Diagnose a Broad Range of Metabolic Disorders with a Single Test, Global
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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. -
Propionic Acidemia: an Extremely Rare Cause of Hemophagocytic Lymphohistiocytosis in an Infant
Case report Arch Argent Pediatr 2020;118(2):e174-e177 / e174 Propionic acidemia: an extremely rare cause of hemophagocytic lymphohistiocytosis in an infant Sultan Aydin Kökera, MD, Osman Yeşilbaşb, MD, Alper Kökerc, MD, and Esra Şevketoğlud, Assoc. Prof. ABSTRACT INTRODUCTION Hemophagocytic lymphohystiocytosis (HLH) may be primary Hemophagocytic lymphohistiocytosis (inherited/familial) or secondary to infections, malignancies, rheumatologic disorders, immune deficiency syndromes (HLH) is a life-threatening disorder in and metabolic diseases. Cases including lysinuric protein which there is uncontrolled proliferation of intolerance, multiple sulfatase deficiency, galactosemia, activated lymphocytes and histiocytes. The Gaucher disease, Pearson syndrome, and galactosialidosis have diagnosis of HLH is based on fulfilling at least previously been reported. It is unclear how the metabolites trigger HLH in metabolic diseases. A 2-month-old infant five of eight criteria (fever, splenomegaly, with lethargy, pallor, poor feeding, hepatosplenomegaly, bicytopenia, hypertriglyceridemia and/ fever and pancytopenia, was diagnosed with HLH and the or hypofibrinogenemia, hemophagocytosis, HLH-2004 treatment protocol was initiated. Analysis for low/absent natural killer cell activity, primary HLH gene mutations and metabolic screening tests were performed together; primary HLH gene mutations were hyperferritinemia, and high soluble interleukin- negative, but hyperammonemia and elevated methyl citrate 2-receptor levels). HLH includes both familial were detected. Propionic acidemia was diagnosed with tandem and reactive disease triggered by infection, mass spectrometry in neonatal dried blood spot. We report this immunologic disorder, malignancy, or drugs. case of HLH secondary to propionic acidemia. Both metabolic disorder screening tests and gene mutation analysis may be Clinical presentations of patients with primary performed simultaneously especially for early diagnosis in (familial) and secondary (reactive) HLH are infants presenting with HLH. -
United States Patent 19 11 Patent Number: 5,780,253 Subramanian Et Al
III USOO5780253A United States Patent 19 11 Patent Number: 5,780,253 Subramanian et al. (45) Date of Patent: Jul. 14, 1998 54 SCREENING METHOD FOR DETECTION OF 4.433.999 2/1984 Hyzak ....................................... 71.03 HERBCDES 4.6–552 2/1987 Anoti et al. if O3. 4,802,912 2/1989 Baker ........................................ 7/103 Inventors: Wenkiteswaran Subramanian Danville: Anne G. Toschi. Burlingame. OTHERTHER PPUBLICATION CATIONS both of Calif. Heim et al. Pesticide Biochem & Physiol; vol. 53, pp. 138-145 (1995). 73) Assignee: Sandoz Ltd., Basel. Switzerland Hatch. MD.: Phytochem. vol. 6... pp. 115 to 119, (1967). Haworth et al. J. Agric. Food Chem, vol. 38, pp. 1271-1273. 21 Appl. No.:752.990 1990. Nishimura et al: Phytochem: vol. 34, pp. 613-615. (1993). 22 Filed: Nov. 21, 1996 Primary Examiner-Louise N. Leary Related U.S. Application Data Attorney, Agent, or Firm-Lynn Marcus-Wyner: Michael P. Morris 63 Continuation of Ser. No. 434.826, May 4, 1995, abandoned. 6 57 ABSTRACT 51 Int. Cl. ............................... C12Q 1/48: C12Q 1/32: C12Q 1/37; C12O 1/00 This invention relates to novel screening methods for iden 52 U.S. Cl. ................................. 435/15:435/18: 435/26: tifying compounds that specifically inhibit a biosynthetic 435/23: 435/4, 536/23.6:536/23.2:536/24.3 pathway in plants. Enzymes which are specifically affected 536/26.11:536/26.12:536/26.13 by the novel screening method include plant purine biosyn 58 Field of Search .................................. 435/15, 8, 26, thetic pathway enzymes and particularly the enzymes 435/23 4: 536/23.6, 23.2, 24.3, 26.1, involved in the conversion of inosine monophosphate to 26.12, 26.13 adenosine monophosphate and inosine monophosphate to guanosine monophosphate. -
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 -
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. -
EXTENDED CARRIER SCREENING Peace of Mind for Planned Pregnancies
Focusing on Personalised Medicine EXTENDED CARRIER SCREENING Peace of Mind for Planned Pregnancies Extended carrier screening is an important tool for prospective parents to help them determine their risk of having a child affected with a heritable disease. In many cases, parents aren’t aware they are carriers and have no family history due to the rarity of some diseases in the general population. What is covered by the screening? Genomics For Life offers a comprehensive Extended Carrier Screening test, providing prospective parents with the information they require when planning their pregnancy. Extended Carrier Screening has been shown to detect carriers who would not have been considered candidates for traditional risk- based screening. With a simple mouth swab collection, we are able to test for over 419 genes associated with inherited diseases, including Fragile X Syndrome, Cystic Fibrosis and Spinal Muscular Atrophy. The assay has been developed in conjunction with clinical molecular geneticists, and includes genes listed in the NIH Genetic Test Registry. For a list of genes and disorders covered, please see the reverse of this brochure. If your gene of interest is not covered on our Extended Carrier Screening panel, please contact our friendly team to assist you in finding a gene test panel that suits your needs. Why have Extended Carrier Screening? Extended Carrier Screening prior to pregnancy enables couples to learn about their reproductive risk and consider a complete range of reproductive options, including whether or not to become pregnant, whether to use advanced reproductive technologies, such as preimplantation genetic diagnosis, or to use donor gametes. -
Birth Prevalence of Disorders Detectable Through Newborn Screening by Race/Ethnicity
©American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Birth prevalence of disorders detectable through newborn screening by race/ethnicity Lisa Feuchtbaum, DrPH, MPH1, Jennifer Carter, MPH2, Sunaina Dowray, MPH2, Robert J. Currier, PhD1 and Fred Lorey, PhD1 Purpose: The purpose of this study was to describe the birth prev- Conclusion: The California newborn screening data offer a alence of genetic disorders among different racial/ethnic groups unique opportunity to explore the birth prevalence of many through population-based newborn screening data. genetic dis orders across a wide spectrum of racial/ethnicity classifications. The data demonstrate that racial/ethnic subgroups Methods: Between 7 July 2005 and 6 July 2010 newborns in Cali- of the California newborn population have very different patterns fornia were screened for selected metabolic, endocrine, hemoglobin, of heritable disease expression. Determining the birth prevalence and cystic fibrosis disorders using a blood sample collected via heel of these disorders in California is a first step to understanding stick. The race and ethnicity of each newborn was self-reported by the short- and long-term medical and treatment needs faced by the mother at the time of specimen collection. affected communities, especially those groups that are impacted by Results: Of 2,282,138 newborns screened, the overall disorder detec- more severe disorders. tion rate was 1 in 500 births. The disorder with the highest prevalence Genet Med 2012:14(11):937–945 among all groups was primary congenital hypothyroidism (1 in 1,706 births). Birth prevalence for specific disorders varied widely among Key Words: birth prevalence; disorders; newborn screening; race different racial/ethnic groups. -
35 Disorders of Purine and Pyrimidine Metabolism
35 Disorders of Purine and Pyrimidine Metabolism Georges van den Berghe, M.- Françoise Vincent, Sandrine Marie 35.1 Inborn Errors of Purine Metabolism – 435 35.1.1 Phosphoribosyl Pyrophosphate Synthetase Superactivity – 435 35.1.2 Adenylosuccinase Deficiency – 436 35.1.3 AICA-Ribosiduria – 437 35.1.4 Muscle AMP Deaminase Deficiency – 437 35.1.5 Adenosine Deaminase Deficiency – 438 35.1.6 Adenosine Deaminase Superactivity – 439 35.1.7 Purine Nucleoside Phosphorylase Deficiency – 440 35.1.8 Xanthine Oxidase Deficiency – 440 35.1.9 Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency – 441 35.1.10 Adenine Phosphoribosyltransferase Deficiency – 442 35.1.11 Deoxyguanosine Kinase Deficiency – 442 35.2 Inborn Errors of Pyrimidine Metabolism – 445 35.2.1 UMP Synthase Deficiency (Hereditary Orotic Aciduria) – 445 35.2.2 Dihydropyrimidine Dehydrogenase Deficiency – 445 35.2.3 Dihydropyrimidinase Deficiency – 446 35.2.4 Ureidopropionase Deficiency – 446 35.2.5 Pyrimidine 5’-Nucleotidase Deficiency – 446 35.2.6 Cytosolic 5’-Nucleotidase Superactivity – 447 35.2.7 Thymidine Phosphorylase Deficiency – 447 35.2.8 Thymidine Kinase Deficiency – 447 References – 447 434 Chapter 35 · Disorders of Purine and Pyrimidine Metabolism Purine Metabolism Purine nucleotides are essential cellular constituents 4 The catabolic pathway starts from GMP, IMP and which intervene in energy transfer, metabolic regula- AMP, and produces uric acid, a poorly soluble tion, and synthesis of DNA and RNA. Purine metabo- compound, which tends to crystallize once its lism can be divided into three pathways: plasma concentration surpasses 6.5–7 mg/dl (0.38– 4 The biosynthetic pathway, often termed de novo, 0.47 mmol/l). starts with the formation of phosphoribosyl pyro- 4 The salvage pathway utilizes the purine bases, gua- phosphate (PRPP) and leads to the synthesis of nine, hypoxanthine and adenine, which are pro- inosine monophosphate (IMP). -
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 -
Amino Acid Disorders
471 Review Article on Inborn Errors of Metabolism Page 1 of 10 Amino acid disorders Ermal Aliu1, Shibani Kanungo2, Georgianne L. Arnold1 1Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 2Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA Contributions: (I) Conception and design: S Kanungo, GL Arnold; (II) Administrative support: S Kanungo; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: E Aliu, GL Arnold; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Georgianne L. Arnold, MD. UPMC Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Suite 1200, Pittsburgh, PA 15224, USA. Email: [email protected]. Abstract: Amino acids serve as key building blocks and as an energy source for cell repair, survival, regeneration and growth. Each amino acid has an amino group, a carboxylic acid, and a unique carbon structure. Human utilize 21 different amino acids; most of these can be synthesized endogenously, but 9 are “essential” in that they must be ingested in the diet. In addition to their role as building blocks of protein, amino acids are key energy source (ketogenic, glucogenic or both), are building blocks of Kreb’s (aka TCA) cycle intermediates and other metabolites, and recycled as needed. A metabolic defect in the metabolism of tyrosine (homogentisic acid oxidase deficiency) historically defined Archibald Garrod as key architect in linking biochemistry, genetics and medicine and creation of the term ‘Inborn Error of Metabolism’ (IEM). The key concept of a single gene defect leading to a single enzyme dysfunction, leading to “intoxication” with a precursor in the metabolic pathway was vital to linking genetics and metabolic disorders and developing screening and treatment approaches as described in other chapters in this issue.