DOCSLIB.ORG

Isolation and Expression of Rat Liver Sepiapterin Reductase Cdna

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Isolation and Expression of Rat Liver Sepiapterin Reductase Cdna Proc. Nat!. Acad. Sci. USA Vol. 87, pp. 6436-6440, August 1990 Genetics Isolation and expression of rat liver sepiapterin reductase cDNA (tetrahydrobiopterin/biopterin/pyruvoyltetrahydropterin/aromatic amino acid hydroxylase/molecular cloning) BRUCE A. CITRON*, SHELDON MILSTIEN*, JOANNE C. GUTIERREZt, ROBERT A. LEVINE, BRENDA L. YANAK*§, AND SEYMOUR KAUFMAN*¶ *Laboratory of Neurochemistry, Room 3D30, Building 36, and tLaboratory of Cell Biology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892; and tLaboratory of Molecular Neurobiology, Lafayette Clinic, 951 East Lafayette, Detroit, MI 48207 Contributed by Seymour Kaufman, June 7, 1990 ABSTRACT Sepiapterin reductase (7,8-dihydrobiopterin: either case, the final carbonyl reduction to form tetrahydro- NADP+ oxidoreductase, EC 1.1.1.153) catalyzes the terminal biopterin must be catalyzed by sepiapterin reductase. step in the biosynthetic pathway for tetrahydrobiopterin, the In the present study, we have screened a rat liver cDNA cofactor necessary for aromatic amino acid hydroxylation. We library with a specific antibody that reacts positively to the report here the isolation of a cDNA clone for rat liver sepia- enzyme band on Western blots (19). These clones were used pterin reductase. The cDNA has been excised from a lambda to further characterize the enzyme and to begin to elucidate vector and the DNA sequence was determined. The insert the functional sites ofthe enzymes in the tetrahydrobiopterin contains the coding sequence for at least 95% of the rat enzyme biosynthetic pathway. 11 and is fused to the Escherichia coli (3-galactosidase N-terminal segment and the lac promoter. The N-terminal region of the clone contains an extraordinarily high G+C content. The MATERIALS AND METHODS amino acid sequence deduced from the clone is in agreement Screening. Sepiapterin reductase from rat erythrocytes was with the size and composition of the enzyme and was matched purified according to the procedure of Sueoka and Katoh (7). to several tryptic peptide sequences. The enzyme encoded by Antibodies to the enzyme were isolated and tested as de- the cDNA insert was shown to have sepiapterin reductase scribed (19). All commercial reagents were used according to activity after expression in E. cohl. Structural similarities were the manufacturers' recommendations. Antibody screens identified between this protein and several enzymes that should were carried out with the use ofthe Protoblot immunoscreen- contain similar nucleotide and pteridine binding sites. ing system (Promega) with our rabbit anti-rat erythrocyte sepiapterin reductase together with goat anti-rabbit IgG con- The cofactor 5,6,7,8-tetrahydrobiopterin is an absolute re- jugated to alkaline phosphatase. A rat liver cDNA library (Stratagene) in the lambda ZAP II vector (20) containing 2 x quirement for the activity of the three aromatic amino acid 106 primary inserts was tested for the presence of sepiapterin hydroxylases phenylalanine hydroxylase, tyrosine hydroxy- reductase clones. Additional screening with a labeled DNA lase, and tryptophan hydroxylase (1). The latter two hydrox- oligomer was carried out according to Church and Gilbert ylases catalyze rate-limiting steps in the biosynthesis of the (21) conditions to identify full-length sepiapterin reductase neurotransmitters dopamine, norepinephrine, and serotonin. inserts in phage vectors transferred in situ to Amersham Whereas the aromatic amino acid hydroxylases have ex- Hybond N nylon membranes. Positive candidates with either tremely limited tissue distribution, the biosynthetic enzymes procedure were purified through three subsequent rounds of for tetrahydrobiopterin, and tetrahydrobiopterin itself, are isolation and then manipulated according to standard recom- present in most cell types examined. This divergent tissue binant procedures (22, 23). DNA sequence analysis was distribution may reflect broader roles for the cofactor than carried out according to the dideoxynucleotide chain- have yet been fully identified (2-4). Such widespread expres- termination method ofSanger et al. (24). The genotypes ofthe sion suggests that tetrahydrobiopterin may be important in bacterial strains used have been described by Sambrook et al. some very basic cellular processes (4). In any case, the role (22). of the cofactor in aromatic amino acid hydroxylation is Sequence Analysis. DNA and protein sequence compari- critical to normal neurological function and several examples sons were made with the aid of the University of Wisconsin of cofactor deficiency disorders have been described (re- Genetics Computing Group Programs version 6.1 (25). The viewed in ref. 5). data bases that were screened for similar sequences included Sepiapterin reductase (7,8-dihydrobiopterin:NADP+ oxi- the National Biomedical Research Foundation protein data doreductase, EC 1.1.1.153) was first discovered in the base (version 35.0), which contained 12,476 protein se- chicken and rat liver by Matsubara et al. (6). The purification quences, and the GenBank (26) (version 62.0), and the and characterization of sepiapterin reductase from rat eryth- European Molecular Biology Laboratory (27) (version 19.0) rocytes has demonstrated it to be an acidic protein composed nucleic acid data bases, which held 31,232 different se- oftwo 28-kDa subunits (7). This enzyme is involved in one or quences. The sepiapterin reductase amino acid sequence was both of the two final reductions of the de novo tetrahydro- compared to the protein sequence data base and also to all of biopterin biosynthetic pathway necessary to convert 6- the theoretical translations ofthe nucleic acid entries with the pyruvoyltetrahydropterin to tetrahydrobiopterin (7-12), de- aid of the programs FASTA and TFASTA, respectively, both picted in Fig. 1 (dashed line). There are two possible routes with a word size of 2 (28). The sepiapterin reductase cDNA for single-step reductions of each of the carbonyl groups of sequence was matched to the nucleic acid data bases by using 6-pyruvoyltetrahydropterin, with one pathway using only with a word size of 6. sepiapterin reductase for both reductions and the other using FASTA and WORDSEARCH, each a different reductase to carry out the first reduction (9). In §Present address: Biology Department, Colgate University, Hamil- ton, NY 13346. The publication costs of this article were defrayed in part by page charge $To whom reprint requests should be addressed. payment. This article must therefore be hereby marked "advertisement" "The sequence reported in this paper has been deposited in the in accordance with 18 U.S.C. §1734 solely to indicate this fact. GenBank data base (accession no. M36410). 6436 Downloaded by guest on September 25, 2021 Genetics: Citron et al. Proc. Natl. Acad. Sci. USA 87 (1990) 6437 GTP the disappearance of sepiapterin spectrophotometrically at 410 nm at 370C in a reaction mixture containing 50 mM GTP potassium phosphate (pH 6.5), 200 AM NADPH, and 50 ,uM Cyclohydrolase sepiapterin (29). 7,8-Dihydroneopterin Triphosphate RESULTS Isolation of Sepiapterin Reductase cDNA. Rabbit anti-rat 6-Pyruvoyltetrahydrolpterin Synthase sepiapterin reductase antibody was used to screen 855,000 rat liver cDNA inserts in a A library. Eight clones retained a positive signal after three rounds of screening and isolation. 6-Pyruvoyltetr,ahydropterin This frequency is 2- to 10-fold lower than the value predicted by the prevalence of the protein (0.01-0.2%) (7) and the I Seplapterin Reductase likelihood that the insert should have been in-frame with the I5T ,B-galactosidase peptide on the vector. Three ofthese cDNAs were excised to form phagemids for restriction site mapping, 5,6,7,8-TetrahyFdroblopterin sequence analysis, and expression. The restriction patterns for two were indistinguishable and one ofthese, pBLY1, was FIG. 1. The tetrahydrobiopterin biosynthetic pathway (11, 13- sequenced and is depicted in Figs. 2 and 3. 18). The last two reductions are carbonyl reductions, which may both pBLY1 contains a 787-base open reading frame linked to an be carried out by sepiapterin reductase or an alternative reductase E. coli d3-galactosidase N-terminal fragment. The 8-galacto- may catalyze the first carbonyl reduction of 6-pyruvoyltetrahydro- pterin. sidase translation frame in this plasmid is under the control of an E. coli lac promoter. When induced, this composite Peptide Sequencing. Purified sepiapterin reductase was DNA molecule sbould produce a 298-residue fusion protein, reduced and carboxymethylated and then digested with tryp- the last 259 amino acids of which are derived from the cDNA sin [1% (wt/wt)]; the peptide fragments were separated by insert. The molecular weight of a sepiapterin reductase subunit has been reported to be 27,500 (7). This value is HPLC (reverse-phase Vydac C8, 15 x 0.46 cm) and col- consistent with a protein containing 230-270 lected. The tryptic peptides were sequenced on an amino acids and Applied indicated that our clone was missing just a few N-terminal Biosystems 470A sequencer equipped with a 120A PTH residues. analyzer. Peptides that yielded ambiguous data at all cycles We searched for clones containing the complete N- were further separated by microbore reverse-phase HPLC terminal sequence by repeating the screening of the cDNA (Brownlee C18, 30 x 2.1 mm) and the peaks were reanalyzed library with a 38-base DNA oligomer corresponding to the to produce distinct sequences. extreme 5' end ofthe insert in pBLY1. Surprisingly, only one Expression.
Load more

Recommended publications
  • Relevance to Neurological Damage
    Postgrad Med J: first published as 10.1136/pgmj.62.724.113 on 1 February 1986. Downloaded from Postgraduate Medical Journal (1986) 62, 113-123 Pteridines and mono-amines: relevance to neurological damage I. Smith, D.W. Howells and K. Hyland Institute ofChildHealth (University ofLondon), 30 Guilford Street, London WCIN2NR, UK. Summary: Patients with phenylalanine hydroxylase deficiency show increased concentrations of biopterins and neopterins, and reduced concentrations ofserotonin and catecholamines, when phenylalan- ine concentrations are raised. The pterin rise reflects increased synthesis of dihydroneopterin and tetrahydrobiopterin, and the amine fall a reduction in amine synthesis due to inhibition by phenylalanine of tyrosine and typtophan transport into neurones. The pterin and amine changes appear to be independent of each other and are present in the central nervous system as well as the periphery; they disappear when phenylalanine concentrations are reduced to normal. Patients with arginase deficiency show a similar amine disturbance but have normal pterin levels. The amine changes probably contribute neurological symptoms but pterin disturbance is not known to affect brain function. Patients with defective biopterin metabolism exhibit severely impaired amine synthesis due to tetrahydrobiopterin deficiency. Pterin concentrations vary with the site of the defect. Symptoms include profound hypokiesis and other features of basal ganglia disease. Neither symptoms nor amine changes are relieved by controlling phenylalanine concentrations. Patients with dihydropteridine reductase (DHPR) deficiency accumulate dihydrobiopterins and develop secondary folate deficiency which resembles that occurring in patients with defective 5,10-methylene tetrahydrofolate reductase activity. The latter disorder is also associated writh Parkinsonisn and defective amine and pterin turnover in the and a occurs in In central nervous system, demyelinating illness both disorders.
    [Show full text]
  • Massive Parallel Sequencing As a New Diagnostic Approach For
    Chaiyasap et al. BMC Medical Genetics (2017) 18:102 DOI 10.1186/s12881-017-0464-x RESEARCH ARTICLE Open Access Massive parallel sequencing as a new diagnostic approach for phenylketonuria and tetrahydrobiopterin-deficiency in Thailand Pongsathorn Chaiyasap1, Chupong Ittiwut1,2, Chalurmpon Srichomthong1,2, Apiruk Sangsin3, Kanya Suphapeetiporn1,2,4* and Vorasuk Shotelersuk1,2 Abstract Background: Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, and BH4 deficiency caused by alterations in genes involved in tetrahydrobiopterin (BH4) biosynthesis pathway. Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability. However, the same dietary intervention in BH4 deficiency patients is not as effective, as BH4 is also a cofactor in many neurotransmitter syntheses. Method: We utilized next generation sequencing (NGS) technique to investigate four unrelated Thai patients with hyperphenylalaninemia. Result: We successfully identified all eight mutant alleles in PKU or BH4-deficiency associated genes including three novel mutations, one in PAH and two in PTS, thus giving a definite diagnosis to these patients. Appropriate management can then be provided. Conclusion: This study identified three novel mutations in either the PAH or PTS gene and supported the use of NGS as an alternative molecular genetic approach for definite diagnosis of hyperphenylalaninemia, thus leading to proper management of these patients in Thailand. Keywords: Next generation sequencing, Exome, Hyperphenylalaninemia, Phenylketonuria, Tetrahydrobiopterin deficiency, Newborn screening Background 120 μmol/l (2 mg/dl), the individual is considered to be Phenylketonuria (PKU) is an autosomal recessive metabolic hyperphenylalaninemia (HPA) and needs further diagnosis disorder, characterized by progressive intellectual disability, [4].
    [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]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Gene Transfer As a Potential Treatment for Tetralujdrobiopterin Deficient States
    Gene Transfer as a Potential Treatment for Tetralujdrobiopterin Deficient States Rickard F oxton Division of Neurochemistry Department of Molecular Neuroscience Institute of Neurology University College London Submitted November 2006 Funded by Brain Research Trust Thesis submitted for the degree of Doctor of Philosophy, University of London. I, Richard Hartas Foxton, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' 1 UMI Number: U592813 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U592813 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT Tetrahydrobiopterin (BH4) is an essential cofactor for dopamine (DA), noradrenaline (NA), serotonin and nitric oxide (NO) synthesis in the brain. Inborn errors of BH4 metabolism including GTP cyclohydrolase 1 (GTP-CH) deficiency are debilitating diseases in which BH4, DA, 5-HT and NO metabolism are impaired. Current treatment for these disorders is typically monoamine replacement +/- BH4. Whilst correction of the primary defect is the ideal, BH4 treatment is problematic as it is expensive and inefficacious.
    [Show full text]
  • Biosynthesis of Tetrahydrobiopterin in Man
    J. tnher. Metab. Dis. 8 Suppl. 1 (I985) 28-33 Biosynthesis of Tetrahydrobiopterin in Man H.-CH. CURTIUS, D. HEINTEL, S. GHISLA1, TH. KUSTER, W. LEIMBACHER and A. NIEDERWIESER Division of Clinical Chemistry, Department of Pediatrics, University of Zurich, Switzerland t Department of Biology, University of Constance, POB 5560, D-7750 Constance, FRG The biosynthesis oftetrahydrobiopterin (BH4) from dihydroneopterin triphosphate (NHzP3) was studied in human liver extract. The phosphate-eliminating enzyme (PEE) was purified ~ 750-fold. The conversion of NH2P3 to BH~ was catalyzed by this enzyme in the presence of partially purified sepiapterin reductase, Mg z ÷ and NADPH. The PEE is heat stable when heated at 80 °C for 5 min. It has a molecular weight of 63 000 daltons. One possible intermediate 6-(l'-hydroxy-2'-oxopropyl)5,6,7,8-tetrahydropterin(2'-oxo-tetrahydro- pterin) was formed upon incubation of BH4 in the presence of sepiapterin reductase and NADP ÷ at pH 9.0. Reduction of this compound with NaBD4 yielded monodeutero threo and erythro-BH4, the deuterium was incorporated at the 2' position. This and the UV spectra were consistent with a 2'-oxo-tetrahydropterin structure. Dihydrofolate reductase (DHFR) catalyzed the reduction of BH2 to BH4 and was found to be specific for the pro-R-NADPH side. The sepiapterin reductase catalyzed the transfer of the pro-S hydrogen of NADPH during the reduction of sepiapterin to BHa. In the presence of crude liver extracts the conversion of NHzP3 to BH4 requires NADPH. Two deuterium atoms were incorporated from (4S-2H)NADHP in the 1' and 2' position of the BH4 side chain.
    [Show full text]
  • Natalis Information Sheet V03
    Sema4 Natalis Clinical significance of panel Sema4 has designed and validated Natalis, a supplemental newborn screening panel offered for newborns, infants, and young children. This test may be offered to parents as an addition to the state mandated newborn screening that their child received at birth. This panel includes next-generation sequencing, targeting genotyping, and multiplex ligation-dependent probe amplification in a total of 166 genes to screen for 193 conditions that have onset in infancy or early childhood and for which there is treatment or medical management that, when administered early in an infant or child’s life, will significantly improve the clinical outcome. Conditions included in this panel were curated based on criteria such as: inclusion on current state mandated newborn screening panels, onset of symptoms occurring <10 years of age, evidence of high penetrance (>80%), and availability of a treatment or improvement in life due to early intervention. Sema4 has also designed and validated a pediatric pharmacogenetic (PGx) genotyping panel as an adjunct test to the Natalis assay. This panel includes 10 genes and 41 sequence variants involved in drug response variability. The genes and variants in the PGx genotyping panel inform on more than 40 medications that can be prescribed during childhood. Currently, there is evidence supporting the clinical utility of testing for certain PGx variants for which there are genotype-directed clinical practice recommendations for selected gene/drug pairs. Approximately 95% of all individuals will carry at least one clinically actionable variant in the PGx panel. Testing methods, sensitivity, and limitations A cheek swab, saliva sample, or blood sample is provided by the child and a biological parent.
    [Show full text]
  • Epithelial Cell Line Derived from Endometriotic Lesion Mimics Macrophage Nervous Mechanism of Pain Generation on Proteome and Metabolome Levels
    biomolecules Article Epithelial Cell Line Derived from Endometriotic Lesion Mimics Macrophage Nervous Mechanism of Pain Generation on Proteome and Metabolome Levels Benjamin Neuditschko 1,2,† , Marlene Leibetseder 1,† , Julia Brunmair 1 , Gerhard Hagn 1 , Lukas Skos 1, Marlene C. Gerner 3 , Samuel M. Meier-Menches 1,2,4 , Iveta Yotova 5 and Christopher Gerner 1,4,* 1 Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 38, 1090 Vienna, Austria; [email protected] (B.N.); [email protected] (M.L.); [email protected] (J.B.); [email protected] (G.H.); [email protected] (L.S.); [email protected] (S.M.M.-M.) 2 Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, 1090 Vienna, Austria 3 Division of Biomedical Science, University of Applied Sciences, FH Campus Wien, Favoritenstraße 226, 1100 Vienna, Austria; [email protected] 4 Joint Metabolome Facility, Faculty of Chemistry, University of Vienna, Waehringer Straße 38, 1090 Vienna, Austria 5 Department of Obstetrics and Gynaecology, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; [email protected] Citation: Neuditschko, B.; * Correspondence: [email protected] Leibetseder, M.; Brunmair, J.; Hagn, † Authors contributed equally. G.; Skos, L.; Gerner, M.C.; Meier-Menches, S.M.; Yotova, I.; Abstract: Endometriosis is a benign disease affecting one in ten women of reproductive age world- Gerner, C. Epithelial Cell Line wide. Although the pain level is not correlated to the extent of the disease, it is still one of the Derived from Endometriotic Lesion cardinal symptoms strongly affecting the patients’ quality of life.
    [Show full text]
  • Downloaded from the App Store and Nucleobase, Nucleotide and Nucleic Acid Metabolism 7 Google Play
    Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 https://doi.org/10.1186/s13023-021-01727-2 REVIEW Open Access Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app Eva M. M. Hoytema van Konijnenburg1†, Saskia B. Wortmann2,3,4†, Marina J. Koelewijn2, Laura A. Tseng1,4, Roderick Houben6, Sylvia Stöckler‑Ipsiroglu5, Carlos R. Ferreira7 and Clara D. M. van Karnebeek1,2,4,8* Abstract Background: The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disabil‑ ity (collectively ‘treatable IDs’). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identifcation of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation. Methods: Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classifcation of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is avail‑ able. Data on clinical symptoms, diagnostic testing, treatment strategies, efects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features. Results: Our review identifed 116 treatable IDs (139 genes), of which 44 newly identifed, belonging to 17 ICIMD categories.
    [Show full text]
  • Treatable Inborn Errors of Metabolism Presenting As Cerebral Palsy Mimics
    Leach et al. Orphanet Journal of Rare Diseases 2014, 9:197 http://www.ojrd.com/content/9/1/197 RESEARCH Open Access Treatable inborn errors of metabolism presenting as cerebral palsy mimics: systematic literature review Emma L Leach1,2, Michael Shevell3,4,KristinBowden2, Sylvia Stockler-Ipsiroglu2,5,6 and Clara DM van Karnebeek2,5,6,7,8* Abstract Background: Inborn errors of metabolism (IEMs) have been anecdotally reported in the literature as presenting with features of cerebral palsy (CP) or misdiagnosed as ‘atypical CP’. A significant proportion is amenable to treatment either directly targeting the underlying pathophysiology (often with improvement of symptoms) or with the potential to halt disease progression and prevent/minimize further damage. Methods: We performed a systematic literature review to identify all reports of IEMs presenting with CP-like symptoms before 5 years of age, and selected those for which evidence for effective treatment exists. Results: We identified 54 treatable IEMs reported to mimic CP, belonging to 13 different biochemical categories. A further 13 treatable IEMs were included, which can present with CP-like symptoms according to expert opinion, but for which no reports in the literature were identified. For 26 of these IEMs, a treatment is available that targets the primary underlying pathophysiology (e.g. neurotransmitter supplements), and for the remainder (n = 41) treatment exerts stabilizing/preventative effects (e.g. emergency regimen). The total number of treatments is 50, and evidence varies for the various treatments from Level 1b, c (n = 2); Level 2a, b, c (n = 16); Level 4 (n = 35); to Level 4–5 (n = 6); Level 5 (n = 8).
    [Show full text]
  • Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment
    Published online: 2018-10-29 2 Review Article Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment Heiko Brennenstuhl1 Sabine Jung-Klawitter1 Birgit Assmann1 Thomas Opladen1 1 Division of Neuropediatrics and Metabolic Medicine, Department of Address for correspondence Prof. Dr. Thomas Opladen, MD, Division General Pediatrics, University Children’s Hospital Heidelberg, of Neuropediatrics and Metabolic Medicine, Department of General Heidelberg, Germany Pediatrics, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany (e-mail: [email protected]). Neuropediatrics 2019;50:2–14. Abstract Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH4). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin. Symptoms can occur already in the neonatal period. Keywords Classical signs are hypotonia, movement disorders, autonomous dysregulations, and ► inherited monoamine impaired development. Diagnosis depends on quantitative detection of neurotrans- neurotransmitter mitters in cerebrospinal
    [Show full text]
  • Pet-1 Controls Tetrahydrobiopterin Pathway and Slc22a3 Transporter Genes in Serotonin Neurons Steven C Wyler, Lauren J Donovan, Mia Yeager, and Evan Deneris ACS Chem
    Subscriber access provided by CASE WESTERN RESERVE UNIV Article Pet-1 controls tetrahydrobiopterin pathway and Slc22a3 transporter genes in serotonin neurons Steven C Wyler, Lauren J Donovan, Mia Yeager, and Evan Deneris ACS Chem. Neurosci., Just Accepted Manuscript • Publication Date (Web): 02 Feb 2015 Downloaded from http://pubs.acs.org on February 5, 2015 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts. ACS Chemical Neuroscience is published by the American Chemical Society.
    [Show full text]