1 a Clinical Approach to Inherited Metabolic Diseases
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Hyperammonemia in Review: Pathophysiology, Diagnosis, and Treatment
Pediatr Nephrol DOI 10.1007/s00467-011-1838-5 EDUCATIONAL REVIEW Hyperammonemia in review: pathophysiology, diagnosis, and treatment Ari Auron & Patrick D. Brophy Received: 23 September 2010 /Revised: 9 January 2011 /Accepted: 12 January 2011 # IPNA 2011 Abstract Ammonia is an important source of nitrogen and is the breakdown and catabolism of dietary and bodily proteins, required for amino acid synthesis. It is also necessary for respectively. In healthy individuals, amino acids that are not normal acid-base balance. When present in high concentra- needed for protein synthesis are metabolized in various tions, ammonia is toxic. Endogenous ammonia intoxication chemical pathways, with the rest of the nitrogen waste being can occur when there is impaired capacity of the body to converted to urea. Ammonia is important for normal animal excrete nitrogenous waste, as seen with congenital enzymatic acid-base balance. During exercise, ammonia is produced in deficiencies. A variety of environmental causes and medica- skeletal muscle from deamination of adenosine monophos- tions may also lead to ammonia toxicity. Hyperammonemia phate and amino acid catabolism. In the brain, the latter refers to a clinical condition associated with elevated processes plus the activity of glutamate dehydrogenase ammonia levels manifested by a variety of symptoms and mediate ammonia production. After formation of ammonium signs, including significant central nervous system (CNS) from glutamine, α-ketoglutarate, a byproduct, may be abnormalities. Appropriate and timely management requires a degraded to produce two molecules of bicarbonate, which solid understanding of the fundamental pathophysiology, are then available to buffer acids produced by dietary sources. differential diagnosis, and treatment approaches available. -
Effect of Propionic Acid on Fatty Acid Oxidation and U Reagenesis
Pediat. Res. 10: 683- 686 (1976) Fatty degeneration propionic acid hyperammonemia propionic acidemia liver ureagenesls Effect of Propionic Acid on Fatty Acid Oxidation and U reagenesis ALLEN M. GLASGOW(23) AND H. PET ER C HASE UniversilY of Colorado Medical Celller, B. F. SlOlillsky LaboralOries , Denver, Colorado, USA Extract phosphate-buffered salin e, harvested with a brief treatment wi th tryps in- EDTA, washed twice with ph os ph ate-buffered saline, and Propionic acid significantly inhibited "CO z production from then suspended in ph os ph ate-buffe red saline (145 m M N a, 4.15 [I-"ejpalmitate at a concentration of 10 11 M in control fibroblasts m M K, 140 m M c/, 9.36 m M PO" pH 7.4) . I n mos t cases the cells and 100 11M in methyl malonic fibroblasts. This inhibition was we re incubated in 3 ml phosph ate-bu ffered sa lin e cont aining 0.5 similar to that produced by 4-pentenoic acid. Methylmalonic acid I1Ci ll-I4Cj palm it ate (19), final concentration approximately 3 11M also inhibited ' 'C0 2 production from [V 'ejpalmitate, but only at a added in 10 II I hexane. Increasing the amount of hexane to 100 II I concentration of I mM in control cells and 5 mM in methyl malonic did not impair palmit ate ox id ation. In two experiments (Fig. 3) the cells. fibroblasts were in cub ated in 3 ml calcium-free Krebs-Ringer Propionic acid (5 mM) also inhibited ureagenesis in rat liver phosphate buffer (2) co nt ain in g 5 g/ 100 ml essent iall y fatty ac id slices when ammonia was the substrate but not with aspartate and free bovine se rum albumin (20), I mM pa lm itate, and the same citrulline as substrates. -
Newborn Screening Laboratory Manual of Services
Newborn Screening Laboratory Manual of Services Test Panel: Please see the following links for a detailed description of testing in the Newborn Screening section. Information about the Newborn Screening program is available here. Endocrine Disorders Congenital adrenal hyperplasia (CAH) Congenital hypothyroidism (TSH) Hemoglobinopathies Sickle cell disease (FS) Alpha (Barts) Sickle βeta Thalassemia (FSA) Other sickling hemoglobinopathies such as: FAS FAC FAD FAE Homozygous conditions such as: FC FD FE Metabolic Disorders Biotinidase deficiency Galactosemia Cystic fibrosis (CF) first tier screening for elevated immunoreactive trypsinogen (IRT) Cystic fibrosis second tier genetic mutation analysis on the top 4% IRT concentrations. Current alleles detected : F508del, I507del, G542X, G85E, R117H, 621+1G->T, 711+1G->T, R334W, R347P, A455E, 1717-1G->A, R560T, R553X, G551D, 1898+1G->A, 2184delA, 2789+5G->A, 3120+1G->A, R1162X, 3659delC, 3849+10kbC->T, W1282X, N1303K, IVS polyT T5/T7/T9 *Currently validating a mutation panel that includes the above alleles in addition to the following: 1078delT, Y122X, 394delTT, R347H, M1101K, S1255X, 1898+5G->T, 2183AA->G, 2307insA, Y1092X, 3876delA, 3905insT, S549N, S549R_1645A->C, S549R-1647T->G, S549R-1647T->G, V520F, A559T, 1677delTA, 2055del9->A, 2143delT, 3199del6, 406-1G->A, 935delA, D1152H, CFTRdele2, E60X, G178R, G330X, K710X, L206W, Q493X, Q890X, R1066C, R1158X, R75X, S1196X, W1089X, G1244E, G1349D, G551S, R560KT, S1251N, S1255P Amino acid disorders Phenylketonuria (PKU) / Hyperphenylalaninemia Maple -
CBS, MET Act Sheet
Newborn Screening ACT Sheet Increased Methionine Homocystinuria (CBS Deficiency) / Hypermethioninemia (MET) Differential Diagnosis: Classical homocystinuria (cystathionine β-synthase (CBS) deficiency); hypermethioninemia (MET) due to methionine adenosyltransferase I/III MAT I/III deficiency; glycine n-methyltransferase GNMT deficiency; adenosylhomocysteine hydrolase deficiency; liver disease; hyperalimentation. Condition Description: Methionine from ingested protein is normally converted to homocysteine. In classical homocystinuria due to CBS deficiency, homocysteine cannot be converted to cystathionine. As a result, the concentration of homocysteine and its precursor, methionine, will become elevated. In MAT I/III deficiency and the other hypermethioninemias, methionine is increased in the absence of, or only with, a slightly increased level of homocysteine. You Should Take the Following IMMEDIATE Actions • Contact family to inform them of the newborn screening result and ascertain clinical status. • Consult with pediatric metabolic specialist. (See attached list.) • Evaluate the newborn with attention to liver disease and refer as appropriate. • Initiate confirmatory/diagnostic tests in consultation with metabolic specialist. • Initial testing: Plasma quantitative amino acids and plasma total homocysteine. • Repeat newborn screen if second screen has not been done. • Educate family about homocystinuria and its management as appropriate. • Report findings to newborn screening program. Diagnostic Evaluation: Plasma quantitative amino -
Disorders Included in the Newborn Screening Panel Disorders
Disorders Included in the Newborn Screening Panel Disorders Detected by Tandem Mass Spectrometry Acylcarnitine Profile Amino Acid Profile Fatty Acid Oxidation Disorders Amino Acid Disorders Carnitine/Acylcarnitine Translocase Deficiency Argininemia 1 Carnitine Palmitoyl Transferase Deficiency Type I Argininosuccinic Aciduria 1 3-Hydroxy Long Chain Acyl-CoA Dehydrogenase 5-Oxoprolinuria 1 Deficiency Carbamoylphosphate Synthetase Deficiency 1 2,4-Dienoyl-CoA Reductase Deficiency Citrullinemia Medium Chain Acyl-CoA Dehydrogenase Deficiency Homocystinuria Multiple Acyl-CoA Dehydrogenase Deficiency Hypermethioninemia Neonatal Carnitine Palmitoyl Transferase Deficiency Hyperammonemia, Hyperornithinemia, Homocitrullinuria Type II Syndrome1 1 Short Chain Acyl-CoA Dehydrogenase Deficiency Hyperornithinemia with Gyral Atrophy Short Chain Hydroxy Acyl-CoA Dehydrogenase Maple Syrup Urine Disease Deficiency Phenylketonuria Trifunctional Protein Deficiency Classical/Hyperphenylalaninemia Very Long Chain Acyl-CoA Dehydrogenase Deficiency Biopterin Cofactor Deficiencies Tyrosinemia Organic Acid Disorders Transient Neonatal Tyrosinemia 2 Tyrosinemia Type I 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency Tyrosinemia Type II Glutaric Acidemia Type I Tyrosinemia Type III Isobutyryl-CoA Dehydrogenase Deficiency Isovaleric Acidemia 2-Methylbutyryl-CoA Dehydrogenase Deficiency 3-Methylcrotonyl-CoA Carboxylase Deficiency Other Observations 3-Methylglutaconyl-CoA Hydratase Deficiency Methylmalonic Acidemias Hyperalimentation Methylmalonyl-CoA Mutase Deficiency -
Incidence of Inborn Errors of Metabolism by Expanded Newborn
Original Article Journal of Inborn Errors of Metabolism & Screening 2016, Volume 4: 1–8 Incidence of Inborn Errors of Metabolism ª The Author(s) 2016 DOI: 10.1177/2326409816669027 by Expanded Newborn Screening iem.sagepub.com in a Mexican Hospital Consuelo Cantu´-Reyna, MD1,2, Luis Manuel Zepeda, MD1,2, Rene´ Montemayor, MD3, Santiago Benavides, MD3, Hector´ Javier Gonza´lez, MD3, Mercedes Va´zquez-Cantu´,BS1,4, and Hector´ Cruz-Camino, BS1,5 Abstract Newborn screening for the detection of inborn errors of metabolism (IEM), endocrinopathies, hemoglobinopathies, and other disorders is a public health initiative aimed at identifying specific diseases in a timely manner. Mexico initiated newborn screening in 1973, but the national incidence of this group of diseases is unknown or uncertain due to the lack of large sample sizes of expanded newborn screening (ENS) programs and lack of related publications. The incidence of a specific group of IEM, endocrinopathies, hemoglobinopathies, and other disorders in newborns was obtained from a Mexican hospital. These newborns were part of a comprehensive ENS program at Ginequito (a private hospital in Mexico), from January 2012 to August 2014. The retrospective study included the examination of 10 000 newborns’ results obtained from the ENS program (comprising the possible detection of more than 50 screened disorders). The findings were the following: 34 newborns were confirmed with an IEM, endocrinopathies, hemoglobinopathies, or other disorders and 68 were identified as carriers. Consequently, the estimated global incidence for those disorders was 3.4 in 1000 newborns; and the carrier prevalence was 6.8 in 1000. Moreover, a 0.04% false-positive rate was unveiled as soon as diagnostic testing revealed negative results. -
Mutation of the Fumarase Gene in Two Siblings with Progressive Encephalopathy and Fumarase Deficiency T
Mutation of the Fumarase Gene in Two Siblings with Progressive Encephalopathy and Fumarase Deficiency T. Bourgeron,* D. Chretien,* J. Poggi-Bach, S. Doonan,' D. Rabier,* P. Letouze,I A. Munnich,* A. R6tig,* P. Landneu,* and P. Rustin* *Unite de Recherches sur les Handicaps Genetiques de l'Enfant, INSERM U393, Departement de Pediatrie et Departement de Biochimie, H6pital des Enfants-Malades, 149, rue de Sevres, 75743 Paris Cedex 15, France; tDepartement de Pediatrie, Service de Neurologie et Laboratoire de Biochimie, Hopital du Kremlin-Bicetre, France; IFaculty ofScience, University ofEast-London, UK; and IService de Pediatrie, Hopital de Dreux, France Abstract chondrial enzyme (7). Human tissue fumarase is almost We report an inborn error of the tricarboxylic acid cycle, fu- equally distributed between the mitochondria, where the en- marase deficiency, in two siblings born to first cousin parents. zyme catalyzes the reversible hydration of fumarate to malate They presented with progressive encephalopathy, dystonia, as a part ofthe tricarboxylic acid cycle, and the cytosol, where it leucopenia, and neutropenia. Elevation oflactate in the cerebro- is involved in the metabolism of the fumarate released by the spinal fluid and high fumarate excretion in the urine led us to urea cycle. The two isoenzymes have quite homologous struc- investigate the activities of the respiratory chain and of the tures. In rat liver, they differ only by the acetylation of the Krebs cycle, and to finally identify fumarase deficiency in these NH2-terminal amino acid of the cytosolic form (8). In all spe- two children. The deficiency was profound and present in all cies investigated so far, the two isoenzymes have been found to tissues investigated, affecting the cytosolic and the mitochon- be encoded by a single gene (9,10). -
Inherited Metabolic Disease
Inherited metabolic disease Dr Neil W Hopper SRH Areas for discussion • Introduction to IEMs • Presentation • Initial treatment and investigation of IEMs • Hypoglycaemia • Hyperammonaemia • Other presentations • Management of intercurrent illness • Chronic management Inherited Metabolic Diseases • Result from a block to an essential pathway in the body's metabolism. • Huge number of conditions • All rare – very rare (except for one – 1:500) • Presentation can be non-specific so index of suspicion important • Mostly AR inheritance – ask about consanguinity Incidence (W. Midlands) • Amino acid disorders (excluding phenylketonuria) — 18.7 per 100,000 • Phenylketonuria — 8.1 per 100,000 • Organic acidemias — 12.6 per 100,000 • Urea cycle diseases — 4.5 per 100,000 • Glycogen storage diseases — 6.8 per 100,000 • Lysosomal storage diseases — 19.3 per 100,000 • Peroxisomal disorders — 7.4 per 100,000 • Mitochondrial diseases — 20.3 per 100,000 Pathophysiological classification • Disorders that result in toxic accumulation – Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects) – Disorders of carbohydrate intolerance – Lysosomal storage disorders • Disorders of energy production, utilization – Fatty acid oxidation defects – Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) – Mitochondrial disorders – Peroxisomal disorders IMD presentations • ? IMD presentations • Screening – MCAD, PKU • Progressive unexplained neonatal -
Regulation of Skeletal Muscle Glucose Transport and Glucose Metabolism by Exercise Training
nutrients Review Regulation of Skeletal Muscle Glucose Transport and Glucose Metabolism by Exercise Training Parker L. Evans 1,2,3, Shawna L. McMillin 1,2,3 , Luke A. Weyrauch 1,2,3 and Carol A. Witczak 1,2,3,4,* 1 Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA; [email protected] (P.L.E.); [email protected] (S.L.M.); [email protected] (L.A.W.) 2 Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA 3 East Carolina Diabetes & Obesity Institute, East Carolina University, Greenville, NC 27834, USA 4 Department of Biochemistry & Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA * Correspondence: [email protected]; Tel.: +1-252-744-1224 Received: 8 September 2019; Accepted: 8 October 2019; Published: 12 October 2019 Abstract: Aerobic exercise training and resistance exercise training are both well-known for their ability to improve human health; especially in individuals with type 2 diabetes. However, there are critical differences between these two main forms of exercise training and the adaptations that they induce in the body that may account for their beneficial effects. This article reviews the literature and highlights key gaps in our current understanding of the effects of aerobic and resistance exercise training on the regulation of systemic glucose homeostasis, skeletal muscle glucose transport and skeletal muscle glucose metabolism. Keywords: aerobic exercise; blood glucose; functional overload; GLUT; hexokinase; insulin resistance; resistance exercise; SGLT; type 2 diabetes; weightlifting 1. Introduction Exercise training is defined as planned bouts of physical activity which repeatedly occur over a duration of time lasting from weeks to years. -
Management of Liver Complications in Sickle Cell Disease
| MANAGEMENT OF SICKLE CELL DISEASE COMPLICATIONS BEYOND ACUTE CHEST | Management of liver complications in sickle cell disease Abid R. Suddle Institute of Liver Studies, King’s College Hospital, London, United Kingdom Downloaded from https://ashpublications.org/hematology/article-pdf/2019/1/345/1546038/hem2019000037c.pdf by DEUSCHE ZENTRALBIBLIOTHEK FUER MEDIZIN user on 24 December 2019 Liver disease is an important cause of morbidity and mortality in patients with sickle cell disease (SCD). Despite this, the natural history of liver disease is not well characterized and the evidence basis for specific therapeutic intervention is not robust. The spectrum of clinical liver disease encountered includes asymptomatic abnormalities of liver function; acute deteriorations in liver function, sometimes with a dramatic clinical phenotype; and decompensated chronic liver disease. In this paper, the pathophysiology and clinical presentation of patients with acute and chronic liver disease will be outlined. Advice will be given regarding initial assessment and investigation. The evidence for specific medical and surgical interventions will be reviewed, and management recommendations made for each specific clinical presen- tation. The potential role for liver transplantation will be considered in detail. S (HbS) fraction was 80%. The patient was managed as having an Learning Objectives acute sickle liver in the context of an acute vaso-occlusive crisis. • Gain an understanding of the wide variety of liver pathology Treatment included IV fluids, antibiotics, analgesia, and exchange and disease encountered in patients with SCD blood transfusion (EBT) with the aim of reducing the HbS fraction • Develop a logical approach to evaluate liver dysfunction and to ,30% to 40%. With this regimen, symptoms and acute liver dys- disease in patients with SCD function resolved, but bilirubin did not return to the preepisode baseline. -
Peripheral Neuropathy in Complex Inherited Diseases: an Approach To
PERIPHERAL NEUROPATHY IN COMPLEX INHERITED DISEASES: AN APPROACH TO DIAGNOSIS Rossor AM1*, Carr AS1*, Devine H1, Chandrashekar H2, Pelayo-Negro AL1, Pareyson D3, Shy ME4, Scherer SS5, Reilly MM1. 1. MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK. 2. Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK. 3. Unit of Neurological Rare Diseases of Adulthood, Carlo Besta Neurological Institute IRCCS Foundation, Milan, Italy. 4. Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA 5. Department of Neurology, University of Pennsylvania, Philadelphia, PA 19014, USA. * These authors contributed equally to this work Corresponding author: Mary M Reilly Address: MRC Centre for Neuromuscular Diseases, 8-11 Queen Square, London, WC1N 3BG, UK. Email: [email protected] Telephone: 0044 (0) 203 456 7890 Word count: 4825 ABSTRACT Peripheral neuropathy is a common finding in patients with complex inherited neurological diseases and may be subclinical or a major component of the phenotype. This review aims to provide a clinical approach to the diagnosis of this complex group of patients by addressing key questions including the predominant neurological syndrome associated with the neuropathy e.g. spasticity, the type of neuropathy, and the other neurological and non- neurological features of the syndrome. Priority is given to the diagnosis of treatable conditions. Using this approach, we associated neuropathy with one of three major syndromic categories - 1) ataxia, 2) spasticity, and 3) global neurodevelopmental impairment. Syndromes that do not fall easily into one of these three categories can be grouped according to the predominant system involved in addition to the neuropathy e.g. -
Summary Current Practices Report
18/10/2011 EU Tender “Evaluation of population newborn screening practices for rare disorders in Member States of the European Union” Short Executive Summary of the Report on the practices of newborn screening for rare disorders implemented in Member States of the European Union, Candidate, Potential Candidate and EFTA Countries Authors: Peter Burgard1, Martina Cornel2, Francesco Di Filippo4, Gisela Haege1, Georg F. Hoffmann1, Martin Lindner1, J. Gerard Loeber3, Tessel Rigter2, Kathrin Rupp1, 4 Domenica Taruscio4,Luciano Vittozzi , Stephanie Weinreich2 1 Department of Pediatrics , University Hospital - Heidelberg (DE) 2 VU University Medical Centre - Amsterdam (NL) 3 RIVM - Bilthoven (NL) 4 National Centre for Rare Diseases - Rome (IT) The opinions expressed in this document are those of the Contractor only and do not represent the official position of the Executive Agency for Health and Consumers. This work is funded by the European Union with a grant of Euro 399755 (Contract number 2009 62 06 of the Executive Agency for Health and Consumers) 1 18/10/2011 Abbreviations 3hmg 3-Hydroxy-3-methylglutaric aciduria 3mcc 3-Methylcrotonyl-CoA carboxylase deficiency/3-Methylglutacon aciduria/2-methyl-3-OH- butyric aciduria AAD Disorders of amino acid metabolism arg Argininemia asa Argininosuccinic aciduria bio Biotinidase deficiency bkt Beta-ketothiolase deficiency btha S, beta 0-thalassemia cah Congenital adrenal hyperplasia cf Cystic fibrosis ch Primary congenital hypothyroidism citI Citrullinemia type I citII Citrullinemia type II cpt I Carnitin