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Newborn screening for homocystinurias: recent recommendations versus current practice

  • R. Keller
  • P. Chrastina
  • M. Pavlíková
  • S. Gouveia
  • A. Ribes
  • S. Kölker
  • H. J. Blom
  • M. R. Baumgartner
  • J. Bártl
  • C. Dionisi Vici
  • F. Gleich
  • A. A. Morris
  • V. KožichEmail author
  • M. HuemerEmail author
  • and individual contributors of the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD)
  • I. Barić
  • T. Ben-Omran
  • J. Blasco-Alonso
  • M. A. Bueno Delgado
  • C. Carducci
  • M. Cassanello
  • R. Cerone
  • M. L. Couce
  • E. Crushell
  • C. Delgado Pecellin
  • E. Dulin
  • M. Espada
  • G. Ferino
  • R. Fingerhut
  • I. Garcia Jimenez
  • I. Gonzalez Gallego
  • Y. González-Irazabal
  • G. Gramer
  • M. J. Juan Fita
  • E. Karg
  • J. Klein
  • V. Konstantopoulou
  • G. la Marca
  • E. Leão Teles
  • V. Leuzzi
  • F. Lilliu
  • R. M. Lopez
  • A. M. Lund
  • P. Mayne
  • S. Meavilla
  • S. J. Moat
  • J. G. Okun
  • E. Pasquini
  • C. Pedron-Giner
  • G. Z. Racz
  • M. A. Ruiz Gomez
  • L. Vilarinho
  • R. Yahyaoui
  • M. Zerjav Tansek
  • R. H. Zetterström
  • M. Zeyda
Original Article

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 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.

Abbreviations

C2

Acetylcarnitine

C3

Propionylcarnitine

C17

Heptadecanoylcarnitine

CBSD

Cystathionine beta-synthase deficiency

CLIR

Collaborative Laboratory Integrated Reports

cbl

Cobalamin

cRMD

Combined remethylation disorder

DBS

Dried blood spots

E-HOD

European Network and Registry for Homocystinurias and Methylation Defects

iRMD

Isolated remethylation disorder

MATI/IIID

Methionine adenosyltransferase I/III deficiency

MMA

Methylmalonic acid

Met

Methionine

MoM

Multiples of the median

MTHFRD

Methylenetetrahydrofolate reductase deficiency

NBS

Newborn screening

Phe

Phenylalanine

RMD

Remethylation defect

ROC

Receiver operating characteristic

tHcy

Total homocysteine

Notes

Acknowledgements

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.

Supplementary material

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Copyright information

© SSIEM 2018

Authors and Affiliations

  • R. Keller
    • 1
    • 2
  • P. Chrastina
    • 3
  • M. Pavlíková
    • 3
    • 4
  • S. Gouveia
    • 5
  • A. Ribes
    • 6
  • S. Kölker
    • 7
  • H. J. Blom
    • 8
  • M. R. Baumgartner
    • 1
    • 2
  • J. Bártl
    • 3
  • C. Dionisi Vici
    • 9
  • F. Gleich
    • 7
  • A. A. Morris
    • 10
  • V. Kožich
    • 3
    Email author
  • M. Huemer
    • 1
    • 2
    • 11
    Email author
  • and individual contributors of the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD)
  • I. Barić
    • 12
  • T. Ben-Omran
    • 13
  • J. Blasco-Alonso
    • 14
  • M. A. Bueno Delgado
    • 15
  • C. Carducci
    • 16
  • M. Cassanello
    • 17
  • R. Cerone
    • 18
  • M. L. Couce
    • 5
  • E. Crushell
    • 19
  • C. Delgado Pecellin
    • 15
  • E. Dulin
    • 20
  • M. Espada
    • 21
  • G. Ferino
    • 22
  • R. Fingerhut
    • 1
    • 23
  • I. Garcia Jimenez
    • 24
  • I. Gonzalez Gallego
    • 25
  • Y. González-Irazabal
    • 26
  • G. Gramer
    • 7
  • M. J. Juan Fita
    • 25
  • E. Karg
    • 27
  • J. Klein
    • 28
  • V. Konstantopoulou
    • 29
  • G. la Marca
    • 30
    • 31
  • E. Leão Teles
    • 32
  • V. Leuzzi
    • 33
  • F. Lilliu
    • 22
  • R. M. Lopez
    • 6
  • A. M. Lund
    • 34
  • P. Mayne
    • 35
  • S. Meavilla
    • 36
  • S. J. Moat
    • 37
  • J. G. Okun
    • 7
  • E. Pasquini
    • 38
  • C. Pedron-Giner
    • 39
  • G. Z. Racz
    • 27
  • M. A. Ruiz Gomez
    • 40
  • L. Vilarinho
    • 41
  • R. Yahyaoui
    • 42
  • M. Zerjav Tansek
    • 43
  • R. H. Zetterström
    • 44
    • 45
  • M. Zeyda
    • 29
  1. 1.Division of Metabolism and Children’s Research CenterUniversity Children’s Hospital ZürichZürichSwitzerland
  2. 2.radiz—Rare Disease Initiative Zürich, Clinical Research Priority ProgramUniversity of ZürichZürichSwitzerland
  3. 3.Department of Pediatrics and Adolescent MedicineCharles University—First Faculty of Medicine and General University HospitalPraha 2Czech Republic
  4. 4.Department of Probability and Mathematical StatisticsCharles University—Faculty of Mathematics and PhysicsPragueCzech Republic
  5. 5.Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, S. Neonatology, Department of PediatricsHospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS)Santiago de CompostelaSpain
  6. 6.Division of Inborn Errors of Metabolism, Department of Biochemistry and Molecular GeneticsHospital Clinic de Barcelona, CIBERERBarcelonaSpain
  7. 7.Division of Neuropaediatrics and Metabolic Medicine, Centre for Paediatric and Adolescent MedicineUniversity Hospital HeidelbergHeidelbergGermany
  8. 8.Department of Internal MedicineVU Medical CenterAmsterdamThe Netherlands
  9. 9.Division of MetabolismBambino Gesù Children’s Research HospitalRomeItaly
  10. 10.Manchester Centre for Genomic MedicineManchester University Hospitals NHS TrustManchesterUK
  11. 11.Department of PaediatricsLandeskrankenhaus BregenzBregenzAustria
  12. 12.School of MedicineUniversity Hospital Centre Zagreb and University of ZagrebZagrebCroatia
  13. 13.Clinical and Metabolic Genetics, Department of PediatricsHamad Medical CorporationDohaQatar
  14. 14.Gastroenterology and Nutrition UnitHospital Regional Universitario de MálagaMálagaSpain
  15. 15.Clinical Laboratory of Metabolic Diseases and Occidental Andalucia Newborn Screening CenterHospital Universitario Virgen del RocíoSevillaSpain
  16. 16.Department of Experimental MedicineSapienza University of RomeRomeItaly
  17. 17.Laboratory for the Study of Inborn Errors of MetabolismIstituto Giannina GasliniGenoaItaly
  18. 18.Regional Center for Neonatal Screening and Diagnosis of Metabolic DiseasesUniversity Department of Pediatrics—Istituto Giannina GasliniGenoaItaly
  19. 19.National Centre for Inherited Metabolic DisordersTemple Street Children’s University HospitalDublinIreland
  20. 20.Hospital Gregorio MarañonMadridSpain
  21. 21.Clinical Chemistry UnitPublic Health Laboratory of BilbaoEuskadiSpain
  22. 22.Regional Center for Newborn Screening, Pediatric Hospital A. CaoAOB BrotzuCagliariItaly
  23. 23.Swiss Newborn Screening LaboratoryUniversity Children’s Hospital ZurichZurichSwitzerland
  24. 24.Unidad de MetabolismoHospital Infantil Miguel ServetZaragozaSpain
  25. 25.Sección Metabolopatías Centro de Bioquímica y GeneticaHospital Virgen de la ArrixacaMurciaSpain
  26. 26.Unidad de Metabolopatias, Servicio de Bioquímica ClínicaHospital Universitario Miguel ServetZaragozaSpain
  27. 27.Department of PediatricsUniversity of SzegedSzegedHungary
  28. 28.Newborn Screening LaboratoryCharité—University Medicine BerlinBerlinGermany
  29. 29.Austrian Newborn Screening, Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
  30. 30.Newborn Screening, Clinical Chemistry and Pharmacology LabA. Meyer Children’s University HospitalFlorenceItaly
  31. 31.Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
  32. 32.Metabolic Unit, Department of PediatricsSan Joao HospitalPortoPortugal
  33. 33.Department of Human NeuroscienceSapienza University of RomeRomeItaly
  34. 34.Centre for Inherited Metabolic Diseases, Departments of Paediatrics and Clinical GeneticsCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  35. 35.National Newborn Bloodspot Screening LaboratoryTemple Street Children’s University HospitalDublinIreland
  36. 36.Gastroenterology, Hepatology and Nutrition Department, Metabolic UnitSant Joan de Déu Hospital, Barcelona Hospital Sant Joan de DéuBarcelonaSpain
  37. 37.Wales Newborn Screening Laboratory, Department of Medical Biochemistry, Immunology & Toxicology and School of MedicineCardiff UniversityCardiffWales, UK
  38. 38.Metabolic and Newborn Screening Clinical Unit, Department of NeurosciencesA. Meyer Children’s University HospitalFlorenceItaly
  39. 39.Division of Gastroenterology and NutritionHospital Infantil Universitario Niño JesúsMadridSpain
  40. 40.Clinical Lead in Metabolic Pediatric and Neurometabolic DiseasesSon Espases University Hospital, PalmaMallorca UnitPalma de MallorcaSpain
  41. 41.Newborn Screening, Metabolism & Genetics UnitNational Institute of HealthPortoPortugal
  42. 42.Laboratory and Eastern Andalusia Newborn Screening CentreMálaga Regional University Hospital, Institute of Biomedical Research in Málaga (IBIMA)MálagaSpain
  43. 43.Department of Diabetes, Endocrinology and Metabolic DiseasesUniversity Children’s Hospital, UMC LjubljanaLjubljanaSlovenia
  44. 44.Centre for Inherited Metabolic DiseasesKarolinska University HospitalStockholmSweden
  45. 45.Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden

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