title: Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines.
abstract: Newborn screening (NBS) is justified if early intervention is effective in a disorder generally not detected early in life on a clinical basis, and if sensitive and specific biochemical markers exist. Experience with NBS for homocystinurias and methylation disorders is limited. However, there is robust evidence for the success of early treatment with diet, betaine and/or pyridoxine for CBS deficiency and good evidence for the success of early betaine treatment in severe MTHFR deficiency. These conditions can be screened in dried blood spots by determining methionine (Met), methionine-to-phenylanine (Met/Phe) ratio, and total homocysteine (tHcy) as a second tier marker. Therefore, we recommend NBS for cystathionine beta-synthase and severe MTHFR deficiency. Weaker evidence is available for the disorders of intracellular cobalamin metabolism. Early treatment is clearly of advantage for patients with the late-onset cblC defect. In the early-onset type, survival and non-neurological symptoms improve but the effect on neurocognitive development is uncertain. The cblC defect can be screened by measuring propionylcarnitine, propionylcarnitine-to-acetylcarnitine ratio combined with the second tier markers methylmalonic acid and tHcy. For the cblE and cblG defects, evidence for the benefit of early treatment is weaker; and data on performance of Met, Met/Phe and tHcy even more limited. Individuals homozygous or compound heterozygous for MAT1A mutations may benefit from detection by NBS using Met, which on the other hand also detects asymptomatic heterozygotes. Clinical and laboratory data is insufficient to develop any recommendation on NBS for the cblD, cblF, cblJ defects, glycineN-methyltransferase-, S-adenosylhomocysteinehydrolase- and adenosine kinase deficiency.
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. martina.huemer@lkhb.at.|Radiz-Rare Disease Initiative Zürich, University Zürich, Zürich, Switzerland. martina.huemer@lkhb.at.|Department of Pediatrics, Landeskrankenhaus Bregenz, Carl-Pedenz-Str. 2, 6900, Bregenz, Austria. martina.huemer@lkhb.at.
authors.forename: Martina
authors.initials: M
authors.lastname: Huemer
authors.affiliation: Institute of Inherited Metabolic Disorders, Charles University in Prague-1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Kožich
authors.affiliation: Department Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Piero
authors.initials: P
authors.lastname: Rinaldo
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland.|Radiz-Rare Disease Initiative Zürich, University Zürich, Zürich, Switzerland.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Facultad de Ciencias, Universidad Autónoma de Madrid, IDIPAZ, CIBER de Enfermedades Raras, Madrid, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Merinero
authors.affiliation: Department of Neuroscience, Newborn Screening Unit, A. Meyer University Children's Hospital, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pasquini
authors.affiliation: Division Inborn Errors of Metabolism, Hospital Clinic, CIBERER, Barcelona, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.affiliation: Laboratory Clinical Biochemistry and Metabolism, Center for Pediatrics and Adolescent Medicine University Hospital, Freiburg, Freiburg, Germany.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
mesh_terms: D000108:Acetylcarnitine / Q000097:blood; D001622:Betaine / Q000627:therapeutic use; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D006712:Homocystinuria / Q000175:diagnosis*; D006801:Humans; D007231:Infant, Newborn; D008715:Methionine / Q000097:blood; D008745:Methylation; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency* / Q000187:drug effects; D008764:Methylmalonic Acid / Q000097:blood; D015997:Neonatal Screening; D017410:Practice Guidelines as Topic
chemical_list: C003223:propionylcarnitine; D001622:Betaine; D000108:Acetylcarnitine; D008764:Methylmalonic Acid; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002331:Carnitine