We report a patient with homocystinuria and hyperoxaluria who was cured of homocystinuria-related disease following liver transplant. The patient was diagnosed with homocystinuria as a newborn and was treated with dietary modifications and supplements. At 22 months, he passed a calcium oxalate stone and was found to have numerous bilateral kidney stones. Genetic testing confirmed primary hyperoxaluria, type 1. He underwent preemptive liver transplant at age four to treat primary hyperoxaluria. Following transplant, his serum methionine and homocysteine levels normalized, thus, demonstrating resolution of homocystinuria. Methionine and homocysteine levels remained normal 6 years later. Homocystinuria is associated with ophthalmologic, skeletal, neurologic, and thromboembolic complications. As cystathionine beta-synthase resides in the liver, transplant was hypothesized to be an effective treatment. Primary hyperoxaluria generally progresses to chronic kidney disease and is treated with combined kidney-liver transplant at the time of end stage kidney disease. Given this patient\'s dual diagnoses, we proceeded with preemptive liver transplantation. Three prior cases of patients with homocystinuria treated with liver transplantation have been reported. In all cases, transplant resolved metabolic effects. However, our case represents a pediatric patient without disease-related complications prior to transplant. This case supports liver-targeted gene therapies as an effective treatment for homocystinuria.

Both genetics and environmental factors play a role in the occurrence of non-syndromic cleft lip/palate (NSCL/P). This meta-analysis evaluated the association between cystathionine beta-synthase (CBS) c.844ins68 polymorphism and risk of NSCL/P in family-based and case-control studies.
The PubMed, Web of Science, Scopus, and Cochrane Library databases were searched for articles published until September 2018. RevMan 5.3 software was used to calculate the odds ratio (OR) for the association between CBS c.844ins68 polymorphism and risk of NSCL/P by using five genetic models in the studies. The transmission disequilibrium test (TDT) was conducted for family-based studies.
Three case-control and three family-based studies were evaluated. Based on the analysis of five genetic models, risk of NSCL/P was not related to CBS c.844ins68 polymorphism in case-control studies. The results of family-based studies did not show any association between the CBS c.844ins68 allele and NSCL/P either.
The results of this meta-analysis showed that there was no association between CBS c.844ins68 polymorphism and risk of NSCL/P; therefore, this polymorphism does not play a role in susceptibility to NSCL/P.

BACKGROUND: Risk factors of cerebral venous sinus thrombosis (CVST) are usually divided into acquired risks (e.g., trauma and pregnancy) and genetic risks (inherited thrombophilia). It is essential but not easy to identify the exact one for each patient.
METHODS: A 14-year-old male patient was admitted in our hospital because of progressively exacerbated severe headache and vomiting for 3 days, accompanied by transient weakness once in his right leg.
METHODS: CVST due to hyperhomocysteinemia with cystathionine-β-synthase (CBS) gene mutation.
METHODS: Persistent oral anticoagulant therapy.
RESULTS: Follow-ups at 4 months and 1 year showed that the patient\'s symptoms alleviated and did not recur, accompanied with improved MRV image; however, the cranial MRV image did not display as a completely normal one.
CONCLUSIONS: We recommend that in case of thrombophilic state, serum homocysteine (Hcy), folic acid, and vitamin B12 levels should be routinely screened; when serum Hcy level is extremely high, congenital diseases caused by gene mutations should be considered. We firstly discovered a new mutation of CBS c.949A>G which had not been reported before.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a serious public health problem, due to its high mortality rate and worldwide rising incidence. OSCC susceptibility is mediated by interactions between genetic and environmental factors. Studies suggest that genetic variants encoding enzymes involved in folate metabolism may modulate OSCC risk by altering DNA synthesis/repair and methylation process.
OBJECTIVE: The goals of this study were to evaluate the association of three genotypic polymorphism (MTHFR C677T, MTHFR A1298C and CBS 844ins68) and oral cancer risk in southeastern Brazilians and evaluate the interactions between polymorphisms and clinical histopathological parameters.
METHODS: This case-control study included 101 cases and 102 controls in the state of Espírito Santo, Brazil. MTHFR genotyping was done by PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) and CBS genotyping by PCR (polymerase chain reaction) analysis.
RESULTS: MTHFR C677T polymorphism was associated with lymph node involvement. Genotype CT+TT acted as a protective factor. MTHFR A1298C AC+CC genotype was associated with tumor differentiation, and possibly with a better prognosis. In risk analysis, no correlation was observed between genotypes and OSCC.
CONCLUSIONS: We concluded that MTHFR C677T, MTHFR A1298C and CBS 844ins68 polymorphisms were not associated with OSCC risk in southeastern Brazilians; however, we suggest a prognosis effect associated with MTHFR C677T and A1298C polymorphisms in OSCC.

Methylenetetrahydrofolate reductase (MTHFR) is necessary for the synthesis of methionine and S-adenosylmethionine, which is necessary for CNS (re-)myelination. The MTHFR variant c.1298A>C was associated with the development of relapsing remitting multiple sclerosis (RRMS) in a German population. This study aimed at analyzing whether further genetic variants of methionine metabolism are associated with the development or the clinical course of RRMS. Therefore, genomic DNA of 147 serial German RRMS patients and 147 matched healthy controls was genotyped for five polymorphic variants of methionine metabolism. Statistical analyses were performed using multivariate binary and linear regression analyses. We show that the insertion allele of cystathionine beta-synthase (CBS) c.844_855ins68bp and the G-allele of reduced folate carrier 1 (RFC1) c.80G>A were associated with an earlier age of onset of MS, suggesting gene-dose effects (median age of onset in years: 25-26-32; standardized regression coefficient beta: 0.216; p=0.030, and 29-31-35 years; beta: 0.282; p=0.005, respectively). Conclusively, mutant variants of CBS and RFC1 may be associated with the age of RRMS onset. Since methionine metabolism can be manipulated by supplementation of vitamins and amino acids, our data provide a rationale for novel ideas of preventive and therapeutic strategies in RRMS.

BACKGROUND: Homocystinuria caused by cystathionine beta synthase (CBS) deficiency is most often diagnosed in childhood and has a variable expressivity. The most frequent abnormalities include intellectual disability, ectopia lentis, myopia, skeletal abnormalities or thromboembolism.
OBJECTIVE: To report a case of homocystinuria unraveled by cerebral venous thrombosis (CVT).
METHODS: A 17 year old female was admitted in our department of neurology for subacute headache and presented seizures in the emergency room. Cerebral imaging revealed CVT. Severe hyperhomocysteinemia was found and led to the diagnosis of homocystinuria due to composite heterozygous mutations in the CBS gene. Further investigations disclosed lens subluxation in association with myopia, mild scoliosis and osteopenia. The patient was treated by heparin followed by warfarin, vitamin therapy and dietary methionine restriction. Total homocysteine and methionine levels became normal in a few weeks and the patient had a complete recovery.
CONCLUSIONS: In patients with CVT, plasma total homocysteine measurement as part of the etiologic work up may reveal severe hyperhomocysteinemia due to CBS or remethylation defects that require specific treatment and management including perhaps protein-restricted diet and/or vitamin therapy for life.

Homocystinuria due to cystathionine β-synthase deficiency is an inborn error of metabolism first described almost 50 years ago, which involves the accumulation of plasma homocysteine and other metabolites. Without early detection and appropriate treatment, common and sometimes lethal consequences include ocular abnormalities, osteoporosis, developmental delays, marfanoid phenotype, vascular disease, and mental retardation. Almost 50% of subjects develop a psychiatric disorder during their life, but only 2.8% present a psychiatric symptom as the initial manifestation. Among this group, psychotic disorders are infrequent. We describe the case of a 17-year-old boy presenting with a first episode psychosis and an unknown homocystinuria due to cystathionine β-synthase deficiency, which led to a lethal outcome.

In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although in most people this process is not complete. Previous studies have identified associations between the proportion of urinary MMA (%MMA) and increased risks of several arsenic-related diseases, although none of these reported on lung cancer. In this study, urinary arsenic metabolites were assessed in 45 lung cancer cases and 75 controls from arsenic-exposed areas in Cordoba, Argentina. Folate has also been linked to arsenic-disease susceptibility, thus an exploratory assessment of associations between single nucleotide polymorphisms in folate metabolizing genes, arsenic methylation, and lung cancer was also conducted. In analyses limited to subjects with metabolite concentrations above detection limits, the mean %MMA was higher in cases than in controls (17.5% versus 14.3%, p=0.01). The lung cancer odds ratio for subjects with %MMA in the upper tertile compared to those in the lowest tertile was 3.09 (95% CI, 1.08-8.81). Although the study size was too small for a definitive conclusion, there was an indication that lung cancer risks might be highest in those with a high %MMA who also carried cystathionine beta-synthase (CBS) rs234709 and rs4920037 variant alleles. This study is the first to report an association between individual differences in arsenic metabolism and lung cancer, a leading cause of arsenic-related mortality. These results add to the increasing body of evidence that variation in arsenic metabolism plays an important role in arsenic-disease susceptibility.

OBJECTIVE: The aim of this study was to evaluate the association of polymorphisms present in genes related to homocysteine (Hcy) metabolism with coronary artery disease (CAD).
METHODS: We examined 8 polymorphisms in the cystathionine beta-synthase (CBS), glutamate carboxypeptidase II (GCPII), methionine synthase (MS), methionine synthase reductase (MSR) and methylenetetrahydrofolate reductase (MTHFR) genes in 140 CAD patients and 113 controls, by means of Chi-square, logistic regression, ANOVA and the Mann-Whitney U test.
RESULTS: The c.66 G allele of MSR conferred an odds-ratio for CAD of 1.76 (95% CI 1.12-2.77), while a CBS haplotype [c.699C-c.844wt-c.1080C] was found over-represented in CAD [OR of 2.16 (1.29-3.63)].
CONCLUSIONS: Our results not only highlight the involvement of the MSR and CBS genes in the etiology of cardiovascular disease, but also emphasize the strength of haplotype analyses in association studies.

Epidemiological evidence suggests that intake of folate and other B-vitamins and genetic variants in the one-carbon metabolism pathway could influence the risk of breast cancer. Previous studies have focused on 2 polymorphisms in the methylenetetrahydrofolate gene (MTHFR A222V and E429A); however, findings are inconclusive. In a large population-based case-control study in Poland (2,386 cases, 2,502 controls), we investigated the association between breast cancer risk and 13 polymorphisms in 6 one-carbon metabolism genes (MTHFR, MTR, MTRR, CBS, SHMT1 and SLC19A1). Data suggested an association between a nonsynonymous change in the gene coding for methionine synthase (MTR D919G) and reduced breast cancer risk: OR (95% CI) = 0.84 (0.73-0.96) and 0.85 (0.62-1.15) for heterozygous and homozygote variant genotypes, respectively, compared with common homozygotes; p-trend = 0.01, false discovery rate = 0.14. We found no significant associations between other variants and breast cancer risk, including MTHFR A222V or E429A. Meta-analyses including published studies of MTHFR A222V (8,330 cases and 10,825 controls) and E429A (6,521 cases and 8,515 controls) supported the lack of an overall association; however, studies suggested an increase in risk among premenopausal women. In conclusion, this report does not support a substantial overall association between the evaluated polymorphisms in the one-carbon metabolism pathway and breast cancer risk.