DOCSLIB.ORG

Tetrahydrobiopterin Deficiency

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tetrahydrobiopterin Deficiency Blau et al.: Tetrahydrobiopterin deficiency Pteridines Vol. 4, 1993. pp. 1-10 Review Tetrahydrobiopterin Deficiency: From Phenotype to Genotype* Nenad Blau i! §, Beat Thonyi!, Claus W. Heizmann i!, and Jean-Louis Dhondt t :I Division of Clinical Chemistry. University Children's Hospital. Steinwiesstr. 75. CH-8032 ZUlich. Switzerland tCentre Hospitalier Sanit-Philbert Faculte Libre de Medecine. Lomme Cedex, France (Received January 10. 1993) Summary As a result of the selective screening worldwide during the last 18 years, approximately 250 patients with tetrahydrobiopterin deficiency were discovered. Most patients suffer from 6-pyruvoyl tetrahydropterin synthase deficiency (58%), followed by dihydropteridine reductase deficiency (35%), GTP cyclohydrolase I deficiency (3%), and "primapterinuria" (4%). The patients can be treated with neurotransmitter precursors, as well as with tetrahydrobiopterin. However, data on long term treatment are still scarce and it is therefore of great value to investigate all newborns with even mild hyperphenylalaninemia. Cloning of the enzymes involved in the biosynthesis and regeneration of tetrahydrobiopterin makes them to be easily accessible for biochemical and biological studies. So far, all proteins expressed heterologous are active in E. coli. Cloning of the wild type gene and mutant analysis of patients allow the rapid identification of the defective gene on the molecular level. Key words: Tetrahydrobiopterin, Deficiency, Hyperphenylalaninemia, Gene cloning, DNA. In troducti on Early detection of tetrahydrobiopterin (BH4) defi­ nine to tyrosine: tyrosine-3-hydroxylase and trypto­ ciency became essential soon after it was recognized phan-5-hydroxylase are the rate-limiting enzymes in that a number of patients with hyperphenylalanin­ the biosynthesis of catecholamines and serotonin, emia (HPA) show progressive neurological illness de­ respectively (4). Thus. any defect in the biosynthesis spite treatment with a low-phenylalanine diet (I. 2). or regeneration of BH4 will result in a deficiency The di sease was initially named "malignant phenyl­ of biogenic amine neurotransmitters accompanied ketonuria (PKU)" because some of these patients by HPA. died early. The first patients with BH4 deficiency About 250 patients with BH4 deficiency were dis­ were described as "a genetic variant of PKU" (3) covered world-wide in the last 18 years (5,6). Be­ and were later characterized as suffering from a de­ cause of the different clinical and biochemical seve­ fect in the regeneration of BH4. BH4 is known to rity, this group of diseases was originally named "atyp­ be the natural cofactor of three aromatic amino acid ical PKU". a term which today is reserved for mild oxidase: phenylalanine-4-hydroxylase (PAH). tyro­ forms of PAH deficiency. sine-3-hydroxylase. and tryptophan-5-hydroxylase. Although a wide range of metabolic defects may PAH is responsible for the conversion of phenylala- exist, the term "typical" or "atypical" form will be used according to the actual need to treat, or not § Author to whom correspondence should he addressed. *lJedicated to ProfCssor Max Viscontini on the occasion of to treat, the patients. his KOth hirthday. Ptcridincs / Vol. 4 I No. I 2 Blau et af.: Tetrahydrohiopterin deficiency a 0 PTPS 58% "'~N GTPCH ... ~N"r-r-r-O<,OPPP ~~NJlNJI ~ HoN~NJL~) ~: 7,8-0Ihydroneopterin triphosphate ~Q 2H.o ~ H~ ;TPsf:oppp ~ 0 ~ 0 0 6-Pyruvoyl tetrahydropterln Total GTP N "II GTPCH 3% NAQPH jr-r-~' NADPH :t.:jc 246 patients PHS/PCD 4% NADU "" N ~ H H U AOP + ~orCR SR ~~ 0 H SR ~Z ';l fl :t__ JlNj~-L-CH, 4-------' "'~ .. Jl j~-~-Oi, H,N N N H:.N~N ~ H 6-Lactoyl tetrahydropterln H 1'-OH-2'-Dxopropyl SR SR or AR tetrahydropterin Figure 3. Results of the screening for tetrahydrohiopterin dcti­ ciency collected from the international register. NA~ :jc0 ~ H H *GADPII NAOP-t N' I NADP HN j9-r-0l, HoN...l.N ~ CH OH 5,6,7,8-T etrahydrobiopterin claimed that neopterin may play an active role in the cell-mediated immune response, cell prolifera­ tion, and differentiation, in one of these patients all Figure l. Biosynthesis of tetrahydrohiopterin including possi­ hie metabolic detects in hyperphenylalaninemia (Hi' ). GTPCH: humoral and cellular functions tested were found GTP cyclohydrolase I: PTPS: 6-pyruvoyl tetrahydropterin to be normal. In cerebrospinal fluid (CSF) neopte­ synthase: SR: sepiapterin rcductase: AR: aldose reductase: CR: rin, biopterin, isoxanthopterin, pterin, as well as the carhonyl reductase. neurotransmitter metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA), were generally low. This enzyme deficiency is rare, with 7 patients detected so far (Fig. 3). 6-Pyruvoyl-tetrahydropterin synthase (PTPS) defi­ ciency (9) is the most common and heterogeneous -~) variant with about 144 patients diagnosed all over YS- ' 7 7 the world, corresponding to about 58% of all patients )l _~ j&.-~-CH 3 with a BH4 deficiency (Fig. 3). Patients with severe, H,N N ! 4 a -pe roxy-Ie ITah yd robiopte rin partial or peripheral, and transient forms have been reported (10). 7,8-Dihydroneopterin triphosphate can not be converted to 6-pyruvoyl tetrahydropterin (Fig. o H 1), resulting in an accumulation of 7,8-dihydroneo­ A~~) L-t-Oi' .-~-- H,N N ~ pterin triphosphate in tissue of these patients. This Tyr 4a-Hydroxy-telrahydrobiopterin (4a-Carbinolamine) intermediate is readily dephosphotylated by pyro­ phosphatase and excreted as dihydroneopterin and Figure 2. Phenylalanine hydroxylating system including possi­ its oxidation product, neopterin. High concentrations hie metabolic defects in hyperphenylalaninemia (Ii' ). PAH: of neopterin, monapterin (isomer of neopterin), and phenylalanine-4-hydroxylase: DHPR: dihydropteridine reduc­ 3' -hydroxysepiapterin, and only traces of biopterin tase: PHS/ PCD: PAH stimulating protein/pterin-4a-carhinol­ are found in the urine of the patients with PTPS amine dehydratase. deficiency. In servere (typical) forms of PTPS defi­ ciency the neurotransmitter status in the CSF is sim­ Biochemical observation ilar to that in patients with GTPCH deficiency. In the peripheral or partial (atypical) forms of PTPS So far four molecular diseases have been known deficiency, normal levels of neurotransmitter meta­ to cause HPA including the classic form with a bolites are measured. It is therefore of practical im­ defect in the apoenzyme of PAH. Patients with the portance to find out whether or not the patient be­ 3 variants suffer primarily from BH4 deficiency, ei­ longs to this type of PTPS deficiency and thus may ther by one of the two defects in the biosynthesis need different treatment (see below). The transient (Fig. I) or one in regeneration (Fig. 2) of the cofac­ form of PTPS deficiency may be due to a matura­ tor (7). They are all inherited autosomal recessive. tion delay of BH4 biosynthesis. In GTP cyclohydrolase I (GTPCH) deficiency (8), In dihydropteridine reductase (DHPR) deficiency the enzyme catalyzing the first step in the biosyn­ (II), the second most common form of BH4 deficien­ thesis of BH4 is deficient and no pterins are synthe­ cy (88 patients detected; Fig. 3), quinonoid-dihyd­ sized. These patients are characterized by a neopte­ robiopterin formed during the hydroxylation of rin and biopterin deficiency. Although it has been phenylalanine to tyrosine accumulates, and the Pteridines / Vol. 4 / No. I Blau 1'1 al.: Tctrahydrohiopterin dcticicncy amount of BH4 synthesized on the de novo pathway convulsions (grand mal or myoclonic attacks), distur­ is insufficient for the normal function of hepatic bances of tone and posture, drowsiness, irritahility, PAH (Fig. 2). Similarly, as in the case of PTPS abnormal movements, recurrent hyperthermia with­ and GTPCH deficiencies, these patients are mostly out infection, hypersalivation, swallowing difficul­ characterized by a depletion of catecholamines and ties. Diunml fluctuation of alertness and neurologic serotonin (12). Since quinonoid-dihydrohiopterin symptoms are also reported. Microcephaly is observ­ tautomerized readily to 7,8-dihydrohiopterin, patients ed in both diseases but with a higher incidence with DHPR deficiency excrete high amounts of total in PTPS deficiency (S2%) than in DHPR deficiency bioptelin (7,8-dihydrohiopterin and hiopterin). In (33%). However, in 13 out of 2S DHPR deficient addition, owing to the lack of BH4 in these patients, patients for whom repeated measurements with in­ there is no feedback inhihition of GTPCH and thus creasing age were available, evolution of head circum­ neopterin biosynthesis is generally activated. ference to progressive microcephaly was observed, Primapterinuria is the recently discovered valiant whether patients were treated or not. of HPA characterized hy the excretion of the 7-sub­ stituted pterins, primapterin (7-biopterin) and ana­ Arypical forms pterin (7-neopterin) in the patient's urine (13, 14). Prima­ pterinuria differs from classic PKU and other vari­ Atypical PTPS deficiency: The absence of clinical ants of BH4 deficiency because obviously these pa­ signs theoretically defines atypical forms. However, tients do not need any treatment. Nine patients have in 2 cases neonatal hypotonia was noticed, 2 were been detected so far (Fig. 3). The first patients were mentally retarded, 1 had local signs on the EEG, described by Dhondt et al. (IS) and Blaskovics and and I presented with acute but transient symptoms Giudici (16). A loading test with BH4 was the first (behaviour prohlems. neurovegetative signs, sleeping indication that primapterin
Load more

Recommended publications
  • 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]
  • 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]
  • 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]
  • Two Filipino Patients with 6-Pyruvoyltetrahydropterin Synthase Deficiency
    CASE REPORT Two Filipino Patients with 6-Pyruvoyltetrahydropterin Synthase Deficiency John Karl L. de Dios1,2, Mary Anne D. Chiong,1,2 1Department of Pediatrics, College of Medicine and Philippine General Hospital, University of the Philippines Manila; 2Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila ABSTRACT enzymes: guanosine triphosphate cyclohydrolase Hyperphenylalaninemia can result from defects in either the (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), phenylalanine hydroxylase (PAH) enzyme or in the synthesis or dihydropteridine reductase (DHPR) and pterin-4a- recycling of the active pterin, tetrahydrobiopterin (BH4), which is an carbinolamine dehydratase (PCD). The first two enzymes are obligate co-factor for the PAH enzyme, as well as tyrosine hydroxylase and tryptophan hydroxylase. One of the most common causes of BH4 involved in the biosynthesis of tetrahydrobiopterin, the last 3 deficiency is a defect in the synthesis of 6-pyruvoyltetrahydropterin two in its regeneration. A third enzyme in the biosynthesis synthase (PTPS) enzyme. Patients present with progressive neurological of BH4 is sepiapterin reductase, but its deficiency is not disease such as mental retardation, convulsions and disturbance of associated with hyperphenylalaninemia 1 (Figure 1). tone and posture despite strict adherence to diet and good metabolic Clinical manifestations for a severe PAH defect or BH4 control. The authors report the first two cases of PTPS deficiency in the synthesis/recycling defect can be similar, with patients Philippines. Both are females with initial phenylalanine levels of more presenting with progressive neurological impairment than 1300 umol/L who continued to develop neurologic deterioration during infancy. Since management of these patients will despite good metabolic control and strict adherence to diet.
    [Show full text]
  • Building Microbial Factories for The
    Contents lists available at ScienceDirect Metabolic Engineering journal homepage: www.elsevier.com/locate/meteng Building microbial factories for the production of aromatic amino acid pathway derivatives: From commodity chemicals to plant-sourced natural products ∗ Mingfeng Caoa,b,1, Meirong Gaoa,b,1, Miguel Suásteguia,b, Yanzhen Meie, Zengyi Shaoa,b,c,d, a Department of Chemical and Biological Engineering, Iowa State University, USA b NSF Engineering Research Center for Biorenewable Chemicals (CBiRC), Iowa State University, USA c Interdepartmental Microbiology Program, Iowa State University, USA d The Ames Laboratory, USA e School of Life Sciences, No.1 Wenyuan Road, Nanjing Normal University, Qixia District, Nanjing, 210023, China ARTICLE INFO ABSTRACT Keywords: The aromatic amino acid biosynthesis pathway, together with its downstream branches, represents one of the Aromatic amino acid biosynthesis most commercially valuable biosynthetic pathways, producing a diverse range of complex molecules with many Shikimate pathway useful bioactive properties. Aromatic compounds are crucial components for major commercial segments, from De novo biosynthesis polymers to foods, nutraceuticals, and pharmaceuticals, and the demand for such products has been projected to Microbial production continue to increase at national and global levels. Compared to direct plant extraction and chemical synthesis, Flavonoids microbial production holds promise not only for much shorter cultivation periods and robustly higher yields, but Stilbenoids Benzylisoquinoline alkaloids also for enabling further derivatization to improve compound efficacy by tailoring new enzymatic steps. This review summarizes the biosynthetic pathways for a large repertoire of commercially valuable products that are derived from the aromatic amino acid biosynthesis pathway, and it highlights both generic strategies and spe- cific solutions to overcome certain unique problems to enhance the productivities of microbial hosts.
    [Show full text]
  • Neurological Aspects of Biopterin Metabolism
    Arch Dis Child: first published as 10.1136/adc.61.2.130 on 1 February 1986. Downloaded from Archives of Disease in Childhood, 1986, 61, 130-137 Neurological aspects of biopterin metabolism I SMITH, R J LEEMING, N P C CAVANAGH, AND K HYLAND Hospital for Sick Children and Institute of Child Health, London, and The General Hospital, Birmingham SUMMARY Plasma total biopterin concentration was measured by bioassay in 59 infants with hyperphenylalaninaemia and in 50 children with developmental regression and or movement disorder with normal plasma phenylalanine concentrations. In infants with raised phenylalanine concentrations plasma biopterin concentrations were significantly raised in proportion to the phenylalanine values. Five patients had plasma biopterin concentrations at the extremes of the range, and of these two had defective biopterin metabolism. One with low plasma biopterin concentration apparently had a partial defect of biopterin synthesis but died before investigations were complete. One with high plasma biopterin concentration, even when phenylalanine concentrations had fallen to the normal range, had dihydropteridine reductase deficiency. In this patient concentrations of homovanillic acid and 5-hydroxyindolacetic acid in the cerebrospinal fluid (CSF) were severely reduced. In children without hyperphenylalaninaemia plasma biopterin concentrations were normal. Twenty two patients were subjected to lumbar puncture, of whom six with developmental regression without movement disorder had normal CSF biopterin concentrations, and 11 withcopyright. movement disorder other than torsion dystonia had significantly lower CSF biopterin concentrations. Five patients with torsion dystonia had normal biopterin concentrations. Tetrahydrobiopterin is the essential cofactor for three hydroxylation reactions, the conversion of GTP http://adc.bmj.com/ phenylalanine to tyrosine, tyrosine to L-dopa, and tryptophan to 5-hydroxytryptophan.' These last two B, BH2 j reactions are the rate limiting steps of catecholamine Ne 2P3 --- NeH2 and serotonin synthesis.
    [Show full text]
  • Oral Berberine Improves Brain Dopa/Dopamine Levels to Ameliorate Parkinson’S Disease by Regulating Gut Microbiota
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans ARTICLE OPEN Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota Yan Wang1, Qian Tong2, Shu-Rong Ma1, Zhen-Xiong Zhao1, Li-Bin Pan1, Lin Cong1, Pei Han1, Ran Peng1, Hang Yu1, Yuan Lin1, Tian-Le Gao1, Jia-Wen Shou1, Xiao-Yang Li1, Xian-Feng Zhang2, Zheng-Wei Zhang1, Jie Fu1, Bao-Ying Wen1, Jin-Bo Yu1, Xuetao Cao3 and Jian-Dong Jiang 1 The phenylalanine–tyrosine–dopa–dopamine pathway provides dopamine to the brain. In this process, tyrosine hydroxylase (TH) is the rate-limiting enzyme that hydroxylates tyrosine and generates levodopa (L-dopa) with tetrahydrobiopterin (BH4) as a coenzyme. Here, we show that oral berberine (BBR) might supply H• through dihydroberberine (reduced BBR produced by bacterial nitroreductase) and promote the production of BH4 from dihydrobiopterin; the increased BH4 enhances TH activity, which accelerates the production of L-dopa by the gut bacteria. Oral BBR acts in a way similar to vitamins. The L-dopa produced by the intestinal bacteria enters the brain through the circulation and is transformed to dopamine. To verify the gut–brain dialog activated by BBR’s effect, Enterococcus faecalis or Enterococcus faecium was transplanted into Parkinson’s disease (PD) mice. The bacteria significantly increased brain dopamine and ameliorated PD manifestation in mice; additionally, combination of BBR with bacteria showed better therapeutic effect than that with bacteria alone. Moreover, 2,4,6-trimethyl-pyranylium tetrafluoroborate (TMP-TFB)- derivatized matrix-assisted laser desorption mass spectrometry (MALDI-MS) imaging of dopamine identified elevated striatal dopamine levels in mouse brains with oral Enterococcus, and BBR strengthened the imaging intensity of brain dopamine.
    [Show full text]
  • Analysis of Catecholamines and Pterins in Inborn Errors of Monoamine Neurotransmitter Metabolism—From Past to Future
    cells Review Analysis of Catecholamines and Pterins in Inborn Errors of Monoamine Neurotransmitter Metabolism—From Past to Future Sabine Jung-Klawitter * and Oya Kuseyri Hübschmann Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany * Correspondence: [email protected]; Tel.: +49-(0)6221-5639586 Received: 30 June 2019; Accepted: 4 August 2019; Published: 9 August 2019 Abstract: Inborn errors of monoamine neurotransmitter biosynthesis and degradation belong to the rare inborn errors of metabolism. They are caused by monogenic variants in the genes encoding the proteins involved in (1) neurotransmitter biosynthesis (like tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC)), (2) in tetrahydrobiopterin (BH4) cofactor biosynthesis (GTP cyclohydrolase 1 (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SPR)) and recycling (pterin-4a-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR)), or (3) in co-chaperones (DNAJC12). Clinically, they present early during childhood with a lack of monoamine neurotransmitters, especially dopamine and its products norepinephrine and epinephrine. Classical symptoms include autonomous dysregulations, hypotonia, movement disorders, and developmental delay. Therapy is predominantly based on supplementation of missing cofactors or neurotransmitter precursors. However, diagnosis is difficult and is predominantly based on quantitative detection of neurotransmitters, cofactors, and precursors in cerebrospinal fluid (CSF), urine, and blood. This review aims at summarizing the diverse analytical tools routinely used for diagnosis to determine quantitatively the amounts of neurotransmitters and cofactors in the different types of samples used to identify patients suffering from these rare diseases. Keywords: inborn errors of metabolism; catecholamines; pterins; HPLC; fluorescence detection; electrochemical detection; MS/MS 1.
    [Show full text]
  • Early Diagnosis of 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency
    Shintaku: Early diagnosis of 6-pyruvoyl-tetrahydropterin synthase deficiency Pteridines Vol. 5, 1994, pp. 18-27 Early Diagnosis of 6-Pyruvoyl-tetrahydropterin Synthase Deficiency Haruo Shintaku Department of Pediatrics, Osaka City University Medical School, Osaka 545, Japan (Received December 10, 1993) Summary 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, which used to be called dihydrobiopterin synthase deficiency, is the most common kind of tetrahydrobiopterin deficiency. Early treatment by administration of tetrahydrobiopterin and neurotransmitter precursors helps to prevent neurological injury, so prompt diag­ nosis of neonates with hyperphenylalaninemia discovered by screening for phenylketonuria is necessary. Three patients with PTPS deficiency were diagnosed by pteridine analysis. All patients had low biopterin and high neopterin levels in the urine, resulting in a neopterin to biopterin ratio (NIB) much higher than that of age-matched controls. The mean NIB in the parents of these patients was twice that of healthy unrelated adults. PTPS activity was measured in one of these patients with PTPS deficiency and in his family members; the patient was homozygous and his parents were heterozygous for PTPS deficiency. This result meant that NIB could be used as an index of PTPS activity. In healthy subjects studied cross­ sectionally, urinary levels of pteridine decreased in groups of increasing age, and the same change was found in subjects with hyperphenylalaninemia studied cross-sectionally. Thus, pteridine values of patients
    [Show full text]
  • Tetrahydropiopterin Deficiencies: Diagnosis, Treatment and Follow-Up
    TETRAHYDROPIOPTERIN DEFICIENCIES: DIAGNOSIS, TREATMENT AND FOLLOW-UP Alberto Burlina Division of Metabolic Disorders Department of Pediatrics - University Hospital Padova, Italy PHENYLALANINE HYDROXYLATING SYSTEM • Phenylalanine hydroxylase deficiency Phenylketonuria Phenylketonuria responsiveness to tetrahydrobiopterin • Tetrahydrobiopterin deficiencies GTP-CH PTPS SR DHPR PAH PCD DE NOVO BIOSYNTHETIC PATHWAY FROM GTP GFRP + BH4 RECYCLING PATHWAY SYNTHESIS OF TETRAHYDROBIOPTERIN (salvage pathway) TETRAHYDROBIOPTERIN COFACTOR DEFICIENCIES WITHOUT HYPERPHENYLALANINEMIA Segawa disease Sepiapterin reductase deficiency (SR) WITH HYPERPHENYLALANINEMIA GTP cyclohydrolase I deficiency (GTPCH) 6-Pyruvoyltetrahydropterin synthase deficiency (PTPS) Dihydropteridine reductase deficiency (DHPR) Pterin-4-α-carbinolamine dehydratase (PCD) DIFFERENTIAL DIAGNOSIS OF BH4 DEFECTS + + + +/- TETRAHYDROBIOPTERIN METABOLISM PATHWAY GTP GTP-Cyclohydrolase NH2TP Neopterin PTPS 6PTP SR BH4 Tyr Trp DHPR PAH TH TPH L-Dopa 5-HTP qBH2 COMT / MAO AADC MAO HVA Dopamine Serotonin 5HIAA DH SNA HIOMT MHPG Norepinephrine N-acetylserotonin Melatonin LOGISTICS OF CSF INVESTIGATIONS • Sample preparation • Freeze CSF immediately at – – preservatives 70º C – snap freezing • Contamination with blood disturb results (centrifuge – volume immediately before freezing) • Sample storage & transport • Chose the right technique (s) • Certain amount of CSF is (very low levels of metabolites necessary (3-4 ml), collect in at in CSF) least 5 fractions 0,5 – 1 ml • Establish own control
    [Show full text]
  • Consensus Guideline for the Diagnosis and Treatment of Tetrahydrobiopterin
    Opladen et al. Orphanet Journal of Rare Diseases (2020) 15:126 https://doi.org/10.1186/s13023-020-01379-8 REVIEW Open Access Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies Thomas Opladen1*†, Eduardo López-Laso2†, Elisenda Cortès-Saladelafont3,4†, Toni S. Pearson5, H. Serap Sivri6, Yilmaz Yildiz6, Birgit Assmann1, Manju A. Kurian7,8, Vincenzo Leuzzi9, Simon Heales10, Simon Pope10, Francesco Porta11, Angeles García-Cazorla3, Tomáš Honzík12, Roser Pons13, Luc Regal14, Helly Goez15, Rafael Artuch16, Georg F. Hoffmann1, Gabriella Horvath17, Beat Thöny18, Sabine Scholl-Bürgi19, Alberto Burlina20, Marcel M. Verbeek21, Mario Mastrangelo9, Jennifer Friedman22, Tessa Wassenberg14, Kathrin Jeltsch1†, Jan Kulhánek12*†, Oya Kuseyri Hübschmann1† and on behalf of the International Working Group on Neurotransmitter related Disorders (iNTD) Abstract Background: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world
    [Show full text]
  • HMT Companyoverview 21060
    HMT Drug and Biomarker Discovery by HMT’s Next-gen Metabolomics Human Metabolome Technologies (HMT) has been providing metabolome analysis service to researchers worldwide since 2003 and contributed to over 6,000 projects with more than 500 publications. Continuously innovating CE-MS-based metabolomics technology, HMT dramatically improved analytical sensitivity and coverage of target metabolites recently and developed a sophisticated chemoinformatics approach for predicting the structure of unknown compounds, with which dozens of new metabolites were successfully identified. Taken together, HMT introduces a novel solution for elucidating drug efficacy and toxicity mechanisms and discovering patient stratification biomarkers using the cutting-edge metabolomics technologies. Human Metabolome Technologies, Inc. Company Profile Basic Information l Business ü Metabolome analysis service ü Biomarker development l Foundation : July 1st, 2003 from Keio University l IPO : TSE Mothers in 2013 l Employees : 78 (As of April 2021) l President : Katsuhito Hashizume l Headquarter: Tsuruoka, Yamagata, Japan l Sales office : Tokyo, Japan l Subsidiary : HMT America (Boston, USA) HMT Europe (Leiden, Netherlands) l Major clients: Academic institutions, pharma, food and cosmetics companies worldwide 2 Metabolomics Market Growth 10000 CAGR (2010-2020): 20.0%!! 9121 9000 “Genome”: 4.2% 8000 “Proteome”: 6.2% 7000 6000 5000 4000 Publication 3000 2000 1472 1000 Search key in PubMed “metabolomic OR metabolome OR 0 metabolomics OR metabonomic OR metabonomics OR 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 metabonome” Year of Publication 3 CE-MS-based Metabolomics Best platform for comprehensive analysis of hydrophilic metabolites Capillary Electrophoresis (CE) Mass Spectrometry (MS) Capillary Compounds are measured separately based on their mass and time.
    [Show full text]