Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes.

• Type of Material: Article
• Authors: Yin-Hsiu Chien, National Taiwan University; Jose E. Abdenur, CHOC Children’s; Federico Baronio, University of Bologna; Allison Anne Bannick, Detroit Medical Center; Fernando Corrales, University of Navarra; Maria Couce, Hospital Clínico Universitario de Santiago; Markus G. Donner, Heinrich Heine University Düsseldorf; Can Ficicioglu, University of Pennsylvania; Cynthia Freehauf, University of Colorado; Deborah Frithiof, Pediatrics Umeå University; Garrett Gotway, University of Texas; Koichi Hirabayashi, Shinshu University; Floris Hofstede, University Medical Center Utrecht; George Hoganson, University of Illinois; Wuh-Liang Hwu, National Taiwan University Hospital; Philip James, Harvard Medical School; Sook Kim, KSZ Children’s Hospital; Stanley H. Korman, Hebrew University; Robin Lachmann, National Hospital for Neurology and Neurosurgery; Harvey Levy, Harvard Medical School; Martin Lindner, University Hospital Heidelberg; Lilia Lykopoulou, University of Athens; Ertan Mayatepek, University Medical Center Hamburg Eppendorf; Ania Muntau, University Medical Center Hamburg Eppendorf; Yoshiyuki Okano, Hyogo College of Medicine; Kimiyo Raymond, Mayo Clinic College of Medicine; Estela Rubio-Gozalbo, Medical University of Innsbruck; Sabine Scholl-Bürgi, Medical University of Innsbruck; Andreas Schulze, The Hospital for Sick Children; Rani Singh, Emory University; Sally Stabler, University of Colorado; Mary Stuy, Indiana University; Janet Thomas, University of Colorado; Conrad Wagner, Vanderbilt University; William G. Wilson, University of Virginia; Saskia Wortmann, Amalia Children’s Hospital; Shigenori Yamamoto, National Shimoshizu Hospital; Maryland Pao, National Institute of Mental Health; Henk J. Blom, University Hospital Freiburg
• Language: English
• Date: 2015
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © Chien et al. 2015
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13023-015-0321-y
• Title of Journal or Parent Work: Orphanet Journal of Rare Diseases
• ISSN: 1750-1172
• Volume: 10
• Issue: 1
• Start Page: 99
• End Page: 99
• Grant/Funding Information: This research was supported in part by National Institute of Mental Health Intramural Research Program and the E-HOD project (No.2012_12_02) of the European Union in the framework of the Health Program.
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics; Health Sciences, General

Abstract

BACKGROUND: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine β-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. PURPOSE OF THE STUDY: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. RESULTS AND DISCUSSION: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 μM or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.