Journal of Pediatric Biochemistry - Volume 4, issue 1

Authors: Johannes Häberle,

Article Type: Other

DOI: 10.3233/JPB-140099

Citation: Journal of Pediatric Biochemistry, vol. 4, no. 1, pp. 1-3, 2014

Authors: Staufner, Christian | Zangerl, Kathrin | Hoffmann, Georg Friedrich | Kölker, Stefan

Article Type: Research Article

Abstract: We present three case reports of a family affected by ornithine transcarbamylase deficiency (OTC-D), the most common urea cycle disorder. The case reports demonstrate the variable clinical phenotype of OTC-D in heterozygous carriers, even in one family. Based on these reports, OTC-D and its biochemical hallmarks are discussed.

Keywords: OTC deficiency, late onset OTC deficiency, urea cycle disorder, metabolic stroke

DOI: 10.3233/JPB-140100

Citation: Journal of Pediatric Biochemistry, vol. 4, no. 1, pp. 5-10, 2014

Authors: Jalan, Anil Bansidhar | Kudalkar, Ketki Vinod | Jalan, Rishikesh Anil

Article Type: Research Article

Abstract: Urea cycle disorders (UCDs) are amongst the commonest disorders detected in critically ill newborns. True incidence of these disorders in developing countries like India may not be known, however they are expected to be very common owing to the high rate of consanguinity in these countries. In this review article we discuss the problems and hardships faced by treating clinicians in a developing country. We present an overview of the strategies to be followed by clinicians …in a developing country for treatment and management of such disorders. Management of disorders like UCDs in a developing country has many complexities and limitations. The outcome in these disorders depends upon many factors like availability of basic investigations, availability of emergency drugs, availability of special diets and their cost-effectiveness. Alternative methods for ammonia detoxification like peritoneal dialysis and hemodialysis may or may not be available at all the centers managing critically ill newborns with UCDs, which may in turn affect the outcome in these children. Liver transplants are rarely available. Thus increasing the awareness about these disorders and educating the primary physicians in treatment and management of such disorders become an essential part in the management of these disorders. Emergency protocols to be followed during treatment have been described in this review. Show more

Keywords: Urea cycle disorders, sodium benzoate, sodium phenylbutyrate, citrullinemia

DOI: 10.3233/JPB-140101

Citation: Journal of Pediatric Biochemistry, vol. 4, no. 1, pp. 11-16, 2014

Authors: Bachmann, Claude

Article Type: Research Article

Abstract: Reliable biochemical results are needed for the diagnosis and follow-up of patients with hyperammonemic disorders. Preanalytical factors influence the results and can lead to erroneous interpretations and medical decisions. I emphasize the need of quality assessment in the laboratory, of adequate time of sampling for ammonia and amino acid analyses after food intake in urea cycle disorders and on the rational estimation whether the intra-individual difference between two sequential results of an analyte is …solely due to analytical variance or not. I present arguments for banning capillary blood samples as well as whole blood samples collected on filter paper for confirming or excluding a suspected diagnosis or for controlling data in the follow-up of a disease or its therapy. Show more

Keywords: Urea cycle disorders, preanalytical factors, sampling time, newborn screening

DOI: 10.3233/JPB-140102

Citation: Journal of Pediatric Biochemistry, vol. 4, no. 1, pp. 17-22, 2014

Authors: Gautschi, Matthias | Eggimann, Sandra | Nuoffer, Jean-Marc

Article Type: Research Article

Abstract: Urea cycle disorders (UCD) are due to defects of any of its six enzymes or two transporters. The definitive diagnosis of defects of the three mitochondrial enzymes, N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase I (CPS1) and ornithine transcarbamylase (OTC) depends on either molecular mutation analysis or measurement of enzyme activity, whereas the diagnosis of deficiencies of the three cytosolic enzymes argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase I (ARG1) is usually straightforward, …based on marker metabolites. Enzyme assays for all UCD have been used since their first description, for disease confirmation and in some instances even for prenatal diagnosis. The genetic bases of the UCD have only been unraveled from the 1980s; the last gene cloned being the NAGS gene in 2002. In this review we discuss the enzymatic assays for all urea cycle enzymes from a historical perspective, their potential and drawbacks, and the current role of enzymatic analysis in UCD in general. Show more

Keywords: Urea cycle defects, urea cycle enzymes, enzymology, enzyme assays

DOI: 10.3233/JPB-140103

Citation: Journal of Pediatric Biochemistry, vol. 4, no. 1, pp. 23-32, 2014

Authors: Rüfenacht, V\'eronique | H\"aberle, Johannes

Article Type: Research Article

Abstract: Urea cycle disorders (UCDs) are a group of autosomal or X-linked, recessively inherited errors of metabolism that lead to severe neurological disease due to insufficient detoxification of excess nitrogen. The resulting hyperammonemia is the key feature of UCDs, but at the same time only a surrogate marker. In the majority of cases, a sole biochemical analysis is indicative but not diagnostic. Therefore, additional means are required and mutation analysis is the method of choice for confirmation …in most cases of UCD. In addition to confirming the diagnosis, mutation analysis enables genetic counseling and prenatal testing and contributes to new research approaches. All genes involved in any of the enzymatic (namely the genes for N-acetylglutamate synthase, NAGS; carbamoylphosphate synthetase, CPS1; ornithine transcarbamylase, OTC; argininosuccinate synthetase, ASS1; argininosuccinate lyase, ASL; arginase, ARG1) or transporter steps (namely the genes for the ornithine/citrulline antiporter ORNT1, SLC25A15; glutamate/aspartate antiporter citrin, SLC25A13) of the urea cycle are known and thus accessible for genetic testing. In most situations, direct Sanger sequencing using DNA from peripheral blood cells can be done but there are exceptions to this such as in the case of the relatively large CPS1 gene which renders RNA based mutation analysis an attractive alternative. With this review, we provide an overview on the current methods used for mutation analysis of each UCD gene, we mention possible pitfalls and their solutions, and discuss alternative methods which may become standard in the future. Show more

Keywords: Urea cycle, mutation analysis, hyperammonemia, inborn error of metabolism

DOI: 10.3233/JPB-140104

Citation: Journal of Pediatric Biochemistry, vol. 4, no. 1, pp. 33-43, 2014

Authors: Martinelli, Diego

Article Type: Research Article

Abstract: Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysis of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and two transporters). The hallmark of urea cycle (UC) dysfunction is hyperammonemia, due to the impossibility of detoxifing ammonia derived from dietary protein intake, muscle catabolism or bacterial production within the intestine. Beside primary defects of one of the enzymes or transporters, other genetic or …acquired conditions can secondary affect, by different mechanisms, UC function, hereby leading to hyperammonemia. Aim of this paper is to review the most important genetic conditions responsible of UC function impairment, to highlight the connection with UC enzymes and to provide the clue for differential diagnosis. Show more

Keywords: UCD, urea cycle, hyperammonemia, secondary hyperammonemia

DOI: 10.3233/JPB-140105

Citation: Journal of Pediatric Biochemistry, vol. 4, no. 1, pp. 45-55, 2014

Authors: Mew, Nicholas Ah | Yudkoff, Marc | Tuchman, Mendel

Article Type: Research Article

Abstract: Stable isotopes have greatly contributed to our understanding of nitrogen metabolism and the urea cycle. The measurement of urea flux via isotopic methods has traditionally been utilized to determine total body protein synthesis in subjects with an intact urea cycle. However, isotopic studies of nitrogen metabolism are also a useful adjunct to conventional clinical investigations in the diagnosis and management of the inherited hyperammonemias. Such studies offer a safe non-invasive method of measuring the …reduction of in vivo hepatic ureagenesis, and thus may provide a more accurate measure of phenotypic severity in affected patients. In addition, isotopic methods are ideally suited to evaluate the efficacy of novel therapies to augment urea production. Show more

Keywords: Stable isotopes, urea cycle disorders, ureagenesis, mass spectrometry

DOI: 10.3233/JPB-140106

Citation: Journal of Pediatric Biochemistry, vol. 4, no. 1, pp. 57-63, 2014

Authors: Viecelli, Hiu Man | Thöny, Beat

Article Type: Research Article

Abstract: Urea cycle disorders (UCDs) are inborn errors of liver metabolism that often result in hyperammonemia and failure of arginine synthesis due to the deficiencies of one of the six enzymes or two mitochondrial transporters involved. Despite current treatment options, including dietary therapy, stimulation of alternative routes of nitrogen disposal and cell therapies (hepatocyte and orthotopic liver transplantation), significant morbidity and mortality still remain. Gene therapy has emerged as an attractive alternative strategy …for providing a definitive cure for patients with metabolic diseases. Successful phenotype correction in pre- clinical animal models is encouraging and research effort is increasingly being focused on translation from the laboratory bench to proof-of-concept human therapy. Gene therapy for UCDs must target the periportal hepatocytes, as these are the only liver cells that express all six enzymes required for full ammonia detoxification. This review explores current efforts to develop and translate liver-directed gene therapy approaches to UCDs caused by each of the defects of the six enzymes. The prominent issues that will need to be addressed and overcome for the future development of clinical trials, including alternatives to mouse mutants and to vectors that are not necessarily conditioned to rodents are also discussed. Show more

Keywords: Urea cycle disorders, UCDs, liver-directed gene therapy, metabolic disease

DOI: 10.3233/JPB-140107

Citation: Journal of Pediatric Biochemistry, vol. 4, no. 1, pp. 65-73, 2014