De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy.

De novo variants (DNVs) cause many genetic diseases. When DNVs are examined in the whole coding regions of genes in next-generation sequencing analyses, pathogenic DNVs often cluster in a specific region. One such region is the last exon and the last 50 bp of the penultimate exon, where truncating DNVs cause escape from nonsense-mediated mRNA decay [NMD(-) region]. Such variants can have dominant-negative or gain-of-function effects. Here, we first developed a resource of rates of truncating DNVs in NMD(-) regions under the null model of DNVs. Utilizing this resource, we performed enrichment analysis of truncating DNVs in NMD(-) regions in 346 developmental and epileptic encephalopathy (DEE) trios. We observed statistically significant enrichment of truncating DNVs in semaphorin 6B (SEMA6B) (p value: 2.8 × 10-8; exome-wide threshold: 2.5 × 10-6). The initial analysis of the 346 individuals and additional screening of 1,406 and 4,293 independent individuals affected by DEE and developmental disorders collectively identified four truncating DNVs in the SEMA6B NMD(-) region in five individuals who came from unrelated families (p value: 1.9 × 10-13) and consistently showed progressive myoclonic epilepsy. RNA analysis of lymphoblastoid cells established from an affected individual showed that the mutant allele escaped NMD, indicating stable production of the truncated protein. Importantly, heterozygous truncating variants in the NMD(+) region of SEMA6B are observed in general populations, and SEMA6B is most likely loss-of-function tolerant. Zebrafish expressing truncating variants in the NMD(-) region of SEMA6B orthologs displayed defective development of brain neurons and enhanced pentylenetetrazole-induced seizure behavior. In summary, we show that truncating DNVs in the final exon of SEMA6B cause progressive myoclonic epilepsy.

Early distribution of18 F-labeled AAV9 vectors in the cerebrospinal fluid after intracerebroventricular or intracisternal magna infusion in non-human primates.

BACKGROUND: The delivery of adeno-associated virus (AAV) vectors via the cerebrospinal fluid (CSF) has emerged as a valuable method for widespread transduction in the central nervous system. Although infusion into the cerebral ventricles is a common protocol in preclinical studies of small animals, the cisterna magna has been recognized as an alternative target for clinical studies because it can be reached in a less invasive manner using an intrathecal catheter via the subarachnoid space from a lumbar puncture. METHODS: We evaluated the early distribution of fluorine-18-labeled AAV9 vectors infused into the lateral ventricle or cisterna magna of four non-human primates using positron emission tomography. The expression of the green fluorescent protein was immunohistochemically determined. RESULTS: In both approaches, the labeled vectors diffused into the broad arachnoid space around the brain stem and cervical spinal cord within 30 min. Both infusion routes efficiently transduced neurons in the cervical spinal cord. CONCLUSIONS: For gene therapy that primarily targets the cervical spinal cord and brainstem, such as amyotrophic lateral sclerosis, cisterna magna infusion would be a feasible and effective administration method.

Investigation of the efficacy and adverse effects of lacosamide over 36 months.

OBJECTIVE: To evaluate the efficacy and retention rate of lacosamide (LCM) over 36 months as a treatment for children and adolescents with focal and generalized epilepsy based on a retrospective study. METHODS: All patients prescribed LCM as monotherapy and add-on therapy between October 2016 and September 2019 at Jichi Children's Medical Center Tochigi were included in the study. The response rate, retention rate, and adverse effects were calculated. RESULTS: A total of 126 (female, n = 73) patients of 1.3 to 34.9 years old (median age: 12.8 years; mean ± SD 13.2 ± 6.6 years) received LCM as monotherapy or add-on treatment for focal, generalized, and combined focal and generalized epilepsy. The response rate was 40.5% at 3 months, 40.5% at 6 months, 38.1% at 9 months, 35.7% at 12 months, 25.9% at 24 months, and 29.4% at 36 months. For 34 patients who were observable for 36 months, the retention rate was 70.6% at 3 months, but then gradually declined to 34.8% at 36 months. According to the number of concomitant anti-seizure medications (ASMs), the retention rate was higher in patients receiving <3 ASMs than in those receiving ≥3 ASMs at all observation points. The most common adverse effects were somnolence in 21 patients (16.7%) and dizziness in 5 patients (39.7%). CONCLUSION: Our response rate was lower and our retention rate was higher in comparison to a previous study that observed patients over 36 months. Further prospective studies in children are required to confirm the response rate and retention rate in patients treated with LCM over 36 months.

Continuous cyclosporine a infusion in patients with severe Kawasaki disease.

BACKGROUND: The efficacy and safety of continuous intravenous infusion of cyclosporine A (CICsA) in patients with intravenous immunoglobulin-resistant Kawasaki disease are unclear. METHODS: Between 2010 and 2020, 83 patients with Kawasaki disease that was not responsive to intravenous immunoglobulin (total dose ≥ 4 g/kg) were enrolled. All patients were started on CICsA (3 mg/kg/day) and switched to oral cyclosporine A (CsA) (4-6 mg/kg/day). Treatment efficacy, occurrence of coronary artery lesions (CALs), and laboratory parameters were evaluated. Patients were divided into two groups according to CICsA response: the responder group (afebrile ≤24 h after CICsA without additional treatment) and the weak responder group (afebrile >24 h after CICsA requiring additional treatment). RESULTS: Fifty-five patients became afebrile within 24 and 74 h became afebrile in less than 72 h. Adverse events included hypertension in four and hyperkalemia in two patients. Thirty-nine patients were defined as responders and 44 patients as weak responders. There were no significant differences in CAL between the two groups. In weak responders, white blood cells, neutrophils, and C-reactive protein levels were higher, and albumin, immunoglobulin G, and CsA concentration were lower than in responders, indicating that weak responders had more severe inflammatory findings. However, there were no significant differences in CAL. Logistic regression analysis revealed that the response to treatment for CICsA was associated with immunoglobulin G levels at baseline and CsA concentrations the day after CICsA. CONCLUSION: Although CICsA required additional treatments in about half of the cases, a favorable clinical course was observed by using this strategy, especially for reducing CAL.

Developmental changes of the neural mechanisms underlying level 2 visual perspective-taking: A functional near-infrared spectroscopy study.

The ability to understand the way other people see the world differs from one's own viewpoint is referred to as ''visual perspective-taking'' (VPT). Previous studies have demonstrated the behavioral performance in level 2 VPT (VPT2), the ability to understand that two different observers can have unique visual experiences of the same scene or object depending on the observers' physical location, changes during childhood. However, the developmental aspects underlying the neural mechanisms of VPT2 remains unknown. We measured the hemodynamic responses to a VPT2 task using functional near-infrared spectroscopy, with mental rotation (MR) as a control task in 7- to 11-year-old and 11- to 16-year-old groups. In the VPT2 task, participants were required to mentally compute the perspective of a toy on the turntable from that of a doll placed in a different location from the observer. For the MR task, participants reported their perspectives after the toy was rotated. We found significantly higher oxy-hemoglobin changes during the VPT2 task than the MR task in the 7- to 11-year-old group but not in the 11- to 16-year-old group, in the right middle and superior temporal, angular gyrus and frontal regions. These findings highlight the important role of the right temporoparietal region in processing perspective, up to 11 years.

An Adolescent Patient with Sick Sinus Syndrome Complicated by Hypothyroidism Carrying an SCN5A Variant.

Previous studies have reported that hypothyroidism can lead to sick sinus syndrome (SSS) or other rhythm disturbances. Variants in the alpha subunit of the cardiac sodium channel (SCN5A) are known to be among the genetic causes of SSS. We encountered an adolescent patient with SSS and hypothyroidism who also harbored an SCN5A variant. The patient was a 13-year-old girl who was referred to our hospital because of bradycardia identified during a school electrocardiography screening. Clinical examination revealed severe hypothyroidism due to Hashimoto thyroiditis and SSS. After levothyroxine supplementation, her symptoms of hypothyroidism improved; however, the SSS did not. Genetic testing revealed a heterozygous variant (c.1066 G>A, p.Asp356Asn) in SCN5A. This is the first report of the coexistence of SSS due to an SCN5A variant and severe hypothyroidism in an adolescent patient. While patients with SCN5A variants exhibit phenotypic heterogeneity due to the presence of various modifiers, the presence of severe hypothyroidism may affect the development of SSS. This case highlights the importance of genetic analysis, including testing for SCN5A variants, in patients with hypothyroidism complicated by SSS or cardiac conduction disorders.

A Case of Infantile Mitochondrial Cardiomyopathy Treated with a Combination of Low-Dose Propranolol and Cibenzoline for Left Ventricular Outflow Tract Stenosis.

Hypertrophic cardiomyopathy is a common cardiac complication in mitochondrial disorders, and the morbidity rate in neonatal cases is up to 40%. The mortality rate within 3 months for neonatal-onset mitochondrial cardiomyopathy is known to be high because there is currently no established treatment.We report the case of a male infant with neonatal-onset mitochondrial disorder presenting lactic acidosis and hypertrophic cardiomyopathy. Genetic analysis of the patient revealed recurrent m.13513G>A, p.Asp393Asn in mitochondrially encoded NADH dehydrogenase 5 gene (MT-ND5). Low-dose propranolol was initially administered for cardiomyopathy; however, he developed hypertrophic obstructive cardiomyopathy (HOCM) at 3 months of age. To reduce the risk of hypoglycemia associated with high-dose propranolol, cibenzoline, a class Ia antiarrhythmic drug, was added at a dose of 2.5 mg/kg/day and increased weekly to 7.5 mg/kg/day with monitoring of the blood concentration of cibenzoline. Left ventricular outflow tract stenosis (LVOTS) dramatically improved from 5.4 to 1.3 m/second in LVOTS peak velocity after 6 weeks, without notable adverse effects. The plasma N-terminal pro-brain natriuretic peptide level decreased from 65,854 to 10,044 pg/mL. Furthermore, myocardial hypertrophy also improved, as the left ventricular mass index decreased from 173.1 to 108.9 g/m2 after 3 months of the treatment.The administration of cibenzoline, in conjunction with low-dose propranolol, may serve an effective treatment for HOCM in infantile patients with mitochondrial disorders.

Intra-cisterna magna delivery of an AAV vector with the GLUT1 promoter in a pig recapitulates the physiological expression of SLC2A1.

Glucose transporter 1 deficiency syndrome (GLUT1DS) is caused by haplo-insufficiency of SLC2A1, which encodes GLUT1, resulting in impaired hexose transport into the brain. Previously, we generated a tyrosine-mutant AAV9/3 vector in which SLC2A1 was expressed under the control of the endogenous GLUT1 promoter (AAV-GLUT1), and confirmed the improved motor function and cerebrospinal fluid glucose levels of Glut1-deficient mice after cerebroventricular injection of AAV-GLUT1. In preparation for clinical application, we examined the expression of transgenes after intra-cisterna magna injection of AAV-GFP (tyrosine-mutant AAV9/3-GFP with the CMV promoter) and AAV-GLUT1. We injected AAV-GFP or AAV-GLUT1 (1.63 × 1012 vector genomes/kg) into the cisterna magna of pigs to compare differential promoter activity. After AAV-GFP injection, exogenous GFP was expressed in broad areas of the brain and peripheral organs. After AAV-GLUT1 injection, exogenous GLUT1 was expressed predominantly in the brain. At the cellular level, exogenous GLUT1 was mainly expressed in the endothelium, followed by glia and neurons, which was contrasted with the neuronal-predominant expression of GFP by the CMV promotor. We consider intra-cisterna magna injection of AAV-GLUT1 to be a feasible approach for gene therapy of GLUT1DS.

Lack of persisting antibody in a post-transplant patient after vaccine-strain varicella.

BACKGROUND: LAVV have historically been avoided in children after solid organ transplantation. However, it has been reported that post-transplant, children without severe immunosuppression can generate anti-varicella antibody after immunization but the duration of the response is not clear. Furthermore, the origin of the varicella virus in immunosuppressed patients who develop varicella after vaccination is often unclear. CLINICAL PROGRESS: A female child received LAVV 30 months after a living donor liver transplant at the age of 2 months. Varicella rash appeared on the trunk 16 days after vaccination and gradually spread over the body. The patient was treated with intravenous acyclovir followed by oral therapy and recovered fully. The virus detected in blisters was derived from the vaccine-type strain. Paired sera before and after the onset of varicella showed an increase in antibody titer. However, 2 years after onset, the antibody titer decreased to undetectable again. CONCLUSIONS: This was an informative case of varicella due to vaccine strain attenuated virus. Antibody levels were not maintained over many years. Although varicella was caused by the vaccine-type strain, repeated vaccinations may be necessary for post-transplant patients who develop varicella.

Glucocorticoid effects on bone strength in children with renal diseases.

AIM: Glucocorticoids (GC) are essential medicines for idiopathic steroid-sensitive nephrotic syndrome (ISSNS) and IgA nephropathy (IgAN), with good clinical results. However, they cause bone fragility. The aim of this study was to elucidate GC effects on bone strength assessed as bone mineral density (BMD) and bone quality, using bone turnover markers (BTM), in children with ISSNS or IgAN. METHODS: Eleven children with ISSNS and 13 with IgAN were included. All the patients received GC treatment according to each protocol. The BMD and BTM-serum alkaline phosphatase (S-ALP), tartrate-resistant acid phosphatase 5b (S-TRACP-5b), and undercarboxylated osteocalcin (S-ucOC)-were measured from the initiation of steroid treatment (STx) to the end of STx in both groups. RESULTS: In ISSNS, S-ALP and S-ucOC levels were decreased significantly at 1 month. BMD and S-TRACP-5b levels showed no significant change through this observation period. In IgAN, BMD and S-ALP levels were decreased significantly at 1 and 3 months, respectively, and recovered to baseline at 10 months after the initiation of GC dosage reduction. S-TRACP-5b levels were decreased significantly at 3 months and remained lower than at baseline through the observation period. In both groups, S-ucOC levels did not directly reflect bone strength. CONCLUSION: This study clarified the following three points regarding GC effects on bone strength in children with ISSNS or IgAN: first, S-ALP is a more sensitive bone quality marker than S-TRACP-5b; second, BMD loss was observed only when both S-ALP and S-TRACP-5b levels decreased, and third, S-ucOC levels do not directly reflect bone strength.

Does culture shape face perception in autism? Cross-cultural evidence of the own-race advantage from the UK and Japan.

Autism spectrum disorders (ASD) are associated with face perception atypicalities, and atypical experience with faces has been proposed as an underlying explanation. Studying the own-race advantage (ORA) for face recognition can reveal the effect of experience on face perception in ASD, although the small number of studies in the area present mixed findings. This study probed the ORA in ASD by comparing two cultural groups simultaneously for the first time. Children with ASD in the UK (N = 16) and Japan (N = 26) were compared with age- and ability-matched typically developing (TD) children in the UK (N = 16) and Japan (N = 26). Participants completed a two-alternative forced-choice task, whereby they had to recognize a just seen face from a foil which was manipulated in one of four ways (IC: identity change; EE: easy eyes; HE: hard eyes; HM: hard mouth). Face stimuli were Asian and Caucasian, and thus the same stimuli were own and other race depending on the cultural group. The ASD groups in the UK and Japan did not show impaired face recognition abilities, or impairments with recognizing faces depending on manipulations to the eye region, and importantly they showed an ORA. There was considerable heterogeneity in the presence of the ORA in ASD and TD and also across cultures. Children in Japan had higher accuracy than children in the UK, and TD children in Japan did not show an ORA. This cross-cultural study challenges the view that atypical experiences with faces lead to a reduced/absent ORA in ASD.

Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency.

In patients with aromatic l-amino acid decarboxylase (AADC) deficiency, a decrease in catecholamines and serotonin levels in the brain leads to developmental delay and movement disorders. The beneficial effects of gene therapy in patients from 1 to 8 years of age with homogeneous severity of disease have been reported from Taiwan. We conducted an open-label phase 1/2 study of population including adolescent patients with different degrees of severity. Six patients were enrolled: four males (ages 4, 10, 15 and 19 years) and one female (age 12 years) with a severe phenotype who were not capable of voluntary movement or speech, and one female (age 5 years) with a moderate phenotype who could walk with support. The patients received a total of 2 × 1011 vector genomes of adeno-associated virus vector harbouring DDC via bilateral intraputaminal infusions. At up to 2 years after gene therapy, the motor function was remarkably improved in all patients. Three patients with the severe phenotype were able to stand with support, and one patient could walk with a walker, while the patient with the moderate phenotype could run and ride a bicycle. This moderate-phenotype patient also showed improvement in her mental function, being able to converse fluently and perform simple arithmetic. Dystonia disappeared and oculogyric crisis was markedly decreased in all patients. The patients exhibited transient choreic dyskinesia for a couple of months, but no adverse events caused by vector were observed. PET with 6-[18F]fluoro-l-m-tyrosine, a specific tracer for AADC, showed a persistently increased uptake in the broad areas of the putamen. In our study, older patients (>8 years of age) also showed improvement, although treatment was more effective in younger patients. The genetic background of our patients was heterogeneous, and some patients suspected of having remnant enzyme activity showed better improvement than the Taiwanese patients. In addition to the alleviation of motor symptoms, the cognitive and verbal functions were improved in a patient with the moderate phenotype. The restoration of dopamine synthesis in the putamen via gene transfer provides transformative medical benefit across all patient ages, genotypes, and disease severities included in this study, with the most pronounced improvements noted in moderate patients.10.1093/brain/awy331_video1awy331media15991361892001.

Percutaneous Atrial Septal Defect Closure in Adult Ebstein's Anomaly with Exertional Hypoxemia.

In Ebstein's anomaly, percutaneous atrial septal defect (ASD) closure for the treatment of hypoxemia due to a right-to-left interatrial shunt remains controversial. We report the case of a 40-year-old woman with Ebstein's anomaly who developed cyanosis and shortness of breath on exercise. Her symptoms improved after percutaneous ASD closure and her clinical course has been good during follow-up. The balloon ASD occlusion test, combined with dobutamine stimulation before the procedure, is useful to confirm treatment indication. A prior electrophysiological evaluation is also important because Ebstein's anomaly is often complicated by atrioventricular recurrent tachycardia.

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.

A Patient-Specific Hollow Three-Dimensional Model for Simulating Percutaneous Occlusion of Patent Ductus Arteriosus.

Percutaneous catheter closure of patent ductus arteriosus (PDA) is difficult when the ductus is large and long or shows calcification. We created a patient-specific 3-dimensional (3D) model for PDA, with which we simulated device deployment, thereby selecting the device/size in a patient-by-patient manner. We assessed whether this 3D model is effective for catheter PDA closure.The 3D model was created in this institute, requiring 3 days and 90 US dollars. After its introduction, 7 consecutive patients (the study group) with severe PDA underwent closure with the aid of the 3D model. The control group consisted of 4 patients before 3D-model introduction, with all having severe PDA: the requirement of computed tomography was considered a criterion of severe or difficult-procedure-requiring PDA.In all study group patients, the devices/sizes could be pre-selected based on the simulation, whereas devices were changed during the procedure in 2 of 4 in the control group. In the study group, compared with the control group, the fluoroscopic (median 31 [interquartile range of 16-42] versus 39 [19-71] minutes, respectively) and total procedural times (median 107 [interquartile range 67-114] versus 124 [78-184] minutes, respectively) were shorter. A questionnaire confirmed the doctors' understanding of the procedure.This 3D model may be effective for percutaneous catheter closure of PDA. This may be especially true in cases of severe or difficult-procedure-requiring PDA.

Gene therapy for Glut1-deficient mouse using an adeno-associated virus vector with the human intrinsic GLUT1 promoter.

BACKGROUND: We generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene, encoding glucose transporter type 1 (GLUT1), was expressed under the human endogenous GLUT1 promoter (AAV-GLUT1). We examined whether AAV-GLUT1 administration could lead to functional improvement in GLUT1-deficient mice. METHODS: We extrapolated human endogenous GLUT1 promoter sequences from rat minimal Glut1 promoter sequences. We generated a tyrosine-mutant AAV9/3 vector in which human SLC2A1-myc-DDK was expressed under the human GLUT1 promoter (AAV-GLUT1). AAV-GLUT1 was administered to GLUT1-deficient mice (GLUT1+/- mice) via intracerebroventricular injection (1.85 × 1010 vg/mouse or 6.5 × 1010 vg/mouse). We analyzed exogenous GLUT1 mRNA and protein expression in the brain and other major organs. We also examined improvements of cerebral microvasculature, motor function using rota-rod and footprint tests, as well as blood and cerebrospinal fluid (CSF) glucose levels. Additionally, we confirmed exogenous GLUT1 protein distribution in the brain and other organs after intracardiac injection (7.8 × 1011 vg/mouse). RESULTS: Exogenous GLUT1 protein was strongly expressed in the cerebral cortex, hippocampus and thalamus. It was mainly expressed in endothelial cells, and partially expressed in neural cells and oligodendrocytes. Motor function and CSF glucose levels were significantly improved following intracerebroventricular injection. Exogenous GLUT1 expression was not detected in other organs after intracerebroventricular injection of AAV-GLUT1, whereas it was detected in the liver and muscle tissue after intracardiac injection. CONCLUSIONS: Exogenous GLUT1 expression after AAV-GLUT1 injection approximated that of physiological human GLUT1 expression. Local central nervous system administration of AAV-GLUT1 improved CSF glucose levels and motor function of GLUT1-deficient mice and minimized off-target effects.

Non-enhanced magnetic resonance imaging versus renal scintigraphy in acute pyelonephritis.

The utility of non-enhanced magnetic resonance imaging (MRI) has not been examined extensively for diagnosing acute pyelonephritis (APN) in children. The aims of this study were to compare non-enhanced MRI with technetium-99 m dimercaptosuccinic acid (99m Tc-DMSA) renal scintigraphy in detecting APN. Six boys and one girl with temperature ≥38°C and positive urine culture received both non-enhanced MRI with whole body diffusion-weighted imaging (DWI) and 99m Tc-DMSA scintigraphy ≤7 days from the fever onset. The sensitivity and specificity of MRI in detecting APN lesions diagnosed on 99m Tc-DMSA scintigraphy were 80% and 100%, respectively. Non-enhanced MRI in children with suspected APN ≤7 days from fever onset might be a suitable replacement for 99m Tc-DMSA scintigraphy for the detection of APN.

Severe demyelination in a patient with a late infantile form of Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is a cholesterol storage disease caused by defective cellular cholesterol transportation. The onset and progression of NPC are variable, and autopsy findings have mainly been reported for the adult and juvenile forms of this disease. Here we report the clinical and pathological findings from a 9-year-old female patient with the late infantile form of NPC due to NPC1 gene mutation. She had notable splenomegaly at 4 months of age. She lost the ability to speak at 18 months of age. She learned to walk, but often fell and could no longer walk after 30 months. At 3 years of age, she was diagnosed with NPC. Sequence analysis of the NPC1 gene revealed compound heterozygous mutation of T2108C (F703S) and C2348G (S813X) (both novel). Thereafter, the patient suffered repeated respiratory infections and died of respiratory failure at 9 years of age. Pathological findings included cerebral atrophy (particularly of white matter), severe demyelination, and the loss of neurons from the cerebrum and from the nuclei of the brain stem. Remnant neuronal cells and microglia in the cerebrum, cerebellum, and brain stem had become swollen and foamy. Neurons of the hippocampal CA1 and Purkinje cells were relatively spared, and senile plaques and axonal spheroids were not present. Foamy cells were also observed in other organs, especially the spleen and bone marrow. The F703S mutation in this patient was localized in a sterol-sensing domain (SSD). Severe neurological phenotypes have been previously reported in patients with missense mutations in an SSD. It is considered that the combination of a nonsense mutation and missense mutation in an SSD was responsible for the severe neurological phenotype of our present patient. While pathological findings of adult/juvenile forms of NPC have included swollen neurons and glia, neuronal cell loss, and NFTs, demyelination may be a predominant finding in the infantile form of NPC.

Occult hepatitis B virus infection in immunized children born to carrier mothers.

BACKGROUND: The prevalence of occult hepatitis B virus (HBV) infection (OBI) in children due to mother-to-child transmission (MTCT) despite immunoprophylaxis remains controversial and is still unknown in Japan. The aim of this study was to determine the OBI prevalence in such children in Japan and identify the genomic mutations that might be associated with the pathogenesis of OBI in children. METHODS: The data on 158 children born to HBV carrier mothers and who received complete passive-active immunoprophylaxis after birth in 2002-2014 were reviewed. HBV markers were detected using commercial enzyme-linked immunosorbent assay kits. HBV-DNA was detected using real-time and nested polymerase chain reaction. Complete genomic sequences were determined. RESULTS: Among the 158 children studied, three had HBV MTCT: two had OBI, and one had resolved HBV infection (RBI). The prevalence of OBI and RBI was estimated to be 1.3% and 0.6%, respectively. The HBV genomes of the two OBI children were wild type and 100% identical to those of their mothers. Of these two children, one received repeated hepatitis B immunoglobulin (HBIG) and developed overt HBV infection. Her HBV genome had a G145R mutation in the S gene that might have been induced by HBIG treatment. The RBI child was persistently positive for antibody to HBV core antigen (10-12 signal/cut-off ratio; S/CO). CONCLUSIONS: A low prevalence of OBI was observed in children who received immunoprophylaxis for preventing MTCT in Japan. The development of overt HBV infection in infants with OBI indicates the necessity of close and long-term monitoring.