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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\u2010to\u2010phenylanine (Met\/Phe) ratio, and total homocysteine (tHcy) as a second tier marker. Therefore, we recommend NBS for cystathionine beta\u2010synthase 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\u2010onset cblC defect. In the early\u2010onset type, survival and non\u2010neurological symptoms improve but the effect on neurocognitive development is uncertain. The cblC defect can be screened by measuring propionylcarnitine, propionylcarnitine\u2010to\u2010acetylcarnitine 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 <jats:italic>MAT1A<\/jats:italic> 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\u2010methyltransferase\u2010, S\u2010adenosylhomocysteinehydrolase\u2010 and adenosine kinase deficiency.<\/jats:p>","DOI":"10.1007\/s10545-015-9830-z","type":"journal-article","created":{"date-parts":[[2015,3,11]],"date-time":"2015-03-11T10:26:00Z","timestamp":1426069560000},"page":"1007-1019","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":116,"title":["Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines"],"prefix":"10.1002","volume":"38","author":[{"given":"Martina","family":"Huemer","sequence":"first","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Z\u00fcrich Z\u00fcrich Switzerland"},{"name":"Radiz\u2013Rare Disease Initiative Z\u00fcrich University Z\u00fcrich Z\u00fcrich Switzerland"},{"name":"Department of Pediatrics Landeskrankenhaus Bregenz Carl\u2010Pedenz\u2010Str. 2 Bregenz 6900 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Ko\u017eich","sequence":"additional","affiliation":[{"name":"Institute of Inherited Metabolic Disorders Charles University in Prague\u20101st Faculty of Medicine and General University Hospital Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Rinaldo","sequence":"additional","affiliation":[{"name":"Department Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias R.","family":"Baumgartner","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Z\u00fcrich Z\u00fcrich Switzerland"},{"name":"Radiz\u2013Rare Disease Initiative Z\u00fcrich University Z\u00fcrich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bego\u00f1a","family":"Merinero","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, Facultad de Ciencias Universidad Aut\u00f3noma de Madrid, IDIPAZ, CIBER de Enfermedades Raras Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Pasquini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Newborn Screening Unit A. 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