Recessive variants in MYO1C as a potential novel cause of proteinuric kidney disease.

Background: Steroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients <25 years of age. Through whole exome sequencing, identification of >65 monogenic causes has rendered insights into disease mechanisms of nephrotic syndrome. Methods: To elucidate novel monogenic causes of NS, we combined homozygosity mapping with ES in a worldwide cohort of 1649 pediatric patients with NS. Results: We identified homozygous missense variants in MYO1C in two unrelated children with nephrotic syndrome (c.292C>T, p.R98W; c.2273 A>T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1Cto be predominantly expressed in podocytes. We then performed structural modeling in molecular viewer PyMol using the super function aligning shared regions within both partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98 binds to nearby D220 within the Myosin Motor Domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants. Conclusion: We here identified recessive variants in MYO1C as a potential novel cause of nephrotic syndrome in children.

Quantitative phenotyping of Nphs1 knockout mice as a prerequisite for gene replacement studies.

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease before the age of 25 yr. Nephrin, encoded by NPHS1, localizes to the slit diaphragm of glomerular podocytes and is the predominant structural component of the glomerular filtration barrier. Biallelic variants in NPHS1 can cause congenital nephrotic syndrome of the Finnish type, for which, to date, no causative therapy is available. Recently, adeno-associated virus (AAV) vectors targeting the glomerular podocyte have been assessed as a means for gene replacement therapy. Here, we established quantitative and reproducible phenotyping of a published, conditional Nphs1 knockout mouse model (Nphs1tm1.1Pgarg/J and Nphs2-Cre+) in preparation for a gene replacement study using AAV vectors. Nphs1 knockout mice (Nphs1fl/fl Nphs2-Cre+) exhibited 1) a median survival rate of 18 days (range: from 9 to 43 days; males: 16.5 days and females: 20 days); 2) an average foot process (FP) density of 1.0 FP/µm compared with 2.0 FP/µm in controls and a mean filtration slit density of 2.64 µm/µm2 compared with 4.36 µm/µm2 in controls; 3) a high number of proximal tubular microcysts; 4) the development of proteinuria within the first week of life as evidenced by urine albumin-to-creatinine ratios; and 5) significantly reduced levels of serum albumin and elevated blood urea nitrogen and creatinine levels. For none of these phenotypes, significant differences between sexes in Nphs1 knockout mice were observed. We quantitatively characterized five different phenotypic features of congenital nephrotic syndrome in Nphs1fl/fl Nphs2-Cre+ mice. Our results will facilitate future gene replacement therapy projects by allowing for sensitive detection of even subtle molecular effects.NEW & NOTEWORTHY To evaluate potential, even subtle molecular, therapeutic effects of gene replacement therapy (GRT) in a mouse model, prior rigorous quantifiable and reproducible disease phenotyping is necessary. Here, we, therefore, describe such a phenotyping effort in nephrin (Nphs1) knockout mice to establish the basis for GRT for congenital nephrotic syndrome. We believe that our findings set an important basis for upcoming/ongoing gene therapy approaches in the field of nephrology, especially for monogenic nephrotic syndrome.

A homozygous truncating ETV4 variant in a Nigerian family with congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of chronic kidney disease that manifests in children. To date ~23 different monogenic causes have been implicated in isolated forms of human CAKUT, but the vast majority remains elusive. In a previous study, we identified a homozygous missense variant in E26 transformation-specific (ETS) Variant Transcription Factor 4 (ETV4) causing CAKUT via dysregulation of the transcriptional function of ETV4, and a resulting abrogation of GDNF/RET/ETV4 signaling pathway. This CAKUT family remains the only family with an ETV4 variant reported so far. Here, we describe one additional CAKUT family with a homozygous truncating variant in ETV4 (p.(Lys6*)) that was identified by exome sequencing. The variant was found in an individual with isolated CAKUT displaying posterior urethral valves and renal dysplasia. The newly identified stop variant conceptually truncates the ETS_PEA3_N and ETS domains that regulate DNA-binding transcription factor activity. The variant has never been reported homozygously in the gnomAD database. To our knowledge, we here report the first CAKUT family with a truncating variant in ETV4, potentially causing the isolated CAKUT phenotype observed in the affected individual.

Associations of Helicobacter pylori seropositivity and gastric inflammation with pediatric asthma.

OBJECTIVE: Controversy exists regarding an association between Helicobacter pylori infection and asthma in children. We examined the hypotheses of inverse associations of H. pylori seroprevalence and pepsinogen (PG) levels, as markers of gastric inflammation, with asthma in children. METHODS: A hospital-based case-control study was conducted among children aged 4.8 to 17.3 years in Israel. Confirmed asthma cases (n = 75) were recruited through a pulmonary clinic, and controls (n = 160) without asthma were enrolled. Using enzyme-linked immunosorbent assays we measured the presence of H. pylori immunoglobulin G (IgG) antibodies, IgG antibodies to cytotoxin-associated gene A antigen (CagA) (virulent factor), serum PG levels and exposure to other enteric pathogens (Shigella flexneri). Multivariable logistic regression models were applied. RESULTS: H. pylori IgG seropositivity was 25% and 40% among cases and controls, respectively (P = .03). H. pylori CagA IgG seropositivity was associated with reduced risk of asthma (adjusted odds ratio [OR], 0.33 [95% CI, 0.11-0.95] but not for the CagA negative serology (adjusted OR, 0.70 [95% CI, 0.32-1.54]). Children who were H. pylori seropositive with a PGI:PGII of ≤6.78 (severe gastric inflammation) had a lower likelihood of asthma (adjusted OR, 0.31 [95% CI, 0.10-0.89]) than did seronegative children. Exposure to Shigella flexneri did not differ between cases and controls, nor according to H. pylori seropositivity. Among the asthmatic children, pulmonary function did not differ according to H. pylori seropositivity. CONCLUSIONS: H. pylori infection and its related gastric inflammation may have a protective role in the risk of pediatric asthma and further research into a potential causal pathway is required.

Energy drinks in children and adolescents: demographic data and immediate effects.

Energy drinks consumption has become increasingly common in the last few years, despite evidence associating these products with vast adverse health effects. This led us to explore the phenomenon of energy drinks consumption in adolescents in the Israeli Arab population of the Nazareth area (Northern Israel), examining their awareness of risks associated with consumption of energy drinks, investigating their immediate effects on the body. Our study revealed that the consumption of energy drinks is very common in adolescents of both sexes, though more common in boys. Of 375 students who filled out the questionnaire, 206 reported that they consumed energy drinks (55%), 91 were male (44.4%), and 115 were female (55.6%). In the experimental stage of this study, we found that energy drinks significantly increased systolic blood pressure in most participants within a brief period of time after drinking.Conclusion: Given the prevalence of energy drinks consumption and their side effects, it is important to increase awareness of the risks associated with their regular use and to combat this phenomenon through the education system in schools. What is Known: • Energy drinks consumption has become popular and frequent among adolescents across the world. • The immediate effects of energy drinks in children and adolescents are poorly described. What is New: • Religious and social norms are not a barrier to ED consumption among the varied investigated population. • Our study describes the immediate effect of energy drinks during the first 2 h after consumption, revealing systolic blood pressure to be significantly increased.

[RECURRENT WANDERING PNEUMONIA AS AN UNUSUAL PRESENTATION OF FOREIGN BODY ASPIRATION].

INTRODUCTION: In cases of recurrent pneumonia that involved both lungs, foreign body aspiration (FBA) requires a high index of suspicion. BACKGROUND: A previously healthy one-year old boy, was admitted to our department, because of right lower lobe pneumonia with a moderate amount of pleural effusion. He was treated with IV Cefuroxime resulting in a good clinical response. Three weeks later, he was referred again due to left lower lobe pneumonia with a mild amount of pleural effusion. Due to two episodes of pneumonia involving two different lungs within a five week period, a suspicion of an underlying immunodeficiency or other systemic disease was raised and a broad investigation revealed no underlying disease. Despite the lack of a history of FBA and the inappropriate clinical presentation (recurrent pneumonia not in the same side), FBA was still highly considered as a potential diagnosis, mainly due to the fact that these two episodes of pneumonia occurred within a short period of time. A flexible bronchoscopy was performed which revealed a FB lodged at the entrance of the left main bronchus, the FB was extracted by rigid bronchoscopy. Since then the child is asymptomatic with no further signs of pneumonia. CONCLUSIONS: FBA should be highly considered in recurrent pneumonia that involves two lungs especially when the episodes of pneumonia occur within a short period of time. DISCUSSION: In cases of recurrent pneumonia that involve both lungs, FBA requires a high index of suspicion. Our assumption in this unusual case was that the FB was stuck in the carina, tilting and obstructing the entry of the right main bronchus leading to right side pneumonia; and in the second episode, later on, tilting to the left side and obstruction to the left main bronchus resulting in left sided pneumonia.

A Case of Infective Endocarditis and Pulmonary Septic Emboli Caused by Lactococcus lactis.

Infective endocarditis is a rare condition in children with normal hearts. We present here a case of previously healthy eleven-year-old girl with infective endocarditis and pulmonary septic emboli caused by a very rare bacterial etiology (Lactococcus lactis). Identification of this pathogen was only made by polymerase chain reaction.

Foreign Body Aspiration in Children with Focus on the Role of Flexible Bronchoscopy: A 5 Year Experience.

BACKGROUND: Foreign body aspiration (FBA) is common in the pediatric population and if not diagnosed and treated properly can lead to major complications. OBJECTIVES: To define the clinical and radiological features of aspirated foreign bodies, characterize the incidence of FBA among the Israeli-Arab population, and evaluate flexible bronchoscopy as a diagnostic tool prior to performing rigid bronchoscopy. METHODS: We reviewed the e-files of 115 children who underwent bronchoscopy for suspected FBA between January 2006 and December 2010 in the pediatric department of the St. Vincent French Hospital, Nazareth. RESULTS: We identified 44 patients (38.3%) who had foreign body aspiration (mean age 31.2 ± 29 months, males 64%). Organic-type foreign body was seen in 70% of cases and location was equally distributed. Statistically significant correlations were found between the presence of a foreign body and a history of choking, abnormal lung auscultation, and abnormal chest X-ray (P < 0.05). The rate of negative finding in rigid bronchoscopy in our study was as low as 15% (in only 8 of 52 rigid bronchoscopies was the finding negative for FBA). Compared with other centers in our region where rigid bronchoscopy was performed without the preceding flexible procedure, we found that our protocol reduced the rate of negative rigid bronchoscopies. CONCLUSIONS: Introducing flexible bronchoscopy initially in FBA management reduced the rate of negative rigid bronchoscopies.