Redox Imbalance in Neurological Disorders in Adults and Children.

Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to numerous pathological consequences. In the human body, the brain is an aerobic organ and for this reason, it is very sensitive to oxygen equilibrium. The consequences of oxygen imbalance are especially devastating when occurring in this organ.

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1.

Menkes disease complicated by concurrent ACY1 deficiency: A case report.

Menkes disease is an X-linked recessive condition caused by mutations in the gene, which leads to severe copper deficiency. Aminoacylase-1 deficiency is a rare inborn error of metabolism caused by homozygous or compound heterozygous variant in the gene, characterized by increased urinary excretion of specific N-acetyl amino acids. We report an infant with neurological findings such as seizures, neurodevelopmental delay and hypotonia.

Striving for a pragmatic contribution of biomarkers results to lifelong health care.

Background: The increased role of preventive medicine in healthcare and the rapid technological advancements, have deeply changed the landscape of laboratory medicine. In particular, increased investments in newborn screening tests and policies have been observed. Aim of this paper is to characterize how laboratory professionals engaged in clinical chemistry or newborn screening, in collaboration with experts in econometric, bioinformatics, and biostatistics may address a pragmatic use of laboratory results in the decision-making process oriented toward improvement of health care outcomes.

Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1.

Background: Deregulation of transcription in the pathogenesis of sporadic Amyotrophic Lateral Sclerosis (sALS) is taking central stage with RNA-sequencing analyses from sALS patients tissues highlighting numerous deregulated long non-coding RNAs (lncRNAs). The oncogenic lncRNA ZEB1-AS1 is strongly downregulated in peripheral blood mononuclear cells of sALS patients. In addition, in cancer-derived cell lines, ZEB1-AS1 belongs to a negative feedback loop regulation with hsa-miR-200c, acting as a molecular sponge for this miRNA.

Individual risk prediction of high grade prostate cancer based on the combination between total prostate-specific antigen (PSA) and free to total PSA ratio.

Objectives: Clinical practice guidelines endorse the stratification of prostate cancer (PCa) risk according to individual total prostate-specific antigen (tPSA) values and age to enhance the individual risk-benefit ratio. We defined two nomograms to predict the individual risk of high and low grade PCa by combining the assay of tPSA and %free/tPSA (%f/tPSA) in patients with a pre-biopsy tPSA between 2 and 10 μg/L.

Methods: The study cohort consisted of 662 patients that had fPSA, tPSA, and a biopsy performed (41.

Reference intervals for thyroid biomarkers to enhance the assessment of thyroid status in childhood and adolescence.

Objectives: The determination of assay-dependent upper and lower reference limits (URL, LRL) of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) during childhood and adolescence, is challenging.

Methods: Thyroid hormones were measured via the Abbott Alinity system in 502 euthyroid children partitioned in the following age groups: ≤2, 2.1-10, and 10.

Approach to Cohort-Wide Re-Analysis of Exome Data in 1000 Individuals with Neurodevelopmental Disorders.

The re-analysis of nondiagnostic exome sequencing (ES) has the potential to increase diagnostic yields in individuals with rare diseases, but its implementation in the daily routines of laboratories is limited due to restricted capacities. Here, we describe a systematic approach to re-analyse the ES data of a cohort consisting of 1040 diagnostic and nondiagnostic samples. We applied a strict filter cascade to reveal the most promising single-nucleotide variants (SNVs) of the whole cohort, which led to an average of 0.

Microdeletions at 19p13.11p12 in five individuals with neurodevelopmental delay.

Only few copy number variants at chromosome 19p13.11 have been reported, thus associated clinical information is scarce. Proximal to these copy number losses, we now identified deletions in five unrelated individuals with neurodevelopmental disorders.

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.

Determination of oligomeric states of proteins via dual-color colocalization with single molecule localization microscopy.

The oligomeric state of plasma membrane proteins is the result of the interactions between individual subunits and an important determinant of their function. Most approaches used to address this question rely on extracting these complexes from their native environment, which may disrupt weaker interactions. Therefore, microscopy techniques have been increasingly used in recent years to determine oligomeric states in situ.

The constitutional gain-of-function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome.

NSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) critical region. Recent descriptions have delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study.

Hereditary chronic kidney disease (CKD) appears to be more frequent than the clinical perception. Exome sequencing (ES) studies in CKD cohorts could identify pathogenic variants in ~10% of individuals. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose.

AutoCaSc: Prioritizing candidate genes for neurodevelopmental disorders.

Routine exome sequencing (ES) in individuals with neurodevelopmental disorders (NDD) remains inconclusive in >50% of the cases. Research analysis of unsolved cases can identify novel candidate genes but is time-consuming, subjective, and hard to compare between labs. The field, therefore, requires automated and standardized assessment methods to prioritize candidates for matchmaking.

The recurrent TCF4 missense variant p.(Arg389Cys) causes a neurodevelopmental disorder overlapping with but not typical for Pitt-Hopkins syndrome.

TCF4 haploinsufficiency by deletions, truncating variants or loss-of-function missense variants within the DNA-binding and protein interacting bHLH domain causes Pitt-Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N-terminus of TCF4 were associated with milder or atypical phenotypes.

Integration of artificial intelligence and plasma steroidomics with laboratory information management systems: application to primary aldosteronism.

Objectives: Mass spectrometry-based steroidomics combined with machine learning (ML) provides a potentially powerful approach in endocrine diagnostics, but is hampered by limitations in the conveyance of results and interpretations to clinicians. We address this shortcoming by integration of the two technologies with a laboratory information management systems (LIMS) model.

Methods: The approach involves integration of ML algorithm-derived models with commercially available mathematical programming software and a web-based LIMS prototype.

The Rhinobiome of Exacerbated Wheezers and Asthmatics: Insights From a German Pediatric Exacerbation Network.

Although the nose, as a gateway for organism-environment interactions, may have a key role in asthmatic exacerbation, the rhinobiome of exacerbated children with asthma was widely neglected to date. The aim of this study is to understand the microbiome, the microbial immunology, and the proteome of exacerbated children and adolescents with wheeze and asthma. Considering that a certain proportion of wheezers may show a progression to asthma, the comparison of both groups provides important information regarding clinical and phenotype stratification.

Genetics of Primary Aldosteronism.

Primary aldosteronism is considered the commonest cause of secondary hypertension. In affected individuals, aldosterone is produced in an at least partially autonomous fashion in adrenal lesions (adenomas, [micro]nodules or diffuse hyperplasia). Over the past decade, next-generation sequencing studies have led to the insight that primary aldosteronism is largely a genetic disorder.

A Novel Homozygous KLHL3 Mutation as a Cause of Autosomal Recessive Pseudohypoaldosteronism Type II Diagnosed Late in Life.

Introduction: Pseudohypoaldosteronism type II (PHA II) is a Mendelian disorder, featuring hyperkalemic acidosis and low plasma renin levels, typically associated with hypertension. Mutations in WNK1, WNK4, CUL3, and KLHL3 cause PHA II, with dominant mutations in WNK1, WNK4, and CUL3 and either dominant or recessive mutations in KLHL3. Fourteen families with recessive KLHL3 mutations have been reported, with diagnosis at the age of 3 months to 56 years, typically in individuals with normal kidney function.

Salt-Sensitive Hypertension in GR Rats Is Accompanied with Dysregulation in Adrenal Soluble Epoxide Hydrolase and Polyunsaturated Fatty Acid Pathways.

Mutations within the glucocorticoid receptor (GR) gene locus lead to glucocorticoid resistance which is characterized by several clinical symptoms such as adrenal gland hyperplasia and salt-sensitive hypertension, although the underlying mechanisms are still unknown. We studied GR haploinsufficient (GR) Sprague Dawley rats which, on a standard diet, showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia accompanied by a normal systolic blood pressure. Following a high salt diet, these rats developed salt-sensitive hypertension and maintained elevated enzyme-soluble epoxide hydrolase (sEH) in adrenal glands, while sEH was significantly decreased in wild-type rats.

Diagnosis and treatment of primary aldosteronism.

Primary aldosteronism is a common cause of secondary hypertension associated with excess cardiovascular morbidities. Primary aldosteronism is underdiagnosed because it does not have a specific, easily identifiable feature and clinicians can be poorly aware of the disease. The diagnostic investigation is a multistep process of screening, confirmatory testing, and subtype differentiation of unilateral from bilateral forms for therapeutic management.

Tracer-Based Cancer Metabolomic Analysis.

Metabolic rewiring/reprogramming is an essential hallmark of cancer. Alteration of metabolic phenotypes is occurred in cancer cells in response to a harsh condition to support cancer cell proliferation, survival, and metastasis. Stable isotope can be used as a tracer to investigate the redistribution of the carbons labeled in glucose in order to elucidate the detailed mechanisms of cellular rewiring and reprogramming in tumor microenvironment.

Proteome changes in muscles, ganglia, and gills in Corbicula fluminea clams exposed to crude oil: Relationship with behavioural disturbances.

The use of online remote control for 24/7 behavioural monitoring can play a key role in estimating the environmental status of aquatic ecosystems. Recording the valve activity of bivalve molluscs is a relevant approach in this context. However, a clear understanding of the underlying disturbances associated with behaviour is a key step.

Prenatal retinoic acid exposure reveals candidate genes for craniofacial disorders.

Syndromes that display craniofacial anomalies comprise a major class of birth defects. Both genetic and environmental factors, including prenatal retinoic acid (RA) exposure, have been associated with these syndromes. While next generation sequencing has allowed the discovery of new genes implicated in these syndromes, some are still poorly characterized such as Oculo-Auriculo-Vertebral Spectrum (OAVS).