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Orphanet J Rare Dis. 2015 Aug 20;10:99. doi: 10.1186/s13023-015-0321-y.

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

Author information

1
Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Children's Hospital Building, Taipei, Taiwan.
2
Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA.
3
Newborn Screening and Inborn Errors of Metabolism Regional Centre, Pediatric Endocrinology Program, Pediatric Unit, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
4
Children's Hospital of Michigan Metabolic Clinic, Detroit Medical Center, Detroit, MI, USA.
5
Department of Hepatology, Proteomics laboratory, Center for Applied Medical Research (CIMA), University of Navarra, IdiSNA, Pamplona, Spain.
6
Head of Metabolic Unit, Department Pediatrics, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
7
Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
8
The Children's Hospital of Philadelphia, Division of Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
9
Department of Pediatrics, University of Colorado, Aurora, CO, USA.
10
Department of Clinical Sciences, Pediatrics Umeå University, SE 901 85, Umeå, Sweden.
11
Department of Pediatrics, Division of Genetics and Metabolism; Department of Internal Medicine, Division of Clinical Genetics; and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
12
Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Japan.
13
Division of Paediatrics, Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
14
Department of Pediatrics, University of Illinois at Chicago, College of Medicine, Chicago, Il, USA.
15
Children's Hospital Boston, Harvard Medical School, Boston, USA.
16
KSZ Children's Hospital/Korea Genetics Research Center, Jikjidaero, Heung Duck Gu, Cheng Ju City, Chung Buk, Republic of Korea.
17
Department of Genetics and Department of Metabolic Diseases, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
18
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
19
Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, Heidelberg, Germany.
20
Department of Neurology, University Children's Hospital Frankfurt, Frankfurt, Germany.
21
First Department of Pediatrics, University of Athens, Agia Sofia Children's Hospital, Athens, Greece.
22
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Duesseldorf, Germany.
23
University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
24
Department of Genetics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Japan.
25
Department of Medicine and Pathology, Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN, USA.
26
Department of Pediatrics and Laboratory Genetic Metabolic Diseases, Maastricht University Medical Center, Maastricht, Netherlands.
27
Medical University of Innsbruck, Clinic for Pediatrics, Inherited Metabolic Disorders, Innsbruck, Austria.
28
Genetics and Genome Biology, Peter Gilgan Center for Research and Learning The Hospital for Sick Children, Toronto, ON, Canada.
29
Department of Human Genetics and Pediatric, Emory University, Atlanta, GA, USA.
30
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
31
Department of Medical and Molecular Genetics Indiana University School of Medicine, Indianapolis, IN, USA.
32
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tn, USA.
33
Division of Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA.
34
Nijmegen Centre for Mitochondrial Disorders (NCMD), RadboudUMC, Amalia Children's Hospital, Nijmegen, The Netherlands.
35
Department of Pediatrics, National Shimoshizu Hospital, Chiba, Japan.
36
Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD, USA.
37
Laboratory for Clinical Biochemistry and Metabolism, Center for Pediatrics and Adolescent Medicine University Hospital Freiburg, 79106, Freiburg, Germany. henk.blom@uniklinik-freiburg.de.

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.

PMID:
26289392
PMCID:
PMC4545930
DOI:
10.1186/s13023-015-0321-y
[Indexed for MEDLINE]
Free PMC Article

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