DOCSLIB.ORG

Defect in Pyruvoyl-Tetrahydropterin Synthase

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Defect in Pyruvoyl-Tetrahydropterin Synthase Defect in pyruvoyl-tetrahydropterin synthase Author: Professor Jean-Louis Dhondt1 Creation Date: April 2001 Updates: May 2003 February 2005 Scientific Editor: Professor Jean-Marie Saudubray 1Centre régional de dépistage néonatal, 68 Rue Sylvere Verhulst, 59000 Lille, France. [email protected] Abstract Keywords Disease name and synonyms Excluded diseases Diagnostic criteria/definition Differential diagnosis Prevalence Clinical description Management including treatment Diagnostic methods Genetic counseling Antenatal diagnosis References Abstract 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, an autosomal recessive genetic disorder, is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. Not only does tetrahydrobiopterin deficiency cause hyperphenylalaninemia, it is also responsible for defective neurotransmission of monoamines because of malfunctioning tyrosine and tryptophan hydroxylases, both tetrahydrobiopterin-dependent hydroxylases. PTPS deficiency should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when hyperphenylalaninemia is moderate. The most effective way to diagnose the disorder is to measure pteridine levels in urine and to confirm the result by measuring neurotransmitters 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid and with by an oral tetrahydrobiopterin-loading test (20 mg/kg). When left untreated, the deficiency causes neurological signs at age 4 or 5 months, although clinical signs are often obvious from birth. The principal symptoms include psychomotor retardation, tonus disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation and difficulty swallowing. Treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of tetrahydrobiopterin) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan). Keywords malignant hyperphenylalaninemia, tetrahydropterin deficiency, defective monoaminonergic neurotransmission, restricted phenylalamine intake. Malignant hyperphenylalaninemia. Disease name and synonyms 6-pyruvoyl-tetrahydropterin synthase (PTPS) Excluded diseases deficiency; Other hyperphenylalaninemias (phenylketonuria Biopterin-synthetase deficiency; (PKU), mild hyperphenylalaninemia, etc.); other Tetrahydrobiopterin deficiency; tetrahydrobiopterin deficiencies (GTP- Dhondt JL. Defect in pyruvoyl-tetrahydropterin synthase. Orphanet encyclopedia, February 2005. http://www.orpha.net/data/patho/GB/uk-ptps.pdf 1 cyclohydrolase (GTPch) deficiency, mean minus standard deviations for age) is dihydropteridin reductase (DHPR), pterin-4α- observed in half of the cases. carbinolamine dehydratase (PCD). The neuroradiological and electrophysiological abnormalities are often less severe than would Diagnostic criteria/definition be expected from the clinical picture. EEG PTPS deficiency is one of the etiologies of tracings and changes with age are not specific. "malignant hyperphenylalaninemia" resulting Considering data obtained before 1 year of age, from tetrahydrobiopterin deficiency. In addition to EEG was normal in 69% of PTPS-deficient being hyperphenylalaninemic, patients lacking patients, paroxysmal activity (hypsarrhythmia, tetrahydrobiopterin are deficient in the sharp waves, epileptic discharges) was neurotransmitters whose syntheses depend on observed in 17% of the patients. the normal activity of tetrahydrobiopterin- Neuroanatomical investigations (CT scan & dependent tyrosine and tryptophan hydroxylases MRI) showed frequent and rather early brain (EC.1.14.16.2 and EC.1.14.16.4). atrophy. Differential diagnosis Atypical forms Although the incidence of tetrahydrobiopterin The absence of clinical signs is one of the deficiencies remains low, it is important to be criteria applied to classify patients in this group. sure that patients with hyperphenylalaninemia However, clinical abnormalities have been noted are not tetrahydrobiopterin deficient so that a in some of them. confident prediction of good outcome with a low The report of normal cerebrospinal fluid (CSF) phenylalanine diet can be made. neurotransmitter and biopterin levels led to the It is recommended that all infants with introduction of the term,"peripheral" form of hyperphenylalaninemia be screened for defects PTPS deficiency. in tetrahydrobiopterin metabolism,even in the absence of neurological symptoms, and Management including treatment regardless of the degree of Typical forms hyperphenylalaninemia (mild, transient, The goal is to control hyperphenylalaninemia by persistent, ...). dietary restriction of phenylalanine or tetrahydrobiopterin administration, and to restore Prevalence neurotransmitter homeostasis by oral PTPS deficiency is the most frequent condition administration of amine precursors L-dopa and resulting from tetrahydrobiopterin deficiency: 196 5-hydroxy-tryptophane (5HT). Carbidopa, an cases are known (58% of which are inhibitor of peripheral aromatic amino-acid tetrahydrobiopterin-deficient patients) (in France decarboxylase, enables reduction of the : 17 cases). therapeutic dose of L-dopa. Consanguinity exists in 1/3 of the cases. The doses usually given are L-dopa/carbidopa : In countries where the incidence of PKU is low 5-10 mg/kg body weight (bw)/day 5HT : 5-10 (Japan, Taiwan, etc.), the relative frequency mg/kg bw/ day. However, doses can vary, and (mainly PTPS deficiency) may appear high. indeed have to be adapted to each individual. Neurotransmitter doses are usually divided into Clinical description three equal portions during the day. However, Typical forms diurnal fluctuations are often observed and The median age at which clinical signs became require changes in the schedule of drug evident was 4-5 months, but symptoms do not administration. The optimal dose should be necessarily correlate with age at diagnosis, even adjusted to the requirements of each patient with in a given family. However, during the neonatal monitoring for adverse effects and the possible period, abnormal signs (poor sucking, decreased disappearance of neurological symptoms when spontaneous movements, floppy baby) can be they exist. Unfortunately, there are no observed. biochemical parameters measurable in the The main symptoms were mental retardation, periphery (except hyperprolactinemia which is a convulsions, disturbances of tonicity and good indicator of the hypothalamic dopamine posture, drowsiness, irritability, abnormal deficiency) adequately monitor treatment; movements, recurrent hyperthermia without consequently, analyzing neurotransmitter infection, hypersalivation, swallowing difficulties. metabolites in CSF, obtained by lumbar Diurnal fluctuation of alertness and neurological puncture, represents the most direct way to symptoms are often reported. Convulsions evaluate its efficacy, at least from a biochemical (grand mal or myoclonic attacks) are frequently point of view. reported. Although tetrahydrobiopterin-deficient subjects Considering growth parameters, most PTPS- exhibit higher dietary phenylalanine tolerance deficient patients showed mild to severe failure than classical PKU patients, a factor limiting the to thrive. Microcephaly (head circumference < response to neurotransmitter precursor therapy might be the plasma phenylalanine fluctuations, Dhondt JL. Defect in pyruvoyl-tetrahydropterin synthase. Orphanet encyclopedia, February 2005. http://www.orpha.net/data/patho/GB/uk-ptps.pdf 2 which could alter the dose-effect relationships of cases, biopterin excretion was at the lower limit these substances, by interfering with their of the normal range. In such a situation, membrane transport or by competitive inhibition developmental changes, infectious disease or of tyrosine and tryptophan hydroxylases. The renal failure must be taken in account. use of tetrahydrobiopterin to control blood In contrast, CSF pterins usually contain higher phenylalanine levels appears to be effective and biopterin levels, which are, in some patients, at is recommended. Relatively low doses of the upper limit of the normal range. tetrahydrobiopterin (5-10 mg/kg/d) normalize Nevertheless, a high N/B ratio confirms the blood phenylalanine levels and offer an existence of impaired tetrahydrobiopterin alternative to a phenylalanine-restricted diet. metabolism. Neurotransmitter levels in CSF are usually Atypical forms reported to be normal. However, a decrease of These forms theoretically do not require a CSF 5-HIAA levels exceeding that expected treatment, and thus the decision to treat or not is because of increasing age, has been observed. not evident. With regard to the obvious These observations suggest that patients heterogeneity and the unclear prognosis, it exhibiting such a phenotype during the first seems appropriate to treat newborns with the so- months of life should be reevaluated after called "peripheral" form at least with infancy. tetrahydrobiopterin, to monitor their development carefully and to reevaluate the metabolic status Genetic counseling at 6 months of age. PTPS deficiency is a genetic disorder with autosomal recessive inheritance, the disease Diagnostic methods occurs in both sexes and consanguinity is The diagnosis has to be considered for all common. The gene (PTS) has been located on conditions with hyperphenylalaninemia. PTPS chromosome 11q22.3-q23.3 (6 exons), 33 deficiency can be surmised
Load more

Recommended publications
  • Guide for Hyperphenylalaninemia
    TM Guide For Hyperphenylalaninemia Laurie Bernstein, MS, RD, FADA Cindy Freehauf, RN, CGC Laurie Bernstein, MS, RD, FADA Fellow of the American Dietetic Association Assistant Professor- Department of Pediatrics Director, IMD Nutrition The Children's Hospital, Aurora CO Cindy Freehauf, RN, CGC Assistant Professor- Department of Pediatrics Clinical Coordinator, IMD Clinic The Children's Hospital, Aurora CO A special thank you to: Kathleen M. Martin, BS, BA for her enthusiasm for learning and excellent graphic skills. Intern, IMD Clinic The Children's Hospital, Aurora CO Second Edition Review Committee: Casey Burns, RD Janet A. Thomas, MD Metabolic Nutritionist Associate Professor, Pediatrics The Children's Hospital, Aurora CO Director, IMD Clinic The Children's Hospital, Aurora CO Sommer Myers, RD Metabolic Nutritionist Erica L. Wright, MS, CGC The Children's Hospital, Aurora CO Certified Genetic Counselor The Children's Hospital, Aurora CO Shannon L. Scrivner, MS, CGC Certified Genetic Counselor The Children's Hospital, Aurora CO Acknowledgments: Educational grant provided by Nutricia North America The Genetic Counseling Graduate Students of The University of Colorado at Denver and Health Sciences Center. TCH logo is a Licensed Trademark, all rights reserved. The Inherited Metabolic Clinic at The Children’s Hospital in Aurora, CO serves the Rocky Mountain Plains Region and at least 130 individuals with hyperphenylalaninemia (PKU). Children and families require a great deal of complex information, most often new and alien to their experience, in order to establish and maintain consistent and effective treatment. Our experience with the process of sharing such information with families motivated us develop this anticipatory guidance book with teaching aids.
    [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]
  • Malignant Hyperphenylalaninemia Tetrahydrobiopterin (BH4) Phenylalanine
    Pediat. Res. 13: 1 150-1 155 (1979) Dihydropterine reductase (DHPR) phenylketonuria malignant hyperphenylalaninemia tetrahydrobiopterin (BH4) phenylalanine Malignant Hyperphenylalaninemia-Clinical Features, Biochemical Findings, and Experience with Administration of Biopterins D. M. DANKS, P. SCHLESINGER, F. FIRGAIRA, R. G. H. COTTON. B. M. WATSON, H. REMBOLD. AND G. HENNINGS Genetics Research Unit, Royal Children S Hospital Research Foundation, and Department of Paediatrics, Universi1.y of Melbourne, Parkville, Australia (D. M. D., P. S., F. F.. R. G. H. C., B. M. W.) and Max Planck Institutfur Biochemie. Germany (H. R., G. H.) Summary has been attributed to defective production of neurotransmitters derived from hydroxylation of tyrosine and of tryptophan (3, 4). Four cases of malignant hyperphenylalaninemia (MHPA) are The results of treatment with L-dopa and 5-hydroxytryptophan described. Pretreatment serum phenylalanine levels were 1.5, 3.0, support this contention (2, 3. 7). 2.4, and 0.9 mmoles/l. Dihydropteridine reductase (DHPR) defi- Four patients with MHPA seen in Melbourne since 1963 are ciency was proven in one patient by assays on cultured fibroblastic presented. One patient has been shown to have DHPR deficiency cells and was presumed in her sibling and in another deceased and her sister is presumed to have died of this defect. Both parents patient whose parents' fibroblastic cells show approximately 50% of another baby had DHPR levels in the heterozygote range of normal enzyme activity. DHPR and phenylalanine hydroxylase suggesting DHPR deficiency as the cause of her death. The 4th deficiency were excluded by assays on liver obtained at autopsy in baby had neither PH or DHPR deficiency and defective BH4 the 4th patient.
    [Show full text]
  • Tetrahydrobiopterin Loading Test in Hyperphenylalaninemia
    003 1-399819113005-0435$03.00/0 PEDIATRIC RESEARCH Vol. 30, No. 5, 1991 Copyright 0 199 1 International Pediatric Research Foundation, Inc. Pr~ntc.d in U.S. A Tetrahydrobiopterin Loading Test in Hyperphenylalaninemia ALBERT0 PONZONE, ORNELLA GUARDAMAGNA, SILVIO FERRARIS, GIOVANNI B. FERRERO, IRMA DIANZANI, AND RICHARD G. H. COTTON InstiflifeofPediatric Clinic(A.P., O.G., S.F., G.B.F., I.D.], University of Torino, 10126 Torino, Italy and Olive Miller Laboratory [R.G.H.C.],Murdoch Institute, Royal Children's Hospital, Vicroria,Australia 3052 ABSTRACT. Some cases of primary hyperphenylalanine- PKU to describe some cases clinically unresponsive to a Phe- mia are not caused by the lack of phenylalanine hydroxyl- restricted diet and later shown to be due to BH4 deficiency ase, but by the lack of its cofactor tetrahydrobiopterin. ( 1-4). These patients are not clinically responsive to a phenylal- By analyzing all the essential components of the complex anine-restricted diet, but need specific substitution therapy. hydroxylation system of aromatic amino acids, it became appar- Thus, it became necessary to examine all newborns ent that a defect in the BH4 recycling enzyme DHPR (EC screened as positive with the Guthrie test for tetrahydro- 1.66.99.7) and two defects in BH4 synthetic pathway enzymes, biopterin deficiency. Methods based on urinary pterin or guanosine triphosphate cyclohydrolase I (EC 3.5.4.16) and 6- on specific enzyme activity measurements are limited in PPH4S, may lead to cofactor deficiency resulting in HPA and in their availability, and the simplest method, based on the impaired production of dopamine and serotonin (5-7).
    [Show full text]
  • Different Strategies in the Treatment of Dihydropteridine Reductase Deficiency
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 1996 Different Strategies In the Treatment of Dihydropteridine Reductase Deficiency Spada, M ; Blau, N ; Meli, C ; Ferrero, G B ; de Sanctis, L ; Ferraris, S ; Ponzone, A DOI: https://doi.org/10.1515/pteridines.1996.7.3.107 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-155067 Journal Article Published Version Originally published at: Spada, M; Blau, N; Meli, C; Ferrero, G B; de Sanctis, L; Ferraris, S; Ponzone, A (1996). Different Strategies In the Treatment of Dihydropteridine Reductase Deficiency. Pteridines, 7(3):107-109. DOI: https://doi.org/10.1515/pteridines.1996.7.3.107 Spada et al.: Treatment of DHPR deficiency Pteridines Vol. 7, 1996, pp. 107 - 109 Different Strategies In the Treatment of Dihydropteridine Reductase Deficiency 2 l M . Spada', N. Blau , C. Meli\ G . B. rerrero', L. de Sanctis\ S. Ferraris and A. Ponzone'· 4§ IDipartimento di Scienze Pediatriche e dell'Adolcscenza, Universita'degli Studi di Torino, Italy 2Division of Clinical Chemistry, University Children's Hospital, Zurich, Switzerland 3 C linica Pediatrica, Universita'di Catania, Italy 4Facolta'di Magistero, Universita'di Messina, Italy (Received July IS, 1996) Introduction mal serum Phe levels. Despite substantial amounts of peripherally ad- Inherited deficiency of dihydropteridine reduc- ministered BH4 can be found in cerebrospinal tase (DHPR, EC 1.66.99.7) impairs the re- fluid (CSr), only some patients respond at the generation of tetrahydrobiopterin (BH 4), the es- central level to BH4 monotherapy (3,4).
    [Show full text]
  • Blueprint Genetics Hyperphenylalaninemia Panel
    Hyperphenylalaninemia Panel Test code: ME2001 Is a 6 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of hyperphenylalaninaemias including hyperphenylalaninemia due to BH4 deficiency. The genes on this panel are included in the Comprehansive Metabolism Panel. About Hyperphenylalaninemia Hyperphenylalaninemias (HPA) are errors in metabolism resulting in characterics of elevated levels of phenylalanine amino acid in the blood. Phenylketonuria (PKU) results in hyperphenylalaninemia if left untreated. Elevated levels if phenylalanine will make a severe risk of intellectual disability for a child. Unborn babies with mutation in homozygous state are unaffected as mother’s circulation prevents buildup. After birth, phenylalanine-restricted diet prevents intellectual problems and the persons with homozygous mutated genotype have normal mental development. However, maternal PKU without metabolic control predisposes babies to severe mental retardation and heart defects. This is an example of a genetic disease of a baby based on mother’s genotype. Classical PKU is caused by mutations in PAH, but some 2% of all HPAs result from impaired synthesis or recycling of tetrahydrobiopterin (BH4). Causative mutations in these cases are in GCH1, PCBD1, PTS or QDPR genes. The worldwide prevalence of PKU is estimated at 1:10 000 births having, however, rather big variation in different populations. The prevalence of tetrahydrobiopterin is estimated at <1:500 000 newborns. However, in certain populations
    [Show full text]
  • Gene Function
    Gene Function Chapter 12 The Central Dogma of Biology GATC transcription GAUC translation 20 amino acids Gene Control of Enzyme Structure • Genes encode proteins, including enzymes. • Genes work in sets to accomplish biochemical pathways. • Genes often work in cooperation with other genes. • These discoveries are the foundation of modern molecular genetics. Genetic Approach to Studying the Gene – Enzyme Connection Beadle (Drosophila geneticist) and Tatum (biochemist), 1940’s • Tried for 6 years (1935- 1941) to link genes to chemical reactions in Drosophila. • Switched to a simpler organism: Neurospora crassa • Irradiated and isolated many arginine auxotrophs. Beadle and Tatum and Neurospora mutants • Mutagenized normal Neurospora cells; undergo meiosis… • Isolated individual cells (ascospores) into separate tubes with complete media (growth media that is rich with amino acids, nucleotides, etc… opposite of minimal media). • Tested each for the ability to grow on minimal media. Neurospora Mutants Certain cells did not grow on minimal medium. The type of auxotrophy was tested on media with various supplements. Arginine Mutants Identified • After isolating mutants deficient in amino acid production, specific amino acid deficiencies were identified. • For the purpose of our discussion, we will focus on the arginine mutants. • Several independent arginine mutants were isolated. arg X arg mutant 1 mutant 2 Only if strains are mutant for heterokaryon: a different transient diploid genes How Do We Figure Out The Pathway? Each complementation group responded differently to supplements which were thought to be intermediates in the biochemical synthesis pathway leading to arginine. l ornithine a m i n i m citrulline - - - arginine Next, figure out at which step in the pathway each complementation group (gene) acts… Mutant minimal citrulline ornithine arginine arg-1 - + + + arg-2 - + - + arg-3 - - - + arg-1 arg-2 arg-3 enz.
    [Show full text]
  • Diosynrhesis of Neopterin, Sepioprerin, Ond Diopterin in Rar Ond Humon Oculor Tissues
    768 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / May 1985 Vol. 26 before and after the addition of beta-glucuronidase.4 ported by the Juvenile Diabetes Foundation and by the University In circumstances where the actual plasma free fluo- of London, Central Research Fund. The HPLC was purchased with an MRC grant to Dr. Michael J. Neal. Submitted for publi- rescein has not been measured, the term "plasma- cation: April 12, 1984. Reprint requests: Dr. P. S. Chahal, Depart- free fluorescence" should be quoted. It is then better ment of Medicine, Hammersmith Hospital, Du Cane Road, London to measure overall fluorescence (fluorescein and the W12 OHS, England. glucuronide metabolite) in protein-free plasma ultra- filtrate and the fluorescence appearing in the ocular References compartments using the same excitor and emission filters. 1. Araie M, Sawa M, Nagataki S, and Mishima S: Aqueous Fluorescein glucuronide is a potential source of humor dynamics in man as studied by oral fluorescein. Jpn J Ophthalmol 24:346, 1980. variability in studies of blood-ocular dynamics using 2. Zeimer RC, Blair NP, and Cunha-Vaz JG: Pharmacokinetic fluorescein. Its exact role has yet to be established. interpretation of vitreous fluorophotometry. Invest Ophthalmol VisSci 24:1374, 1983. Key words: Blood-ocular barriers, diabetes, plasma ultrafil- 3. Chen SC, Nakamura H, and Tamura Z: Studies on metabolite trate, fluorescein glucuronide, fluorescence, protein-binding of fluorescein in rabbit and human urine. Chem Pharmacol Acknowledgments. Technical assistance was given by Dr. Bull 28:1403, 1980. J. Cunningham, Ian Joy, and Margaret Foster. 4. Chen SC, Nakamura H, and Tamura Z: Determination of fluorescein and fluorescein monoglucuronide excreted in urine.
    [Show full text]
  • Screening for Inherited Metabolic Disease in Wales Using Urine-Impregnated Filter Paper
    Arch Dis Child: first published as 10.1136/adc.50.4.264 on 1 April 1975. Downloaded from Archives of Disease in Childhood, 1975, 50, 264. Screening for inherited metabolic disease in Wales using urine-impregnated filter paper D. M. BRADLEY From the Department of Medicine, Welsh National School of Medicine, Heath Park, Cardiff Bradley, D. M. (1975). Archives of Disease in Childhood, 50, 264. Screening for inherited metabolic disease in Wales using urine-impregnated filter paper. Urine specimens from 135 295 infants have been collected on filter paper and tested for 7 abnormal urinary constituents using spot tests and paper chromato- graphy. The method has detected 5 infants with phenylketonuria, 4 with histidinae- mia, 5 with cystinuria, 5 with diabetes mellitus, and one with alcaptonuria. Transient abnormalities such as tyrosyluria, generalized aminoaciduria, cystinuria, and glyco- suria have been noted. 2 phenylketonuric infants failed to excrete a detectable quantity of o-hydroxyphenylacetic acid at the time of testing. The findings show that the detection of this compound in urine is an unreliable method of screening for phenylketonuria. Early detection of phenylketonuria became Method essential when it was found that the severe mental Collection of urine specimens. The recom- retardation associated with this disorder could be mended time of testing is between the 10th and 14th prevented by introducing a low phenylalanine diet day of life. In practice, 53% of all specimens are in the first months of life (Bickel, Gerrard, and collected by the 14th day, rising to 98% by the 28th Hickmans, 1953). The Medical Research Council day (Table I).
    [Show full text]
  • Living with Classical Homocystinuria
    Living with Classical Homocystinuria This brochure will help you understand what classical homocystinuria is, how it affects your body, and how you can manage your condition A few words about this brochure What is homocystinuria? Has your doctor diagnosed you or your child You may have heard the word “homocystinuria” with homocystinuria (HO-mo-SIS-tin-YUR- for the first time when your doctor talked to ee-uh)? There are three types of genetic you about possibly having this condition. disorders that cause homocystinuria. Each Homocystinuria is a rare disorder involving type has a different cause and different the amino acid homocysteine (HO-mo-SIS- health issues. This brochure will talk about teen). Amino acids are building blocks that your classical homocystinuria. The information body uses to make proteins. Homocystinuria will help you understand classical occurs when there is a buildup of the amino acid homocystinuria and how you can manage homocysteine in your blood and urine. your condition. High levels of homocysteine can be harmful to your body. You may be reading this brochure because you have classical homocystinuria or Why is there homocysteine because your child or a sibling or a friend in your body? has it. Or perhaps you’re a healthcare professional. Please note the brochure It starts with the foods you eat. Your body addresses “you,” but it’s understood that makes homocysteine from another amino acid “you,” the reader, may not have classical called methionine (meh-THIGH-uh-neen). Most homocystinuria yourself. foods contain some methionine. But high-protein foods such as meat, fish, eggs, or cheese tend to have the most methionine.
    [Show full text]
  • The PAH Gene, Phenylketonuria, and a Paradigm Shift
    HUMAN MUTATION 28(9), 831^845, 2007 WILEY 200TH ANNIVERSARY TRIBUTE ARTICLE The PAH Gene, Phenylketonuria, and a Paradigm Shift Charles R. Scriver1–4Ã 1Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; 2Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; 3Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; 4Department of Biology, Faculty of Science, McGill University, Montreal, Quebec, Canada Communicated by Johannes Zschocke ‘‘Inborn errors of metabolism,’’ first recognized 100 years ago by Garrod, were seen as transforming evidence for chemical and biological individuality. Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype, was identified in 1934 by Asbjo¨rn Fo¨lling. It is a disease with impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (HPA). Its metabolic phenotype is accountable to multifactorial origins both in nurture, where the normal nutritional experience introduces L-phenylalanine, and in nature, where mutations (4500 alleles) occur in the phenylalanine hydroxylase gene (PAH) on chromosome 12q23.2 encoding the L-phenylalanine hydroxylase enzyme (EC 1.14.16.1). The PAH enzyme converts phenylalanine to tyrosine in the presence of molecular oxygen and catalytic amounts of tetrahydrobiopterin (BH4), its nonprotein cofactor. PKU is among the first of the human genetic diseases to enter, through newborn screening, the domain of public health, and to show a treatment effect. This effect caused a paradigm shift in attitudes about genetic disease. The PKU story contains many messages, including: a framework on which to appreciate the complexity of PKU in which phenotype reflects both locus-specific and genomic components; what the human PAH gene tells us about human population genetics and evolution of modern humans; and how our interest in PKU is served by a locus-specific mutation database (http://www.pahdb.mcgill.ca; last accessed 20 March 2007).
    [Show full text]
  • Molecular Patterns Behind Immunological and Metabolic Alterations in Lysinuric Protein Intolerance
    MOLECULAR PATTERNS BEHIND IMMUNOLOGICAL AND METABOLIC ALTERATIONS IN LYSINURIC PROTEIN INTOLERANCE Johanna Kurko TURUN YLIOPISTON JULKAISUJA – ANNALES UNIVERSITATIS TURKUENSIS Sarja - ser. D osa - tom. 1220 | Medica - Odontologica | Turku 2016 University of Turku Faculty of Medicine Institute of Biomedicine Department of Medical Biochemistry and Genetics Turku Doctoral Programme of Molecular Medicine (TuDMM) Supervised by Adjunct Professor Juha Mykkänen, Ph.D Professor Harri Niinikoski, MD, Ph.D Research Centre of Applied and Department of Paediatrics and Preventive Cardiovascular Medicine Adolescent Medicine University of Turku Turku University Hospital Turku, Finland University of Turku Turku, Finland Reviewed by Adjunct Professor Risto Lapatto, MD, Ph.D Adjunct Professor Outi Monni, Ph.D Department of Paediatrics Research Programs’ Unit and Institute of Helsinki University Hospital Biomedicine University of Helsinki University of Helsinki Helsinki, Finland Helsinki, Finland Opponent Adjunct Professor Päivi Saavalainen, Ph.D Research Programs Unit University of Helsinki Helsinki, Finland The originality of this thesis has been checked in accordance with the University of Turku quality assurance system using the Turnitin OriginalityCheck service. ISBN 978-951-29-6399-7 (PRINT) ISBN 978-951-29-6400-0 (PDF) ISSN 0355-9483 (PRINT) ISSN 2343-3213 (ONLINE) Painosalama Oy - Turku, Finland 2016 ‘Nothing has such power to broaden the mind as the ability to investigate systematically and truly all that comes under thy observation in life.’ Marcus
    [Show full text]