{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:05:06Z","timestamp":1760238306543,"version":"build-2065373602"},"reference-count":23,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T00:00:00Z","timestamp":1656288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Methionine adenosyltransferase I\/III deficiency is an inborn error of metabolism due to mutations in the MAT1A gene. It is the most common cause of hypermethioninemia in newborn screening. Heterozygotes are often asymptomatic. In contrast, homozygous or compound heterozygous individuals can develop severe neurological symptoms. Less than 70 cases with biallelic variants have been reported worldwide. A methionine-restricted diet is recommended if methionine levels are above 500\u2013600 \u00b5mol\/L. In this study, we report on a female patient identified with elevated methionine concentrations in a pilot newborn screening program. The patient carries a previously described variant c.1132G&gt;A (p.Gly378Ser) in homozygosity. It is located at the C-terminus of MAT1A. In silico analysis suggests impaired protein stability by \u03b2-turn disruption. On a methionine-restricted diet, her serum methionine concentration ranged between 49\u2013605 \u00b5mol\/L (median 358 \u00b5mol\/L). Her clinical course was characterized by early-onset muscular hypotonia, mild developmental delay, delayed myelination and mild periventricular diffusion interference in MRI. At 21 months, the girl showed age-appropriate neurological development, but progressive diffusion disturbances in MRI. Little is known about the long-term outcome of this disorder and the necessity of treatment. Our case demonstrates that neurological symptoms can be transient and even patients with initial neurologic manifestations can show normal development under dietary management.<\/jats:p>","DOI":"10.3390\/genes13071163","type":"journal-article","created":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T22:31:14Z","timestamp":1656369074000},"page":"1163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Methionine Adenosyltransferase I\/III Deficiency Detected by Newborn Screening"],"prefix":"10.3390","volume":"13","author":[{"given":"Vanessa","family":"H\u00fcbner","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Metabolic Disease Center, Klinikum Reutlingen, Steinenbergstr. 31, 72764 Reutlingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0911-5758","authenticated-orcid":false,"given":"Luciana","family":"Hannibal","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology, University Medical Center, Faculty of Medicine, University of Freiburg, Mathildenstra\u00dfe 1, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2313-3311","authenticated-orcid":false,"given":"Nils","family":"Janzen","sequence":"additional","affiliation":[{"name":"Screening Laboratory Hannover, Box 91 10 09, 30430 Hannover, Germany"},{"name":"Division of Laboratory Medicine, Centre for Children and Adolescents, Kinder- und Jugendkrankenhaus Auf der Bult, Janusz-Korczak-Allee 12, 30173 Hannover, Germany"},{"name":"Department of Clinical Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5986-0468","authenticated-orcid":false,"given":"Sarah Catharina","family":"Gr\u00fcnert","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology, University Medical Center, Faculty of Medicine, University of Freiburg, Mathildenstra\u00dfe 1, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1675-9372","authenticated-orcid":false,"given":"Peter","family":"Freisinger","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Metabolic Disease Center, Klinikum Reutlingen, Steinenbergstr. 31, 72764 Reutlingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.2119\/molmed.2015.00254","article-title":"Determination of Autosomal Dominant or Recessive Methionine Adenosyltransferase I\/III Deficiencies Based on Clinical and Molecular Studies","volume":"22","author":"Kim","year":"2016","journal-title":"Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/ajmg.c.30293","article-title":"Hypermethioninemias of genetic and non-genetic origin: A review","volume":"157","author":"Mudd","year":"2011","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lauinger, L., and Kaiser, P. (2021). Sensing and Signaling of Methionine Metabolism. Metabolites, 11.","DOI":"10.3390\/metabo11020083"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s13023-015-0321-y","article-title":"Mudd\u2019s disease (MAT I\/III deficiency): A survey of data for MAT1A homozygotes and compound heterozygotes","volume":"10","author":"Chien","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"225","DOI":"10.2147\/TCRM.S151732","article-title":"Methionine adenosyltransferase I\/III deficiency: Beyond the central nervous system manifestations","volume":"14","author":"Nashabat","year":"2018","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1016\/0140-6736(91)92373-A","article-title":"Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway","volume":"338","author":"Surtees","year":"1991","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S233","DOI":"10.1007\/s10545-008-0811-3","article-title":"Hypermethioninaemia due to methionine adenosyltransferase I\/III (MAT I\/III) deficiency: Diagnosis in an expanded neonatal screening programme","volume":"31","author":"Couce","year":"2008","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.ymgme.2013.08.003","article-title":"Clinical and metabolic findings in patients with methionine adenosyltransferase I\/III deficiency detected by newborn screening","volume":"110","author":"Couce","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/8904_2011_124","article-title":"Methionine Adenosyltransferase I\/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands","volume":"6","author":"Martins","year":"2012","journal-title":"JIMD Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.ymgme.2012.08.002","article-title":"Methionine adenosyltransferase I\/III deficiency: Neurological manifestations and relevance of S-adenosylmethionine","volume":"107","author":"Furujo","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10545-016-9972-7","article-title":"Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders","volume":"40","author":"Staufner","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1042\/BJ20121580","article-title":"Insight into S-adenosylmethionine biosynthesis from the crystal structures of the human methionine adenosyltransferase catalytic and regulatory subunits","volume":"452","author":"Shafqat","year":"2013","journal-title":"Biochem. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1007\/s00018-008-8516-1","article-title":"Structure-function relationships in methionine adenosyltransferases","volume":"66","author":"Markham","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/45977","article-title":"Identification of in vivo substrates of the chaperonin GroEL","volume":"402","author":"Houry","year":"1999","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1172\/JCI118862","article-title":"Demyelination of the brain is associated with methionine adenosyltransferase I\/III deficiency","volume":"98","author":"Chamberlin","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_16","first-page":"2705","article-title":"Characteristic MR imaging changes in severe hypermethioninemic states","volume":"26","author":"Braverman","year":"2005","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_17","first-page":"1843","article-title":"Reversible white matter lesion in methionine adenosyltransferase I\/III deficiency","volume":"25","author":"Tada","year":"2004","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/S1096-7192(03)00066-0","article-title":"Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: A diagnostic trap","volume":"79","author":"Mudd","year":"2003","journal-title":"Mol. Genet. Metab."},{"key":"ref_19","first-page":"44","article-title":"The effect of methionine and S-adenosylmethionine on S-adenosylmethionine levels in the rat brain","volume":"30","author":"Young","year":"2005","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1086\/302752","article-title":"Methionine Adenosyltransferase I\/III Deficiency: Novel Mutations and Clinical Variations","volume":"66","author":"Chamberlin","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/ng1322","article-title":"Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations","volume":"36","author":"Inoue","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1023\/A:1022829214415","article-title":"Methionine adenosyltransferase I\/III deficiency: Two Korean compound heterozygous siblings with a novel mutation","volume":"25","author":"Kim","year":"2003","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1001\/jama.1995.03530110064037","article-title":"Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study","volume":"274","author":"Cohen","year":"1995","journal-title":"JAMA"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1163\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:19Z","timestamp":1760139559000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,27]]},"references-count":23,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["genes13071163"],"URL":"https:\/\/doi.org\/10.3390\/genes13071163","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2022,6,27]]}}}