Role of amniotic fluid homocysteine level and of fetal 5, 10-methylenetetrahydrafolate reductase genotype in the etiology of neural tube defects

A mutation in the gene 5,10-methylenetetrahydrofolate reductase (MTHFR), leading to altered homocysteine metabolism, has been identified in parents and fetuses with fetal neural tube defects. We sought to determine which is of greater importance in fetal neural tube defect formation: the fetal MTHFR mutation or elevated amniotic fluid homocysteine level. We retrieved stored amniotic fluid from cases of isolated fetal neural tube defect diagnosed from 1988 to 1998 (n = 80), and from normal controls matched for race, month and year of amniocentesis, and maternal age. The presence or absence of the 677C-->T mutation of MTHFR was determined and homocysteine levels were measured; cases and controls were compared. Significantly more cases than controls were heterozygous or homozygous for the 677C-->T MTHFR mutation (44% vs 17%, P < or = 0.001). Cases were also significantly more likely than controls to have an amniotic fluid homocysteine level above the 90th centile (>1.85 micromol per liter); 27% vs 10%, P = 0.02. Thirty one cases and 12 controls had an abnormal genotype; however, amniotic fluid homocysteine levels were not significantly different between these two groups (6/31, or 19% of cases had an elevated homocysteine compared to 1/12, or 8% of controls; P = 0.65). In contrast, 40 cases and 60 controls had a normal genotype; the neural tube defect cases had significantly higher homocysteine levels (13/40, or 32% of cases had an elevated homocysteine level compared to only 6/60, or 10% of controls; P = 0.008). Although both abnormal fetal MTHFR genotype and abnormal amniotic fluid homocysteine concentration are significantly associated with neural tube defects, the association with amniotic fluid homocysteine concentration is significant regardless of the fetal MTHFR genotype. The relationship between maternal and fetal homocysteine metabolism is complex.     

Amniotic fluid homocysteine levels, 5,10‐methylenetetrahydrafolate reductase genotypes,and neural tube closure sites

A specific gene mutation leading to altered homocysteine metabolism has been identified in parents and fetuses with neural tube defects (NTDs). In addition, current animal and human data indicate that spine closure occurs simultaneously in five separate sites that then fuse. We sought to determine whether either this mutation or abnormal amniotic fluid homocysteine levels are associated with all five neural tube closure sites. We retrieved stored amniotic fluid from cases of isolated fetal neural tube defect diagnosed from 1988 to 1998 (n = 80) and from normal controls matched for race, month and year of amniocentesis, and maternal age. Cases were categorized according to defect site by using all available medical records. The presence or absence of the 677C→T mutation of 5,10‐methylenetetrahydrafolate reductase (MTHFR) gene was determined, and homocysteine levels were measured; case and controls were compared. Significantly more cases than controls were heterozygous or homozygous for the 677C→T MTHFR mutation (44% vs. 17%, P ≤ 0.001). Likewise, cases were significantly more likely than controls to have amniotic fluid homocysteine levels >90th centile (>1.85 μmol/L), 27% vs. 10%, P = 0.02. Most (83%) of control cases had both normal MTHFR alleles and normal amniotic fluid homocysteine levels (normal/normal), whereas only 56% of NTD case were normal/normal (P = 0.001). When evaluated by defect site, only defects involving the cervical‐lumbar spine, lumbosacral spine, and occipital encephalocele were significantly less likely to be normal/normal than controls (P = 0.007, 0.0003, and 0.007, respectively), suggesting a strong association with the 677C→T allele. In contrast, anencephaly, exencephaly, and defects confined to the sacrum included many cases that had both normal MTHFR alleles and normal homocysteine and were not significantly different from controls. The 677C→T MTHFR mutation and elevated homocysteine levels appear to be disproportionately associated with defects spanning the cervical‐lumbar spine, lumbosacral spine, and occipital encephalocele. In contrast, anencephaly, exencephaly, and defects confined to the sacrum may not be related to altered homocysteine metabolism. Am. J. Med. Genet. 90:6–11, 2000. © 2000 Wiley‐Liss, Inc.     

Amniotic fluid homocysteine levels, 5,10-methylenetetrahydrafolate reductase genotypes, and neural tube closure sites

A specific gene mutation leading to altered homocysteine metabolism has been identified in parents and fetuses with neural tube defects (NTDs). In addition, current animal and human data indicate that spine closure occurs simultaneously in five separate sites that then fuse. We sought to determine whether either this mutation or abnormal amniotic fluid homocysteine levels are associated with all five neural tube closure sites. We retrieved stored amniotic fluid from cases of isolated fetal neural tube defect diagnosed from 1988 to 1998 (n = 80) and from normal controls matched for race, month and year of amniocentesis, and maternal age. Cases were categorized according to defect site by using all available medical records. The presence or absence of the 677C-->T mutation of 5, 10-methylenetetrahydrafolate reductase (MTHFR) gene was determined, and homocysteine levels were measured; case and controls were compared. Significantly more cases than controls were heterozygous or homozygous for the 677C-->T MTHFR mutation (44% vs. 17%, P < or = 0. 001). Likewise, cases were significantly more likely than controls to have amniotic fluid homocysteine levels >90th centile (>1.85 micromol/L), 27% vs. 10%, P = 0.02. Most (83%) of control cases had both normal MTHFR alleles and normal amniotic fluid homocysteine levels (normal/normal), whereas only 56% of NTD case were normal/normal (P = 0.001). When evaluated by defect site, only defects involving the cervical-lumbar spine, lumbosacral spine, and occipital encephalocele were significantly less likely to be normal/normal than controls (P = 0.007, 0.0003, and 0.007, respectively), suggesting a strong association with the 677C-->T allele. In contrast, anencephaly, exencephaly, and defects confined to the sacrum included many cases that had both normal MTHFR alleles and normal homocysteine and were not significantly different from controls. The 677C-->T MTHFR mutation and elevated homocysteine levels appear to be disproportionately associated with defects spanning the cervical-lumbar spine, lumbosacral spine, and occipital encephalocele. In contrast, anencephaly, exencephaly, and defects confined to the sacrum may not be related to altered homocysteine metabolism.     

Methylenetetrahydrofolate reductase and spina bifida: evaluation of level of defect and maternal genotypic risk in Hispanics

The C677T and A1298C mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are each associated with reduced MTHFR activity. The C677T mutation in the heterozygous and homozygous state correlates with increased enzyme thermolability, with homozygous mutant genotypes showing significantly elevated plasma homocysteine levels and decreased plasma folate levels. The A1298C mutation results in decreased MTHFR activity, but changes in neither homocysteine nor folate levels are associated with A1298C variant genotypes. Our study determined the frequencies of the C677T and A1298C MTHFR mutations for spina bifida (SB) cases, mothers and fathers of SB cases, and controls in Hispanics of Mexican-American descent. In addition, our subject population was further categorized as to whether the spina bifida lesion occurred as an upper or lower level defect, according to the Van Allen "multi-site closure" model. Hispanic SB cases with upper level defects and their mothers were homozygous for the C677T variant allele at a higher rate than their respective controls (OR = 1.5 [95% CI 0.8-2.9], P = 0.30; OR = 2.3 [1.1-4.8], P = 0.04, respectively), with statistically significant results seen only for the maternal homozygous genotype. Homozygosity for the A1298C mutation was seen at a higher rate only in Hispanic mothers of both upper and lower level SB cases when compared to controls, but these results were not statistically significant. Our study provides evidence that the maternal C677T MTHFR homozygous mutant genotype is a risk factor for upper level spina bifida defects in Hispanics.     

Influence of combined methionine synthase (MTR 2756A > G) and methylenetetrahydrofolate reductase (MTHFR 677C > T) polymorphisms to plasma homocysteine levels in Korean patients with ischemic stroke

PURPOSE: Methionine synthase (MTR) and 5,10-methylenetetrahydrofolate reductase (MTHFR) are the main regulatory enzymes for homocysteine metabolism. The present case- control study was conducted to determine whether there is an association between the MTR 2756A > G or MTHFR 677C > T polymorphism and plasma homocysteine concentration in Korean subjects with ischemic stroke. MATERIALS AND METHODS: DNA samples of 237 patients who had an ischemic stroke and 223 age and sex-matched controls were studied. MTR 2756A > G and MTHFR 677C > T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Frequencies of mutant alleles for MTR and MTHFR polymorphisms were not significantly different between the controls and cases. The patient group, however, had significantly higher homocysteine concentrations of the MTR 2756AA and MTHFR 677TT genotypes than the control group (p=0.04 for MTR, p=0.01 for MTHFR). The combined MTR 2756AA and MTHFR 677TT genotype (p= 0.04) and the homocysteine concentrations of the patient group were also higher than those of the controls. In addition, the genotype distribution was significant in the MTHFR 677TT genotype (p=0.008) and combined MTR 2756AA and MTHFR 677TT genotype (p=0.03), which divided the groups into the top 20% and bottom 20% based on their homocysteine levels. CONCLUSION: The results of the present study demonstrate that the MTR 2756A > G and MTHFR 677C > T polymorphisms interact with elevated total homocysteine (tHcy) levels, leading to an increased risk of ischemic stroke.     

A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677C-->T and 1298A-->C variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients and 601 apparently healthy controls. The mean specific and residual MTHFR activities were significantly lower in 677CT and 677TT individuals (both P<0.001). The 1298A-->C mutation alone showed no effect on MTHFR activities. However, when the 677C-->T genotype was taken into account, the 1298A-->C mutation also caused a significant decrease in MTHFR activities, which was observed in both the homozygous 1298CC (P<0.001) and the heterozygous 1298AC states (P=0.005). Both the 677TT as the 677CT genotypes were associated with significantly higher fasting and postload homocysteine levels than 677CC (P<0.001 and P=0.003, respectively). The 1298A-->C mutation had no effect on fasting or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, these findings indicate that the 1298A-->C mutation cannot be considered a major risk factor for CVD.     

Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: Low folate status alone may be the critical factor

Thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) is the first folate-related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocysteine levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relationship between folate status and presence of the common mutation MTHFR C677T in 82 NTD-affected and 260 control mothers. Homozygosity for the TT genotype was associated with very low folate status among both the cases (n = 13) and the controls (n = 21). However, after exclusion of TT homozygotes, only 10% of the remaining 240 controls had RCF levels less than 200 μg/L compared with 29% of the 69 cases (odds ratio, 3.67; 95% confidence interval, 1.88–7.18; P < 0.001), and those with RCF less than 150 μg/L had eight times higher risk of NTD than subjects with levels over 400 μg/L. Plasma homocysteine levels of non-TT cases were also higher than those of controls (P = 0.047). This study shows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD-affected mothers. Thus, a strategy of genetic screening of all childbearing women for this variant would be ineffective as a method of primary prevention of NTDs. The data suggest that low maternal folate status is itself the major determinant of NTD risk, or else that other folate-dependent genetic variants confer risk through the reduction of folate levels. These results emphasize the importance of a food-fortification program as a population strategy for reducing the occurrence of NTDs. Am. J. Med. Genet. 78:155–159, 1998. © 1998 Wiley-Liss, Inc.     

Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene

Around 6% of infants born to mothers taking anticonvulsants have malformations, including neural tube defects, and a further proportion show developmental delay in later childhood. Three commonly used anticonvulsants, carbamazepine, phenytoin and sodium valproate, interfere with folic acid metabolism. We investigated the common 677 C>T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in samples from 57 patients and their parents and 152 controls to determine its contribution to the risk of fetal anticonvulsant syndrome. The 677 C>T mutation frequency was significantly higher in the mothers than in the controls, but there was no significant difference in 677 C>T frequency in the patients or in the fathers. Genotype frequencies in the mothers were significantly different from controls, there being an excess of 677 C>T homozygotes. Amongst the patients, there was an apparent excess of heterozygotes (not statistically significant), and the fathers were not significantly different from controls. Mutation in the MTHFR gene in a mother taking sodium valproate, phenytoin or carbamazepine during pregnancy is associated with fetal anticonvulsant syndrome in her offspring. The skewed distribution of genotypes in the affected children probably reflects the association of fetal anticonvulsant syndrome with the maternal genotype.     

MTHFR基因C677T多态性与神经管缺损的相关性研究

目的探讨5,10-甲基四氢叶酸还原酶（5,10-methylenetetrahydrofolate reductase,MTHFR）基因C677T突变与神经管缺损（neuraltube defectes,NTD）发病的相关性。方法应用PCR—RFLP法,对67名正常儿童和48例NTD患儿（NTD组）（其中无脑儿16例,脊柱裂32例）进行MTHFR基因C677T突变分析。结果NTD组胎儿MTHFR基因TT基因型频率（68．7％）和T等位基因频率（0．820）均显著高正常对照组儿童（31．3％和0．54）（x^2=15．71,P〈0．01和x^2=17．18,P〈0．01）。与MTHFR基因CC基因型相比,携带TT基因型的胎儿发生NTD的相对风险增加6．28倍（95％CI：2．01～19．62）。结论MTHFR基因C677T多态性与潍坊地区人胎儿NTD发病有关联。     

Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy

Previous studies have shown conflicting findings in linking polymorphic variation in folate-related genes to the risk of neural tube defect pregnancy. Recent evidence points to maternal genotype being important in determining NTD risk. A case-control study was undertaken in 97 mothers of NTD cases from the northern region of the UK. Pregnant controls (n = 190) from a regional DNA bank and non-pregnant controls (n = 100) from the same geographical area were recruited. MTHFR 677C >T, MTHFR 1298A >C, MTRR 66A >G, SHMT 1420C >T, CbetaS 844ins68, and RFC-1 80G >A allele and genotype frequencies were determined and odds ratios (OR) calculated. Erythrocyte folate levels for cases and controls were also measured and a comparison made of median erythrocyte folate levels stratified according to genotype. The MTHFR 677C >T variant was not shown to be an independent NTD risk factor in mothers of NTD-affected pregnancy. A second polymorphism in MTHFR, 1298A >C, was less frequently observed in mothers of NTD cases (OR [95% CI]=0.57 [0.33, 0.97]). Possession of compound 1298A >C and 677C >T variants elevated risk of NTD pregnancy considerably (TT/AC+TT/CC vs CC/AA OR [95% CI]=6.56 [1.10, 39.33]). Erythrocyte folate levels were persistently lower in NTD mothers (p = 0.001) despite assays being conducted many years after the index pregnancy (17.6+/-12.6 years). Erythrocyte folate levels were depressed in the presence of the MTHFR 677C >T variant.     

Polymorphisms of methylenetetrahydrofolate reductase gene among women of childbearing age from Shiyan areaCSCD

Objective: To assess the association of methylenetetrahydrofolate reductase (MTHFR) gene 677C>T polymorphism with blood homocysteine (Hey) level among women of childbearing age from Shiyan area. Methods: PCR - chip hybridization was used to determine the genotype of MTHFR 6770T, and a biochemical assay was used to determine the total Hey level among 428 healthy women of childbearing age. Association of MTHFR 677>T with total Hey level was assessed. Results: Heterozygous CT mutation was most common form for the MTHFR 677>T polymorphisms and amounted for 49. 77% among the group, while the CC wild type and homozygous TT mutation respectively accounted for 30. 61% and 19. 63%. These gave a frequency of 44. 51% for the 677T allele. The dominant genotype among different age groups were the CT type. Of note, the proportion of MTHFR 677CC is higher in women above 30 years of age. The distribution of MTHFR 677>T genotypes has differed significantly among different age groups (P<0. 05). Compared with those with wild type alleles, carriers of MTHFR mutations had a higher plasma Hey level. The genotypic frequencies of MTHFR C677T in Shiyan region differed significantly from those of Sichuan, Hebei, Henan and Shandong (P < 0. 05) but were similar to those of Jiangsu, Guangdong, Ningxia and Xinjiang. Conclusion: The distribution of MTHFR C677T polymorphism among women of childbearing age in Shiyan area is influenced by age and is geographically specific and associated with plasma Hey level. Nearly 50% of women have carried the high risk alleles, for whom folic acid supplementation is crucial for the reduction of birth defect rate. © 2018 MeDitorial Ltd. All rights reserved.     

Maternal homozygosity for the common MTHFR mutation as a potential risk factor for offspring with limb defects

A common mutation, C677T, in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene leads to altered homocysteine metabolism, and has been associated with the occurrence of neural tube defects (NTD). Administration of folic acid decreases this risk. There is also evidence that periconceptional supplementation of mothers with folic acid can decrease the risk of limb defects in the offspring. Here we describe a child with a transverse terminal defect of one hand, whose mother is homozygous for the C677T MTHFR mutation. We suggest that homozygosity for the MTHFR mutation may be a risk factor for transverse terminal limb defect/s by an effect mediated through altered folate and homocysteine metabolism. Further studies of mothers of infants with limb reduction defects for the MTHFR mutation may be of help in establishing this association. A simple intervention in the form of folic acid supplementation would be protective, should an association be established.     

神经管畸形与MTHFRC677T、MTHFRA1298C、MSA2756G基因多态性的相关性研究

目的对MTHFRC677T、MTHFRA1298C、MSA2756G基因的多态性进行综合性分析,了解这3个基因多态性位点同神经管畸形发生的关系,明确神经管畸形发生的遗传学基础,为制定有效的预防及筛查方案提供依据.方法采用PCR-RFLP技术,对50例有两次或两次以上神经管畸形生育史的妇女及40例有正常生育史的妇女,MTHFRC677T、MTHFRA1298C、MSA2756G进行多态性研究.结果①MTHFRC677T及MTHFRA1298C基因型构成在病例组与对照组之间均存在显著性差异,而MSA2756G在两组之间无显著性差异.②MTHFR677TT、MTHFR1298CC和MS2756GGG中任意两种纯和突变并存时OR值明显增加.结论MTHFR677TT基因型和MTHFR1298CC基因型均可能是神经管畸形的危险因素;MS2756GG基因型虽不是独立危险因素,但与其它突变并存时会增加神经管畸形的危险性.     

Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case-control study.

Evidence for an involvement of aberrant homocysteine metabolism in the aetiology of schizophrenia is limited and controversial. A case-control study was performed to quantify the risk of schizophrenia in the presence of elevated homocysteine concentrations or homozygosity for the 677C --> T polymorphism (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene in subjects of Dutch ancestry. We determined the 677C --> T MTHFR genotype distribution in 254 well-defined patients and 414 healthy controls. Plasma homocysteine concentrations were measured in 62 patients with schizophrenia and 432 control subjects. When homocysteine concentrations were stratified into quartiles of the control distribution, we calculated an increased risk for schizophrenia in the fourth and third quartile versus the lowest quartile [odds ratio (OR) = 3.3; 95% confidence interval (CI): 1.2-9.2, and OR = 3.1; 95% CI: 1.2-8.0, respectively]. A significant dose-response relation of increasing homocysteine levels and increasing risk for schizophrenia was observed (P = 0.036). The 677TT genotype was associated with an OR of 1.6 [95% CI: 0.96-2.8] of having schizophrenia. Heterozygosity for the T allele compared to 677CC subjects accounted for an OR of 1.3 [95% CI: 0.91-1.8]. Elevated homocysteine levels and the MTHFR 677TT genotype are associated with an increased risk for schizophrenia. These observations support a causal relation between disturbed homocysteine metabolism and schizophrenia.     

Homocysteine levels--before and after methionine loading--in 51 Dutch families

Elevated levels of homocysteine are a risk factor for vascular disease, thrombosis, neural tube defects and dementia. The 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene appears to be the most important single determinant of plasma homocysteine concentration. In the current study, we estimated heritability and fit a series of models of inheritance for both fasting and postmethionine-load homocysteine levels in the HOFAM-study (HOmocysteine in FAMilies study), which included 306 participants from 51 pedigrees, ascertained through a hyperhomocysteinemic proband. The crude heritability was 21.6% for fasting and 67.5% for postloading homocysteine. After adjustment for MTHFR 677C>T genotype, heritability dropped to 5.2 and 63.9%, respectively. Segregation analysis revealed that a nongenetic model with equal transmission was the best fitting and most parsimonious model for fasting homocysteine levels, while a two-distribution, Mendelian model with residual familial correlation was best for postmethionine-load homocysteine levels. This study shows that postload homocysteine levels have a stronger genetic determination than do fasting homocysteine levels. The heritability of postload homocysteine levels were not strongly affected by adjustment for MTHFR 677C>T genotype, in contrast to fasting homocysteine levels. Further studies are needed to identify the genes responsible for the inheritance of postload homocysteine levels.     

Decreased methylene tetrahydrofolate reductase activity due to the 677C→T mutation in families with spina bifida offspring

 Periconceptional folate intake reduces both the occurrence and recurrence risk of neural tube defects. Plasma homocysteine levels can be elevated in mothers of a child with a neural tube defect, suggesting a dysfunctional folate metabolism. Very recently we showed that a common 677C→T mutation in the 5,10-methylene tetrahydrofolate reductase gene, causing thermolability of the enzyme, is a risk factor for spina bifida offspring. Restriction enzyme analysis of the genomic 5,10-methylene tetrahydrofolate reductase polymerase chain reaction fragment revealed a significantly higher prevalence of a +/+ genotype among spina bifida patients and their mothers. The risk for spina bifida offspring is the strongest if both the mother and her child have the mutation in the homozygous state. Enzymatic analysis showed that homozygosity for the 677C→T mutation causes a decreased 5,10-methylene tetrahydrofolate reductase activity, resulting in elevated plasma homocysteine and red blood cell folate levels and lowered plasma folate and cysteine values. This extended study demonstrates that a nucleotide substitution in the coding region of 5,10-methylene tetrahydrofolate reductase, resulting in reduced activity and an impaired homocysteine and folate metabolism, is a genetic risk factor for spina bifida. Received: 24 May 1996 / Accepted: 14 August 1996     

糖尿病视网膜病MTHFR基因多态性及其与血浆同型半胱氨酸水平的关系

目的：研究亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR）基因多态性及血浆同型半胱氨酸水平与2型糖尿病视网膜病的关系。方法：应用聚合酶链反应－限制性内切酶片段长度多态性技术检测208例2型糖尿病患者（其中110例伴视网膜病）及57名正常对照的MTHFR C677T基因型，采用高效液相色谱法测定血浆同型半胱氨酸水平。结果：糖尿病视网膜病组MTHFR基因TT纯合基因型、CT杂合基因型及T等位基因频率（分别为28．18％、41．82％、49．09％）均明显高于糖尿病不伴视网膜病组（分别为18．37％、29．59％、33．16％）及正常对照组（分别为17．54％、28．07％、31．58％），基因型和等位基因频率分布差异均有显著性（P＜0．01），而MTHFR基因多态性在糖尿病不伴视网膜病组与正常对照组之间差异无显著性（P＞0．05），T等位基因与糖尿病视网膜病的发生密切相关（OR＝1．94，95％CI；1．31－2．88）。糖尿病视网膜病组、糖尿病不伴视网膜病组及正常对照组中，MTHFR基因有C677T突变者血浆同型半胱氨酸水平均显著高于无基因突变者。结论：MTHFR基因C677T位碱基突变致血浆同型半胱氨酸水平升高可能是糖尿病视网膜病发病的重要遗传因素。     

Association of MTHFR C677T polymorphism with elevated homocysteine level and disease development in vitiligo

Increasing evidence on the association of MTHFR gene polymorphism and serum homocysteine levels with autoimmune diseases such as vitiligo has made the MTHFR gene a very interesting candidate to be evaluated in different ethnicities and populations. We aimed to evaluate the levels of serum homocysteine and vitamin B12 and their associations with MTHFR C677T polymorphism in the Iranian population. This case–control study included 104 patients with vitiligo and 100 age‐ and sex‐matched healthy control subjects. Serum vitamin B12 and homocysteine levels were measured by a chemiluminescence assay. Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) analysis was used for genotyping the polymorphism. The mean serum homocysteine levels were significantly higher in cases than controls and associated with disease activity (p < .001). Furthermore, the homozygous MTHFR C677T variant genotype was associated with vitiligo development (adjusted OR: 3.52, 95% CI: 1.09–11.32, p = .02) and elevated homocysteine level (p < .001). There was no association between serum vitamin B12 levels and the MTHFR C677T genotype. The homozygous variant MTHFR C677T may be considered as a risk factor for both elevated homocysteine levels and the development of vitiligo in the Iranian population. Although these results are not conclusive, they could elucidate the contribution of genetic and immune‐mediated inflammatory factors to the pathogenesis of vitiligo.     

Prenatal diagnosis of neural tube defects: predictive value of AF-AFP in a low-risk population

Amniotic fluid alpha-fetoprotein (AF-AFP) determinations were performed on 1,215 women who were at low risk for fetal neural tube defects and who were undergoing mid-trimester amniocentesis for cytogenetic indications, primarily age-related aneuploidy. Maternal sera obtained before amniocentesis and amniotic fluids were assayed in duplicate for alpha-fetoprotein by radioimmunoassay. Of the 1,215 low-risk women, eight (0.7%) had significant elevations of AF-AFP (greater than or equal to +5 SD). In none of the cases was the elevation associated with a fetal neural tube defect. Two cases with elevated AF-AFP were associated with chromosome aberrations; one with impending fetal demise; one with fetal blood contamination; and one case was due to a laboratory error. In one case, no source for the elevated AFP was found, and a normal infant was delivered at term. In the final two cases, the cause of the elevated AF-AFP was a fetal abdominal wall defect (one gastroschisis and one omphalocele). The predictive value of an elevated AFP varies with the population screened, and is reduced by routine ultrasonography before amniocentesis, which at least identifies anencephaly. In a low-risk population, an elevated AF-AFP is most often not associated with a fetal neural tube defect. Because of the low predictive value and the nonspecificity of AF-AFP, genetic counselors should reconsider the recommendation of routine AF-AFP in low-risk maternal populations.     

Prenatal diagnosis of severe congenital malformations associated with elevated amniotic fluid alpha–feto protein

Two cases of severely malformed infants with abnormal fetal images on B-scan sonography and markedly elevated amniotic fluid AFP are presented. There was no evidence of neural tube anomalies. The importance of an amniocentesis and AFP in pregnancies with an abnormal fetal image on B-scan sonography is emphasized, taking into consideration that most pregnancies with elevated fluid AFP have serious fetal anomalies.