Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes.
Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes.
复制标题
DOI：
10.1186/s13023-015-0321-y
复制
发表时间：
2015-08-20
影响因子：
3.7
通讯作者：
Blom HJ
中科院分区：
文献类型：
--
作者：
Chien YH;Abdenur JE;Baronio F;Bannick AA;Corrales F;Couce M;Donner MG;Ficicioglu C;Freehauf C;Frithiof D;Gotway G;Hirabayashi K;Hofstede F;Hoganson G;Hwu WL;James P;Kim S;Korman SH;Lachmann R;Levy H;Lindner M;Lykopoulou L;Mayatepek E;Muntau A;Okano Y;Raymond K;Rubio-Gozalbo E;Scholl-Bürgi S;Schulze A;Singh R;Stabler S;Stuy M;Thomas J;Wagner C;Wilson WG;Wortmann S;Yamamoto S;Pao M;Blom HJ
本文总结了一个小组的努力，汇集了世界各地的患者谁是纯合子或复合杂合子突变MAT 1A的可用数据的结果。MAT 1A编码形成两种甲硫氨酸腺苷转移酶同工酶（四聚体MAT I和二聚体MAT III）的亚基，其催化甲硫氨酸和ATP转化为S-腺苷甲硫氨酸（MATMet）。MAT I/III活性低于正常可导致高甲硫氨酸血症。由于杂合子中的MAT 1A突变之一导致相对轻度和临床上良性的高甲硫氨酸血症而患有高甲硫氨酸血症的个体目前通常在测量甲硫氨酸升高的筛选程序中被标记，以鉴定具有缺陷型胱硫醚β-合酶活性的新生儿。MAT 1A突变的纯合子或复合杂合子较少见。一些但不是全部，这样的个体表现出脱髓鞘或其他CNS异常。目前努力的目标是确定这种异常的频率，找到如何最好地预测它们是否会发生，并评估各种治疗方案的结果。收集了64例患者的数据，其中32例有CNS异常的证据（主要基于MRI结果），32例没有此类证据。结果表明，平均血浆蛋氨酸浓度提供了给定患者所属组的最佳指示：平均值为800 μM或更高的患者通常有CNS异常的证据，而平均值较低的患者通常没有。报告了个体患者的MAT 1A基因型、血浆甲硫氨酸、总同型半胱氨酸（tHcy）和蛋氨酸浓度、肝功能研究、15例妊娠的结果以及饮食甲硫氨酸限制和/或蛋氨酸补充的结果。可能的病理生理机制，可能有助于中枢神经系统的损害进行了讨论，并提出了初步建议，以优化管理。
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. 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. 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.