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urea cycle defect

Soumen Bera, Sanjay Lamba, Mubasher Rashid, Anuj K Sharma, Alexander B Medvinsky, Claudia Acquisti, Amit Chakraborty, Bai-Lian Li
Impaired glutamate dehydrogenase (GDH) sensitivity to its inhibitors causes excessive insulin secretion by pancreatic beta-cells and defective ammonia metabolism in the liver. These symptoms are commonly associated with hyperinsulinism/hyperammonemia syndrome (HI/HA), which causes recurrent hypoglycaemia in early infancy. Hepatic localization of GDH amination and deamination activities linked with the urea cycle is known to be involved in ammonia metabolism and detoxification. Although deamination activities of hepatic GDH in the periportal zones of liver lobules and its connection to the urea cycle have been exhaustively investigated, physiological roles of GDH amination activity observed at pericentral zones have often been overlooked...
October 17, 2016: Integrative Biology: Quantitative Biosciences From Nano to Macro
Phillip L Pearl
Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, including early onset epileptic encephalopathy (refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalopathy), infantile spasms, or mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood...
May 2016: Seminars in Pediatric Neurology
Caroline Unsinn, Anibh Das, Vassili Valayannopoulos, Eva Thimm, Skadi Beblo, Alberto Burlina, Vassiliki Konstantopoulou, Sebene Mayorandan, Pascale de Lonlay, Jörg Rennecke, Jens Derbinski, Georg F Hoffmann, Johannes Häberle
BACKGROUND: Urea cycle disorders (UCDs) are rare inherited metabolic defects of ammonia detoxification. In about half of patients presenting with a UCD, the first symptoms appear within a few days after birth. These neonatal onset patients generally have a severe defect of urea cycle function and their survival and outcome prognoses are often limited. To understand better the current situation of neonatal onset in UCDs, we have performed a multicentre, retrospective, non-interventional case series study focussing on the most severe UCDs, namely defects of carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (ASS)...
August 19, 2016: Orphanet Journal of Rare Diseases
Stefano Patassini, Paul Begley, Jingshu Xu, Stephanie J Church, Suzanne J Reid, Eric H Kim, Maurice A Curtis, Mike Dragunow, Henry J Waldvogel, Russell G Snell, Richard D Unwin, Richard L M Faull, Garth J S Cooper
Huntington's disease (HD) is a genetically-mediated neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein (Htt) through lengthening of its polyglutamine tract, thus initiating a cascade that ultimately leads to premature death. However, neurodegeneration typically manifests in HD only in middle age, and mechanisms linking the causative mutation to brain disease are poorly understood. Brain metabolism is severely perturbed in HD, and some studies have indicated a potential role for mutant Htt as a driver of these metabolic aberrations...
September 2016: Biochimica et Biophysica Acta
Richard E Frye, Manuel F Casanova, S Hossein Fatemi, Timothy D Folsom, Teri J Reutiman, Gregory L Brown, Stephen M Edelson, John C Slattery, James B Adams
This manuscript reviews biological abnormalities shared by autism spectrum disorder (ASD) and epilepsy. Two neuropathological findings are shared by ASD and epilepsy: abnormalities in minicolumn architecture and γ-aminobutyric acid (GABA) neurotransmission. The peripheral neuropil, which is the region that contains the inhibition circuits of the minicolumns, has been found to be decreased in the post-mortem ASD brain. ASD and epilepsy are associated with inhibitory GABA neurotransmission abnormalities including reduced GABAA and GABAB subunit expression...
2016: Frontiers in Neuroscience
Susan E Waisbren, Andrea L Gropman, Mark L Batshaw
The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of eight enzyme deficiencies/transporter defects associated with the urea cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN])...
July 2016: Journal of Inherited Metabolic Disease
Faisal Saud Dar, Abu Bakar Hafeez Bhatti, Syeda Shaheera Hashmi, Haseeb Zia, Munir Iqbal Malik
Auxiliary partial orthotopic liver transplant (APOLT) is a treatment option for certain liver disorders where liver structure is preserved. It includes Criggler Najjar syndrome (CNS), urea cycle defects and familial hypercholesterolaemia. Liver transplant as a treatment modality has only recently become available in Pakistan. Here we report two paediatric cases of CNS type 1 where auxiliary liver transplant was performed to correct jaundice and prevent inevitable brain damage. Both recipients and their respective living donors had successful surgery and are doing well...
May 2016: JPMA. the Journal of the Pakistan Medical Association
Maki Yamaguchi, Tatsuki R Kataoka, Takahiro Shibayama, Akinari Fukuda, Atsuko Nakazawa, Sachiko Minamiguchi, Takaki Sakurai, Aya Miyagawa-Hayashino, Toru Yorifuji, Mureo Kasahara, Shinji Uemoto, Hironori Haga
The hepatocyte paraffin 1 (Hep Par 1) antibody is widely used as a hepatocyte marker, recognizing carbamoyl phosphate synthetase 1 (CPS1), an essential component of the urea cycle. Various missense, nonsense, and frameshift mutations occur in the CPS1 gene. In neonatal patients with homozygous CPS1 deficiency (CPS1D), urea cycle defects with resulting severe hyperammonemia can be fatal, though liver transplantation provides a complete cure for CPS1D. We performed Hep Par 1 immunostaining in the explanted livers of 10 liver transplant patients with CPS1D...
June 2016: Pathology International
Anne-Els van de Logt, Leo A J Kluijtmans, Marleen C D G Huigen, Mirian C H Janssen
A 59-year-old woman, with a medical history of intellectual disability after perinatal asphyxia, was admitted because of coma due to hyperammonemia after she was treated for a fracture of the pelvis. The ammonia level was 280 μM. Acquired disorders as explanation for the hyperammonemia were excluded. Metabolic investigations showed an elevated glutamine and alanine and low citrulline, suspect for a urea cycle defect (UCD). Orotic acid could not be demonstrated in urine. DNA investigations were negative for mutations or deletions in the OTC and CPS1 gene, but revealed a homozygous c...
May 5, 2016: JIMD Reports
Jaume Campistol, María Díez-Juan, Laura Callejón, Aroa Fernandez-De Miguel, Mercedes Casado, Angels Garcia Cazorla, Reymundo Lozano, Rafael Artuch
AIM: To perform metabolic testing on 406 patients (age range 3-22y [mean 6.71, SD 4.15], 343 males and 63 females) with nonsyndromic autism spectrum disorders (ASD) to assess the diagnostic yield. In addition, we reviewed our hospital's clinical database of 8500 patients who had undergone metabolic testing to be identified for inborn errors of metabolism (IEM), and described the characteristics of those with IEM and nonsyndromic ASD. METHOD: Neuropsychological evaluation included the Social Communication Questionnaire and Child Behavior Checklist...
August 2016: Developmental Medicine and Child Neurology
Enea Sancho-Vaello, Clara Marco-Marín, Nadine Gougeard, Leonor Fernández-Murga, Véronique Rüfenacht, Merima Mustedanagic, Vicente Rubio, Johannes Häberle
N-acetyl-L-glutamate synthase (NAGS) deficiency (NAGSD), the rarest urea cycle defect, is clinically indistinguishable from carbamoyl phosphate synthetase 1 deficiency, rendering the identification of NAGS gene mutations key for differentiation, which is crucial, as only NAGSD has substitutive therapy. Over the last 13 years, we have identified 43 patients from 33 families with NAGS mutations, of which 14 were novel. Overall, 36 NAGS mutations have been found so far in 56 patients from 42 families, of which 76% are homozygous for the mutant allele...
July 2016: Human Mutation
Saikat Santra, Jessie M Cameron, Casper Shyr, Linhua Zhang, Britt Drögemöller, Colin J Ross, Wyeth W Wasserman, Ron A Wevers, Richard J Rodenburg, Girish Gupte, Mary Anne Preece, Clara D van Karnebeek
We report a patient from a consanguineous family who presented with transient acute liver failure and biochemical patterns suggestive of disturbed urea cycle and mitochondrial function, for whom conventional genetic and metabolic investigations for acute liver failure failed to yield a diagnosis. Whole exome sequencing revealed a homozygous 12-bp deletion in PCK1 (MIM 614168) encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK); enzymatic studies subsequently confirmed its pathogenic nature. We propose that PEPCK deficiency should be considered in the young child with unexplained liver failure, especially where there are marked, accumulations of TCA cycle metabolites on urine organic acid analysis and/or an amino acid profile with hyperammonaemia suggestive of a proximal urea cycle defect during the acute episode...
May 2016: Molecular Genetics and Metabolism
Jingshu Xu, Paul Begley, Stephanie J Church, Stefano Patassini, Katherine A Hollywood, Mia Jüllig, Maurice A Curtis, Henry J Waldvogel, Richard L M Faull, Richard D Unwin, Garth J S Cooper
Alzheimer's disease (AD) is an age-related neurodegenerative disorder that displays pathological characteristics including senile plaques and neurofibrillary tangles. Metabolic defects are also present in AD-brain: for example, signs of deficient cerebral glucose uptake may occur decades before onset of cognitive dysfunction and tissue damage. There have been few systematic studies of the metabolite content of AD human brain, possibly due to scarcity of high-quality brain tissue and/or lack of reliable experimental methodologies...
June 2016: Biochimica et Biophysica Acta
Mikael Oscarson, Daphne Vassiliou, Anna Nordenström, Ricard Nergårdh, Anna Wedell, Ulrika von Döbeln
Inherited metabolic diseases usually present in the neonatal period or before school age. A growing portion of the disorders can be treated successfully, and an increasing number of patients are now treated in adult medicine. Several of the disorders also exist as attenuated variants without distinct symptoms in childhood. They can present as an acute onset event during metabolic stress in adulthood. We describe three patients with acute clinical decompensation in adulthood with severe sequelae and propose investigations to help diagnose such patients...
February 1, 2016: Läkartidningen
Corinne Inauen, Véronique Rüfenacht, Amit V Pandey, Liyan Hu, Henk Blom, Jean-Marc Nuoffer, Johannes Häberle
INTRODUCTION: Cysteamine is used to treat cystinosis via the modification of cysteine residues substituting arginine in mutant proteins. OBJECTIVES: We investigated the effect of cysteamine on mutant argininosuccinate lyase (ASL), the second most common defect in the urea cycle. METHODS: In an established mammalian expression system, 293T cell lysates were produced after transfection with all known cysteine for arginine mutations in the ASL gene (p...
April 2016: Molecular Diagnosis & Therapy
Amy A Gelfand, Renata C Gallagher
BACKGROUND: Inborn errors of metabolism are on the differential for patients presenting with a cyclic vomiting syndrome phenotype. Classes of disorders to consider include: mitochondrial disorders, fatty acid oxidation disorders, urea cycle defects, organic acidurias, and acute intermittent porphyria. AIM: This article reviews the metabolic differential diagnosis and approach to screening for inborn errors in children and adults presenting with a cyclic or recurrent vomiting phenotype...
January 2016: Headache
Figen Özçay, Zeren Barış, Gökhan Moray, Nihan Haberal, Adnan Torgay, Mehmet Haberal
Urea cycle defects are a group of metabolic disorders caused by enzymatic disruption of the urea cycle pathway, transforming nitrogen to urea for excretion from the body. Severe cases present in early infancy with life-threatening metabolic decompensation, and these episodes of hyperammonemia can be fatal or result in permanent neurologic damage. Despite the progress in pharmacologic treatment, long-term survival is poor especially for severe cases. Liver transplant is an alternative treatment option, providing sufficient enzymatic activity and decreasing the risk of metabolic decompensation...
November 2015: Experimental and Clinical Transplantation
Thomas Opladen, Martin Lindner, Anibh M Das, Thorsten Marquardt, Aneal Khan, Sukru H Emre, Barbara K Burton, Bruce A Barshop, Thea Böhm, Jochen Meyburg, Kathrin Zangerl, Sebene Mayorandan, Peter Burgard, Ulrich H N Dürr, Bernd Rosenkranz, Jörg Rennecke, Jens Derbinski, Marc Yudkoff, Georg F Hoffmann
BACKGROUND: The hepatic urea cycle is the main metabolic pathway for detoxification of ammonia. Inborn errors of urea cycle function present with severe hyperammonemia and a high case fatality rate. Long-term prognosis depends on the residual activity of the defective enzyme. A reliable method to estimate urea cycle activity in-vivo does not exist yet. The aim of this study was to evaluate a practical method to quantify (13)C-urea production as a marker for urea cycle function in healthy subjects, patients with confirmed urea cycle defect (UCD) and asymptomatic carriers of UCD mutations...
January 2016: Molecular Genetics and Metabolism
Chaeyoun Oh, Sanghoon Lee, Jeong-Meen Seo, Suk-Koo Lee
BACKGROUND/PURPOSE: Internal jugular vein (IJV) access is commonly performed in neonates and infants with open cut-down method. We report the results of ultrasound guided percutaneous venous access in newborn patients in the neonatal intensive care unit (NICU). METHODS: We retrospectively examined the medical records of NICU patients who underwent therapeutic percutaneous IJV access under ultrasound guidance from October 2015 to May 2015. Under general anesthesia, IJV was punctured with a 21 gauge needle after identification by ultrasound...
April 2016: Journal of Pediatric Surgery
Stefano Patassini, Paul Begley, Suzanne J Reid, Jingshu Xu, Stephanie J Church, Maurice Curtis, Mike Dragunow, Henry J Waldvogel, Richard D Unwin, Russell G Snell, Richard L M Faull, Garth J S Cooper
Huntington's disease (HD) is a neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein through the lengthening of a polyglutamine tract and initiates a cascade that ultimately leads to dementia and premature death. However, neurodegeneration typically manifests in HD only in middle age, and processes linking the causative mutation to brain disease are poorly understood. Here, our objective was to elucidate further the processes that cause neurodegeneration in HD, by measuring levels of metabolites in brain regions known to undergo varying degrees of damage...
December 4, 2015: Biochemical and Biophysical Research Communications
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