Rebecca Keller1,2, Petr Chrastina3, Markéta Pavlíková3,4, Sofía Gouveia5, Antonia Ribes6, Stefan Kölker7, Henk J Blom8, Matthias R Baumgartner1,2, Josef Bártl3, Carlo Dionisi-Vici9, Florian Gleich7, Andrew A Morris10, Viktor Kožich3, Martina Huemer1,2,11, Ivo Barić12, Tawfeq Ben-Omran13, Javier Blasco-Alonso14, Maria A Bueno Delgado15, Claudia Carducci16, Michela Cassanello17, Roberto Cerone18, Maria Luz Couce5, Ellen Crushell19, Carmen Delgado Pecellin15, Elena Dulin20, Mercedes Espada21, Giulio Ferino22, Ralph Fingerhut1,23, Immaculada Garcia Jimenez24, Immaculada Gonzalez Gallego25, Yolanda González-Irazabal26, Gwendolyn Gramer7, Maria Jesus Juan Fita25, Eszter Karg27, Jeanette Klein28, Vassiliki Konstantopoulou29, Giancarlo la Marca30,31, Elisa Leão Teles32, Vincenzo Leuzzi33, Franco Lilliu22, Rosa Maria Lopez6, Allan M Lund34, Philip Mayne35, Silvia Meavilla36, Stuart J Moat37, Jürgen G Okun7, Elisabeta Pasquini38, Consuélo Carmen Pedron-Giner39, Gabor Zoltan Racz27, Maria Angeles Ruiz Gomez40, Laura Vilarinho41, Raquel Yahyaoui42, Moja Zerjav Tansek43, Rolf H Zetterström44,45, Maximilian Zeyda29. 1. Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. 2. radiz-Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zürich, Switzerland. 3. Department of Pediatrics and Adolescent Medicine, Charles University-First Faculty of Medicine and General University Hospital, Ke Karlovu 2, 128 08 Praha 2, Czech Republic. 4. Department of Probability and Mathematical Statistics, Charles University-Faculty of Mathematics and Physics, Prague, Czech Republic. 5. 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. 6. Division of Inborn Errors of Metabolism, Department of Biochemistry and Molecular Genetics, Hospital Clinic de Barcelona, CIBERER, Barcelona, Spain. 7. Division of Neuropaediatrics and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. 8. Department of Internal Medicine, VU Medical Center, Amsterdam, The Netherlands. 9. Division of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy. 10. Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Trust, Manchester, UK. 11. Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria. 12. School of Medicine, University Hospital Centre Zagreb and University of Zagreb, Zagreb, Croatia. 13. Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar. 14. Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Málaga, Málaga, Spain. 15. Clinical Laboratory of Metabolic Diseases and Occidental Andalucia Newborn Screening Center, Hospital Universitario Virgen del Rocío, Sevilla, Spain. 16. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. 17. Laboratory for the Study of Inborn Errors of Metabolism, Istituto Giannina Gaslini, Genoa, Italy. 18. Regional Center for Neonatal Screening and Diagnosis of Metabolic Diseases, University Department of Pediatrics-Istituto Giannina Gaslini, Genoa, Italy. 19. National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland. 20. Hospital Gregorio Marañon, Madrid, Spain. 21. Clinical Chemistry Unit, Public Health Laboratory of Bilbao, Euskadi, Spain. 22. Regional Center for Newborn Screening, Pediatric Hospital A. Cao, AOB Brotzu, Cagliari, Italy. 23. Swiss Newborn Screening Laboratory, University Children's Hospital Zurich, Zurich, Switzerland. 24. Unidad de Metabolismo, Hospital Infantil Miguel Servet, Zaragoza, Spain. 25. Sección Metabolopatías Centro de Bioquímica y Genetica, Hospital Virgen de la Arrixaca, Murcia, Spain. 26. Unidad de Metabolopatias, Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Zaragoza, Spain. 27. Department of Pediatrics, University of Szeged, Szeged, Hungary. 28. Newborn Screening Laboratory, Charité-University Medicine Berlin, Berlin, Germany. 29. Austrian Newborn Screening, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. 30. Newborn Screening, Clinical Chemistry and Pharmacology Lab, A. Meyer Children's University Hospital, Florence, Italy. 31. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. 32. Metabolic Unit, Department of Pediatrics, San Joao Hospital, Porto, Portugal. 33. Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy. 34. Centre for Inherited Metabolic Diseases, Departments of Paediatrics and Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark. 35. National Newborn Bloodspot Screening Laboratory, Temple Street Children's University Hospital, Dublin, Ireland. 36. Gastroenterology, Hepatology and Nutrition Department, Metabolic Unit, Sant Joan de Déu Hospital, Barcelona Hospital Sant Joan de Déu, Barcelona, Spain. 37. Wales Newborn Screening Laboratory, Department of Medical Biochemistry, Immunology & Toxicology and School of Medicine, Cardiff University, Cardiff, Wales, UK. 38. Metabolic and Newborn Screening Clinical Unit, Department of Neurosciences, A. Meyer Children's University Hospital, Florence, Italy. 39. Division of Gastroenterology and Nutrition, Hospital Infantil Universitario Niño Jesús, Madrid, Spain. 40. Clinical Lead in Metabolic Pediatric and Neurometabolic Diseases, Son Espases University Hospital, PalmaMallorca Unit, Palma de Mallorca, Spain. 41. Newborn Screening, Metabolism & Genetics Unit, National Institute of Health, Porto, Portugal. 42. Laboratory and Eastern Andalusia Newborn Screening Centre, Málaga Regional University Hospital, Institute of Biomedical Research in Málaga (IBIMA), Málaga, Spain. 43. Department of Diabetes, Endocrinology and Metabolic Diseases, University Children's Hospital, UMC Ljubljana, Ljubljana, Slovenia. 44. Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden. 45. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Abstract
PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.
PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionineadenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS:NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.
Authors: Song Sun; Jochen Weile; Marta Verby; Yingzhou Wu; Yang Wang; Atina G Cote; Iosifina Fotiadou; Julia Kitaygorodsky; Marc Vidal; Jasper Rine; Pavel Ješina; Viktor Kožich; Frederick P Roth Journal: Genome Med Date: 2020-01-30 Impact factor: 11.117
Authors: Chris Stinton; Hannah Fraser; Julia Geppert; Rebecca Johnson; Martin Connock; Samantha Johnson; Aileen Clarke; Sian Taylor-Phillips Journal: Front Pediatr Date: 2021-03-19 Impact factor: 3.418
Authors: Charles Austin Pickens; Maya Sternberg; Mary Seeterlin; Víctor R De Jesús; Mark Morrissey; Adrienne Manning; Sonal Bhakta; Patrice K Held; Joanne Mei; Carla Cuthbert; Konstantinos Petritis Journal: Int J Neonatal Screen Date: 2020-09-17
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