Tonetti Carole, Saudubray Jean-Marie, Echenne Bernard, Landrieu Pierre, Giraudier Stéphane, Zittoun Jacqueline
Service Central d'Hématologie, Hopital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010, Creteil, France.
Clinique Génétique Médicale, Hôpital Necker-Enfants-Malades, Paris, France.
Eur J Pediatr. 2003 Jul;162(7-8):466-475. doi: 10.1007/s00431-003-1196-9. Epub 2003 May 6.
Methylenetetrahydrofolate reductase (MTHFR) deficiency is an autosomal recessive disorder resulting in elevated homocysteine levels in plasma and urine. MTHFR catalyses the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, a cofactor for homocysteine remethylation to methionine. MTHFR deficiency may be diagnosed from infancy to adulthood with a broad spectrum of clinical symptoms. A molecular analysis of the MTHFR gene combined with an assessment of MTHFR activity, plasma homocysteine and folate in plasma and red blood cells (RBC), especially methylfolate, was assessed in the members of 11 families from children affected with this disorder. This study was performed to try to define the impact of the mutations found in the MTHFR gene on symptoms and biological abnormalities. A total of 14 mutations were found and 10 of them were identified for the first time. Two were found in two families, two more in two other families and one in three families. The position of the mutation spread all over the gene does not predict the degree of biological abnormalities found in parents or healthy siblings bearing the mutation. Two different mutations located not far apart on the same exon may cause mild or severe abnormalities. The thermolabile variant C677T when expressed in an homozygote state in some parents was associated with lower MTHFR activity, higher homocysteine levels, lower folate levels, mainly methylfolate in RBC than in parents without the mutation; conversely, two or more mutations on the same allele had mild effects when the other allele was normal.
Given the heterogeneity of mutations, no one seems preponderant to predict neurological and/or vascular symptoms.
亚甲基四氢叶酸还原酶（MTHFR）缺乏症是一种常染色体隐性疾病，会导致血浆和尿液中同型半胱氨酸水平升高。MTHFR催化亚甲基四氢叶酸还原为甲基四氢叶酸，后者是同型半胱氨酸再甲基化为蛋氨酸的一种辅助因子。MTHFR缺乏症可在从婴儿期到成年期的任何阶段被诊断出来，临床症状范围广泛。对11个患有该疾病儿童的家庭中的成员进行了MTHFR基因的分子分析，并评估了MTHFR活性、血浆同型半胱氨酸以及血浆和红细胞（RBC）中的叶酸，尤其是甲基叶酸。进行这项研究是为了确定MTHFR基因中发现的突变对症状和生物学异常的影响。总共发现了14个突变，其中10个是首次鉴定出来的。两个突变在两个家庭中被发现，另外两个突变在另外两个家庭中被发现，还有一个突变在三个家庭中被发现。突变在整个基因上的位置并不能预测携带该突变的父母或健康兄弟姐妹中发现的生物学异常程度。位于同一外显子上相距不远的两个不同突变可能会导致轻度或重度异常。热不稳定变体C677T在一些父母中以纯合子状态表达时，与较低的MTHFR活性、较高的同型半胱氨酸水平、较低的叶酸水平相关，主要是红细胞中的甲基叶酸水平低于没有该突变的父母；相反，当另一个等位基因正常时，同一等位基因上的两个或更多突变具有轻度影响。
鉴于突变的异质性，似乎没有一个突变在预测神经和/或血管症状方面占主导地位。
