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

TY - JOUR

T1 - Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes

AU - Chien, Yin-Hsiu

AU - Abdenur, Jose E

AU - Baronio, Federico

AU - Bannick, Allison Anne

AU - Corrales, Fernando

AU - Couce, Maria

AU - Donner, Markus G

AU - Ficicioglu, Can

AU - Freehauf, Cynthia

AU - Frithiof, Deborah

AU - Gotway, Garrett

AU - Hirabayashi, Koichi

AU - Hofstede, Floris

AU - Hoganson, George

AU - Hwu, Wuh-Liang

AU - James, Philip

AU - Kim, Sook

AU - Korman, Stanley H

AU - Lachmann, Robin

AU - Levy, Harvey

AU - Lindner, Martin

AU - Lykopoulou, Lilia

AU - Mayatepek, Ertan

AU - Muntau, Ania

AU - Okano, Yoshiyuki

AU - Raymond, Kimiyo

AU - Rubio-Gozalbo, Estela

AU - Scholl-Bürgi, Sabine

AU - Schulze, Andreas

AU - Singh, Rani

AU - Stabler, Sally

AU - Stuy, Mary

AU - Thomas, Janet

AU - Wagner, Conrad

AU - Wilson, William G

AU - Wortmann, Saskia

AU - Yamamoto, Shigenori

AU - Pao, Maryland

AU - Blom, Henk J

PY - 2015/8/20

Y1 - 2015/8/20

N2 - 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.

AB - 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.

U2 - 10.1186/s13023-015-0321-y

DO - 10.1186/s13023-015-0321-y

M3 - SCORING: Journal article

C2 - 26289392

VL - 10

SP - Art. 99

JO - ORPHANET J RARE DIS

JF - ORPHANET J RARE DIS

SN - 1750-1172

ER -