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.

Centro de Diagnóstico de Enfermedades Moleculares Facultad de Ciencias Universidad Autónoma de Madrid IDIPAZ CIBER de Enfermedades Raras Madrid Spain

Department Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Neuroscience Newborn Screening Unit A Meyer University Children's Hospital Florence Italy

Department of Pediatrics Landeskrankenhaus Bregenz Carl Pedenz Str 2 6900 Bregenz Austria

Division Inborn Errors of Metabolism Hospital Clinic CIBERER Barcelona Spain

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

Institute of Inherited Metabolic Disorders Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Laboratory Clinical Biochemistry and Metabolism Center for Pediatrics and Adolescent Medicine University Hospital Freiburg Freiburg Germany

Radiz Rare Disease Initiative Zürich University Zürich Zürich Switzerland

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Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency