Dapagliflozin's impact on hormonal regulation and ketogenesis in type 1 diabetes: a randomised controlled crossover trial.

Aims/hypothesis: This study aimed to assess the impact of adding dapagliflozin to insulin therapy on key hormonal determinants of glucose regulation and ketogenesis. We hypothesise that dapagliflozin increases glucagon-like peptide 1 (GLP-1), glucagon and ketone body concentrations, based on the results of a pilot study.

Methods: The study was designed as a randomised, placebo-controlled, open-label, crossover intervention study with two periods (dapagliflozin and placebo intake), including patients of the Department of Diabetes, Endocrinology, Clinical Nutrition & Metabolism, Inselspital, Bern University Hospital, University of Bern.

Novel Treatment Strategy for Patients With Urea Cycle Disorders: Pharmacological Chaperones Enhance Enzyme Stability and Activity in Patient-Derived Liver Disease Models.

Urea cycle disorders (UCDs) are inherited diseases causing recurrent life-threatening metabolic decompensations due to impaired hepatic ammonia detoxification and decreased ureagenesis. Ornithine transcarbamylase (OTC) deficiency (OTCD) is X-linked and the most common and often fatal UCD. In male hemizygous patients, disease severity primarily depends on the pathogenic sequence variant, while in heterozygous females, disease severity also depends on the X-chromosomal inactivation (XCI) pattern.

Characterization and treatment monitoring of ureagenesis disorders using stable isotopes.

Urea cycle disorders (UCDs) are a group of rare conditions, possibly life-threatening and without definitive cure besides liver transplantation. Traditional biochemical analyses/biomarkers cannot reliably determine changes in the UC-function from baseline to post-intervention. We describe a UHPLC-HRMS method to assess ureagenesis in plasma and dried blood spots for [N]urea and [N]amino acids, using [N]ammonium chloride as tracer.

Intra- and extracellular real-time analysis of perfused fibroblasts using an NMR bioreactor: A pilot study.

Introduction: Metabolomic discrimination of different mitochondrial defects is challenging. We describe an NMR-based bioreactor allowing real-time intra- and extracellular metabolic investigation of perfused fibroblasts.

Objectives: The objective of this study is (I) determining whether metabolic investigations of perfused fibroblasts overall and separated for intra- and extracellular contributions by real-time NMR allows for discrimination of different representative mitochondrial defects in a feasibility study and (II) gaining insight into physiological consequences of mitochondrial dysfunction in basal condition and during glycolysis inhibition.

Specific GAG ratios in the diagnosis of mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) screening is tedious and still performed by analysis of total glycosaminoglycans (GAG) using 1,9-dimethylmethylene blue (DMB) photometric assay, although false positive and negative tests have been reported. Analysis of differentiated GAGs have been pursued classically by gel electrophoresis or more recently by quantitative LC-MS assays. Secondary elevations of GAGs have been reported in urinary tract infections (UTI).

Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency.

Unlabelled: Mitochondrial malate dehydrogenase 2 (MDH2) is crucial to cellular energy generation through direct participation in the tricarboxylic acid (TCA) cycle and the malate aspartate shuttle (MAS). Inherited MDH2 deficiency is an ultra-rare metabolic disease caused by bi-allelic pathogenic variants in the gene, resulting in early-onset encephalopathy, psychomotor delay, muscular hypotonia and frequent seizures. Currently, there is no cure for this devastating disease.

Levels of Circulating Ketone Bodies in Patients Undergoing Cardiac Surgery on Cardiopulmonary Bypass.

Ketone bodies (KBs) are energy-efficient substrates utilized by the heart depending on its metabolic demand and substrate availability. Levels of circulating KBs have been shown to be elevated in acute and chronic cardiovascular disease and are associated with severity of disease in patients with heart failure and functional outcome after myocardial infarction. To investigate whether this pattern similarly applies to patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB), we analysed prospectively collected pre- and postoperative blood samples from 192 cardiac surgery patients and compared levels and perioperative changes in total KBs with Troponin T as a marker of myocardial cell injury.

Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency.

A 3-year-old, male neutered Cavalier King Charles Spaniel (CKCS) presented with complex focal seizures and prolonged lethargy. The aim of the study was to investigate the clinical signs, metabolic changes and underlying genetic defect. Blood and urine organic acid analysis revealed increased medium-chain fatty acids and together with the clinical findings suggested a diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

Metabolomics analysis of antiquitin deficiency in cultured human cells and plasma: Relevance to pyridoxine-dependent epilepsy.

Deficiency of antiquitin (α-aminoadipic semialdehyde dehydrogenase), an enzyme involved in lysine degradation and encoded by ALDH7A1, is the major cause of vitamin B -dependent epilepsy (PDE-ALDH7A1). Despite seizure control with high dose pyridoxine (PN), developmental delay still occurs in approximately 70% of patients. We aimed to investigate metabolic perturbations due to possible previously unidentified roles of antiquitin, which may contribute to developmental delay, as well as metabolic effects of high dose pyridoxine supplementation reflecting the high doses used for seizure control in patients with PDE-ALDH7A1.

The role of ERNDIM diagnostic proficiency schemes in improving the quality of diagnostic testing for inherited metabolic diseases.

External quality assurance (EQA) is crucial to monitor and improve the quality of biochemical genetic testing. ERNDIM (www.erndim.

Diagnosis of atypical myopathy based on organic acid and acylcarnitine profiles and evolution of biomarkers in surviving horses.

Background: Atypical myopathy (AM), an acquired multiple acyl-CoA dehydrogenase deficiency (MADD) in horses, induce changes in mitochondrial metabolism. Only few veterinary laboratories offer diagnostic testing for this disease. Inborn and acquired MADD exist in humans, therefore determination of organic acids (OA) in urine and acylcarnitines (AC) in blood by assays available in medical laboratories can serve as AM diagnostics.

Decrease of disease-related metabolites upon fasting in a hemizygous knock-in mouse model (-ko/ki) of methylmalonic aciduria.

Methylmalonyl-CoA mutase (MMUT) is part of the propionyl-CoA catabolic pathway, responsible for the breakdown of branched-chain amino acids, odd-chain fatty acids and the side-chain of cholesterol. Patients with deficient activity of MMUT suffer from isolated methylmalonic aciduria (MMAuria), frequently presenting in the newborn period with failure to thrive and metabolic crisis. Even well managed patients remain at risk for metabolic crises, of which one known trigger is acute illness, which may lead to poor feeding and vomiting, putting the patient in a catabolic state.

Solute carrier SLC16A12 is critical for creatine and guanidinoacetate handling in the kidney.

A heterozygous mutation (c.643C.A; p.

LC-MS/MS method for the differential diagnosis of treatable early onset inherited metabolic epilepsies.

Rapid diagnosis and early specific treatment of metabolic epilepsies due to inborn errors of metabolism (IEMs) is crucial to avoid irreversible sequalae. Nowadays, besides the profile analysis of amino- and organic acids, a range of additional targeted assays is used for the selective screening of those diseases. This strategy can lead to long turn-around times, repeated sampling and diagnostic delays.

Condensation of delta-1-piperideine-6-carboxylate with ortho-aminobenzaldehyde allows its simple, fast, and inexpensive quantification in the urine of patients with antiquitin deficiency.

Antiquitin (ATQ) deficiency leads to tissue, plasma, and urinary accumulation of alpha-aminoadipic semialdehyde (AASA) and its Schiff base delta-1-piperideine-6-carboxylate (P6C). Although genetic testing of ALDH7A1 is the most definitive diagnostic method, quantifications of pathognomonic metabolites are important for the diagnosis and evaluation of therapeutic and dietary interventions. Current metabolite quantification methods use laborious, technically highly complex, and expensive liquid chromatography-tandem mass spectro-metry, which is available only in selected laboratories worldwide.

In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria.

Isolated methylmalonic aciduria (MMAuria) is primarily caused by deficiency of methylmalonyl-CoA mutase (MMUT or MUT). Biochemically, MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-carnitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma or even death, with kidney and neurological impairment frequently identified in the long-term.

Validation of a Food Frequency Questionnaire to Assess Intake of Polyunsaturated Fatty Acids in Switzerland.

Population-based data suggest that high intake of omega-3 ( polyunsaturated fatty acids (PUFA) may be beneficial in a variety of health conditions. It is likely that mainly those patients with preexisting deficiency are those that benefit most from fatty acid supplementation. Therefore, for targeted interventions, a fast and reliable screening tool for PUFA intake is necessary.

New insights into human lysine degradation pathways with relevance to pyridoxine-dependent epilepsy due to antiquitin deficiency.

Deficiency of antiquitin (ATQ), an enzyme involved in lysine degradation, is the major cause of vitamin B -dependent epilepsy. Accumulation of the potentially neurotoxic α-aminoadipic semialdehyde (AASA) may contribute to frequently associated developmental delay. AASA is formed by α-aminoadipic semialdehyde synthase (AASS) via the saccharopine pathway of lysine degradation, or, as has been postulated, by the pipecolic acid (PA) pathway, and then converted to α-aminoadipic acid by ATQ.

Antiquitin Deficiency with Adolescent Onset Epilepsy: Molecular Diagnosis in a Mother of Affected Offsprings.

Antiquitin deficiency is the most prevalent form of pyridoxine-dependent epilepsy. While most patients present with neonatal onset of therapy-resistant seizures, a few cases with late-onset during infancy have been described. Here, we describe the juvenile onset of epilepsy at the age of 17 years due to antiquitin deficiency in an Indian female with homozygosity for the most prevalent ALDH7A1 missense mutation, c.

Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: a randomised parallel-group trial.

Background: Vitamin B12 (VB12) deficiency can be treated with oral high-dose substitution or intramuscular (i.m.) injection of VB12.

Confirmation of mutations in as a novel cause of vitamin B -dependent epilepsy.

Vitamin-B-dependent epilepsies are a heterogenous group of treatable disorders due to mutations in several genes ( or ). In neonatal seizures, defects in explain a major fraction of cases. Very recently biallelic mutations in were shown to be a novel cause in five families.

A simple dried blood spot-method for in vivo measurement of ureagenesis by gas chromatography-mass spectrometry using stable isotopes.

Background: Clinical management of inherited or acquired hyperammonemia depends mainly on the plasma ammonia level which is not a reliable indicator of urea cycle function as its concentrations largely fluctuate. The gold standard to assess ureagenesis in vivo is the use of stable isotopes.

Methods: Here we developed and validated a simplified in vivo method with [N]ammonium chloride ([N]HCl) as a tracer.

Novel Mouse Models of Methylmalonic Aciduria Recapitulate Phenotypic Traits with a Genetic Dosage Effect.

Methylmalonic aciduria (MMAuria), caused by deficiency of methylmalonyl-CoA mutase (MUT), usually presents in the newborn period with failure to thrive and metabolic crisis leading to coma or even death. Survivors remain at risk of metabolic decompensations and severe long term complications, notably renal failure and neurological impairment. We generated clinically relevant mouse models of MMAuria using a constitutive Mut knock-in (KI) allele based on the p.

The value of plasma vitamin B6 profiles in early onset epileptic encephalopathies.

Background: Recent decades have unravelled the molecular background of a number of inborn errors of metabolism (IEM) causing vitamin B6-dependent epilepsy. As these defects interfere with vitamin B6 metabolism by different mechanisms, the plasma vitamin B6 profile can give important clues for further molecular work-up. This has so far been investigated in only a small number of patients.