Long term treatment with betaine in methylenetetrahydrofolate reductase deficiency

Acquired isolated ophthalmoplegia in childhood has many potential causes. Although other ophthalmological or clinical features may aid lesion localisation, the absence of these does not preclude structural pathology. Two cases of cavernous sinus pseudotumour presented as ophthalmoplegia with and without pain. Magnetic resonance imaging of the cavernous sinus revealed the presence of enhancing tissue consistent in appearance with pseudotumour in both cases, and they responded well to steroid treatment. These cases emphasise the importance of detailed imaging of the cavernous sinus in the investigation of these symptoms in order to exclude this treatable condition.     

Long term treatment with betaine in methylenetetrahydrofolate reductase deficiency.

A girl aged 7.5 years with deficiency of 5,10-methylenetetrahydrofolate reductase was treated from early infancy with betaine, 3-6 g daily. She has slight microcephaly, moderate developmental delay, and impaired vision but there have been no obvious signs of folate deficiency. From 4 years of age, she developed an unexplained extreme increase in appetite and weight. Recent magnetic resonance imaging of her brain was normal. The plasma methionine levels have been normal but in the lower range, and the total plasma homocysteine concentrations have been moderately increased (54 to 85 mumol/l) without obvious correlation with the different betaine doses given. Folic acid has sometimes been added.     

Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms and protection from microvascular complications in adolescents with type 1 diabetes

Abstract:  Folate status has been associated with endothelial dysfunction in adolescents with type 1 diabetes, and elevated total plasma homoocyst(e)ine (tHcy) is a risk for vascular disease in the non-diabetic population. Polymorphisms in genes involved in folate and homocysteine metabolism are implicated in vascular disease. We aimed to determine whether polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are risk factors for early microvascular disease in a large group of adolescents with type 1 diabetes. Four hundred and eighty adolescents were screened annually for retinopathy and microalbuminuria for a median of 4 yr. Molecular analysis for the polymorphisms 677C→T, 1298A→C in MTHFR, and 66A→G in MTRR was performed. The MTRR 66GG genotype reduced the risk for elevated albumin excretion rate (AER) (OR 0.47, CI 0.25, 0.88, p = 0.018) and showed a trend to reduced risk for microalbuminuria (OR 0.27, CI 0.06–1.21, p = 0.09). Survival without elevated AER was increased with the MTRR 66GG genotype (12.4 vs. 9.7 yr, p = 0.04) and with the MTHFR 1298CC genotype (15.2 vs. 10.2 yr, p = 0.007). Conversely, survival without retinopathy was reduced with the MTHFR 677TT and MTRR 66GG combined genotype (6.2 vs. 10.2 yr, p = 0.015). The MTRR 66GG and MTHFR 1298 CC genotypes may confer protection against early nephropathy, possibly because they are associated with lower tHcy. The MTHFR 677 TT was only related to earlier onset retinopathy in combination with MTRR 66GG.     

早发型亚甲基四氢叶酸还原酶缺陷症 1 例临床及基因分析

目的探究MTHFR基因突变引起的亚甲基四氢叶酸还原酶缺陷患儿的临床特点、治疗及预后。方法回顾分析1例MTHFR缺陷导致癫痫、脑积水患儿的临床资料和MTHFR基因检测结果,并复习相关文献。结果女性患儿生后第10天出现抽搐、呼吸不规律、喂养困难、肌张力低下,血同型半胱氨酸水平明显升高(147.9μmol/L);基因测序示MTHFR基因存在复合杂合突变(c.1319_c.1320 insTT,c.1262 GA),其中c.1319_c.1320 insTT以往未见报道。予甜菜碱、亚叶酸钙、维生素B_6、维生素B_(12)治疗2周后,患儿血清总同型半胱氨酸水平下降,临床症状好转,但随后一个月内出现明显脑积水,精神运动发育明显迟缓。结论早发型亚甲基四氢叶酸还原酶缺陷患儿可在生后早期即有表现,血同型半胱氨酸测定及基因检测有助于早期诊断和干预。     

Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency

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. CONCLUSION: Given the heterogeneity of mutations, no one seems preponderant to predict neurological and/or vascular symptoms.     

Typical technetium dimercaptosuccinic acid distribution patterns in acute pyelonephritis

Technetium dimercaptosuccinic acid renal scintiscans in 37 children with clinical diagnosis of acute pyelonephritis were reviewed. In 18 children, follow-up scintigraphy was obtained after an interval ranging from 5 to 8 months. Uptake abnormalities were found in 89% of the children (74% of the kidneys). We were able to identify four typical pathological uptake patterns: (i) pole defect(s), usually wedge shaped (60%); (ii) lateral wedge shaped defect (4%); (ii) scattered multiple defects (21Yo); and (iv) swollen kidney without areas of diminished uptake (15%). Remaining pathology at follow-up was found in 52% of the kidneys. Vesicoureteric reflux was present in 33% of the children with scintigraphic signs of pyelonephritis. Frequencies of parenchymal changes in the acute phase and at follow-up were not significantly correlated to the presence of reflux.     

急性白血病患儿MTHFR基因G1793A多态性的相关研究

目的 研究亚甲基四氢叶酸还原酶(MTHFR)基因G1793A多态性在AL患儿中的等位基因频率和基因型分布特征,及其与儿童AL发病风险的相关性.方法 应用反转录-PCR-变性梯度凝胶电泳结合DNA测序技术,对109例AL患儿和120例对照儿童的cDNA MTHFR G1793A基因型进行检测.结果 在AL组、ALL组、急性髓细胞白血病(AML)组和对照组中MTHFR 1793 GG、GA、AA基因型频率分别为83.5％、15.6％、0.9％;82.8％、16.1％、1.1％;86.4％、13.6％、0和89.2％、7.5％、3.3％;而MTHFR 1793A等位基因频率分别为8.7％、9.2％、6.8％和7.1％;分别将各病例组人群A等位基因频率及基因型分布与对照组进行比较,发现差异均无统计学意义(P均＞0.05);MTHFR 1793 GA+ AA增加了AL、ALL和AML发病风险(AL:OR=1.71,95％ CI:0.77～3.80,P=0.19;ALL:OR =2.00,95％ CI:0.85 ～4.49,P=0.12;AML:OR=1.36,95％ CI:0.33～5.62,P=0.67),但差异均无统计学意义(P均＞0.05);全部标本中A等位基因总频率为7.9％,与德国犹太人、巴西人、奥地利人、伊朗人及中国哈尔滨人群的差异均具有统计学意义(P均＜0.05).结论 MTHFRG1793A基因多态性与汉族儿童AL的发病无相关性,但该位点多态性分布具有种族差异性.     

Treatment of patients with primary antibody deficiencies in Germany

BACKGROUND: Primary antibody deficiencies are the most common forms of primary immunodeficiencies (PID). Recurrent bacterial infections and the risk of progressive structural tissue damage are the most serious complications of these diseases. Substitution therapy with polyvalent immunoglobulins (Ig) has been established as the standard therapy in PID for several decades now. METHODS: During summer 2002 German PID treaters were interviewed in a survey in order to assess the present status of immunoglobulin therapy in German patients with antibody deficiencies. A disease questionnaire was used during standardized interviews. Information was sought on the treating physician and center, the kind of immunodeficiency and its complications. Furthermore, details on the Ig therapy, routine diagnostic procedures and concomitant medication were asked. RESULTS: 13 pediatricians and 5 specialists for internal medicine who treated a total of about 230 patients with CVID/XLA participated in the interviews. Most of the patients received Ig substitution therapy, most frequently as intravenous immunoglobulin (IVIG) infusions in a hospital outpatient setting. Approximately 14 % of the substituted patients received subcutaneous immunoglobulin (SCIG), mostly as self-infusions at home. At the time of the interviews SCIG had not yet been licensed in Germany. The mean monthly dose was 0.4 g per kg bodyweight, both in IVIG and SCIG treatment and most centers aimed at trough IgG levels of 5 to 6 g/l. CONCLUSIONS: The majority of centers followed current guidelines concerning monthly immunoglobulin doses and desired IgG trough levels, but often aimed at the lower end of these recommendations.     

Thrombus obstructing the right ventricle outflow tract in a neonate with methylenetetrahydrofolate reductase 677TT genotype

At her first day of life, a neonate presented with severe cyanosis and a mass obstructing the right ventricle outflow tract. Prostagladin E1 was necessary to provide pulmonary blood flow. The mass was removed using extracorporeal bypass surgery; the right ventricle was dilated, and the pulmonary valve leaflets were damaged. Sternal closure was delayed because of bleeding and poor cardiac performance. Histology demonstrated that the mass was a mixed thrombus. Investigation revealed homozygous 677TT genotype of the methylenetetrahydrofolate reductase. In conclusion, a life-threatening thrombotic event such as an intracardiac thrombus obstructing the right ventricle outflow tract can occur in a neonatal age. Since the event can be a result of a combination of acquired and congenital thrombogenic risk factors, an extensive screening including DNA-based mutation analysis should be performed.     

亚甲基四氢叶酸还原酶基因C677T突变、同型半胱氨酸水平与1型糖尿病微血管并发症相关性研究

国内外大量研究表明 ,高同型半胱氨酸 (Hcy)血症是心、脑及外周血管疾病的重要危险因素之一[1 ] 。亚甲基四氢叶酸还原酶 (MTHFR)基因C6 77T突变是导致该酶活性降低并引起高Hcy血症的主要遗传机制。 2型糖尿病 (DM)血管病变患者MTHFR基因C6 77T纯合突变率及Hcy水平明显升高[2 ,3] 。本研究旨在探讨MTHFR基因C6 77T突变、Hcy水平与 1型DM年轻患者糖尿病微血管并发症的关系。对象1型DM患者 6 8例 ,男 2 9例 ,女 39例 ,年龄 (17 2± 4 0 )岁 ,病程 (9 0± 3 4 )年 (5 0～ 18 5年 ) ,病例符合 1999年WHO的诊断标准。根据是否合…     

Hyperlysinemia with saccharopinuria due to combined lysine-ketoglutarate reductase and saccharopine dehydrogenase deficiencies presenting as cystinuria

A 7-year-old boy with speech delay, hyperactive behavior, and minor neurologic abnormalities had been found in the past to have "intermittent cystinuria." A more detailed investigation revealed hyperlysinemia and hyperlysinuria, with lesser increases in urinary excretion of arginine and cystine. The plasma and urine abnormalities increased on a diet of 3 gm of protein/kg body weight/day. Saccharopine, a normal metabolite of lysine not found in the body fluids of normal people, was present in plasma, cerebrospinal fluid, and urine of the patient. Lysine-ketoglutarate reductase and saccharopine dehydrogenase activities were not detectable in extracts of cultured skin fibroblasts. Re-examination of the urine of previously studied cases of this double enzyme deficiency suggests that saccharopinuria of variable degree is the rule and not the exception.     

急性淋巴细胞白血病患儿MTHFR基因多态性与大剂量甲氨蝶呤毒副反应的关系

目的：探讨亚甲基四氢叶酸还原酶（MTHFR）基因单核苷酸多态性对急性淋巴细胞白血病（ALL）患儿使用大剂量甲氨蝶呤（HD-MTX）化疗后毒副反应的影响。方法：应用RT-PCR-变性梯度凝胶电泳结合DNA测序技术,对52例ALL患儿MTHFR C677T、A1298C和G1793A基因型进行检测。按照国立癌症研究所常规毒性判定标准（NCI-CTC）对患儿HD-MTX化疗后的不良反应统一评价。结果：MTHFR 1298AC基因型患儿发生血小板减少的风险较AA型提高了13.7倍（OR=13.7,95%CI=1.18～159.36,P=0.036）。MTHFR C677T和G1793A各基因型发生各类HD-MTX化疗不良反应的差异无统计学意义（P>0.05）。结论：MTHFR A1298C多态性可能与ALL患儿HD-MTX化疗后的毒副反应相关。     

亚甲基四氢叶酸还原酶基因多态性与儿童急性淋巴细胞 白血病化疗中甲氨蝶呤毒性相关性的 meta 分析

目的评价亚甲基四氢叶酸还原酶(MTHFR)基因C 677 T位点多态性与儿童急性淋巴细胞白血病(ALL)化疗用药甲氨蝶呤(MTX)不良反应易感性的关联。方法计算机检索The Cochrane Library、Pub Med、EMbase、EMCC、OVID、CNKI、VIP和Wan Fang Data数据库,检索时间均为建库至2016年3月。2名研究者独立筛选文献、提取资料数据并评价纳入研究的偏倚风险后,采用Rev Man 5.3和Stata 12.0软件,分别以隐性、显性、共显性、加性和等位基因模型对基因多态性与MTX化疗时不良反应的关联进行meta分析。结果共纳入12项研究,均为病例-对照研究,其中病例组1 419例,对照组2 188例。Meta分析结果显示,纳入的研究中MTHFR基因多态性在5种分析模型下与ALL患儿予以MTX化疗时中性粒细胞减少、血小板减少、血红蛋白减少、黏膜损害以及肝功能损害的不良反应均无关联。共显性模型下,MTHFR基因多态位点C677T与MTX总不良反应易感性的关联具有统计学意义(OR=1.39,95%CI:1.02~1.91,P=0.04)。隐性基因模型下,MTHFR的C677T多态性和MTX化疗时胃肠道不良反应的发生风险减少有关(OR=3.31,95%CI:1.03~10.59,P=0.04)。显性基因模型下,MTHFR的C 677 T多态性和MTX化疗时皮肤损害不良反应的风险减少存在关联(OR=3.05,95%CI:1.25~7.41,P=0.01)。结论 MTHFR的C 677 T多态性和MTX化疗时不良反应并无显著关联,但仍需行更大样本研究分析。     

Coeliac disease, folic acid deficiency and epilepsy with cerebral calcifications

Two cases of focal occipital epilepsy with cerebral calcifications poorly responsive to antiepileptic treatment are described. In both cases coeliac disease was diagnosed and folic acid deficiency documented. A gluten-free diet and a brief supplementation with folic acid lead to a complete EEG and clinical normalization in one case and to a significant improvement of EEG and seizure control in the other.