Froese D Sean, Huemer Martina, Suormala Terttu, Burda Patricie, Coelho David, Guéant Jean-Louis, Landolt Markus A, Kožich Viktor, Fowler Brian, Baumgartner Matthias R
Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, CH-8032, Switzerland.
Radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zürich, Switzerland.
Hum Mutat. 2016 May;37(5):427-38. doi: 10.1002/humu.22970. Epub 2016 Mar 18.
Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.
严重的5,10-亚甲基四氢叶酸还原酶（MTHFR）缺乏症由MTHFR基因突变引起，会导致高同型半胱氨酸血症以及疾病严重程度各异，从新生儿致死到成人发病不等。包括此处描述的病例在内，已在171个家庭中报告了109种MTHFR突变，其中包括70种错义突变、17种主要影响剪接的突变、11种无义突变、7种小缺失、2种不停突变、1种小重复和1种大重复。只有36%的突变在不相关家庭中复发，这表明大多数突变是“私有的”。最常见的突变是c.1530A>G（编号基于NM_005957.4，p.Lys510 = ），会导致剪接缺陷，在13个家庭中发现；最常见的错义突变是c.1129C>T（p.Arg377Cys），在10个家庭中被鉴定出。为了增进对该疾病的了解，我们报告了所有已发表患者的酶活性、检测到的突变以及临床发病信息（早发，<1岁；或晚发，>1岁），表明早发患者的残余酶活性低于晚发患者。我们还综述了动物模型、诊断方法、临床表现和治疗选择。这是首次对MTHFR突变进行的大型综述，突出了致病突变的广泛谱系。
