UvA-DARE (Digital Academic Repository) Classical galactosemia A cloud with a silver lining Welling, L. Publication date 2017 Document Version Final published version License Other Link to publication Citation for published version (APA): Welling, L. (2017). Classical galactosemia: A cloud with a silver lining. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. 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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:07 Oct 2021 UITNODIGING Lindsey Welling A cloud with a silver lining GALACTOSEMIA CLASSICAL CLASSICAL GALACTOSEMIA A cloud with a silver lining Lindsey Welling Graag nodig ik u uit voor het bijwonen van de openbare verdediging van mijn proefschrift: CLASSICAL GALACTOSEMIA A cloud with a silver lining Donderdag 05 oktober 2017 14:00 uur Agnietenkapel Oudezijds Voorburgwal 231 1012 EZ Amsterdam Na afloop bent u van harte welkom op de receptie Lindsey Welling [email protected] Paranimfen: Roxanne Welling [email protected] Elton Dudink [email protected] Lees de thesis online: Scan de QR code of volg de URL http://www.digitaalproefschrift.nl/ ebooks/lindsey_welling/ Classical Galactosemia A cloud with a silver lining Lindsey Welling Classical Galactosemia - A cloud with a silver lining Academic Thesis, University of Amsterdam, The Netherlands Author: Lindsey Welling Printing and lay-out: Proefschriftmaken ǁ www.proefschriftmaken.nl Cover, chapter pages and illustration: Esther Beekman ǁ www.estherontwerpt.nl ISBN: 978-94-629-5699-5 The research in this thesis was partially funded by grants from Stichting Stofwis- selkracht and Stichting Noortje. Financial support for the printing of this thesis was kindly provided by: Academic Medical Center Amsterdam, Emma Children’s Hospital, Department of Inherited Metabolic Diseases; Chiesi Pharmaceuticals; Galactosemie Vereniging Nederland; Mediq Tefa; Shire Copyright © Lindsey Welling, Amsterdam, The Netherlands, 2017 Classical Galactosemia A cloud with a silver lining ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. ir. K.I.J. Maex ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op donderdag 5 oktober 2017, te 14:00 uur door Lindsey Welling geboren te Hoorn Promotiecommissie: Promotores: Prof. Dr. F.A. Wijburg AMC-UvA Prof. Dr. C.E.M. Hollak AMC-UvA Copromotor: Dr. A.M. Bosch AMC-UvA Overige leden: Prof. Dr. J.B. van Goudoever AMC-UvA Dr. M. Langeveld AMC-UvA Prof. Dr. G.S. Salomons Vrije Universiteit Amsterdam Prof. Dr. B.T. Poll-The AMC-UvA Prof. Dr. R.J.A. Wanders AMC-UvA Dr. M. Williams Erasmus Universiteit Rotterdam Faculteit der Geneeskunde Table of contents Chapter 1 General introduction and outline of the thesis 8 Part I Newborn screeningand patients with a variant presentation of galactosemia 22 Chapter 2 Nine years of newborn screening for classical galactosemia in the Netherlands: Effectiveness of screening methods, and identification of patients with previously unreported phenotypes 24 Chapter 3 Profiling of intracellular metabolites produced from galactose and its potential for galactosemia research 42 Part II Management of classical galactosemia 58 Chapter 4 International clinical guideline for the management of classical galactosemia: diagnosis, treatment and follow-up 60 Part III Long-term complications studied in more depth 108 Chapter 5 Systematic review and meta-analysis of intelligence quotient in early-treated individuals with classical galactosemia 110 Chapter 6 Bone health in classic galactosemia: systematic review and meta-analysis 130 Chapter 7 The need for additional care in patients with classical galactosemia 152 Chapter 8 Social responsiveness in classical galactosemia 168 Summary, discussion and future perspectives Chapter 9 Summary, general discussion and future perspectives 178 Chapter 10 Samenvatting (Dutch summary) 196 Appendices 208 List of co-authors 210 PhD Portfolio 215 List of publications 216 Dankwoord (Acknowledgements) 218 Chapter 1 General introduction 1 and outline of the thesis Chapter 1 General introduction 1 and outline of the thesis General introduction and outline of the thesis Chapter 1 General introduction and outline of the thesis The first report to describe a probable case of galactosemia dates back to 1908 1. 1 Chapter Not until decades later it was demonstrated that classical galactosemia (CG, OMIM 230400) is an autosomal recessive inborn error of metabolism, caused by a severe deficiency of the third enzyme of the Leloir pathway, galactose-1-phosphate urid- yltransferase (GALT, EC 2.7.7.12)2. This enzyme deficiency results from variations in the gene encoding GALT (NM_000155.3), which is located on chromosome 9p13, in which over 300 variations have been reported so far 3. The incidence of CG varies extremely worldwide, with an estimated incidence of 1 case per 19.000 to 96.000 individuals in various countries in Europe and the United States 4–8, to 1 case per 400.000 to 800.000 individuals in Asian countries, including Taiwan and Japan 9,10. Diagnosis and enzymatic defect The gold standard for the diagnosis of CG is demonstration of a deficiency of GALT activity in erythrocytes and/or two known pathogenic variations in the GALT gene. There is currently no exact biochemical or clinical definition of CG, however, pa- tients with the typical classical form of galactosemia usually have absent or barely detectable residual GALT enzyme activities in erythrocytes. In the Netherlands, all individuals with an erythrocyte GALT enzyme activity <15% of healthy controls are considered to have CG and are treated accordingly. β-D-galactose is metabolized in four steps by four different enzymes, collectively designated as the Leloir pathway (Figure 1): galactose mutarotase, galactokinase (GALK), GALT and UDP-galactose-4-epimerase (GALE). In the first step, galactose is converted to galactose-1-phosphate (Gal-1-P) by GALK. After this step, Gal-1-P and uridine diphosphate-glucose (UDP-glucose) are converted into glucose-1-phos- phate and UDP-galactose by GALT. In the final step of the pathway, GALE catalyz- es the conversion of UDP-galactose to UDP-glucose, as well as their N-acetylated forms: UDP-N-acetylglucosamine (UDP-GlcNAc) to UDP-N-acetylgalactosamine (UDP-GalNAc). Glucose-1-phosphate is then converted to glucose-6-phosphate and 11 is oxidized to CO2 by the glycolytic pathway and the tricarboxylic acid cycle . As a consequence of GALT deficiency, galactose and Gal-1-P accumulate in the body. Galactose is partially shunted to galactitol (by the enzyme aldose reductase), and galactonate (by the enzyme galactose dehydrogenase). 11 Chapter 1 Galactose ATP UDP GALK + ADP Gluc-1-P Gal-1-P UDP-glucose UDP-galNAc GALT GALE Gluc-1-P UDP-galactose UDP-glucNAc Phosphoglucomutase Gluc-6-P Figure 1. Leloir pathway Early signs and symptoms After ingesting galactose from breast milk or infant formula, affected newborn infants generally develop a life-threatening illness in the first week of life. They may present with hypotonia, feeding problems, vomiting, sepsis-like symptoms, E. Coli sepsis, liver disease (hepatomegaly, jaundice, bleeding diathesis), renal tubular dysfunction and bilateral cataract. If CG is not recognized early and left untreated, the mortality rate in this period is high. Early diagnosis and timely start of a galactose-restricted diet is life-saving. Several countries, including the Nether- lands, have therefore introduced CG into the newborn screening (NBS) program, aiming to prevent critical illness and death in the newborn period 12–14. There are, however, risks of NBS, such as false-positive cases, and because of uncertainties about the balance between these risks and the aforementioned benefits, several countries have decided not to include CG in their NBS programs 15. Treatment A lactose-free and galactose-restricted diet is currently the only available treatment for CG and this diet is the advised treatment for life. Products with a high galactose content are eliminated from the diet, including all animal milks and other dairy products 16,17. However, there is a remarkably wide variation in the extent to which less obvious sources of galactose (fruits and vegetables, other foods containing trace amounts of lactose) are restricted between countries and between treatment centers within countries. 12 General introduction and outline of the thesis Pathophysiological processes Despite early initiation of the diet, and good compliance with this strict diet, pa- tients are at risk for late complications including neurological complications (includ- 1 Chapter ing cognitive impairment), speech and language problems, psychosocial problems,