Newborn screening for homocystinurias: recent recommendations versus current practice
To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations.
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.
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.
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.
Cystathionine beta-synthase deficiency
Collaborative Laboratory Integrated Reports
Combined remethylation disorder
Dried blood spots
European Network and Registry for Homocystinurias and Methylation Defects
Isolated remethylation disorder
Methionine adenosyltransferase I/III deficiency
Multiples of the median
Methylenetetrahydrofolate reductase deficiency
Receiver operating characteristic
We thank Professor Burkhardt Seifert, Dept. of Biostatistics, University of Zürich for the statistical advice, Erica L. Wright for providing information on the Colorado and Wyoming screening programme and Marike Groenendijk (E-HOD project) for her continuous support. PCh, JB, MP and VK received institutional support from the Ministry of Health (project DRO VFN64165) and from the Charles University (project PROGRES Q26). This publication arises from the E-HOD project (Chafea grant no. 2012 12 02), which has received funding from the European Union, in the framework of the Health Programme. Many programmes cooperate closely with Piero Rinaldo and co-workers (Mayo Clinic, Rochester, Minnesota, USA) and wish to acknowledge the ongoing support provided by the R4S and CLIR initiatives (http://clir.mayo.edu).
Compliance with ethical standards
All procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000. This study was part of the E-HOD project and has ethical approval in Zürich (KEK Switzerland no. 2012–0020) and in local centres as required.
Conflict of interest
M Huemer has received research grants from Nutricia and SOBI and honorariums for lectures from Nutricia, Recordati Rare Disease Foundation, Shire and Genzyme. HJ Blom received a research grant from Orphan Europe. S Kölker receives financial support for the E-HOD registry management by the European Union, for the Cystadane Surveillance Protocol by Orphan Europe and for a pilot newborn screening study including homocystinurias and methylation defects by the Dietmar Hopp Foundation, St. Leon-Rot, Germany. MR Baumgartner declares that the University Children’s Hospital Zurich has received educational and research grants from Actelion, Genzyme and Milupa Metabolics, and receives support for the E-HOD Registry/Cystadane surveillance programme from Orphan Europe. AA Morris has received honoraria for lectures from Nutricia and Recordati Rare Disease Foundation. V Kožich declares that the Charles University—First Faculty of Medicine has received support from the Recordati Rare Disease Foundation for organising an educational course on homocystinurias and methylation defects, and reimbursement for laboratory analyses from Orphan Technologies. C Dionisi-Vici has received research grants, speaker and consultancy honoraria from Nutricia, Medifood, SOBI and Dr. Schär Medical Nutrition. AM Lund and RH Zetterström have received grants and travel reimbursement from Orphan Europe, Nutricia and SOBI. E Crushell has received an honorarium for a lecture from Nutricia Metabolics. G la Marca has received travel reimbursement from Nutricia and research grants from Genzyme. C Pedron-Giner has received support from Vitafló-Nestlé España to attend SSIEM meetings. I Barić has received speaker’s honorarium and travel support from the Recordati Rare Disease Foundation. G Gramer receives financial support for a pilot newborn screening study including homocystinurias and methylation defects by the Dietmar Hopp Foundation, St. Leon-Rot, Germany and received speaker honoraria from MetaX, Friedberg, Germany and the Recordati Rare Disease Foundation. E Pasquini has received speaker’s honorarium and travel support from SANOFI Genzyme, Shire, Alexion. R Keller, P Chrastina, J Bártl, S Gouveia, A Ribes, F Gleich and M Pavlíková declare that they have no relevant conflict of interest.
- Centers for Disease Control and Prevention (CDC) (2017) 2016 quality control program report. Volume 27, no.2, issued: February 2017Google Scholar
- Huemer M, Diodato D, Schwahn B, Schiff M, Bandeira A, Benoist Jean-Francois, Burlina A, Cerone R, Couce ML, Garcia-Cazorla A, la Marca G, Pasquini Elisabetta, Vilarinho L, Weisfeld-Adams JD, Kožich Viktor, Blom H, Baumgartner MR, Dionisi-Vici C, (2017) Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. Journal of Inherited Metabolic Disease 40 (1):21-48Google Scholar
- Minter Baerg MM, Stoway SD, Hart J et al (2017) Precision newborn screening for lysosomal disorders. Genet Med. https://doi.org/10.1038/gim.2017.194
- Morris A AM, Kožich V, Santra S, Andria G, Ben-Omran T IM., Chakrapani AB., Crushell E, Henderson MJ., Hochuli M, Huemer M, Janssen M CH., Maillot F, Mayne PD., McNulty J, Morrison TM., Ogier H, O’Sullivan S, Pavlíková M, de Almeida IT, Terry A, Yap S, Blom HJ, Chapman KA, (2017) Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. Journal of Inherited Metabolic Disease 40 (1):49-74Google Scholar