DOCSLIB.ORG

Included in Newborn Screening Panels

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Included in Newborn Screening Panels SUPPLEMENT ARTICLE Naming and Counting Disorders (Conditions) Included in Newborn Screening Panels Lawrence Sweetman, PhDa, David S. Millington, PhDb, Bradford L. Therrell, PhDc, W. Harry Hannon, PhDd, Bradley Popovich, PhDe, Michael S. Watson, PhDf, Marie Y. Mann, MD, MPHg, Michele A. Lloyd-Puryear, MD, PhDg, Peter C. van Dyck, MD, MPHg aInstitute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas; bBiochemical Genetics Laboratory, Duke University, Research Triangle Park, North Carolina; cNational Newborn Screening and Genetics Resource Center, Austin, Texas; dNewborn Screening Branch, Centers for Disease Control and Prevention, Atlanta, Georgia; eSirius Genomics Inc, Vancouver, British Columbia, Canada; fAmerican College of Medical Genetics, Washington, DC; gMaternal and Child Health Bureau, Health Resources and Services Administration, Washington, DC The authors have indicated they have no financial relationships relevant to this article to disclose. ABSTRACT The rapid introduction of new technologies for newborn screening is affecting decisions about the disorders (conditions) that are required or offered as an option through public and private newborn screening. An American College of Medical www.pediatrics.org/cgi/doi/10.1542/ peds.2005-2633J Genetics report to the Health Resources and Services Administration summarized doi:10.1542/peds.2005-2633J an extensive effort by a group of experts, with diverse expertise within the The opinions stated herein are those of the newborn screening system, to determine a process for selecting a uniform panel of authors and not necessarily those of the newborn screening disorders. The expert panel did not propose a mechanism for Centers for Disease Control and Prevention, the Health Resources and Services counting or naming conditions. Differences in the nomenclature used to identify Administration, or the Department of disorders have resulted in difficulties in developing a consensus listing and count- Health and Human Services. ing scheme for the disorders in the recommended uniform panel. We suggest a Key Words system of nomenclature that correlates the screening panel of disorders recom- newborn screening, disorders, nomenclature mended in the American College of Medical Genetics report with the screening Abbreviations analyte and accepted standardized nomenclature. This nomenclature system is ACMG—American College of Medical proposed to remove ambiguity and to increase national uniformity in naming and Genetics MS/MS—tandem mass spectrometry counting screening disorders. Accepted for publication Dec 27, 2005 Address correspondence to Lawrence Sweetman, PhD, Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm St, Dallas, TX 75226. E-mail: [email protected] . PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275); published in the public domain by the American Academy of Pediatrics S308 PEDIATRICS Volume 117, Number 5, May 2006 Downloaded from www.aappublications.org/news by guest on September 30, 2021 HE RAPID INTRODUCTION of new technologies for ferent analyte, from which more information can be Tnewborn screening is affecting decisions about the obtained to improve the overall identification process. In disorders (conditions) that are required or offered as an most cases, newborn screening involves a single analysis option through public and private newborn screening. that detects a single marker; in recent years, however, There is general agreement that it is preferable to have a newer technologies have allowed for the simultaneous uniform panel of disorders required and offered nation- detection of multiple analytes through a single analytical wide, rather than the variability among programs that process. In newborn screening, multianalyte analyses exists currently. To provide direction for national uni- have included flow chemical assays for some metabolic formity, the American College of Medical Genetics conditions, electrophoretic and chromatographic assays (ACMG)1 recently recommended a decision-making for hemoglobinopathies, and, more recently, MS/MS as- process and a resultant core panel of disorders to be says for metabolic conditions. Because of the ability of considered for adoption and implementation by all US MS/MS to detect markers that may identify Ͼ1 disorder, newborn screening programs. naming and counting the disorders associated with Differences in the nomenclature used to identify dis- MS/MS technology have been particularly challenging. orders, sometimes confounded by multiple clinical vari- The primary analytes detected through MS/MS new- ations, have resulted in difficulties in developing a con- born screening and the associated disorders are listed in sensus listing and counting scheme for the disorders in Tables 1 and 2, which illustrate the potential breadth of the recommended uniform panel. For example, confu- the naming and counting difficulties. Perhaps the sim- sion results from choosing either the name of the disor- plest description of the spectrum of disorders detectable der, the name of the analyte deficiency, or the name of through MS/MS newborn screening, which identifies the screening analytes in a nonsystematic way. Counting multiple amino acid and acylcarnitine analytes, is the disorders creates even more confusion, because multiple phrase “MS/MS-detectable disorders of amino acid, or- variations of a disorder sometimes are counted in differ- ganic acid, and fatty acid metabolism.” However, many, ent ways or are not counted at all. The naming and including some physicians, legislators, and parents, seem counting problem is especially apparent with multiana- to prefer a specific list of newborn screening disorders. lyte test systems, such as tandem mass spectrometry As a consequence, there has been a competition among (MS/MS) tests for biochemical disorders, that detect si- screening programs (public and private) to offer the multaneously large numbers of different analytes (and largest number of screening disorders. To some extent, therefore disorders) in a single assay from a single dried this has been driven by the consumer perception that blood spot punch.2,3 more is better. Therefore, whereas some newborn We suggest a system of nomenclature that correlates screening programs report screening panels that detect the screening panel of disorders recommended in the 25 to 35 disorders,4,5 others report detecting Ͼ50 disor- ACMG report with the screening analytes and accepted ders6 by using similar systems and screening for the same standardized nomenclature. This classification system analytes. Also, misleading information about the num- would require general use in the newborn screening and ber of disorders covered by a test panel occurs when the subspecialty communities to become a consensus prod- number of disorders is inflated by counting disorder uct. Standardization of screening panels, including no- variants, while still failing to test for all disorders in the menclature, screening methods, and case definitions, ACMG recommended panel.7 The difference arises from would improve the quality of reported data. Good data a lack of uniformity in naming and counting disorders. quality is necessary for learning more about the natural history of the disorders, validating the utility of the screen- ACMG Report ing strategy, encouraging screening uniformity, and pro- The ACMG report1 summarized an extensive effort by a viding for more-uniform program quality assurance. We group of experts with diverse expertise within the new- also identify and comment on concerns related to the fact born screening system to determine a process for select- that some disorders listed in the ACMG report have not yet ing a uniform panel of newborn screening disorders. been identified through newborn screening, although the This expert group recognized that quantification and analytical procedure has been used to detect the disorder categorization of newborn screening disorders are im- among older patients in diagnostic laboratory settings. perfect and inconsistent and, until they are standardized, there will continue to be confusion about the extent of METHODS screening in individual programs and throughout the Background nation. The group recommended a common nomencla- Newborn screening laboratory testing procedures do not ture for the objective and scientifically valid screening identify disorders specifically; rather, they identify bio- test panel described. chemical markers (analytes) that are related to the dis- The ACMG expert group reviewed and modified tra- orders in question. In some cases, a second analytical ditional selection criteria for screening disorders,8 which process performed with the same sample detects a dif- originated in the 1960s and were established on the basis SUPPLEMENT S309 Downloaded from www.aappublications.org/news by guest on September 30, 2021 TABLE 1 Nomenclature for Conditions Included in the ACMG Recommended Uniform Panel for Newborn Screening Programs Condition/Disorder ACMG Code Primary Preferred Screening Analyte/Biomarker Strategy Endocrine disorders Thyroid disorders Primary congenital hypothyroidism CH T4 and TSH T4 and TSH immunoassay Disorders of adrenal steroidogenesis Congenital adrenal hyperplasia (MIM 201910) (steroid 21-hydroxylase CAH 17-OHP 17-OHP immunoassay deficiency ͓EC 1.14.99.10͔), salt-wasting, simple virilizing, or nonclassic Metabolic disorders Organic acid disorders Acylcarnitines by MS/MS Propionic acidemia (MIM 606054) (propionyl-CoA carboxylase deficiency PROPa C3
Load more

Recommended publications
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • ATP-Citrate Lyase Has an Essential Role in Cytosolic Acetyl-Coa Production in Arabidopsis Beth Leann Fatland Iowa State University
    Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 2002 ATP-citrate lyase has an essential role in cytosolic acetyl-CoA production in Arabidopsis Beth LeAnn Fatland Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Molecular Biology Commons, and the Plant Sciences Commons Recommended Citation Fatland, Beth LeAnn, "ATP-citrate lyase has an essential role in cytosolic acetyl-CoA production in Arabidopsis " (2002). Retrospective Theses and Dissertations. 1218. https://lib.dr.iastate.edu/rtd/1218 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. ATP-citrate lyase has an essential role in cytosolic acetyl-CoA production in Arabidopsis by Beth LeAnn Fatland A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Plant Physiology Program of Study Committee: Eve Syrkin Wurtele (Major Professor) James Colbert Harry Homer Basil Nikolau Martin Spalding Iowa State University Ames, Iowa 2002 UMI Number: 3158393 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted.
    [Show full text]
  • Counsyl Foresight™ Carrier Screen Disease List
    COUNSYL FORESIGHT™ CARRIER SCREEN DISEASE LIST The Counsyl Foresight Carrier Screen focuses on serious, clinically-actionable, and prevalent conditions to ensure you are providing meaningful information to your patients. 11-Beta-Hydroxylase- Bardet-Biedl Syndrome, Congenital Disorder of Galactokinase Deficiency Deficient Congenital Adrenal BBS1-Related (BBS1) Glycosylation, Type Ic (ALG6) (GALK1) Hyperplasia (CYP11B1) Bardet-Biedl Syndrome, Congenital Finnish Nephrosis Galactosemia (GALT ) 21-Hydroxylase-Deficient BBS10-Related (BBS10) (NPHS1) Gamma-Sarcoglycanopathy Congenital Adrenal Bardet-Biedl Syndrome, Costeff Optic Atrophy (SGCG) Hyperplasia (CYP21A2)* BBS12-Related (BBS12) Syndrome (OPA3) Gaucher Disease (GBA)* 6-Pyruvoyl-Tetrahydropterin Bardet-Biedl Syndrome, Cystic Fibrosis GJB2-Related DFNB1 Synthase Deficiency (PTS) BBS2-Related (BBS2) (CFTR) Nonsyndromic Hearing Loss ABCC8-Related Beta-Sarcoglycanopathy and Deafness (including two Cystinosis (CTNS) Hyperinsulinism (ABCC8) (including Limb-Girdle GJB6 deletions) (GJB2) Muscular Dystrophy, Type 2E) D-Bifunctional Protein Adenosine Deaminase GLB1-Related Disorders (SGCB) Deficiency (HSD17B4) Deficiency (ADA) (GLB1) Biotinidase Deficiency (BTD) Delta-Sarcoglycanopathy Adrenoleukodystrophy: GLDC-Related Glycine (SGCD) X-Linked (ABCD1) Bloom Syndrome (BLM) Encephalopathy (GLDC) Alpha Thalassemia (HBA1/ Calpainopathy (CAPN3) Dysferlinopathy (DYSF) Glutaric Acidemia, Type 1 HBA2)* Canavan Disease Dystrophinopathies (including (GCDH) (ASPA) Alpha-Mannosidosis Duchenne/Becker Muscular
    [Show full text]
  • 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.
    [Show full text]
  • Child Neurology: Hereditary Spastic Paraplegia in Children S.T
    RESIDENT & FELLOW SECTION Child Neurology: Section Editor Hereditary spastic paraplegia in children Mitchell S.V. Elkind, MD, MS S.T. de Bot, MD Because the medical literature on hereditary spastic clinical feature is progressive lower limb spasticity B.P.C. van de paraplegia (HSP) is dominated by descriptions of secondary to pyramidal tract dysfunction. HSP is Warrenburg, MD, adult case series, there is less emphasis on the genetic classified as pure if neurologic signs are limited to the PhD evaluation in suspected pediatric cases of HSP. The lower limbs (although urinary urgency and mild im- H.P.H. Kremer, differential diagnosis of progressive spastic paraplegia pairment of vibration perception in the distal lower MD, PhD strongly depends on the age at onset, as well as the ac- extremities may occur). In contrast, complicated M.A.A.P. Willemsen, companying clinical features, possible abnormalities on forms of HSP display additional neurologic and MRI abnormalities such as ataxia, more significant periph- MD, PhD MRI, and family history. In order to develop a rational eral neuropathy, mental retardation, or a thin corpus diagnostic strategy for pediatric HSP cases, we per- callosum. HSP may be inherited as an autosomal formed a literature search focusing on presenting signs Address correspondence and dominant, autosomal recessive, or X-linked disease. reprint requests to Dr. S.T. de and symptoms, age at onset, and genotype. We present Over 40 loci and nearly 20 genes have already been Bot, Radboud University a case of a young boy with a REEP1 (SPG31) mutation. Nijmegen Medical Centre, identified.1 Autosomal dominant transmission is ob- Department of Neurology, PO served in 70% to 80% of all cases and typically re- Box 9101, 6500 HB, Nijmegen, CASE REPORT A 4-year-old boy presented with 2 the Netherlands progressive walking difficulties from the time he sults in pure HSP.
    [Show full text]
  • 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
    [Show full text]
  • A Polyketoacyl-Coa Thiolase-Dependent Pathway for the Synthesis of Polyketide Backbones
    ARTICLES https://doi.org/10.1038/s41929-020-0471-8 A polyketoacyl-CoA thiolase-dependent pathway for the synthesis of polyketide backbones Zaigao Tan1,3, James M. Clomburg1,2, Seokjung Cheong1, Shuai Qian1 and Ramon Gonzalez 1,2 ✉ Polyketides found in nature originate from backbones synthesized through iterative decarboxylative Claisen condensations catalysed by polyketide synthases (PKSs). However, PKSs suffer from complicated architecture, energy inefficiencies, complex regulation, and competition with essential metabolic pathways for extender unit malonyl-CoA, all combining to limit the flux of polyketide biosynthesis. Here we show that certain thiolases, which we term polyketoacyl-CoA thiolases (PKTs), catalyse polyketide backbone formation via iterative non-decarboxylative Claisen condensations, hence offering a synthetic and effi- cient alternative to PKSs. We show that PKTs can synthesize polyketide backbones for representative lactone, alkylresorcinolic acid, alkylresorcinol, hydroxybenzoic acid and alkylphenol polyketide families, and elucidate the basic catalytic mechanism and structural features enabling this previously unknown activity. PKT-catalysed reactions offer a route to polyketide formation that leverages the simple architecture of thiolases to achieve higher ATP efficiencies and reduced competition with essential metabolic pathways, all of which circumvent intrinsic inefficiencies of PKSs for polyketide product synthesis. olyketides represent a large class of secondary metabolites that Here we show that enzymes other
    [Show full text]
  • 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.
    [Show full text]
  • WO 2013/180584 Al 5 December 2013 (05.12.2013) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/180584 Al 5 December 2013 (05.12.2013) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12N 1/21 (2006.01) C12N 15/74 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C12N 15/52 (2006.01) C12P 5/02 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, C12N 15/63 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/NZ20 13/000095 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, (22) International Filing Date: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 4 June 2013 (04.06.2013) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 61/654,412 1 June 2012 (01 .06.2012) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant: LANZATECH NEW ZEALAND LIMITED MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, [NZ/NZ]; 24 Balfour Road, Parnell, Auckland, 1052 (NZ).
    [Show full text]