DOCSLIB.ORG

Disorders of the Pentose Phosphate Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Disorders of the Pentose Phosphate Pathway 8 Disorders of the Pentose Phosphate Pathway Mirjam M.C. Wamelink, Vassili Valayannopoulos, Cornelis Jakobs 8.1 Ribose-5-Phosphate Isomerase Deficiency – 153 8.2 Transaldolase Deficiency – 153 References – 155 J.-M. Saudubray et. al (Eds.), Inborn Metabolic Diseases, DOI 10.1007/978-3-642-15720-2_8, © Springer- Verlag Berlin Heidelberg 2012 152 Chapter 8 · Disorders of the Pentose Phosphate Pathway The Pentose Phosphate Pathway phate to a pentose-phosphate and CO2, and the sec- The pentose phosphate pathway (PPP; ⊡ Fig. 8.1) con- ond part, a nonoxidative, reversible pathway, produces sists of two distinct parts, which fulfil two specific roles: ribose for nucleotide and nucleic acid synthesis and the first part, an oxidative, nonreversible pathway, al- connects pentose phosphates to glycolytic intermedi- lows reduction of nicotinamide adenine dinucleotide ates. To date, three inborn errors in the PPP have been phosphate (NADP+) while converting glucose-6-phos- described. 8 ⊡ Fig. 8.1. The pentose phosphate pathway. The conversion of the sugar phosphates into their corresponding sugars and polyols (dot- ted arrows) has not been proven in humans. NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced form; 1, glucose-6- phosphate dehydrogenase; 2, ribose-5-phosphate isomerase ; 3, transaldolase ; 4, sedoheptulokinase Three inborn errors in the pentose phosphate pathway (PPP) duced haemolytic anaemia is the main presenting symptom are known. of this defect. G6PD deficiency is an X-linked disorder. As this Glucose-6-phosphate dehydrogenase deficiency is a is a haematological disorder it is not discussed further. defect in the first, irreversible step of the pathway. As a con- Deficiency of ribose-5-phosphate isomerase has sequence, NADPH production is decreased, making erythro- been described in one patient, who presented with develop- cytes vulnerable to oxidative stress. Drug- and fava bean-in- mental delay and a slowly progressive leukoencephalopathy. 153 8.2 · Transaldolase Deficiency 8 Transaldolase deficiency has been diagnosed in ten 5-phosphate, and xylulose and arabitol from ribulose-5- unrelated families. All patients presented in the neonatal or phosphate via xylulose-5-phosphate. The concentrations antenatal period with hepatosplenomegaly, liver function of ribitol and arabitol displayed a steep descending brain/ problems, hepatic fibrosis and haemolytic anaemia. CSF/plasma gradient. Moreover, the most common, 57-kb deletion in neph- ropathic cystinosis patients, has been shown also to cause deficiency of sedoheptulokinase, resulting in urinary accu- 8.1.3 Genetics mulation of sedoheptulose [1] ( Chapter 43). Essential pentosuria is the result of a partial defi- The human RPIA gene is located at locus 2p11.2 and has ciency of L-xylulose reductase (xylitol dehydrogenase ) and nine exons. Human RPIA consists of a monomer of 311 affects the related glucuronic acid pathway . Whereas the amino acids. In the RPI-deficient patient two mutant PPP involves D-stereoisomers, glucuronic acid gives rise to alleles were demonstrated: a 1-bp deletion (c.540delG), L-xylulose , which is subsequently converted into xylitol and resulting in a frameshift at codon 181 and a predicted D-xylulose . Affected individuals excrete large amounts of truncated protein of 196 amino acids, and a missense L-xylulose in urine. Pentosuria occurs almost exclusively in mutation c.182C>T, resulting in an ala-to-val substitution Jewish people. This is a benign disorder and is not discussed (p.A61V). The finding of two mutant alleles in the patient further here. and apparently healthy parents suggests autosomal reces- sive inheritance. 8.1 Ribose-5-Phosphate Isomerase Deficiency 8.1.4 Diagnostic Tests 8.1.1 Clinical Presentation The diagnosis of RPI deficiency can be made by the analysis of sugars and polyols in urine, plasma or CSF. The one patient recorded with ribose-5-phosphate Urinary ribitol and arabitol, as well as xylulose, are ele- isomerase (RPI) deficiency, a boy, was born after an un- vated (more than 10 times the upper limit of the reference complicated pregnancy as the only child of healthy, unre- ranges). Extremely high concentrations of these pentitols lated parents [2, 3]. He had psychomotor retardation from are also found in CSF. The myo-inositol concentration early in life and developed epilepsy at the age of 4 years. in CSF is decreased. In vivo brain MRS reveals elevated From the age of 7 years a slow neurological regression oc- peaks in the 3.5- to 4.0-ppm region, which correspond to curred, with prominent cerebellar ataxia, some spasticity, arabitol and ribitol. optic atrophy and a mild sensorimotor neuropathy. Neither The diagnosis can be confirmed by an enzyme assay organomegaly nor dysfunction of the internal organs was in fibroblasts or lymphoblasts, and by sequence analysis present. His growth parameters were normal. He is now of the RPIA gene. in his twenties. Magnetic resonance imaging (MRI) of the brain at 11 and 14 years showed extensive abnormalities of the cerebral white matter with prominent involvement of 8.1.5 Treatment and Prognosis the U-fibres and a slightly swollen appearance with some widening of the gyri. He has a slowly progressive leuko- Therapeutic options for RPI deficiency have not yet been encephalopathy. Magnetic resonance spectroscopy (MRS) identified. The prognosis is unclear. revealed highly elevated peaks in the 3.5-4.0 ppm region, or the sugar and polyol region of the spectrum, which were identified as representing ribitol and d-arabitol. 8.2 Transaldolase Deficiency 8.2.1 Clinical Presentation 8.1.2 Metabolic Derangement Transaldolase (TALDO) deficiency was first described RPI is an enzyme of the reversible part of the PPP. In in 2001 [4] in a single patient presenting with cirrhosis, theory, this defect leads to a decreased capacity to in- with nine additional patients reported from five different terconvert ribulose-5-phosphate and ribose-5-phosphate families [4-9]. and results in the accumulation of sugars and polyols: The patients were each born to consanguineous ribose and ribitol from ribose-5-phosphate or ribulose- couples native to Turkey, the United Arabic Emirates, 154 Chapter 8 · Disorders of the Pentose Phosphate Pathway Pakistan or Poland, suggesting rare alleles in the human in the majority in whom assessment was possible (three population. patients died before the age of 6 months). In contrast to Wide phenotypic variability has been reported in those with RPI deficiency, brain MRI and MRS did not TALDO-deficient patients (⊡ Table 8.1) [4-7, 9, 10]. Most reveal abnormalities in patients with TALDO deficiency. patients display the first symptoms of the disease in the neonatal or antenatal period, when intrauterine growth retardation, oligohydramnios and hydrops fetalis have 8.2.2 Metabolic Derangement been described, leading to a medical termination of preg- nancy in the case of a 28-week fetus presenting also with TALDO is located in the reversible part of the PPP a polymalformative syndrome [6]. Neonates present with and recycles pentose phosphates into glycolytic inter- hepatosplenomegaly, bleeding, abnormal liver function mediates in concerted action with transketolase. Its tests, cholestatic jaundice and elevated liver enzymes. deficiency results in the accumulation of polyols derived Hepatic fibrosis and cirrhosis (in older patients) are the from the pathway intermediates and seven-carbon sug- pathological liver hallmarks. Haemolytic anaemia is also ars from sedoheptulose-7-phosphate . In a majority of a constant feature found in all patients. TALDO-deficient patients elevated urinary concentra- Most patients showed dysmorphic features (antimon- tion of the citric acid cycle intermediates 2-oxoglutaric goloid slant, low-set ears and cutis laxa, hypertrichosis), acid and fumaric acid were detected, indicating a pos- neonatal oedema and congenital heart defects (septal sible disturbed mitochondrial metabolism in TALDO defects, cardiomyopathy, tetralogy of Fallot). deficiency [11]. 8 Renal manifestations (tubulopathy, renal failure, nephrocalcinosis) and endocrine disorders have fre- quently been reported, leading to intermittent hypogly- 8.2.3 Genetics caemia, and testicular or ovarian insufficiency leading to cryptorchidism, clitoris enlargement, intermittent hy- The human TALDO gene (TALDO1) is located on chro- poglycaemia and bone development abnormalities with mosome 11p15.5-p15.4, and a pseudogene, on chromo- rickets. some 1p34.1-p33. The mode of inheritance is autosomal Mild transient hypotonia was described in several recessive. Mutations detected in the TALDO1 gene in- patients, but mental and motor development were normal clude missense mutations, deletions and a duplication. ⊡ Table 8.1. Principal clinical manifestations in reported patients with TALDO deficiency Patient no. [ref.] 1 [4] 2 [5] 3 [6] 4 [6] 5 [6] 6 [6] 7 [8] 8 [10] 9 [9] 10 [9] Dysmorphism or cutis laxa - +++++++- - Consanguinity ++++++++++ IUGR + - +++++++- Neonatal oedema/oligoamnios - + - ++ - + + - + - Liver + + + + + + + + + + – function + + + + + + + + + + – fibrosis/cirrhosis Anaemia +++- +++- ++ Cardiac +++++++- - - Renal +++? +++- - - Endocrine - ? + ? - + ---- Psychomotor development n† ?† n† ?† n n Mild Mild nn delay delay IUGR, intrauterine growth retardation; +, presence; -, absence; ?, unknown; †, deceased patient 155 References 8 8.2.4 Diagnostic Tests References Diagnosis of TALDO deficiency is achieved by detecting [1] Wamelink MM, Struys EA, Jansen EE et al. (2008) Sedoheptuloki-
Load more

Recommended publications
  • Mitochondrial Involvement and Erythronic Acid As a Novel Biomarker in Transaldolase Deficiency Udo F.H
    Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency Udo F.H. Engelke, Fokje S.M. Zijlstra, Fanny Mochel, Vassili Valayannopoulos, Daniel Rabier, Leo A.J. Kluijtmans, András Perl, Nanda M. Verhoeven-Duif, Pascale de Lonlay, Mirjam M.C. Wamelink, et al. To cite this version: Udo F.H. Engelke, Fokje S.M. Zijlstra, Fanny Mochel, Vassili Valayannopoulos, Daniel Rabier, et al.. Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency. Biochimica et Biophysica Acta - Molecular Basis of Disease, Elsevier, 2010, 1802 (11), pp.1028. 10.1016/j.bbadis.2010.06.007. hal-00623290 HAL Id: hal-00623290 https://hal.archives-ouvertes.fr/hal-00623290 Submitted on 14 Sep 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ÔØ ÅÒÙ×Ö ÔØ Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency Udo F.H. Engelke, Fokje S.M. Zijlstra, Fanny Mochel, Vassili Valayannopou- los, Daniel Rabier, Leo A.J. Kluijtmans, Andr´asPerl, Nanda M. Verhoeven- Duif, Pascale de Lonlay, Mirjam M.C. Wamelink, Cornelis Jakobs, Eva´ Morava, Ron A. Wevers PII: S0925-4439(10)00117-1 DOI: doi: 10.1016/j.bbadis.2010.06.007 Reference: BBADIS 63115 To appear in: BBA - Molecular Basis of Disease Received date: 23 April 2010 Revised date: 11 June 2010 Accepted date: 11 June 2010 Please cite this article as: Udo F.H.
    [Show full text]
  • Table S1. Disease Classification and Disease-Reaction Association
    Table S1. Disease classification and disease-reaction association Disorder class Associated reactions cross Disease Ref[Goh check et al.
    [Show full text]
  • Inborn Defects in the Antioxidant Systems of Human Red Blood Cells
    Free Radical Biology and Medicine 67 (2014) 377–386 Contents lists available at ScienceDirect Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed Review Article Inborn defects in the antioxidant systems of human red blood cells Rob van Zwieten a,n, Arthur J. Verhoeven b, Dirk Roos a a Laboratory of Red Blood Cell Diagnostics, Department of Blood Cell Research, Sanquin Blood Supply Organization, 1066 CX Amsterdam, The Netherlands b Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands article info abstract Article history: Red blood cells (RBCs) contain large amounts of iron and operate in highly oxygenated tissues. As a result, Received 16 January 2013 these cells encounter a continuous oxidative stress. Protective mechanisms against oxidation include Received in revised form prevention of formation of reactive oxygen species (ROS), scavenging of various forms of ROS, and repair 20 November 2013 of oxidized cellular contents. In general, a partial defect in any of these systems can harm RBCs and Accepted 22 November 2013 promote senescence, but is without chronic hemolytic complaints. In this review we summarize the Available online 6 December 2013 often rare inborn defects that interfere with the various protective mechanisms present in RBCs. NADPH Keywords: is the main source of reduction equivalents in RBCs, used by most of the protective systems. When Red blood cells NADPH becomes limiting, red cells are prone to being damaged. In many of the severe RBC enzyme Erythrocytes deficiencies, a lack of protective enzyme activity is frustrating erythropoiesis or is not restricted to RBCs. Hemolytic anemia Common hereditary RBC disorders, such as thalassemia, sickle-cell trait, and unstable hemoglobins, give G6PD deficiency Favism rise to increased oxidative stress caused by free heme and iron generated from hemoglobin.
    [Show full text]
  • Pentose Phosphate Pathway in Health and Disease: from Metabolic
    UNIVERSIDADE DE LISBOA FACULDADE DE FARMÁCIA DEPARTAMENTO DE BIOQUÍMICA PENTOSE PHOSPHATE PATHWAY IN HEALTH AND DISEASE: FROM METABOLIC DYSFUNCTION TO BIOMARKERS Rúben José Jesus Faustino Ramos Orientador: Professora Doutora Maria Isabel Ginestal Tavares de Almeida Mestrado em Análises Clínicas 2013 Pentose Phosphate Pathway in health and disease: From metabolic dysfunction to biomarkers . Via das Pentoses Fosfato na saúde e na doença: Da disfunção metabólica aos biomarcadores Dissertação apresentada à Faculdade de Farmácia da Universidade de Lisboa para obtenção do grau de Mestre em Análises Clínicas Rúben José Jesus Faustino Ramos Lisboa 2013 Orientador: Professora Doutora Maria Isabel Ginestal Tavares de Almeida The studies presented in this thesis were performed at the Metabolism and Genetics group, iMed.UL (Research Institute for Medicines and Pharmaceutical Sciences), Faculdade de Farmácia da Universidade de Lisboa, Portugal, under the supervision of Prof. Maria Isabel Ginestal Tavares de Almeida, and in collaboration with the Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Dr. Mirjam Wamelink. De acordo com o disposto no ponto 1 do artigo nº 41 do Regulamento de Estudos Pós- Graduados da Universidade de Lisboa, deliberação nº 93/2006, publicada em Diário da Republica – II série nº 153 – de 5 julho de 2003, o autor desta dissertação declara que participou na conceção e execução do trabalho experimental, interpretação dos resultados obtidos e redação dos manuscritos. Para os meus pais e
    [Show full text]
  • Pentose Phosphate Pathway Biochemistry, Metabolism and Inherited Defects
    Pentose phosphate pathway biochemistry, metabolism and inherited defects Amsterdam 2008 Mirjam M.C. Wamelink The research described in this thesis was carried out at the Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands. The publication of this thesis was financially supported by: Department of Clinical Chemistry, VU University Medical Center Amsterdam E.C. Noyons Stichting ter bevordering van de Klinische Chemie in Nederland J.E. Jurriaanse Stichting te Rotterdam Printed by: Printpartners Ipskamp BV, Enschede ISBN: 978-90-9023415-1 Cover: Representation of a pathway of sugar Copyright Mirjam Wamelink, Amsterdam, The Netherlands, 2008 2 VRIJE UNIVERSITEIT Pentose phosphate pathway biochemistry, metabolism and inherited defects ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Geneeskunde op donderdag 11 december 2008 om 13.45 uur in de aula van de universiteit, De Boelelaan 1105 door Mirjam Maria Catharina Wamelink geboren te Alkmaar 3 promotor: prof.dr.ir. C.A.J.M. Jakobs copromotor: dr. E.A. Struijs 4 Abbreviations 6PGD 6-phosphogluconate dehydrogenase ADP adenosine diphosphate ATP adenosine triphosphate CSF cerebrospinal fluid DHAP dihydroxyacetone phosphate G6PD glucose-6-phosphate dehydrogenase GA glyceraldehyde GAPDH glyceraldehyde-3-phosphate dehydrogenase GSG oxidized glutathione
    [Show full text]
  • Diagnose a Broad Range of Metabolic Disorders with a Single Test, Global
    PEDIATRIC Assessing or diagnosing a metabolic disorder commonly requires several tests. Global Metabolomic Assisted Pathway Screen, commonly known as Global MAPS, is a unifying test GLOBAL MAPS™ for analyzing hundreds of metabolites to identify changes Global Metabolomic or irregularities in biochemical pathways. Let Global MAPS Assisted Pathway Screen guide you to an answer. Diagnose a broad range of metabolic disorders with a single test, Global MAPS Global MAPS is a large scale, semi-quantitative metabolomic profiling screen that analyzes disruptions in both individual analytes and pathways related to biochemical abnormalities. Using state-of-the-art technologies, Global Metabolomic Assisted Pathway Screen (Global MAPS) provides small molecule metabolic profiling to identify >700 metabolites in human plasma, urine, or cerebrospinal fluid. Global MAPS identifies inborn errors of metabolism (IEMs) that would ordinarily require many different tests. This test defines biochemical pathway errors not currently detected by routine clinical or genetic testing. IEMs are inherited metabolic disorders that prevent the body from converting one chemical compound to another or from transporting a compound in or out of a cell. NORMAL PROCESS METABOLIC ERROR These processes are necessary for essentially all bodily functions. Most IEMs are caused by defects in the enzymes that help process nutrients, which result in an accumulation of toxic substances or a deficiency of substances needed for normal body function. Making a swift, accurate diagnosis
    [Show full text]
  • SSIEM Classification of Inborn Errors of Metabolism 2011
    SSIEM classification of Inborn Errors of Metabolism 2011 Disease group / disease ICD10 OMIM 1. Disorders of amino acid and peptide metabolism 1.1. Urea cycle disorders and inherited hyperammonaemias 1.1.1. Carbamoylphosphate synthetase I deficiency 237300 1.1.2. N-Acetylglutamate synthetase deficiency 237310 1.1.3. Ornithine transcarbamylase deficiency 311250 S Ornithine carbamoyltransferase deficiency 1.1.4. Citrullinaemia type1 215700 S Argininosuccinate synthetase deficiency 1.1.5. Argininosuccinic aciduria 207900 S Argininosuccinate lyase deficiency 1.1.6. Argininaemia 207800 S Arginase I deficiency 1.1.7. HHH syndrome 238970 S Hyperammonaemia-hyperornithinaemia-homocitrullinuria syndrome S Mitochondrial ornithine transporter (ORNT1) deficiency 1.1.8. Citrullinemia Type 2 603859 S Aspartate glutamate carrier deficiency ( SLC25A13) S Citrin deficiency 1.1.9. Hyperinsulinemic hypoglycemia and hyperammonemia caused by 138130 activating mutations in the GLUD1 gene 1.1.10. Other disorders of the urea cycle 238970 1.1.11. Unspecified hyperammonaemia 238970 1.2. Organic acidurias 1.2.1. Glutaric aciduria 1.2.1.1. Glutaric aciduria type I 231670 S Glutaryl-CoA dehydrogenase deficiency 1.2.1.2. Glutaric aciduria type III 231690 1.2.2. Propionic aciduria E711 232000 S Propionyl-CoA-Carboxylase deficiency 1.2.3. Methylmalonic aciduria E711 251000 1.2.3.1. Methylmalonyl-CoA mutase deficiency 1.2.3.2. Methylmalonyl-CoA epimerase deficiency 251120 1.2.3.3. Methylmalonic aciduria, unspecified 1.2.4. Isovaleric aciduria E711 243500 S Isovaleryl-CoA dehydrogenase deficiency 1.2.5. Methylcrotonylglycinuria E744 210200 S Methylcrotonyl-CoA carboxylase deficiency 1.2.6. Methylglutaconic aciduria E712 250950 1.2.6.1. Methylglutaconic aciduria type I E712 250950 S 3-Methylglutaconyl-CoA hydratase deficiency 1.2.6.2.
    [Show full text]
  • 1 a Clinical Approach to Inherited Metabolic Diseases
    1 A Clinical Approach to Inherited Metabolic Diseases Jean-Marie Saudubray, Isabelle Desguerre, Frédéric Sedel, Christiane Charpentier Introduction – 5 1.1 Classification of Inborn Errors of Metabolism – 5 1.1.1 Pathophysiology – 5 1.1.2 Clinical Presentation – 6 1.2 Acute Symptoms in the Neonatal Period and Early Infancy (<1 Year) – 6 1.2.1 Clinical Presentation – 6 1.2.2 Metabolic Derangements and Diagnostic Tests – 10 1.3 Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond) – 11 1.3.1 Clinical Presentation – 11 1.3.2 Metabolic Derangements and Diagnostic Tests – 19 1.4 Chronic and Progressive General Symptoms/Signs – 24 1.4.1 Gastrointestinal Symptoms – 24 1.4.2 Muscle Symptoms – 26 1.4.3 Neurological Symptoms – 26 1.4.4 Specific Associated Neurological Abnormalities – 33 1.5 Specific Organ Symptoms – 39 1.5.1 Cardiology – 39 1.5.2 Dermatology – 39 1.5.3 Dysmorphism – 41 1.5.4 Endocrinology – 41 1.5.5 Gastroenterology – 42 1.5.6 Hematology – 42 1.5.7 Hepatology – 43 1.5.8 Immune System – 44 1.5.9 Myology – 44 1.5.10 Nephrology – 45 1.5.11 Neurology – 45 1.5.12 Ophthalmology – 45 1.5.13 Osteology – 46 1.5.14 Pneumology – 46 1.5.15 Psychiatry – 47 1.5.16 Rheumatology – 47 1.5.17 Stomatology – 47 1.5.18 Vascular Symptoms – 47 References – 47 5 1 1.1 · Classification of Inborn Errors of Metabolism 1.1 Classification of Inborn Errors Introduction of Metabolism Inborn errors of metabolism (IEM) are individually rare, but collectively numerous.
    [Show full text]
  • Genetic Disorders
    Kingdom of Saudi Arabia Ministry of Higher Education King Saud University College of Science Biochemistry Department Disorders of the Pentose Phosphate Pathway Dr. Mohamed Saad Daoud Dr. Mohamed Saad Daoud 1 Three inborn errors in the pentose phosphate pathway are known. In glucose-6-phosphate dehydrogenase deficiency, there is a defect in the first, irreversible step of the pathway. As a consequence NADPH production is decreased, making erythrocytes susceptible to oxidative stress. Drug-and fava bean-induced haemolytic anaemia is the main presenting symptom of this defect. Dr. Mohamed Saad Daoud 2 Deficiency of ribose-5-phosphate isomerase has been described in one patient who suffered from a progressive leucoencephalopathy and developmental delay. Transaldolase deficiency has been diagnosed in three unrelated families. All patients presented in the newborn period with liver problems. Dr. Mohamed Saad Daoud 3 Essential pentosuria, due to a defect in the enzyme xylitol dehydrogenase, affects the related glucuronic acid pathway. Whereas the pentose phosphate pathway involves D stereoisomers, glucuronic acid gives rise to L- xylulose which is subsequently converted into xylitol and D- xylulose. Affected individuals excrete large amounts of L- xylulose in urine. Dr. Mohamed Saad Daoud 4 Ribose-5-Phosphate Isomerase Deficiency Genetics The presence of two mutant alleles in the ribose-5- phosphate isomerase gene with one of these in the patient’s mother (the father could not be investigated) suggest autosomal recessive inheritance. Dr. Mohamed Saad Daoud 5 Metabolic disorders Ribose-5-phosphate isomerase deficiency is a block in the reversible part of the pentose phosphate pathway. In theory, this defect leads to a decreased capacity to interconvert ribulose-5-phosphate and ribose-5- phosphate and results in the formation of sugars and polyols: ribose and ribitol from ribose-5-phosphate and xylulose and arabitol from ribulose-5-phosphate via xylulose-5-phosphate.
    [Show full text]
  • Liver Disorders in Inherited Metabolic Disorders
    Steatosis/f Fibrosis/c Liver Name Hepatomegaly Elevated transaminases ALF Cholestasis atty liver irrhosis tumor Other Diagnostic markers Specific treatment Representative references (PMID or DOI) DISORDERS OF NITROGEN-CONTAINING COMPOUNDS Disorders of ammonia detoxification Protein restriction, ammonia scavengers N-acetylglutamate synthase deficiency X Ammonia (B), Urea (P), Amino acids (P) (carglumic acid), citrulline 28900784, 11131349 Protein restriction, ammonia Carbamoylphosphate synthetase I deficiency X X X X Ammonia (B), ASAT/ALAT (P), Urea (P), Amino acids (P) scavengers, citrulline, liver transplant 28900784 Ammonia (B), ASAT/ALAT (P), Urea (P), Amino acids (P), Protein restriction, ammonia 28900784, 22129577, 24485820, 21884343, Ornithine transcarbamylase deficiency X X X X X HCC Orotic acid (U) scavengers, citrulline, liver transplant 27070778, 24485820, 28887792 Ammonia (B), ASAT/ALAT (P), Urea (P), Amino acids (P), Protein restriction, ammonia Argininosuccinate synthetase deficiency X X X X HCC Orotic acid (U) scavengers, arginine, liver transplant 28900784, 29209134, 15334737 Ammonia (B), ASAT/ALAT (P), Urea (P), Amino acids (P, U), Protein restriction, ammonia Argininosuccinate lyase deficiency X X X X HCC Orotic acid (U) scavengers, arginine, liver transplant 28900784 Ammonia (B), ASAT/ALAT (P), Urea (P), Amino acids (P), Arginase deficiency X X X X X HCC Orotic acid (U) Protein restriction, ammonia scavengers 28900784, 22964440 Ammonia (B), ASAT/ALAT (P), Urea (P), Amino acids (P, U), Protein restriction, ammonia Mitochondrial
    [Show full text]
  • Metabolic Disorders (Children)
    E06/S/b 2013/14 NHS STANDARD CONTRACT METABOLIC DISORDERS (CHILDREN) PARTICULARS, SCHEDULE 2 – THE SERVICES, A – SERVICE SPECIFICATION Service Specification E06/S/b No. Service Metabolic Disorders (Children) Commissioner Lead Provider Lead Period 12 months Date of Review 1. Population Needs 1.1 National/local context and evidence base National Context Inherited Metabolic Disorders (IMDs) cover a group of over 600 individual conditions, each caused by defective activity in a single enzyme or transport protein. Although individually metabolic conditions are rare, the incidence being less than 1.5 per 10,000 births, collectively they are a considerable cause of morbidity and mortality. The diverse range of conditions varies widely in presentation and management according to which body systems are affected. For some patients presentation may be in the newborn period, whereas for others with the same disease (but a different genetic mutation) onset may be later, including adulthood. Without early identification and/or introduction of specialist diet or drug treatments, patients face severe disruption of metabolic processes in the body such as energy production, manufacture of breakdown of proteins, and management and storage of fats and fatty acids. The result is that patients have either a deficiency of products essential to health or an accumulation of unwanted or toxic products. Without treatment many conditions can lead to severe learning or physical disability and death at an early age. The rarity and complex nature of IMD requires an integrated specialised clinical and laboratory service to provide satisfactory diagnosis and management. This is in keeping with the recommendation of the 1 NHS England E06/S/b © NHS Commissioning Board, 2013 The NHS Commissioning Board is now known as NHS England Department of Health’s UK Plan for Rare Disorders consultation to use specialist centres Approximately 10-12,000 paediatric and adult patients attend UK specialist IMD centres, but a significant number of patients remain undiagnosed or are ‘lost to follow-up’.
    [Show full text]
  • Clinical, Biochemical, and Molecular Overview of Transaldolase Deficiency and Evaluation of the Endocrine Function: Update of 34 Patients
    DOI: 10.1002/jimd.12036 ORIGINAL ARTICLE Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: Update of 34 patients Monique Williams1 | Vassili Valayannopoulos2,3 | Ruqaiah Altassan4 | Wendy K. Chung5 | Annemieke C. Heijboer6,7 | Wei Teik Keng8 | Risto Lapatto9 | Patricia McClean10 | Margot F. Mulder11 | Anna Tylki-Szymanska 12 | Marie-Jose E. Walenkamp11 | Majid Alfadhel4 | Hajar Alakeel4 | Gajja S. Salomons1 | Wafaa Eyaid4 | Mirjam M. C. Wamelink1 1Metabolic Laboratory, Department of Clinical Chemistry, Amsterdam Abstract Neuroscience, VU University Medical Background: Transaldolase deficiency (TALDO-D) is a rare autosomal recessive Center, Amsterdam, The Netherlands inborn error of the pentose phosphate pathway. Since its first description in 2001, 2 Sanofi Genzyme, Cambridge, several case reports have been published, but there has been no comprehensive Massachusetts, USA overview of phenotype, genotype, and phenotype–genotype correlation. 3Reference Center for Inherited Metabolic Disease, Institut IMAGINE, Hopital Methods: We performed a retrospective questionnaire and literature study of clinical, Universitaire Necker - Enfants Malades, biochemical, and molecular data of 34 patients from 25 families with proven TALDO- Paris, France D. In some patients, endocrine abnormalities have been found. To further evaluate 4King Abdulaziz Medical City-Riyadh, National Guard Health Affairs, King Abdullah these abnormalities, we performed biochemical investigations on blood of 14 patients.
    [Show full text]