What Disorders Are Screened for by the Newborn Screen?
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Cystinosis, Has Been Reported Previomly in 3 Patients Using (1
, PKU GENE - WSSIBLE CAUSE OF NON-SPECIFIC UENTAL RE- RARE PHENOTYPES OF PLACENTAL ALKALINE PHOSPHATASE: AN 523 TARDATION. Atsuko Fujimoto and Samuel P. Bes-n, ANALYSIS OF RELATIONSHIPS WITH SOME NEONATAL AND b USC Hed. Sch., Dept. Pediatrics, Los Angeles MATERNAL VARIABLES. F. Gloria-Bottini, A. Polzonetti, The Justification Hypothesis (J. Ped. 81:834, 1972) proposes . Bentivoglia, P. Lucarelli and E. Bottini (Spon. by C.D. Cook). that deficiencies in non-essential amino acids might cause mental Jniv. of Camerino, Dept. of Genetics and Computer Center and retardation. The mother heterozygous for synthesis of any one of Jniv. of Rome, Dept. of Pediatrics. the non-essential amino acids would deprive her fetus partially The large number (>15) and frequency (-2%) of rare placental and the heterozygous or homozygous fetus would be more or less alkaline phosphatase (PI) alleles represent a very special case unable to make up for the deficiency. Berman and Ford (Lancet i: among polymorphic enzymes. Since the PI gene is active only dur- 767, 1977) showed that such concatenation of heterozygous mother ing intrauterine life, the allelic diversity and its maintenance and heterozygous fetus is associated with significantly lower IQ. nay be connected with intrauterine environment and with fetal Our own wark has verified this finding. The possibility that development. 1700 newborn infants ( 1271 Caucasians, 337 Negroes heterozygosity for PKU in mother and fetus might be a cause of a and 92 Puerto Ricans), collected at Yale-New Haven Hospital from 1arq.e amount of "non-specific" mental retardation was tested by 1968-1971, were studied. An analysis of the relationship between looking for associated heterozygosity for PKU in mother and child rare PI phenotype and the following 14variableswas carried out: among.12 families in a genetic clinic. -
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 -
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. -
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. -
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 105
AMINO ACID DISORDERS 105 Massaro, A. S. (1995). Trypanosomiasis. In Guide to Clinical tions in biological fluids relatively easy. These Neurology (J. P. Mohrand and J. C. Gautier, Eds.), pp. 663– analyzers separate amino acids either by ion-ex- 667. Churchill Livingstone, New York. Nussenzweig, V., Sonntag, R., Biancalana, A., et al. (1953). Ac¸a˜o change chromatography or by high-pressure liquid de corantes tri-fenil-metaˆnicos sobre o Trypanosoma cruzi in chromatography. The results are plotted as a graph vitro: Emprego da violeta de genciana na profilaxia da (Fig. 1). The concentration of each amino acid can transmissa˜o da mole´stia de chagas por transfusa˜o de sangue. then be calculated from the size of the corresponding O Hospital (Rio de Janeiro) 44, 731–744. peak on the graph. Pagano, M. A., Segura, M. J., DiLorenzo, G. A., et al. (1999). Cerebral tumor-like American trypanosomiasis in Most amino acid disorders can be diagnosed by acquired immunodeficiency syndrome. Ann. Neurol. 45, measuring the concentrations of amino acids in 403–406. blood plasma; however, some disorders of amino Rassi, A., Trancesi, J., and Tranchesi, B. (1982). Doenc¸ade acid transport are more easily recognized through the Chagas. In Doenc¸as Infecciosas e Parasita´rias (R. Veroesi, Ed.), analysis of urine amino acids. Therefore, screening 7th ed., pp. 674–712. Guanabara Koogan, Sa˜o Paulo, Brazil. Spina-Franc¸a, A., and Mattosinho-Franc¸a, L. C. (1988). for amino acid disorders is best done using both South American trypanosomiasis (Chagas’ disease). In blood and urine specimens. Occasionally, analysis of Handbook of Clinical Neurology (P. -
Arginine-Provider-Fact-Sheet.Pdf
Arginine (Urea Cycle Disorder) Screening Fact Sheet for Health Care Providers Newborn Screening Program of the Oklahoma State Department of Health What is the differential diagnosis? Argininemia (arginase deficiency, hyperargininemia) What are the characteristics of argininemia? Disorders of arginine metabolism are included in a larger group of disorders, known as urea cycle disorders. Argininemia is an autosomal recessive inborn error of metabolism caused by a defect in the final step in the urea cycle. Most infants are born to parents who are both unknowingly asymptomatic carriers and have NO known history of a urea cycle disorder in their family. The incidence of all urea cycle disorders is estimated to be about 1:8,000 live births. The true incidence of argininemia is not known, but has been estimated between 1:350,000 and 1:1,000,000. Argininemia is usually asymptomatic in the neonatal period, although it can present with mild to moderate hyperammonemia. Untreated, argininemia usually progresses to severe spasticity, loss of ambulation, severe cognitive and intellectual disabilities and seizures Lifelong treatment includes a special diet, and special care during times of illness or stress. What is the screening methodology for argininemia? 1. An amino acid profile by Tandem Mass Spectrometry (MS/MS) is performed on each filter paper. 2. Arginine is the primary analyte. What is an in-range (normal) screen result for arginine? Arginine less than 100 mol/L is NOT consistent with argininemia. See Table 1. TABLE 1. In-range Arginine Newborn Screening Results What is an out-of-range (abnormal) screen for arginine? Arginine > 100 mol/L requires further testing. -
Novel Insights Into the Pathophysiology of Kidney Disease in Methylmalonic Aciduria
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 Novel Insights into the Pathophysiology of Kidney Disease in Methylmalonic Aciduria Schumann, Anke Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-148531 Dissertation Published Version Originally published at: Schumann, Anke. Novel Insights into the Pathophysiology of Kidney Disease in Methylmalonic Aciduria. 2017, University of Zurich, Faculty of Medicine. Novel Insights into the Pathophysiology of Kidney Disease in Methylmalonic Aciduria Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Anke Schumann aus Deutschland Promotionskommission Prof. Dr. Olivier Devuyst (Vorsitz und Leitung der Dissertation) Prof. Dr. Matthias R. Baumgartner Prof. Dr. Stefan Kölker Zürich, 2017 DECLARATION I hereby declare that the presented work and results are the product of my own work. Contributions of others or sources used for explanations are acknowledged and cited as such. This work was carried out in Zurich under the supervision of Prof. Dr. O. Devuyst and Prof. Dr. M.R. Baumgartner from August 2012 to August 2016. Peer-reviewed publications presented in this work: Haarmann A, Mayr M, Kölker S, Baumgartner ER, Schnierda J, Hopfer H, Devuyst O, Baumgartner MR. Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up. Mol Genet Metab. 2013 Dec;110(4):472-6. doi: 10.1016/j.ymgme.2013.08.021. Epub 2013 Sep 17. Schumann A, Luciani A, Berquez M, Tokonami N, Debaix H, Forny P, Kölker S, Diomedi Camassei F, CB, MK, Faresse N, Hall A, Ziegler U, Baumgartner M and Devuyst O. -
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