Newborn screening for homocystinurias: Recent recommendations versus current practice

Rebecca Keller, Petr Chrastina, Markéta Pavlíková, Sofía Gouveia, Antonia Ribes, Stefan Kölker, Henk J. Blom, Matthias R. Baumgartner, Josef Bártl, Carlo Dionisi-Vici, Florian Gleich, Andrew A. Morris, Viktor Kožich, Martina Huemer, Ivo Barić, Tawfeq Ben-Omran, Javier Blasco-Alonso, Maria A. Bueno Delgado, Claudia Carducci, Michela CassanelloRoberto Cerone, Maria Luz Couce, Ellen Crushell, Carmen Delgado Pecellin, Elena Dulin, Mercedes Espada, Giulio Ferino, Ralph Fingerhut, Immaculada Garcia Jimenez, Immaculada Gonzalez Gallego, Yolanda González-Irazabal, Gwendolyn Gramer, Maria Jesus Juan Fita, Eszter Karg, Jeanette Klein, Vassiliki Konstantopoulou, Giancarlo la Marca, Elisa Leão Teles, Vincenzo Leuzzi, Franco Lilliu, Rosa Maria Lopez, Allan M. Lund, Philip Mayne, Silvia Meavilla, Stuart J. Moat, J. rgen G. Okun, Elisabeta Pasquini, Consuélo Carmen Pedron-Giner, Gabor Zoltan Racz, Maria Angeles Ruiz Gomez, and individual contributors of the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD), Maria Angeles Ruiz Gomez, Laura Vilarinho, Raquel Yahyaoui, Moja Zerjav Tansek, Rolf H. Zetterström, Maximilian Zeyda

Research output: Contribution to journalArticleAcademicpeer-review


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 favourable 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, e.g. birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalJournal of Inherited Metabolic Disease
Issue number1
Early online date15 Jun 2018
Publication statusPublished - 2019

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