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Orphanet J Rare Dis. 2019 Apr 27;14(1):86. doi: 10.1186/s13023-019-1047-z.

The natural history of classic galactosemia: lessons from the GalNet registry.

Author information

1
Department of Pediatrics and Clinical Genetics, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, P. Debyelaan 25, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. estela.rubio@mumc.nl.
2
Department of Pediatrics and Clinical Genetics, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, P. Debyelaan 25, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
3
Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children's Hospital, Amsterdam, Netherlands.
4
Institute of Biomedical Sciences of the Faculty of Medicine of Vilnius University, Vilnius, Lithuania.
5
Metabolic Center, Department of Gastroenterology-Hepatology, Leuven University Hospitals and KU Leuven, Leuven, Belgium.
6
Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, S. Neonatology, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
7
Department of Endocrinology, Queen Elizabeth Hospital Birmingham, London, UK.
8
Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
9
Section of Metabolic Diseases, Beatrix Children's Hospital, and Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
10
Antwerp University Hospital, Antwerp, Belgium.
11
Hospital Clinic Barcelona, Barcelona, Spain.
12
Metabolic Medicine Department, Great Ormond Street Hospital, Institute for Child Health UCL, London, UK.
13
Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
14
Department of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.
15
APHP, HUPS, Hôpital Antoine Béclère, Centre de Référence Maladies Héréditaires Hépatiques, Clamart, France.
16
Université Paris Sud-Paris Saclay, and INSERM U 1195, Paris, France.
17
Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
18
Department of Pediatrics, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal.
19
Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
20
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Temple Street, Dublin, Ireland.
21
Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
22
Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
23
Department for Pediatrics and Adolescent Medicine, Inborn Errors of Metabolism, Medical University of Vienna, Vienna, Austria.
24
Clinical Research Center, Department of Medicine I, University Hospital RWTH Aachen, Aachen, Germany.
25
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
26
Department of Clinical Genetics, United Laboratories and Institute of Clinical Medicine, Tartu University Hospital, Tartu, Estonia.
27
Department of Pediatrics, University Hospital Centre, Zagreb, Croatia.
28
Research Institute for Medicines (iMed.ULisboa), and Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
29
Universitätsklink für Pädiatrie, Tirol Kliniken GmbH, Innsbruck, Austria.
30
Mark Holland Metabolic Unit, Adult Inherited Metabolic Disorders Department, Salford Royal NHS Foundation Trust, Salford, M6 8HD, UK.
31
Vrije Universiteit Amsterdam, Internal Medicine, Amsterdam UMC, Amsterdam, Netherlands.
32
Center for Molecular Diseases, Division of Genetic Medicine, University Hospital Lausanne, Lausanne, Switzerland.
33
Department of Paediatric Inherited Metabolic Disease, Evelina London Children's Hospital, London, UK.
34
Department of Pediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands.
35
Department of Methodology and Statistics, CAPHRI School for Primary Care and Public Health, Faculty Health Medicine and Life Sciences, Maastricht, The Netherlands.
36
Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands.
37
Department of Pediatrics, Division of Genomics and Genetics, Harvard Medical School and Boston Children's Hospital, Boston, USA.
38
University Children's Hospital, Parcelsus Medical University (PMU), Salzburg, Austria.
39
Department of Pediatrics and Institute of Clinical Chemistry, Inselspital, University Hospital Bern, Bern, Switzerland.
40
National Centre for Inherited Metabolic Disorders, Mater Misericordiae University Hospital, Dublin 7, Ireland.

Abstract

BACKGROUND:

Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients.

METHODS:

Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018.

RESULTS:

Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome.

CONCLUSION:

This study describes the natural history of classic galactosemia based on the hitherto largest data set.

KEYWORDS:

GALT deficiency; Galactosemia; Galactosemia network; Natural history; Registry

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