, such as encephalitis, meningitis, and polyneuritis. Peripheral facial nerve palsy associated with Bartonella infection is rare; few reported pediatric and adult cases exist and the precise pathogenesis is unknown. Case report A previously healthy 7-year-old boy presented with fever, cervical lymphadenopathy, and peripheral facial nerve palsy associated with serologically confirmed cat scratch disease. The stapedius muscle reflex was absent on the left side and brain magnetic resonance imaging revealed a mass lesion at the left internal auditory meatus. The patient’s symptoms and imaging findings were gradually resolved after the antibiotics and corticosteroids treatment. Conclusions The suspected granulomatous lesion was considered to have resulted from the host’s immune reaction to Bartonella infection and impaired the facial nerve. This is the first case report providing direct evidence of peripheral facial nerve palsy caused by a suspected granulomatous lesion associated with cat scratch disease and its treatment course.

Case report.We report here on an 18-month-old boy with brachytelephalangic chondrodysplasia punctata (BCDP), whose atlantoaxial instability was successfully managed with occipitocervical instrumented fusion (OCF) using screw and rod instrumentations.Recently, there have been a number of reports on BCDP with early onset of cervical myelopathy. Surgical OCF is a vital intervention to salvage affected individuals from the life-threatening morbidity. Despite recent advancement of instrumentation techniques, however, rigid OCF is technically demanding in very young children with small and fragile osseous elements. To our best knowledge, this is the first report on application of the instrumentation technique to a toddler patient with BCDP.A 16-month-old boy with BCDP presented with tetraplegia and swallow obstacle. Hypoplasia of the odontoid process and atlantoaxial instability were present in lateral radiographs. T2-weighted magnetic resonance (MR) images revealed a high signal region in the spinal cord at the C1-2 and C7-T1 levels. Cervical computed tomography (CT) showed that the pedicles and lateral masses in the cervical spine were small and immature, but the laminae were comparatively thick.One week before surgery, the patient was fitted with a Halo-body jacket. We performed plate-rod placement with occipital cortical screws and C2/C3 interlaminar screws, and added an autogenous bone graft using the right 8 and 9 ribs. Rigid fixation of the occipito-cervical spine was completed successfully without major complications. Postoperative halo-body jacket immobilization was continued for 3 months, after which Aspen collar was fitted. CT confirmed occipitocervical bone fusion at 6 months after surgery. Mild clinical improvements in motor power of the affected muscles and swallowing were witnessed at 1 year postoperatively.Rigid fixation using screw, rod, and occipital plate instrumentation was successful in an 18-month-old toddler with BCDP and atlantoaxial instability. Bone fusion was achieved at postoperative 6 months.5.

Infection by Theiler’s murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis. T-cell immunoglobulin and mucin domain-3 (TIM-3) has been demonstrated to play a crucial role in the maintenance of peripheral tolerance. In this study, we examined the regulatory role of the TIM-3 pathway in the development of TMEV-induced demyelinating disease (TMEV-IDD). The expression of TIM-3 was increased at both protein and mRNA levels in the spinal cords of mice with TMEV-IDD compared with naive controls. In addition, by utilizing a blocking mAb, we demonstrate that TIM-3 negatively regulates TMEV-specific ex vivo production of IFN-γ and IL-10 by CD4+ T cells and IFN-γ by CD8+ T cells from the CNS of mice with TMEV-IDD at 36 days post-infection (dpi). In vivo blockade of TIM-3 by using the anti-TIM-3 mAb resulted in significant exacerbation of the development of TMEV-IDD both clinically and histologically. The number of infiltrating mononuclear cells in the CNS was also increased in mice administered with anti-TIM-3 mAb both at the induction phase (10 dpi) and at the effector phase (36 dpi). Flow cytometric analysis of intracellular cytokines revealed that the number of CD4+ T cells producing TNF, IL-4, IL-10 and IL-17 was significantly increased at the effector phase in the CNS of anti-TIM-3 mAb-treated mice. These results suggest that the TIM-3 pathway plays a critical role in the regulation of TMEV-IDD.

There have been no large, nationwide, birth cohort studies in Japan examining the effects of house renovation during pregnancy on congenital abnormality. This study examined the impact of (1) prenatal exposure to house renovation and (2) maternal occupational exposure to organic solvents and/or formaldehyde on the incidence of congenital abnormality. The fixed data of 67,503 singleton births from a large national birth cohort study that commenced in 2011 were used to evaluate the presence of congenital abnormalities and potential confounding factors. We employed multiple logistic regression analysis to search for correlations between maternal exposure to house renovation or organic solvents and/or formaldehyde during pregnancy and such congenital abnormalities as congenital heart disease, cleft lip and/or palate, male genital abnormality, limb defect, and gastrointestinal obstruction. After controlling for potential confounding factors, we observed that house renovation was significantly associated with male genital abnormality (OR 1.81, 95% CI 1.03-3.17, P = 0.04) when stratified by congenital abnormality, with no other remarkable relations to house renovation or occupational use of organic solvents and/or formaldehyde during pregnancy. There were also significant correlations for maternal BMI before pregnancy, history of ovulation induction through medication, maternal diabetes mellitus/gestational diabetes mellitus, and hypertensive disorder of pregnancy with an increased risk of congenital abnormality. In conclusion, this large nationwide survey provides important information on a possible association of house renovation during pregnancy with congenital male genital abnormality which needs confirmation in future studies.