End-stage ADPKD with a low-frequency PKD1 mosaic variant accelerated by chemoradiotherapy.

Autosomal dominant polycystic kidney disease (ADPKD) is commonly caused by PKD1, and mosaic PKD1 variants result in milder phenotypes. We present the case of a 32 year-old male with chronic active Epstein-Barr virus who underwent bone marrow transplantation with chemoradiotherapy at age 9. Despite a low-frequency mosaic splicing PKD1 variant, he developed severe renal cysts and end-stage renal disease in his 30 s. This case highlights how environmental factors may contribute to the genetic predisposition to ADPKD.

A novel NFKB1 variant in a Japanese pedigree with common variable immunodeficiency.

Recently, heterozygous loss-of-function NFKB1 variants were identified as the primary cause of common variable immunodeficiency (CVID) in the European population. However, pathogenic NFKB1 variants have never been reported in the Japanese population. We present a 29-year-old Japanese woman with CVID. A novel variant, c.136 C > T, p.(Gln46*), was identified in NFKB1. Her mother and daughter carried the same variant, demonstrating the first Japanese pedigree with an NFKB1 pathogenic variant.

Lysinuric protein intolerance exhibiting renal tubular acidosis/Fanconi syndrome in a Japanese woman.

Lysinuric protein intolerance (LPI), caused by pathogenic variants of SLC7A7, is characterized by protein aversion, failure to thrive, hyperammonemia, and hepatomegaly. Recent studies have reported that LPI can cause multiple organ dysfunctions, including kidney disease, autoimmune deficiency, pulmonary alveolar proteinosis, and osteoporosis. We report the case of a 47-year-old Japanese woman who was initially diagnosed with renal tubular acidosis (RTA), Fanconi syndrome, and rickets. At the age of 3 years, she demonstrated a failure to thrive. Urinary amino acid analysis revealed elevated lysine and arginine levels, which were masked by pan-amino aciduria. She was subsequently diagnosed with rickets at 5 years of age and RTA/Fanconi syndrome at 15 years of age. She was continuously treated with supplementation of vitamin D3, phosphate, and bicarbonate. A renal biopsy at 18 years of age demonstrated diffuse proximal and distal tubular damage with endocytosis-lysosome pathway abnormalities. Distinctive symptoms of LPI, such as protein aversion and postprandial hyperammonemia were not observed throughout the patient's clinical course. The patient underwent a panel-based comprehensive genetic testing and was diagnosed with LPI. As the complications of LPI involve many organs, patients lacking distinctive symptoms may develop various diseases, including RTA/Fanconi syndrome. Our case indicates that proximal and distal tubular damages are notable findings in patients with LPI. The possibility of LPI should be carefully considered in the management of RTA/Fanconi syndrome and/or incomprehensible pathological tubular damage, even in the absence of distinctive symptoms; furthermore, a comprehensive genetic analysis is useful for diagnosing LPI.

Effect of stomach inflation during cardiopulmonary resuscitation on return of spontaneous circulation in out-of-hospital cardiac arrest patients: A retrospective observational study.

BACKGROUND: Gastric inflation caused by excessive ventilation is a common complication of cardiopulmonary resuscitation. Gastric inflation may further compromise ventilation via increases in intrathoracic pressure, leading to decreased venous return and cardiac output, which may impair out-of-hospital cardiac arrest (OHCA) outcomes. The purpose of this study was to measure the gastric volume of OHCA patients using computed tomography (CT) scan images and evaluate the effect of gastric inflation on return of spontaneous circulation (ROSC). METHODS: In this single-center, retrospective, observational study, CT scan was conducted after ROSC or immediately after death. Total gastric volume was measured. Primary outcome was ROSC. Achievement of ROSC was compared in the gastric distention group and the no gastric distention group; gastric distension was defined as total gastric volume in the ≥75th percentile. Additionally, factors associated with gastric distention were examined. RESULTS: A total of 446 cases were enrolled in the study; 120 cases (27%) achieved ROSC. The median gastric volume was 400 ml for all OHCA subjects; 1068 ml in gastric distention group vs. 287 ml in no gastric distention group. There was no difference in ROSC between the groups (27/112 [24.1%] vs. 93/334 [27.8%], p = 0.440). Gastric distention did not have a significant impact, even after adjustments (adjusted odds ratio 0.73, 95% confidence interval [0.42-1.29]). Increased gastric volume was associated with longer emergency medical service activity time. CONCLUSIONS: We observed a median gastric volume of 400 ml in patients after OHCA resuscitation. In our setting, gastric distention did not prevent ROSC.

Clinical utility of urinary mulberry bodies/cells testing in the diagnosis of Fabry disease.

Introduction: Variants in the galactosidase alpha (GLA) gene cause Fabry disease (FD), an X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency. Recently, disease-modifying therapies have been developed, and simple diagnostic biomarkers for FD are required to initiate these therapies in the early stages of the disease. Detection of urinary mulberry bodies and cells (MBs/MCs) is beneficial for diagnosing FD. However, few studies have evaluated the diagnostic accuracy of urinary MBs/MCs in FD. Herein, we retrospectively evaluated the diagnostic ability of urinary MBs/MCs for FD. Methods: We analyzed the medical records of 189 consecutive patients (125 males and 64 females) who underwent MBs/MCs testing. Out of these, two female patients had already been diagnosed with FD at the time of testing, and the remaining 187 patients were suspected of having FD and underwent both GLA gene sequencing and/or α-GalA enzymatic testing. Results: Genetic testing did not confirm the diagnosis in 50 females (26.5%); hence, they were excluded from the evaluation. Two patients were previously diagnosed with FD, and sixteen were newly diagnosed. Among these 18 patients, 15, including two who had already developed HCM at diagnosis, remained undiagnosed until targeted genetic screening of at-risk family members of patients with FD was performed. The accuracy of urinary MBs/MCs testing exhibited a sensitivity of 0.944, specificity of 1, positive predictive value of 1, and negative predictive value of 0.992. Conclusions: MBs/MCs testing is highly accurate in diagnosing FD and should be considered during the initial evaluation prior to genetic testing, particularly in female patients.

Germ-cell-specific transcriptome analysis illuminates the chromatin and ubiquitin pathway in autism spectrum disorders.

Accumulating epidemiological studies have suggested a positive association between advanced paternal age at conception and the increased risk of neurodevelopmental outcomes such as autism spectrum disorder (ASD) in their children. Recent biological studies using human sperm have identified increased de novo mutations in aged fathers, and hyper- or hypomethylation has been identified in the sperm from aged rodents. Dysregulation of DNA methylation in sperm may explain the transgenerational effects on the pathogenesis of ASD. However, compared to these epigenetic changes in the sperm of aged males, the effects of inherited predisposition from germ cells are largely unknown. Here, we use single-cell transcriptome data sets from 13 cell lines, including 12 ASD-associated CNVs models and control, that are performed neural differentiation from mouse embryonic stem cells. This study performed comprehensive bioinformatic analyses such as gene ontology (GO), network, pathway, and upstream regulator analyses. Through these analyses, we identify several susceptible pathways, such as chromatin and ubiquitin, in addition to translational and oxidative phosphorylation. Our results suggest that dysregulation of epigenetic chromosome remodeling and ubiquitin-proteasome pathway in the germ cell is a possible modulator for subsequent differentiated cells, sperm, and egg, as a risk factor for the neurodevelopmental disorder.

Dravet syndrome and hemorrhagic shock and encephalopathy syndrome associated with an intronic deletion of SCN1A.

OBJECTIVE: Hemorrhagic shock and encephalopathy syndrome (HSES) is a serious condition that requires intensive care and is associated with a high mortality rate. However, its pathogenesis remains unclear. In the present study, a genetic analysis was performed to determine the genetic background of patients with clinically suspected Dravet syndrome (DS) who developed HSES. METHODS: Whole exome sequencing was performed, followed by minigene analysis of the intron variant detected by whole exome sequencing to confirm its effect on splicing. RESULTS: Whole exome sequencing revealed a novel 21-bp deletion in intron 3 of SCN1A NM_001165963.4 (NC_000002.11:g.166073675_166073695del). This deletion was not found in the patient's parents and was proven to be de novo. Minigene analysis revealed an aberrant mRNA lacking 40 and 106 bp from the 5' end of exon 4 of SCN1A. Therefore, we diagnosed this case as DS due to the deletion in intron 3 of SCN1A. CONCLUSIONS: We report a case of DS with HSES caused by a 21-bp deletion in the intron of SCN1A that was confirmed by minigene analysis. The present case met Levin's criteria for HSES and the splicing analysis of SCN1A is an important finding. This study has important implications for understanding HSES pathogenesis.

Impact after the Change from Voluntary to Universal Oral Rotavirus Vaccination on Consecutive Emergency Department Visits for Acute Gastroenteritis among Children in Kobe City, Japan (2016-2022).

Rotavirus (RV) is the leading cause of acute gastroenteritis (AGE), particularly in infants. In 2006, the high efficacy of oral RV vaccines (RVVs, RotarixTM and RotaTeqTM) was demonstrated. Voluntary RVV started in Japan in 2011, and in October 2020 were launched as universal oral RVVs in Japan. However, the impact of changes from voluntary to universal RVVs has not been studied in a primary emergency medical center in Japan. We investigated changes in the number of pediatric patients with AGE after introducing universal RVVs in our center. A clinical database of consecutive patients aged <16 who presented to Kobe Children's Primary Emergency Medical Center between 1 April 2016 and 30 June 2022 was reviewed. After implementing universal RVVs, fewer children presented with RV-associated AGE (the reduction of proportion of the patients in 2022 was −61.7% (all ages), −57.9% (<1 years), −67.8% (1−<3 years), and −61.4% (3−<5 years) compared to 2019). A similar decrease in those of age who were not covered by the universal RVV was observed. There was a significant decline in the number of patients with AGE during the RV season who presented to the emergency department after implementing universal RVVs.

Influence of UGT1A1 Genetic Variants on Free Bilirubin Levels in Japanese Newborns: A Preliminary Study.

BACKGROUND: Free bilirubin (Bf) is a better marker than total serum bilirubin (TSB) for predicting bilirubin encephalopathy (BE). To date, two UGT1A1 genetic variants (rs4148323 and rs3064744) have been associated with neonatal hyperbilirubinemia; however, the direct association between UGT1A1 variants and Bf levels in newborns has not been elucidated. METHODS: We retrospectively analyzed the clinical data of 484 infants, including the genotype data of two UGT1A1 genetic variants. We divided the infants into a high Bf group (Bf ≥ 1.0 µg/dL, n = 77) and a non-high Bf group (Bf < 1.0 µg/dL, n = 407), based on the peak Bf values. Logistic regression analysis was performed to calculate the odds ratios (ORs) for each variant allele compared to wild-type alleles. RESULTS: The frequencies of the A allele in rs4148323 and (TA)7 allele in rs3064744 in the high Bf group (29% and 4%, respectively) were significantly different from those in the non-high Bf group (16% and 12%, respectively). In logistic regression analysis, for rs4148323, the A allele was significantly associated with an increased risk of hyper-free bilirubinemia over the G allele (adjusted OR: 1.80, 95% confidence interval [CI]: 1.19-2.72, p < 0.01). However, for rs3064744, the (TA)7 allele was significantly associated with a decreased risk of hyper-free bilirubinemia over the (TA)6 allele (adjusted OR: 0.42, 95% CI: 0.18-0.95, p = 0.04). CONCLUSIONS: This study is the first to show that the A allele in rs4148323 is a risk factor and that the (TA)7 allele in rs3064744 is a protective factor for developing hyper-free bilirubinemia in Japanese newborns.

Heterozygous missense variant in TRPC6 in a boy with rapidly progressive infantile nephrotic syndrome associated with diffuse mesangial sclerosis.

Transient receptor potential channel C6 encoded by TRPC6 is involved in slit diaphragm formation in podocytes, and abnormalities of the TRPC6 protein cause various glomerular diseases. The first identified pathogenic variant of TRPC6 was found to cause steroid-resistant nephrotic syndrome that typically developed in adulthood and then slowly led to end-stage renal disease, along with a renal pathology of focal segmental glomerulosclerosis. Here, we report a patient with rapidly progressing infantile nephrotic syndrome and a heterozygous missense TRPC6 variant. The patient, a 2-year-old Japanese boy, developed steroid-resistant nephrotic syndrome at age 11 months. His renal function deteriorated rapidly, and peritoneal dialysis was introduced at age 1 year and 6 months. His renal pathology, obtained at age 1 year and 1 month, was consistent with diffuse mesangial sclerosis (DMS). Clinical exome analysis and custom panel analysis for hereditary renal diseases revealed a reported heterozygous missense variant in TRPC6 (NM_004621.5:c.523C > T:p.Arg175Trp). This is the first report of a patient with a TRPC6-related renal disorder associated with DMS.

A Japanese boy with NAA10-related syndrome and hypertrophic cardiomyopathy.

NAA10-related syndrome is an extremely rare X-chromosomal disorder, the symptoms of which include intellectual disability (ID), ocular anomalies, or congenital heart diseases, such as hypertrophic cardiomyopathy (HCM). Here, we describe a 4-year-old Japanese male patient who exhibited mild ID, HCM, and specific facial features. A hemizygous mutation (NM_003491.3: c.455_458del, p. Thr152Argfs*6) in exon 7 of NAA10 was detected. We recommend that patients undergo precise medical follow-up considering the characteristics of NAA10-related syndrome.

A girl with CLOVES syndrome with a recurrent PIK3CA somatic mutation and pancreatic steatosis.

CLOVES syndrome is characterized by congenital lipomatous overgrowth, vascular malformation, epidermal nevi, and scoliosis/spinal malformation. It is caused by somatic mosaicism of gain-of-function variants of PIK3CA. Here, we describe a novel case of a 5-year-old Japanese girl with CLOVES and concurrent pancreatic steatosis. She had a recurrent somatic mutation in PIK3CA (NM_006218.3: c.1357G>A, p.Glu453Lys), elevated HbA1c levels, and pancreatic steatosis. This case indicates that pancreatic screening is critical for PIK3CA-related disorders.

Portal Venous Gas Following Ingestion of Hydrogen Peroxide Successfully Treated with Hyperbaric Oxygen Therapy.

The primary toxicity of hydrogen peroxide results from its interaction with catalase, which liberates water and oxygen. We report the case of a 14-year-old Japanese girl with portal venous gas that was caused by oxygen liberated from intentionally ingested hydrogen peroxide. Although she had a past history of atrial septal defect, recovery without cardiac or neurological sequelae was achieved using hyperbaric oxygen therapy. Emergency physicians must be aware of the danger of liberated oxygen due to hydrogen peroxide ingestion.

The smallest de novo 20q11.2 microdeletion causing intellectual disability and dysmorphic features.

The 20q11.2 microdeletion is a rare chromosomal aberration characterized by intellectual disability (ID), motor developmental delay, neonatal feeding problems, and facial dysmorphism. Here, a 2-year- and 6-month-old Japanese girl with a 1.2 Mb microdeletion of 20q11.2 showed ID, motor developmental delay, and distinctive facial features without feeding problems. The deleted region was identified by array-based comparative genomic hybridization and is the smallest reported for a 20q11.2 microdeletion.

Direct observation of grain growth from molten silicon formed by micro-thermal-plasma-jet irradiation.

Phase transformation of amorphous-silicon during millisecond annealing using micro-thermal-plasma-jet irradiation was directly observed using a high-speed camera with microsecond time resolution. An oval-shaped molten-silicon region adjacent to the solid phase crystallization region was clearly observed, followed by lateral large grain growth perpendicular to a liquid-solid interface. Furthermore, leading wave crystallization (LWC), which showed intermittent explosive crystallization, was discovered in front of the moving molten region. The growth mechanism of LWC has been investigated on the basis of numerical simulation implementing explosive movement of a thin liquid layer driven by released latent heat diffusion in a lateral direction.