A generic emergency protocol for patients with inborn errors of metabolism causing fasting intolerance: A retrospective, single-center study and the generation of www.emergencyprotocol.net

Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results, and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions, and translations. Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128 (42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration 5 years. Convulsions, coma, or death was not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in nine different languages. Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD

TAT-Mediated Transduction of MafA Protein In Utero Results in Enhanced Pancreatic Insulin Expression and Changes in Islet Morphology

Alongside Pdx1 and Beta2/NeuroD, the transcription factor MafA has been shown to be instrumental in the maintenance of the beta cell phenotype. Indeed, a combination of MafA, Pdx1 and Ngn3 (an upstream regulator of Beta2/NeuroD) was recently reported to lead to the effective reprogramming of acinar cells into insulin-producing beta cells. These experiments set the stage for the development of new strategies to address the impairment of glycemic control in diabetic patients. However, the clinical applicability of reprogramming in this context is deemed to be poor due to the need to use viral vehicles for the delivery of the above factors. Here we describe a recombinant transducible version of the MafA protein (TAT-MafA) that penetrates across cell membranes with an efficiency of 100% and binds to the insulin promoter in vitro. When injected in utero into living mouse embryos, TAT-MafA significantly up-regulates target genes and induces enhanced insulin production as well as cytoarchitectural changes consistent with faster islet maturation. As the latest addition to our armamentarium of transducible proteins (which already includes Pdx1 and Ngn3), the purification and characterization of a functional TAT-MafA protein opens the door to prospective therapeutic uses that circumvent the use of viral delivery. To our knowledge, this is also the first report on the use of protein transduction in utero

Research activity and capability in the European reference network MetabERN

BACKGROUND: MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient's rights in cross border healthcare. MetabERN associates 69 centres in 18 countries, which provide care for patients with Hereditary Metabolic Diseases, and have the mission to reinforce research and provide training for health professionals in this field. MetabERN performed a survey in December 2017 with the aim to produce an overview documenting research activities and potentials within the network. As the centres are multidisciplinary, separated questionnaires were sent to the clinical, university and laboratory teams. Answers were received from 52 out of the 69 centres of the network, covering 16 countries. A descriptive analysis of the information collected is presented. RESULTS: The answers indicate a marked interest of the respondents for research, who expressed high motivation and commitment, and estimated that the conditions to do research in their institution were mostly satisfactory. They are active in research, which according to several indicators, is competitive and satisfies standards of excellence, as well as the education programs offered in the respondent's universities. Research in the centres is primarily performed in genetics, pathophysiology, and epidemiology, and focuses on issues related to diagnosis. Few respondents declared having activity in human and social sciences, including research on patient's quality of life, patient's awareness, or methods for social support. Infrastructures offering services for medical research were rarely known and used by respondents, including national and international biobanking platforms. In contrast, respondents often participate to patient registries, even beyond their specific field of interest. CONCLUSIONS: Taken as a whole, these results provide an encouraging picture of the research capacities and activities in the MetabERN network, which, with respect to the number and representativeness of the investigated centres, gives a comprehensive picture of research on Hereditary Metabolic Diseases in Europe, as well as the priorities for future actions. Marginal activity in human and social sciences points out the limited multidisciplinary constitution of the responding teams with possible consequences on their current capability to participate to patient's empowerment programs and efficiently collaborate with patient's advocacy groups

Functional Studies Of Cyp21a2 Mutants Complement Structural And Clinical Predictions Of Disease Severity In Cah

[No abstract available]765766768Soldin, S.J., Soldin, O.P., Steroid hormone analysis by tandem mass spectrometry (2009) Clinical Chemistry, 55, pp. 1061-1066Robins, T., Carlsson, J., Sunnerhagen, M., Wedell, A., Persson, B., Molecular model of human CYP21 based on mammalian CYP2C5: Structural features correlate with clinical severity of mutations causing congenital adrenal hyperplasia (2006) Molecular Endocrinology, 20 (11), pp. 2946-2964. , http://mend.endojournals.org/cgi/reprint/20/11/2946, DOI 10.1210/me.2006-0172Soardi, F.C., Barbaro, M., Lau, I.F., Lemos-Marini, S.H.V., Baptista, M.T.M., Guerra Jr., G., Wedell, A., De Mello, M.P., Inhibition of CYP21A2 enzyme activity caused by novel missense mutations identified in brazilian and scandinavian patients (2008) Journal of Clinical Endocrinology and Metabolism, 93 (6), pp. 2416-2420. , http://jcem.endojournals.org/cgi/reprint/93/6/2416, DOI 10.1210/jc.2007-2594Lajic, S., Robins, T., Krone, N., Schwarz, H.P., Wedell, A., CYP21 mutations in simple virilizing congenital adrenal hyperplasia (2001) Journal of Molecular Medicine, 79 (10), pp. 581-586. , DOI 10.1007/s001090100261Otyepka, M., Skopalik, J., Anzenbacherova, E., Anzenbacher, P., What common structural features and variations of mammalian P450s are known to date? (2007) Biochimica et Biophysica Acta - General Subjects, 1770 (3), pp. 376-389. , DOI 10.1016/j.bbagen.2006.09.013, PII S030441650600288

Using the five to fifteen-collateral informant questionnaire for retrospective assessment of childhood symptoms in adults with and without autism or ADHD

Due to lack of previous studies, we aimed at evaluating the use of the Five to Fifteen (FTF) questionnaire in adults with neurodevelopmental disorders (NDD) and in controls without NDD. The NDD group consisted of adults with autism spectrum disorder ASD (n = 183) or attention-deficit/hyperactivity disorder (ADHD) (n = 174) without intellectual disability, recruited from a tertiary outpatient clinic. A web survey was used to collect data from general population adult control group without NDD (n = 738). The participants were retrospectively rated by their parents regarding childhood symptoms, using five to fifteen-collateral informant questionnaire (FTF-CIQ). Adults with NDD had higher FTF-CIQ domain and subdomain scores than controls, and displayed similar test profiles as children with corresponding diagnosis in previous studies. Based on the FTF-CIQ domain scores, 84.2% of the study participants (93% of the controls; 64% of the adults with NDD) were correctly classified in a logistic regression analysis. Likewise, Receiver Operating Characteristic (ROC) curve analysis on FTF-CIQ total sum score indicated that a cut-off value of 20.50 correctly classified 90% of the controls and 67% of the clinical cases, whilst a cut-off value of 30.50 correctly classified 84% of the controls and 77% of the clinical cases. The factor analysis revealed three underlying components: learning difficulties, cognitive and executive functions; social skills and emotional/behavioural symptoms; as well as motor and perceptual skills. Whilst not designed as a diagnostic instrument, the FTF-CIQ may be useful for providing information on childhood symptoms and associated difficulties in individuals assessed for NDD as adults

In Vitro Functional Studies Of Rare Cyp21a2 Mutations And Establishment Of An Activity Gradient For Nonclassic Mutations Improve Phenotype Predictions In Congenital Adrenal Hyperplasia

Background: A detailed genotype-phenotype evaluation is presented by studying the enzyme activities of five rare amino acid substitutions (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile) identified in the CYP21A2 gene in patients investigated for Congenital adrenal hyperplasia (CAH). Objective: To investigate whether the mutations identified in the CYP21A2 gene are disease causing and to establish a gradient for the degree of enzyme impairment to improve prediction of patient phenotype. Design and patients: The CYP21A2 genes of seven patients investigated for CAH were sequenced and five mutations were identified. The mutant proteins were expressed in vitro in COS-1 cells, and the enzyme activities towards the two natural substrates were determined to verify the disease-causing state of the mutations. The in vitro activities of these rare mutations were also compared with the activities of four mutations known to cause nonclassic CAH (Pro30Leu, Val281Leu, Pro453Ser and Pro482Ser) in addition to an in silico structural evaluation of the novel mutants. Main outcome measure: To verify the disease-causing state of novel mutations. Results: Five CYP21A2 mutations were identified (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile). All mutant proteins exhibited enzyme activities above 5%, and four mutations were classified as nonclassic and one as a normal variant. By comparing the investigated protein changes with four common mutations causing nonclassic CAH, a gradient for the degree of enzyme impairment could be established. Studying rare mutations in CAH increases our knowledge regarding the molecular mechanisms that render a mutation pathogenic. It also improves phenotype predictions and genetic counselling for future generations. © 2014 John Wiley & Sons Ltd