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Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, a major methyl donor for homocysteine remethylation to methionine. Severe MTHFR deficiency results in marked hyperhomocysteinemia and homocystinuria. Patients display developmental delay and a variety of neurological and vascular symptoms. Cloning of the human cDNA and gene has enabled the identification of 29 rare mutations in homocystinuric patients and two common variants [677C>T (A222V) and 1298A>C (E429A)] with mild enzymatic deficiency. Homozygosity for 677C>T or combined heterozygosity for both polymorphisms is associated with mild hyperhomocysteinemia. In this communication, we describe four novel mutations in patients with homocystinuria: two missense mutations (471C>G, I153M; 1025T>C, M338T), a nonsense mutation (1274G>A, W421X), and a 2-bp deletion (1553delAG). We expressed the 1025T>C mutation as well as two previously reported amino acid substitutions [983A>G (N324S) and 1027T>G (W339G)] and observed decreased enzyme activity at 10%, 36%, and 21% of control levels, respectively, with little or no effect on affinity for 5-methyltetrahydrofolate. One of these mutations, 983A>G (N324S), showed flavin adenine dinucleotide (FAD) responsiveness in vitro. Expression of these mutations in cis with the 677C>T polymorphism, as observed in the patients, resulted in an additional 50% decrease in enzyme activity. This report brings the total to 33 severe mutations identified in patients with severe MTHFR deficiency.

Neural tube defects (NTD) are common malformations resulting from incomplete closure of the neural tube in the first month after conception. Since genetic deficiencies in folate-dependent homocysteine metabolism have been identified in NTD families, we investigated a common variant in betaine-homocysteine methyltransferase (BHMT), 742G-->A (R239Q), as a genetic modifier of NTD risk. Genotypes, nutrient levels, and plasma total homocysteine (tHcy) were assessed in 54 patients with spina bifida, 57 mothers of patients, 93 control children, and 86 mothers of controls. The QQ genotype (present in 17% and 7% of the control and case mothers, respectively, and in 12% and 6% of the control and case children, respectively) was associated with a decreased risk of NTD (odds ratios of 0.52 (95% CI 0.13-2.05) for children and 0.37 (95% CI 0.11-1.22) for mothers). The small sample size limited the statistical power of the analyses, but these decreases, although not statistically significant, are compatible with a protective effect. We did not observe statistically-significant genotype-dependent differences in plasma homocysteine, although women with the QQ genotype did have lower homocysteine; in children, the mean homocysteine level was higher in the QQ group. This inconsistency could be explained by the fact that age is a strong determinant of homocysteine in children and the QQ group was on average older than the other genotype groups. Our study suggests that the Q allele of the R239Q mutation may decrease risk of the condition. This warrants further investigation of its relationship with the development of NTD.

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Hereditary hemochromatosis (HH) is an autosomal recessive disorder that occurs in approximately 1 in 200-250 individuals. Mutations in the HFE gene lead to excess iron absorption. Excess iron in the form of non-transferrin-bound iron (NTBI) causes injury and is readily uptaken by cardiomyocytes, pancreatic islet cells, and hepatocytes. Symptoms greatly vary among patients and include fatigue, abdominal pain, arthralgias, impotence, decreased libido, diabetes, and heart failure. Untreated hemochromatosis can lead to chronic liver disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Many invasive and noninvasive diagnostic tests are available to aid in diagnosis and treatment. MRI has emerged as the reference standard imaging modality for the detection and quantification of hepatic iron deposition, as ultrasound (US) is unable to detect iron overload and computed tomography (CT) findings are nonspecific and influenced by multiple confounding variables. If caught and treated early, HH disease progression can significantly be altered. Area covered: The data on Hemochromatosis, iron overload, and MRI were gathered by searching PubMed. Expert commentary: MRI is a great tool for diagnosis and management of iron overload. It is safe, effective, and a standard protocol should be included in diagnostic algorithms of future treatment guidelines.

Background The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal vein thrombosis (PVT) remains controversial. This study aimed to conduct a systematic review and meta-analysis to evaluate the role of TIPS for the management of PVT in adult patients with liver disease. Patients and methods Multiple databases were searched through April 2017. Data were gathered to estimate the rates of technical success, portal vein recanalization, portal patency, hepatic encephalopathy, and mean change in portal pressure gradient in patients with PVT who underwent TIPS. Estimates were pooled across studies using the random effects model. Results Eighteen studies were included in the analysis. The pooled technical success rate was 86.7% [95% confidence interval (CI)=78.6–92.1%]. Rate of portal vein recanalization was 84.4% (95% CI=78.4–89.0%). The rate of complete recanalization was 73.7% (95% CI=64.3–81.3%). Portal patency was 86.9% (95% CI=79.7–91.8%). Mean change in portal pressure gradient was 14.5 mmHg (95% CI=11.3–17.7 mmHg). Hepatic encephalopathy was 25.3% (95% CI=19.2–32.6%). The number of major adverse events reported across studies was low. The majority of the analyses were not associated with substantial heterogeneity. Conclusion The use of TIPS in the management of PVT is feasible and effective in achieving a significant and sustainable reduction in clot burden with a low risk of major complications. TIPS should be considered as a viable treatment option in patients with PVT. Given the limited amount of randomized comparative studies reported, additional trials are warranted to assess the safety and efficacy of TIPS as a treatment modality in PVT, in comparison to other treatment options, such as anticoagulation.