Martina Huemer1,2,3, Daria Diodato4, Diego Martinelli4, Giorgia Olivieri4, Henk Blom5, Florian Gleich6, Stefan Kölker6, Viktor Kožich7, Andrew A Morris8, Burkhardt Seifert9, D Sean Froese1,2, Matthias R Baumgartner1,2, Carlo Dionisi-Vici4, Carlos Alcalde Martin10, Martina Baethmann11, Diana Ballhausen12, Javier Blasco-Alonso13, Nikolas Boy6, Maria Bueno14, Rosa Burgos Peláez15, Roberto Cerone16, Brigitte Chabrol17, Kimberly A Chapman18, Maria Luz Couce19, Ellen Crushell20, Jaime Dalmau Serra21, Luisa Diogo22, Can Ficicioglu23, Maria Concepcion García Jimenez24, Maria Teresa García Silva25, Ana Maria Gaspar26, Matthias Gautschi27, Domingo González-Lamuño28, Sofia Gouveia19, Stephanie Grünewald29, Chris Hendriksz30, Mirian C H Janssen31, Pavel Jesina7, Johannes Koch32, Vassiliki Konstantopoulou33, Christian Lavigne34, Allan M Lund35, Esmeralda G Martins36, Silvia Meavilla Olivas37, Karine Mention38, Fanny Mochel39, Helen Mundy40, Elaine Murphy41, Stephanie Paquay42, Consuelo Pedrón-Giner43, Maria Angeles Ruiz Gómez44, Saikat Santra45, Manuel Schiff46, Ida Vanessa Schwartz47, Sabine Scholl-Bürgi48, Aude Servais49, Anastasia Skouma50, Christel Tran12, Inmaculada Vives Piñera51, John Walter8,52, James Weisfeld-Adams53. 1. Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, Switzerland. 2. radiz-Rare Disease Initiative Zürich, University Zürich, Zürich, Switzerland. 3. Department of Pediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria. 4. Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy. 5. Department of Internal Medicine, VU Medical Center, Amsterdam, The Netherlands. 6. Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, Heidelberg, Germany. 7. Department of Pediatrics and Adolescent Medicine, Charles University-First Faculty of Medicine and General University Hospital, Prague, Czech Republic. 8. Willink Metabolic Unit, Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK. 9. Department of Biostatistics at Epidemiology, Biostatistics and Prevention Institute, University Zürich, Zürich, Switzerland. 10. Hospital Universitario Río Hortega, Valladolid, Spain. 11. Department of Pediatrics, Sozialpädiatrisches Zentrum, Klinikum Dritter Orden München-Nymphenburg, Munich, Germany. 12. Center for Molecular Diseases, University Hospital Lausanne, Lausanne, Switzerland. 13. Sección de Gastroenterología y Nutrición Pediátrica, Hospital Regional de Málaga, Málaga, Spain. 14. Hospital Universitario Virgen del Rocío, Sevilla, Spain. 15. Nutritional Support Unit, University Hospital Vall d'Hebron, Barcelona, Spain. 16. University Department of Pediatrics, Giannina Gaslini Institute, Genoa, Italy. 17. Centre de Référence des Maladies Héréditaires du Métabolisme, CHU La Timone Enfants, Marseille, France. 18. Children's National Rare Disease Institute, Genetics and Metabolism, Washington, DC, USA. 19. Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Service of Neonatology, Department of PediatricsHospital Clínico Universitario de Santiago, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain. 20. National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland. 21. Unidad de Nutrición y Metabolopatías, Hospital Universitario La Fe, Valencia, Spain. 22. Centro de Referência de Doencas Hereditárias do Metabolismo. Centro de Desenvolvimento da Criança - Hospital Pediátrico - Centro Hospitalar e Universitário De Coimbra, Coimbra, Portugal. 23. Division of Human Genetics, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 24. Hospital Infantil Miguel Servet, Zaragoza, Spain. 25. Universitary Hospital 12 Octubre, Madrid, Spain. 26. Centro Academico de Medicina de Lisboa, Lisbon, Portugal. 27. Interdisciplinary Metabolic Team, Paediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital and University Institute of Clinical Chemistry Inselspital, Berne, Switzerland. 28. Department of Pediatrics, University Hospital Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain. 29. Institute for Child HealthGreat Ormond Street Hospital, University College London, London, UK. 30. Salford Royal NHS Foundation Trust, Salford, UK. 31. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 32. Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria. 33. Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria. 34. Médecine Interne et Maladies Vasculaires, Centre Hospitalier Universitaire Angers, Angers, France. 35. Centre Inherited Metabolic Diseases, Departments of Clinical Genetics and Paediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 36. Reference Center for Inherited Metabolic Diseases, Centro Hospitalar do Porto, Porto, Portugal. 37. Division of Gastroenterology, Hepatology and Nutrition, Sant Joan de Déu Hospital, Barcelona, Spain. 38. Hôpital Jeanne de Flandre, Lille, France. 39. Reference Center for Adult Neurometabolic Diseases, University Pierre and Marie Curie, La Pitié-Salpêtrière University Hospital, Paris, France. 40. Evelina London Children's Hospital, London, UK. 41. Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK. 42. Pediatric Neurology and Metabolic diseases department, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium. 43. Division of Gastroenterology and Nutrition, University Children's Hospital Niño Jesús, Madrid, Spain. 44. Metabolic Neuropediatric Unit, University Hospital Son Espases, Palma de Mallorca, Spain. 45. Clinical Inherited Metabolic Disorders, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK. 46. Reference Center for Inherited Metabolic Diseases, AP-HP, Robert Debré Hospital, University Paris Diderot-Sorbonne Paris Cité and INSERM U1141, Paris, France. 47. Hospital de Clínicas de Porto Alegre and Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 48. Clinic for Pediatrics I, Inherited Metabolic Disorders Medical University of Innsbruck, Innsbruck, Austria. 49. Nephrology Department, Reference Center of Inherited Metabolic Diseases, Necker hospital, AP-HP, University Paris Descartes, Paris, France. 50. Agia Sofia Children's Hospital 1st Department of Pediatrics, University of Athens Thivon & Levadias, Athens, Greece. 51. Hospital Universitario Virgen de la Arrixaca, El Palmar, Spain. 52. Department of Paediatrics, Bradford Royal Infirmary, Bradford, UK. 53. Inherited Metabolic Diseases Clinic, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado.
Abstract
AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.
AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.
Authors: Jochen Weile; Nishka Kishore; Song Sun; Ranim Maaieh; Marta Verby; Roujia Li; Iosifina Fotiadou; Julia Kitaygorodsky; Yingzhou Wu; Alexander Holenstein; Céline Bürer; Linnea Blomgren; Shan Yang; Robert Nussbaum; Rima Rozen; David Watkins; Marinella Gebbia; Viktor Kozich; Michael Garton; D Sean Froese; Frederick P Roth Journal: Am J Hum Genet Date: 2021-07-01 Impact factor: 11.025
Authors: Viktor Kožich; Jitka Sokolová; Andrew A M Morris; Markéta Pavlíková; Florian Gleich; Stefan Kölker; Jakub Krijt; Carlo Dionisi-Vici; Matthias R Baumgartner; Henk J Blom; Martina Huemer Journal: J Inherit Metab Dis Date: 2020-12-28 Impact factor: 4.982