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This review investigates the association between neurodevelopmental disorders (NDD) and variations of the gene HNF1B. Heterozygous intragenetic mutations or heterozygous gene deletions (17q12 microdeletion syndrome) of HNF1B are the cause of a multi-system developmental disorder, termed renal cysts and diabetes syndrome (RCAD). Several studies suggest that in general, patients with genetic variation of HNF1B have an elevated risk for additional neurodevelopmental disorders, especially autism spectrum disorder (ASD) but a comprehensive assessment is yet missing. This review provides an overview including all available studies of patients with HNF1B mutation or deletion with comorbid NDD with respect to the prevalence of NDDs and in how they differ between patients with an intragenic mutation or 17q12 microdeletion. A total of 31 studies was identified, comprising 695 patients with variations in HNF1B, (17q12 microdeletion N = 416, mutation N = 279). Main results include that NDDs are present in both groups (17q12 microdeletion 25.2% vs. mutation 6.8%, respectively) but that patients with 17q12 microdeletions presented more frequently with any NDDs and especially with learning difficulties compared to patients with a mutation of HNF1B. The observed prevalence of NDDs in patients with HNF1B variations seems to be higher than in the general population, but the validity of the estimated prevalence must be deemed insufficient. This review shows that systematical research of NDDs in patients with HNF1B mutations or deletions is lacking. Further studies regarding neuropsychological characteristics of both groups are needed. NDDs might be a concomitant of HFN1B-related disease and should be considered in clinical routine and scientific reports.

Magnesium (Mg2+) is an important intracellular cation and essential to maintain cell function including cell proliferation, immunity, cellular energy metabolism, protein and nucleic acid synthesis, and regulation of ion channels. Consequences of hypomagnesemia affecting multiple organs can be in overt or subtle presentations. Besides detailed history and complete physical examination, the assessment of urinary Mg2+ excretion is help to differentiate renal from extra-renal (gastrointestinal, tissue sequestration, and shifting) causes of hypomagnesemia. Renal hypomagnesemia can be caused by an increased glomerular filtration and impaired reabsorption in proximal tubular cells, thick ascending limb of the loop of Henle or distal convoluted tubules. A combination of renal Mg2+ wasting, familial history, age of onset, associated features, and exclusion of acquired etiologies point to inherited forms of renal hypomagnesemia. Based on clinical phenotypes, its definite genetic diagnosis can be simply grouped into specific, uncertain, and unknown gene mutations with a priority of genetic approach methods. An unequivocal molecular diagnosis could allow for prediction of clinical outcome, providing genetic counseling, avoiding unnecessary studies or interventions, and possibly uncovering the pathogenic mechanism. Given numerous identified genes responsible for Mg2+ transport in renal hypomagnesemia over the past two decades, several potential and specific molecular and cellular therapeutic strategies to correct hypomagnesemia are promising.

Abstract Background The European Rare Kidney Disease Reference Network (ERKNet) recently established ERKReg, a Web-based registry for all patients with rare kidney diseases. The main objectives of this core registry are to generate epidemiological information, identify current patient cohort for clinical research, explore diagnostic and therapeutic management practices, and monitor treatment performance and patient’s outcomes. The registry has a modular design that allows to integrate comprehensive disease-specific registries as extensions to the core database. The diagnosis (Orphacode) and diagnostic information (clinical, imaging, histopathological, biochemical, immunological and genetic) are recorded. Anthropometric, kidney function, and disease-specific management and outcome items informing a set of 61 key performance indicators (KPIs) are obtained annually. Data quality is ensured by automated plausibility checks upon data entry and regular offline database checks prompting queries. Centre KPI statistics and benchmarking are calculated automatically. Results Within the first 24 months since its launch, 7607 patients were enrolled to the registry at 45 pediatric and 12 specialized adult nephrology units from 21 countries. A kidney disease diagnosis had been established in 97.1% of these patients at time of enrolment. While 199 individual disease entities were reported by Orphacode, 50% of the cohort could be classified with 11, 80% with 43 and 95% with 92 codes. Two kidney diagnoses were assigned in 6.5% of patients; 5.9% suffered from syndromic disease. Whereas glomerulopathies (54.8%) and ciliopathies including autosomal dominant polycystic kidney disease (ADPKD) (31.5%) were the predominant disease groups among adults, the pediatric disease spectrum encompassed congenital anomalies of the kidney and urinary tract (CAKUT) (33.7%), glomerulopathies (30.7%), ciliopathies (14.0%), tubulopathies (9.2%), thrombotic microangiopathies (5.6%), and metabolic nephropathies (4.1%). Genetically confirmed diagnoses were reported in 24% of all pediatric and 12% adult patients, whereas glomerulopathies had been confirmed by kidney biopsy in 80.4% adult versus 38.5% pediatric glomerulopathy cases. Conclusions ERKReg is a rapidly growing source of epidemiological information and patient cohorts for clinical research, and an innovative tool to monitor management quality and patient outcomes.

Introduction: There is no standard treatment after resection of colorectal liver metastases and the role of systemic therapy remains controversial. To avoid over- or undertreatment, proper risk stratification with regard to postoperative treatment strategy is highly needed. We recently demonstrated the prognostic relevance of EMT-related (epithelial-mesenchymal transition) genes in stage II/III CRC. As EMT is a major step in CRC progression, we now aimed to analyse the prognostic relevance of EMT-related genes in stage IV CRC using the study cohort of the FIRE-3 trial, an open-label multi-centre randomised controlled phase III trial of patients with metastatic CRC. Methods: Overall and progression free survival were considered as endpoints (n = 350). To investigate the prognostic relevance of EMT-related genes on either endpoint, we compared predictive performance of different models using clinical data only to models using gene data in addition to clinical data, expecting better predictive performance if EMT-related genes have prognostic value. In addition to baseline models (Kaplan Meier (KM), (regularised) Cox), Random Survival Forest (RSF), and gradient boosted trees (GBT) were fit to the data. Repeated, nested five-fold cross-validation was used for hyperparameter optimisation and performance evaluation. Predictive performance was measured by the integrated Brier score (IBS). Results: The baseline KM model showed the best performance (OS: 0.250, PFS: 0.251). None of the other models were able to outperform the KM when using clinical data only according to the IBS scores (OS: 0.253 (Cox), 0.256 (RSF), 0.284 (GBT); PFS: 0.254 (Cox), 0.256 (RSF), 0.276 (GBT)). When adding gene data, performance of GBT improved slightly (OS: 0.262 vs. 0.284; PFS: 0.268 vs. 0.276), however, none of the models performed better than the KM baseline. Conclusion: Overall, the results suggest that the prognostic relevance of EMT-related genes may be stage-dependent and that EMT-related genes have no prognostic relevance in stage IV CRC.

The direct conversion of synthesis gas could open up economically viable routes for the efficient production of ethanol. RhMn/SiO2 represents one of the most active systems reported thus far. Potential improvements were reported by added dopants, i.e., Ir, Ti, and Li. Yet, combining these elements leads to contradicting results, owing to the complexity of the interactions in a multi-promoted system. This complexity is often encountered in heterogeneous catalysis. We report a systematic data-driven approach for the assessment of complex multi-promoter interactions based on a combination of design-of-experiment, high-throughput experimentation, statistical analysis, and mechanistic assessment. We illustrate this approach for the system RhMn/SiO2 promoted with Ir, Li, and Ti. Using this approach, we investigate the impact of promoters’ interactions on a mechanistic level. Our analysis depicts the means to learn hidden correlations in the performance data and, additionally, high performance for ethanol yield for the RhMnIr/SiO2 catalyst. The method presented outlines an efficient way to also elucidate co-promoter interactions in other complex environments.

The term Idiopathic infantile hypercalcemia (IIH) was first introduced almost 70 years ago when symptomatic hypercalcemia developed in children after receiving high doses of vitamin D for the prevention of rickets. The underlying pathophysiology remained unknown until recessive mutations in CYP24A1 encoding Vitamin D3-24-hydroxylase were discovered. The defect in vitamin D degradation leads to an accumulation of active 1,25(OH)2D3 with subsequent hypercalcemia. Enhanced renal calcium excretions lead to hypercalciuria and nephrocalcinosis. Meanwhile, the phenotypic spectrum associated with CYP24A1 mutations has significantly broadened. Patients may present at all age groups with symptoms originating from increased serum calcium levels as well as from increased urinary calcium excretions, i.e. kidney stones. Possible long term sequelae comprise chronic renal failure as well as cardiovascular disease. Here, we present a family with two affected siblings with differing clinical presentation as an example for the phenotypic variability of CYP24A1 defects. Keywords: Idiopathic infantile hypercalcemia, Nephrocalcinosis, Nephrolithiasis, CYP24A1, Vitamin D

We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen (AGT), Ang I, and Ang II levels. The pathogenesis of ARRTD caused by this AGT mutation and the potential therapeutic effect of hydrocortisone were examined by in vitro functional studies. The expression of this truncated AGT protein was relatively low with a dose-dependent manner. This truncated mutation diminished the interaction between mutant AGT and renin. The truncated AGT also altered the glucocorticoid receptor (GR)-dependent transactivation, indicating that AGT may affect the development of proximal convoluted tubule by alteration of glucocorticoid-dependent transactivation. In hepatocytes, hydrocortisone increased the AGT level by accentuating the stability of mutant AGT and increasing its binding with renin. Therefore, hydrocortisone may exert the therapeutic effect through the enhanced stability and interaction with renin of truncated AGT in patients carrying this AGT mutation.

Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet–Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype–phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing “revolution” in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder that is caused by mutation in the genes coding for tight junction proteins Claudin-16 and Claudin-19. Affected individuals usually develop nephrocalcinosis and progressive renal failure; some of them may have ophthalmologic involvement as well. Phenotypic description of three affected individuals from the same Middle Eastern kindred (two sisters and their cousin) is presented. This includes both clinical and laboratory findings upon initial presentation and subsequent follow-up. Molecular analysis of the CLDN19 gene was performed on the three cases and one set of parents. A novel homozygous missense mutation in CLDN19 (c.241C>T, p.Arg81Cys) was detected in all three affected children. The parents were heterozygous. Clinical and laboratory data in the three children with renal and ocular manifestations of FHHNC are described. Genetic analysis revealed a novel mutation in the CLDN19 gene. FHHNC is a rare cause of nephrocalcinosis, and we believe that it should be considered in the presence of nephrocalcinosis with hypercalcuria and hypermagnesuria.

Intellectual disability and seizures are frequently associated with hypomagnesemia and have an important genetic component. However, to find the genetic origin of intellectual disability and seizures often remains challenging because of considerable genetic heterogeneity and clinical variability. In this study, we have identified new mutations in CNNM2 in five families suffering from mental retardation, seizures, and hypomagnesemia. For the first time, a recessive mode of inheritance of CNNM2 mutations was observed. Importantly, patients with recessive CNNM2 mutations suffer from brain malformations and severe intellectual disability. Additionally, three patients with moderate mental disability were shown to carry de novo heterozygous missense mutations in the CNNM2 gene. To elucidate the physiological role of CNNM2 and explain the pathomechanisms of disease, we studied CNNM2 function combining in vitro activity assays and the zebrafish knockdown model system. Using stable Mg(2+) isotopes, we demonstrated that CNNM2 increases cellular Mg2+ uptake in HEK293 cells and that this process occurs through regulation of the Mg(2+)-permeable cation channel TRPM7. In contrast, cells expressing mutated CNNM2 proteins did not show increased Mg(2+) uptake. Knockdown of cnnm2 isoforms in zebrafish resulted in disturbed brain development including neurodevelopmental impairments such as increased embryonic spontaneous contractions and weak touch-evoked escape behaviour, and reduced body Mg content, indicative of impaired renal Mg(2+) absorption. These phenotypes were rescued by injection of mammalian wild-type Cnnm2 cRNA, whereas mammalian mutant Cnnm2 cRNA did not improve the zebrafish knockdown phenotypes. We therefore concluded that CNNM2 is fundamental for brain development, neurological functioning and Mg(2+) homeostasis. By establishing the loss-of-function zebrafish model for CNNM2 genetic disease, we provide a unique system for testing therapeutic drugs targeting CNNM2 and for monitoring their effects on the brain and kidney phenotype.