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.

Austrian Newborn Screening Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Centre for Inherited Metabolic Diseases Departments of Paediatrics and Clinical Genetics Copenhagen University Hospital Copenhagen Denmark

Centre for Inherited Metabolic Diseases Karolinska University Hospital Stockholm Sweden

Clinical and Metabolic Genetics Department of Pediatrics Hamad Medical Corporation Doha Qatar

Clinical Chemistry Unit Public Health Laboratory of Bilbao Euskadi Spain

Clinical Laboratory of Metabolic Diseases and Occidental Andalucia Newborn Screening Center Hospital Universitario Virgen del Rocío Sevilla Spain

Clinical Lead in Metabolic Pediatric and Neurometabolic Diseases Son Espases University Hospital PalmaMallorca Unit Palma de Mallorca Spain

Department of Diabetes Endocrinology and Metabolic Diseases University Children's Hospital UMC Ljubljana Ljubljana Slovenia

Department of Experimental and Clinical Biomedical Sciences University of Florence Florence Italy

Department of Experimental Medicine Sapienza University of Rome Rome Italy

Department of Human Neuroscience Sapienza University of Rome Rome Italy

Department of Internal Medicine VU Medical Center Amsterdam The Netherlands

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Paediatrics Landeskrankenhaus Bregenz Bregenz Austria

Department of Pediatrics and Adolescent Medicine Charles University 1st Faculty of Medicine and General University Hospital Ke Karlovu 2 128 08 Praha 2 Czech Republic

Department of Pediatrics University of Szeged Szeged Hungary

Department of Probability and Mathematical Statistics Charles University Faculty of Mathematics and Physics Prague Czech Republic

Division of Gastroenterology and Nutrition Hospital Infantil Universitario Niño Jesús Madrid Spain

Division of Inborn Errors of Metabolism Department of Biochemistry and Molecular Genetics Hospital Clinic de Barcelona CIBERER Barcelona Spain

Division of Metabolism and Children's Research Center University Children's Hospital Zürich Zürich Switzerland

Division of Metabolism Bambino Gesù Children's Research Hospital Rome Italy

Division of Neuropaediatrics and Metabolic Medicine Centre for Paediatric and Adolescent Medicine University Hospital Heidelberg Heidelberg Germany

Gastroenterology and Nutrition Unit Hospital Regional Universitario de Málaga Málaga Spain

Gastroenterology Hepatology and Nutrition Department Metabolic Unit Sant Joan de Déu Hospital Barcelona Hospital Sant Joan de Déu Barcelona Spain

Hospital Gregorio Marañon Madrid Spain

Laboratory and Eastern Andalusia Newborn Screening Centre Málaga Regional University Hospital Institute of Biomedical Research in Málaga Málaga Spain

Laboratory for the Study of Inborn Errors of Metabolism Istituto Giannina Gaslini Genoa Italy

Manchester Centre for Genomic Medicine Manchester University Hospitals NHS Trust Manchester UK

Metabolic and Newborn Screening Clinical Unit Department of Neurosciences A Meyer Children's University Hospital Florence Italy

Metabolic Unit Department of Pediatrics San Joao Hospital Porto Portugal

National Centre for Inherited Metabolic Disorders Temple Street Children's University Hospital Dublin Ireland

National Newborn Bloodspot Screening Laboratory Temple Street Children's University Hospital Dublin Ireland

Newborn Screening Clinical Chemistry and Pharmacology Lab A Meyer Children's University Hospital Florence Italy

Newborn Screening Laboratory Charité University Medicine Berlin Berlin Germany

Newborn Screening Metabolism and Genetics Unit National Institute of Health Porto Portugal

radiz Rare Disease Initiative Zürich Clinical Research Priority Program University of Zürich Zürich Switzerland

Regional Center for Neonatal Screening and Diagnosis of Metabolic Diseases University Department of Pediatrics Istituto Giannina Gaslini Genoa Italy

Regional Center for Newborn Screening Pediatric Hospital A Cao AOB Brotzu Cagliari Italy

School of Medicine University Hospital Centre Zagreb and University of Zagreb Zagreb Croatia

Sección Metabolopatías Centro de Bioquímica y Genetica Hospital Virgen de la Arrixaca Murcia Spain

Swiss Newborn Screening Laboratory University Children's Hospital Zurich Zurich Switzerland

Unidad de Metabolismo Hospital Infantil Miguel Servet Zaragoza Spain

Unidad de Metabolopatias Servicio de Bioquímica Clínica Hospital Universitario Miguel Servet Zaragoza Spain

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 Santiago de Compostela Spain

Wales Newborn Screening Laboratory Department of Medical Biochemistry Immunology and Toxicology and School of Medicine Cardiff University Cardiff Wales UK

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