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Abstract Background Homocystinuria due to methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. The purpose of this study is to expand the mutation site of the MTHFR gene and provide genetic counseling for this family. Methods A couple came to our hospital for pre-pregnancy genetic counseling. We collected the family history and detailed clinical information, then performed whole-exome sequencing, and analyzed the pathogenicity of the candidate mutations. Results We found that the father of the proband had homocystinuria, the proband and his brother had low blood methionine levels at birth, and the brain MRI showed brain dysplasia. The third fetus was found to have a broadened triangle of the bilateral ventricle at 19 weeks of pregnancy. The compound heterozygous variants of c.602 A > C (p.His201Pro) and c.1316T > C (p.Leu439Pro) of the MTHFR gene in the first three fetuses were found by whole-exome sequencing. The heterozygous c.602 A > C variant of the MTHFR gene is a novel missense variant that has been submitted to the ClinVar with Variation ID 992,662. Conclusion In consideration of the clinical phenotype, family history, and result of genetic testing, we speculated that both patients may have homocystinuria due to MTHFR deficiency. Homocystinuria due to MTHFR deficiency caused by compound heterozygous mutations composed of the MTHFR gene in this family may be associated with cerebral atrophy and cerebral dysplasia. The novel compound heterozygous mutations broaden the mutation spectrum of the MTHFR gene and enhance the application of genetic counseling and carrier screening in rare diseases.

Background: Homocystinuria due to methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. The purpose of this study is to expand the mutation site of the MTHFR gene and provide genetic counseling for this family. Methods: A couple came to our hospital for pre-pregnancy genetic counseling. We collected the family history and detailed clinical information, then performed whole-exome sequencing, and analyzed the pathogenicity of the candidate mutations. Results: We found that the father of the proband had homocystinuria, the proband and his brother had low blood methionine levels at birth, and the brain MRI showed brain dysplasia. The third fetus was found to have a broadened triangle of the bilateral ventricle at 19 weeks of pregnancy. The compound heterozygous variants of c.602 A > C (p.His201Pro) and c.1316T > C (p.Leu439Pro) of the MTHFR gene in the first three fetuses were found by whole-exome sequencing. The heterozygous c.602 A > C variant of the MTHFR gene is a novel missense variant that has been submitted to the ClinVar with Variation ID 992,662. Conclusion: In consideration of the clinical phenotype, family history, and result of genetic testing, we speculated that both patients may have homocystinuria due to MTHFR deficiency. Homocystinuria due to MTHFR deficiency caused by compound heterozygous mutations composed of the MTHFR gene in this family may be associated with cerebral atrophy and cerebral dysplasia. The novel compound heterozygous mutations broaden the mutation spectrum of the MTHFR gene and enhance the application of genetic counseling and carrier screening in rare diseases. [ABSTRACT FROM AUTHOR]

Methylenetetrahydrofolate reductase (MTHFR) defi- ciency is an autosomal recessive disorder that results in hyperhomocysteinemia. Elevated homocysteine levels in the blood can cause arterial and venous thrombosis, atherosclerosis, recurrent pregnancy loss, and neurologic symptoms. Emerging research suggests links to other chronic illnesses as well. Anesthetic management of patients with MTHFR deficiency should focus on decreasing the risk of arterial or venous thrombosis and minimizing elevations in homocysteine levels. Thrombosis prevention includes the use of antiembolism compression stockings, intermittent pneumatic compression sleeves, subcutaneous heparin or low-molecular-weight heparin, early ambulation, and adequate hydration. Nitrous oxide is known to inhibit methionine synthase, a vitamin B12-dependent enzyme responsible for the breakdown of homocysteine, resulting in homocysteine elevation, and should be avoided in these patients. Intravenous vitamin B12 infusion before surgery may help decrease homocysteine levels; however, it is not readily available in most operating rooms. Propofol and sevoflurane do not increase homocysteine levels and are considered safe for patients with MTHFR deficiency. This case study describes a 58-year-old man with known MTHFR defi- ciency and his subsequent uneventful anesthetic care during a total knee replacement. [ABSTRACT FROM AUTHOR]

Urreizti R, Moya-García AA, Pino- Ángeles A, Cozar M, Langkilde A, Fanhoe U, Esteves C, Arribas J, Vilaseca MA, Pérez-Dueñas B, Pineda M, González V, Artuch R, Baldellou, A, Vilarinho L, Fowler B, Ribes A, Sánchez-Jiménez F, Grinberg D, Balcells S. Molecular characterization of five patients with homocystinuria due to severe MTHFR deficiency. Methylenetetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism. Disturbed function of the enzyme results in hyperhomocysteinemia and causes severe vascular and neurological disorders and developmental delay. Five patients suspected of having non-classical homocystinuria due to MTHFR deficiency were examined with respect to their symptoms, MTHFR enzyme activity and genotypes of the MTHFR gene. All patients presented symptoms of severe central nervous system disease. Two patients died, at the ages of 15 months and 14 years. One patient is currently 32 years old, and is being treated with betaine and folinic acid. The other two patients, with an early diagnosis and a severe course of the disease, are currently improving under treatment. MTHFR enzyme activity in the fibroblasts of four of the patients was practically undetectable. We found four novel mutations, three of which were missense changes c.664G> T (p.V218L), c.1316T> C (p.F435S) and c.1733T> G (p.V574G), and the fourth was the 1-bp deletion c.1780delC (p.L590CfsX72). We also found the previously reported nonsense mutation c.1420G> T (p.E470X). All the patients were homozygous. Molecular modelling of the double mutant allele (p.V218L; p.A222V) revealed that affinity for FAD was not affected in this mutant. For the p.E470X mutation, the evidence pointed to nonsense-mediated mRNA decay. In general, genotype-phenotype analysis predicts milder outcomes for patients with missense changes than for those in which mutations led to severe alterations of the MTHFR protein. [ABSTRACT FROM AUTHOR]

Methylentetrahydrofolate reductase (MTHFR) is a key enzymatic component of the folate cycle, converting 5,10-methylentetrahydrofolate into 5-methylentetrahydrofolate. Severe MTHFR deficiency is a rare recessive disease leading to major hyperhomocysteinemia, homocystinuria, and progressive neurological distress within the two first decades of life. We present the case of a young, 21 years old female patient who was admitted and treated in Clinic of Pneumology Tirgu Mures for a posterobasal left pneumonia without favourable radiologic evolution under antibiotic and symptomatic treatment. Thoracotomy was recommended in order to elucidate the diagnosis. The histopatological examination revealed the zone of pulmonary infarction. After 12 weeks from surgical intervention, the patient was admitted in Department of Neurology for stroke attack. The complex laboratory investigations reveal deficiency of methylentrahydrofolate reductase (MTHFR) caused by a genetic mutation. [ABSTRACT FROM AUTHOR]

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), which is used for homocysteine remethylation to methionine, the precursor of S-adenosylmethionine (SAM). Impairment of MTHFR will increase homocysteine levels and compromise SAM-dependent methylation reactions. Mild MTHFR deficiency is common in many populations due to a polymorphism at bp 677. To assess how impaired MTHFR activity affects folate metabolism in various tissues in vivo, we used affinity/HPLC with electrochemical detection to analyze the distribution of folates in plasma, liver, and brain of Mthfr-deficient mice. The most pronounced difference in total folate was observed in plasma. In Mthfr -/- mice, plasma total folate levels were approximately 25% of those in wild-type (Mthfr +/+) mice. Only 40% of plasma folate in Mthfr -/- mice was comprised of 5-methylTHF, compared with at least 80% in the other 2 genotype groups. In liver and brain, there were no differences in total folate. However, the proportion of 5-methylTHF in both tissues was again markedly reduced in mice with the Mthfr -/- genotype. In this genotype group, 5-methylTHF is likely derived from the diet. Our study demonstrated reduced total circulatory folate and altered distribution of folate derivatives in liver and brain in Mthfr deficiency. Decreased methylfolates and increased nonmethylfolates would affect the flux of one-carbon units between methylation reactions and nucleotide synthesis. This altered flux has implications for several common disorders, including cancer and vascular disease. [ABSTRACT FROM AUTHOR]

Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common genetic cause of hyperhomocysteinemia, which is associated with increased risk for cardiovascular disease, stroke and possibly other neurological disorders. Microarray analysis of brain RNA from day 14 Mthfr−/− mice revealed several genes with altered expression. Expression changes in inositol 1,4,5-triphosphate receptor, type 1 (Itpr1), proteolipid protein (Plp), neurogenic differentiation factor 1 (Neurod1), S100 calcium binding protein A8 (S100a8), and methylenetetrahydrofolate dehydrogenase (NAD+ dependent), methenyltetrahydrofolate cyclohydrolase (Mthfd2) were confirmed by RT-PCR. We propose that neuronal damage by hyperhomocysteinemia may involve disruption of intracellular calcium. [Copyright &y& Elsevier]

MTHFR deficiency still deserves an investigation to associate the phenotype to protein structure variations. To this aim, considering the MTHFR wild type protein structure, with a catalytic and a regulatory domain and taking advantage of state-of-the-art computational tools, we explore the properties of 72 missense variations known to be disease associated. By computing the thermodynamic ΔΔG change according to a consensus method that we recently introduced, we find that 61% of the disease-related variations destabilize the protein, are present both in the catalytic and regulatory domain and correspond to known biochemical deficiencies. The propensity of solvent accessible residues to be involved in protein-protein interaction sites indicates that most of the interacting residues are located in the regulatory domain, and that only three of them, located at the interface of the functional protein homodimer, are both disease-related and destabilizing. Finally, we compute the protein architecture with Hidden Markov Models, one from Pfam for the catalytic domain and the second computed in house for the regulatory domain. We show that patterns of disease-associated, physicochemical variation types, both in the catalytic and regulatory domains, are unique for the MTHFR deficiency when mapped into the protein architecture. [ABSTRACT FROM AUTHOR]

This review presents clinical patterns that should trigger homocysteine measurement in blood, as well as the further diagnostic work-up focused on inborn errors of metabolism and disorders of vitamin B12 (cobalamin) absorption and supply. The numerous conditions (e.g. cardiovascular disease, Alzheimer's disease) for which mild-to-moderate hyperhomocysteinaemia caused by genetic polymorphisms or acquired reasons is considered a risk factor are beyond the scope of this review.Homocysteine is a sulphur-containing amino acid, which is derived from the amino acid methionine. Homocysteine is either trans-sulphurated to form cystathionine and then cysteine, or re-methylated to methionine. The trans-sulphuration reaction depends on the enzyme cystathionine beta synthase and its cofactor vitamin B6. The re-methylation reaction not only involves the enzymes methionine synthase and methionine synthase reductase but also depends on the cofactor cobalamin and on the provision of methyl groups from the folate cycle. Because the homocysteine-methionine cycle provides for the vast majority of methyl groups in the body, it is central to numerous pathways that depend on methyl group supply, such as creatine synthesis or DNA methylation. Based on this premise, the severity of clinical presentations of inborn errors of metabolism, such as classical homocystinuria or the cobalamin C (cblC) defect, affecting this pathway is unsurprising.