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


OBJECTIVE
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.


CONCLUSIONS
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.
Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Children's Hospital Building, Taipei, Taiwan.
Yin-Hsiu
YH
Chien
Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA.
Jose E
JE
Abdenur
Newborn Screening and Inborn Errors of Metabolism Regional Centre, Pediatric Endocrinology Program, Pediatric Unit, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
Federico
F
Baronio
Children's Hospital of Michigan Metabolic Clinic, Detroit Medical Center, Detroit, MI, USA.
Allison Anne
AA
Bannick
Department of Hepatology, Proteomics laboratory, Center for Applied Medical Research (CIMA), University of Navarra, IdiSNA, Pamplona, Spain.
Fernando
F
Corrales
Head of Metabolic Unit, Department Pediatrics, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
Maria
M
Couce
Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Markus G
MG
Donner
The Children's Hospital of Philadelphia, Division of Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Can
C
Ficicioglu
Department of Pediatrics, University of Colorado, Aurora, CO, USA.
Cynthia
C
Freehauf
Department of Clinical Sciences, Pediatrics Umeå University, SE 901 85, Umeå, Sweden.
Deborah
D
Frithiof
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.
Garrett
G
Gotway
Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Japan.
Koichi
K
Hirabayashi
Division of Paediatrics, Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Floris
F
Hofstede
Department of Pediatrics, University of Illinois at Chicago, College of Medicine, Chicago, Il, USA.
George
G
Hoganson
Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Children's Hospital Building, Taipei, Taiwan.
Wuh-Liang
WL
Hwu
Children's Hospital Boston, Harvard Medical School, Boston, USA.
Philip
P
James
KSZ Children's Hospital/Korea Genetics Research Center, Jikjidaero, Heung Duck Gu, Cheng Ju City, Chung Buk, Republic of Korea.
Sook
S
Kim
Department of Genetics and Department of Metabolic Diseases, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
Stanley H
SH
Korman
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
Robin
R
Lachmann
Children's Hospital Boston, Harvard Medical School, Boston, USA.
Harvey
H
Levy
Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, Heidelberg, Germany.|Department of Neurology, University Children's Hospital Frankfurt, Frankfurt, Germany.
Martin
M
Lindner
First Department of Pediatrics, University of Athens, Agia Sofia Children's Hospital, Athens, Greece.
Lilia
L
Lykopoulou
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Duesseldorf, Germany.
Ertan
E
Mayatepek
University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
Ania
A
Muntau
Department of Genetics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Japan.
Yoshiyuki
Y
Okano
Department of Medicine and Pathology, Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN, USA.
Kimiyo
K
Raymond
Department of Pediatrics and Laboratory Genetic Metabolic Diseases, Maastricht University Medical Center, Maastricht, Netherlands.
Estela
E
Rubio-Gozalbo
Medical University of Innsbruck, Clinic for Pediatrics, Inherited Metabolic Disorders, Innsbruck, Austria.
Sabine
S
Scholl-Bürgi
Genetics and Genome Biology, Peter Gilgan Center for Research and Learning The Hospital for Sick Children, Toronto, ON, Canada.
Andreas
A
Schulze
Department of Human Genetics and Pediatric, Emory University, Atlanta, GA, USA.
Rani
R
Singh
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Sally
S
Stabler
Department of Medical and Molecular Genetics Indiana University School of Medicine, Indianapolis, IN, USA.
Mary
M
Stuy
Department of Pediatrics, University of Colorado, Aurora, CO, USA.
Janet
J
Thomas
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tn, USA.
Conrad
C
Wagner
Division of Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA.
William G
WG
Wilson
Nijmegen Centre for Mitochondrial Disorders (NCMD), RadboudUMC, Amalia Children's Hospital, Nijmegen, The Netherlands.
Saskia
S
Wortmann
Department of Pediatrics, National Shimoshizu Hospital, Chiba, Japan.
Shigenori
S
Yamamoto
Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD, USA.
Maryland
M
Pao
Laboratory for Clinical Biochemistry and Metabolism, Center for Pediatrics and Adolescent Medicine University Hospital Freiburg, 79106, Freiburg, Germany. henk.blom@uniklinik-freiburg.de.
Henk J
HJ
Blom
D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics*; D008875:Middle Aged; D011795:Surveys and Questionnaires; D055815:Young Adult
C506577:MAT1A protein, human; D008716:Methionine Adenosyltransferase