Methylenetetrahydrofolate Reductase Deficiency Research Articles

Mild Methylenetetrahydrofolate Reductase Deficiency Alters Inflammatory and Lipid Pathways in Liver.

Dietary and genetic folate disturbances can lead to nonalcoholic fatty liver disease (NAFLD). A common variant in methylenetetrahydrofolate reductase (MTHFR 677C→T) causes mild MTHFR deficiency with lower 5-methyltetrahydrofolate for methylation reactions. The goal is to determine whether mild murine MTHFR deficiency contributes to NAFLD-related effects. Wild-type and Mthfr+/- mice, a model for the human variant, are fed control (CD) or high-fat (HFAT) diets for 8 weeks. On both diets, MTHFR deficiency results in decreased S-adenosylmethionine, increased S-adenosylhomocysteine, and decreased betaine with reduced methylation capacity, and changes in expression of several inflammatory or anti-inflammatory mediators (Saa1, Apoa1, and Pon1). On CD, MTHFR deficiency leads to microvesicular steatosis with expression changes in lipid regulators Xbp1s and Cyp7a1. The combination of MTHFR deficiency and HFAT exacerbates changes in inflammatory mediators and introduces additional effects on inflammation (Saa2) and lipid metabolism (Nr1h4, Srebf1c, Ppara, and Crot). These effects are consistent with increased expression of pro-inflammatory HDL precursors and greater lipid accumulation. MTHFR deficiency may enhance liver injury through alterations in methylation capacity, inflammatory response, and lipid metabolism. Individuals with the MTHFR variant may be at increased risk for liver disease and related complications, particularly when consuming high-fat diets.

Early Manifestations of Brain Aging in Mice Due to Low Dietary Folate and Mild MTHFR Deficiency.

Folate is an important B vitamin required for methylation reactions, nucleotide and neurotransmitter synthesis, and maintenance of homocysteine at nontoxic levels. Its metabolism is tightly linked to that of choline, a precursor to acetylcholine and membrane phospholipids. Low folate intake and genetic variants in folate metabolism, such as the methylenetetrahydrofolate reductase (MTHFR) 677 C>T polymorphism, have been suggested to impact brain function and increase the risk for cognitive decline and late-onset Alzheimer's disease. Our study aimed to assess the impact of genetic and nutritional disturbances in folate metabolism, and their potential interaction, on features of cognitive decline and brain biochemistry in a mouse model. Wild-type and Mthfr+/- mice, a model for the MTHFR 677 C>T polymorphism, were fed control or folate-deficient diets from weaning until 8 and 10months of age. We observed short-term memory impairment measured by the novel object paradigm, altered transcriptional levels of synaptic markers and epigenetic enzymes, as well as impaired choline metabolism due to the Mthfr+/- genotype in cortex or hippocampus. We also detected changes in mRNA levels of Presenillin-1, neurotrophic factors, one-carbon metabolic and epigenetic enzymes, as well as reduced levels of S-adenosylmethionine and acetylcholine, due to the folate-deficient diet. These findings shed further insights into the mechanisms by which genetic and dietary folate metabolic disturbances increase the risk for cognitive decline and suggest that these mechanisms are distinct.

WED 209 A case report of hyperhomocystinemia due to homozygous MTHFR mutation

Homocycteine is metabolized via two pathways, remethylation or trans-sulfuration. The former requires 5-methyltetrahydrofolate reductase (MTHFR) and Vitamin B12, the later requires cystathione–beta-synthetase and Vitamin B6. Mutations in the MTHFR genes affect the enzyme activity to various degree and manifestations can be neuropsychiatric, vascular and neurodegenerative. Here we report a case of severe homocysteinemia secondary to two homozygous MTHFR gene mutations.32 year old pregnant female initially presented in 2014 with grand mal seizure. After being seizure free on antiepileptics, she was admitted again to hospital in January 2017 with headaches, confusion, slurred speech and neuropathic pain in feet. She developed spastic paraparesis and her condition remained critical for several weeks due to refractory seizures and low GCS.She was on warfarin for recurrent DVTs and had family history of mental health problems. Homocysteinemia was discovered when he was screened for metabolic causes and leucodystrophies. MRI of the brain showed cerebral, cerebellar and brain stem atrophy. Neurophysiological studies were normal. Genetic testing found her to be homozygous for 2 MTHFR mutations. She was commenced on calcium folinate and parenteral B12, to which she responded really well.Thorough history, targeted investigations and systematic approach are keys for diagnosis of rare metabolic disorders.

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry

High incidence of maternal vitamin B12 deficiency detected by newborn screening: first results from a study for the evaluation of 26 additional target disorders for the German newborn screening panel.

Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel. Since August 2016, a prospective study evaluating 26 additional target disorders (25 metabolic disorders and vitamin B12-deficiency) in addition to the German screening panel is performed at the Newborn Screening Center Heidelberg. First-tier results from tandem-MS screening are complemented by second-tier strategies for 15 of the additional target disorders. NBS results of seven patients diagnosed symptomatically with one of the additional target disorders by selective screening since August 2016 are retrospectively evaluated. Over a 13-month period, 68,418 children participated in the study. Second-tier analyses were performed in 5.4% of samples. Only 59 (0.1%) of study participants had abnormal screening results for one of the additional target disorders. Target disorders from the study panel were confirmed in 12 children: 1 3-hydroxy-3-methylglutaryl coenzyme A(CoA)-lyase deficiency, 1 citrullinemia type I, 1 multiple acyl-CoA dehydrogenase-deficiency, 1 methylenetetrahydrofolate reductase-deficiency, and 8 children with maternal vitamin B12-deficiency. In addition, six of seven patients diagnosed symptomatically outside the study with one of the target disorders would have been identified by the study strategy in their NBS sample. Within 13months, the study "Newborn Screening 2020" identified additional 12 children with treatable conditions while only marginally increasing the recall rate by 0.1%. Maternal vitamin B12-deficiency was the most frequent finding. Even more children could benefit from screening for the additional target disorders by extending the NBS panel for Germany and/or other countries.

Methylenetetrahydrofolate Reductase Deficiency Deregulates Regional Brain Amyloid-β Protein Precursor Expression and Phosphorylation Levels.

Deregulation of the amyloid-β protein precursor (AβPP) plays a critical role in the neurodegenerative cascade of Alzheimer's disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal AβPP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental AβPP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3β (GSK-3β). Lastly, we show that severe disturbances in folate metabolism can also affect AβPP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3β, demethylation of PP2A, and enhanced phosphorylation of AβPP at Thr668, which is known to critically influence neuronal AβPP function and pathological amyloidogenic processing. Deregulation of AβPP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD.

P-220 - MTHFR, TSER and DPYD gene mutation is associated with toxicity and response in pre-operative chemo-radiotherapy for local advanced rectal cancer

Introduction: Radiotherapy and 5 FU based chemotherapy is the most common pre-operative regimen used for cT3-T4, N1 rectal cancer (RC). Evaluation of predictive markers of response and toxicity to radio-chemotherapy is a challenging approach for patients (pts) and drug selection. In the present experience we have analyzed the predictive role of the genetic polymorphisms (MTHFR, TSER and DPYD) on toxicity and response to pre-operative radio-chemotherapy. Methods: We have enrolled eighteen patients with locally advanced RC treated with pre-operative radiotherapy and fluoropyrimidines based chemotherapy. Genetic polymorphisms of MTHFR C677T, MTHFRA 1298C, DPYD IVS 14 + 1G>A, DPYDA 2846T, DPYD T 1679 G, TSER 28 bp VNTR were analyzed by PCR and pyrosequencing of genomic DNA extracted from peripheral blood samples. Genetic markers were correlated with toxicity to treatment (chemotherapy and radio-chemotherapy) and clinical response. Results: Patients characteristics were: male 15 pts, female 3 pts, median age 66 years, ECOG PS 0-1 all pts. We found DPYD IVS 14 + 1 G>A G/G homozygous wild type, DPYD A2846T, T/T homozygous wild type and DPYD T1679 g, T/T homozygous wild type in 100% of pts, homozygous wild type MTHFR C677T in 10% of pts, MTHFR C677T homozygous mutated in 50% of pts, heterozygous MTHFR A1298C in 60% of pts and homozygous wild type MTHFR A 1298C in 40% of pts. Adverse events G-3 (diarrhea, neutropenia, asthenia, mucositis) were observed in 60% of pts with heterozygous MTHFR A 1298C and in 10% of pts with homozygous mutated MTHFR C 677t treated with chemo radiotherapy combination. DPYD homozygous wild type was not associated with severe toxicity. Rectal surgery with TME/TEM will be performed 8 weeks after the end of pre-operative chemo-radiotherapy. We obtained 9 pathological complete response and 9 partial pathological response. Adjuvant chemotherapy was well tolerated without G3-G4 adverse events. Five pts with pathological complete response were treated with Transanal Endoscopic Microsurgery (TEM) and they are alive without recurrence to twelve months after surgery. Conclusion: Concomitant assessment of genetic polymorphisms of MTHFR and DPYD is promising to predict severe toxicity during preoperative chemo-radiotherapy approach for pts with locally advanced rectal cancer. This result does not exclude the need to consider other non-genetic factors that might influence the individual enzyme activities.

Homocystinuria due to a Novel Mutation in MTHFR Gene: A Rare Cause of Non-Immune Hydrops Fetalis

Homocystinuria due to a Novel Mutation in MTHFR Gene: A Rare Cause of Non-Immune Hydrops Fetalis

Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation.

Supplementation with high doses of folic acid, an important mediator of one-carbon transfers for DNA methylation, is used clinically to improve sperm parameters in infertile men. We recently detected an unexpected loss of DNA methylation in the sperm of idiopathic infertile men after 6 months of daily supplementation with 5 mg folic acid (>10× the daily recommended intake-DRI), exacerbated in men homozygous for a common variant in the gene encoding an important enzyme in folate metabolism, methylenetetrahydrofolate reductase (MTHFR 677C>T). To investigate the epigenomic impact and mechanism underlying effects of folic acid on male germ cells, wild-type and heterozygote mice for a targeted inactivation of the Mthfr gene were fed high-dose folic acid (10× the DRI) or control diets (CDs) for 6 months. No changes were detected in general health, sperm counts or methylation of imprinted genes. Reduced representation bisulfite sequencing revealed sperm DNA hypomethylation in Mthfr+/- mice on the 10× diets. Wild-type mice demonstrated sperm hypomethylation only with a very high dose (20×) of folic acid for 12 months. Testicular MTHFR protein levels decreased significantly in wild-type mice on the 20× diet but not in those on the 10× diet, suggesting a possible role for MTHFR deficiency in sperm DNA hypomethylation. In-depth analysis of the folic acid-exposed sperm DNA methylome suggested mouse/human susceptibility of sequences with potential importance to germ cell and embryo development. Our data provide evidence for a similar cross-species response to high dose folic acid supplementation, of sperm DNA hypomethylation, and implicate MTHFR downregulation as a possible mechanism.

Homocysteinemia in relation to anemia in hypothyroid patients

Background Anemia and hypothyroidism are both common diseases in the community. Homocysteine (HCY) levels are increased in patients with hypothyroidism and methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common genetic cause of hyperhomocysteinemia. The aim of the present study was to evaluate the level of serum HCY in patients with hypothyroidism and to study the relation of associated anemia with the serum level of HCY and MTHFR gene in patients with hypothyroidism. Patients and methods The study was conducted on 60 adult women attending the Endocrinology Outpatient Clinic of Al-Zahraa Hospital between September 2014 and June 2015 for proper diagnosis and management. Individuals of the study were divided into two main groups: group I (GI) with 30 hypothyroid patients, where 13 of them were postsurgical cases, and group II (GII) with 30 euthyroid individuals as a control group. Diagnosis was based on thyroid-stimulating hormone level reference values. Patients in GI were further classified into two subgroups: mild hypothyroid (subgroup I) and overt hypothyroid (subgroup II). Patient and control groups also were classified into anemic and nonanemic subgroups according to hemoglobin levels. The selected hypothyroid patients were women under thyroid hormone replacement therapy. Blood sample was obtained for proper investigations. Complete blood count, routine blood chemistry, serum iron level, thyroid function tests, vitamin B12 level, serum homocysteine (HCY), and MTHFR were performed. We performed a pilot study on MTHFR gene polymorphism. The C677T MTHFR gene mutation was detected in three of 10 patients and in two of 10 controls. No evidence of TT MTHFR gene mutation was observed in both patient and control groups. IBM SPSS statistics (version 23.0, USA, 2015) was used for data analysis. Results revealed the presence of anemia according to hemoglobin level (<12 g/dl). In patients group (GI), 50% (15/30) as compared with 13.3% (4/30) in the control group (GII) had anemia. Serum iron level in patients group (GI) was deficient in 40% (11/30), whereas deficient in 16.7% (5/30) in control group (GII). Vitamin B12 deficiency was found to be 44% (11/25) in patients group (GI), whereas in the control group (GII) was 6.7% (2/30). Analysis by Wilcoxon's rank sum test, homocysteine (HCY) serum level showed a highly significant increase among patients (GI) as compared with control (GII). Ranked Spearman's correlation test for the patients (GI) and control (GII) showed a significant negative correlation between homocysteine (HCY) and MTHFR serum levels, whereas the correlation with red cell indices parameters was insignificant. Serum iron and B12 levels were significantly correlated in patient group (GI). Pearson χ 2 tests were done between both patients and control groups for the presence of anemia, iron deficiency, and elevated serum homocysteine (HCY) level and all revealed statistically significant results. Conclusion There is no significant correlation between homocysteinemia and anemia. However, the strong association between anemia and hypothyroidism is attributed mainly owing to combined iron and vitamin B12 deficiencies. This might explain the decreased response to treatment among the selected hypothyroid patients.

The hazards of excessive folic acid intake in MTHFR gene mutation carriers: An obstetric and gynecological perspective

The hazards of excessive folic acid intake in MTHFR gene mutation carriers: An obstetric and gynecological perspective

English

Objectives: The objective of our study was to assess the effectiveness offolic acid in optimizing the red blood cells folate levels and to observe the frequency of folateresistance among Pakistani female patients. Setting: Outpatient Department of Obstetrics &Gynaecology, Jinnah Post graduate Medical Centre (JPMC), Karachi. Period: January–July2016. Methodology: Participants fulfilling the inclusion criteria were included after informedconsent. Detail history and physical examination was done in each participant. All studyparticipants received 5mg (400 μg) folic acid as a daily supplement for 24 weeks. Red bloodcell folate concentrations were measured at baseline and after 24 weeks of therapy. Pairedsample t-test was used to find out significant difference between folate levels. Results: A totalof 44 women (23 pregnant while 21 non pregnant) were included in the study. Mean age of theparticipants was 27.6 ± 5.9years and mean BMI was 23.9 ± 4.1kg/m2 respectively. The meanvalues of Red blood cells folate at baseline and at 24 weeks were 623.6 ± 406.6 and 861.9 ±432.4respectively. Paired sample t-test results showed that there was no significant difference.Thirty-two (70.4%) women showed an increase in RBC folate status while 13 (29.6%) womenhad steady or decreased levels of folate after taking folic acid for 24 weekswhich may be dueto RBS enzyme methylenetetrahydrofolate reductase (MTHFR) deficiency. Conclusion: Simplefolic acid supplementation is not very helpful in improving folate status in female Pakistanipatients. Resistant to improvement may be due to MTHFR deficiency in our study subjects.

FOLIC ACID;

Objectives: The objective of our study was to assess the effectiveness offolic acid in optimizing the red blood cells folate levels and to observe the frequency of folateresistance among Pakistani female patients. Setting: Outpatient Department of Obstetrics &Gynaecology, Jinnah Post graduate Medical Centre (JPMC), Karachi. Period: January–July2016. Methodology: Participants fulfilling the inclusion criteria were included after informedconsent. Detail history and physical examination was done in each participant. All studyparticipants received 5mg (400 μg) folic acid as a daily supplement for 24 weeks. Red bloodcell folate concentrations were measured at baseline and after 24 weeks of therapy. Pairedsample t-test was used to find out significant difference between folate levels. Results: A totalof 44 women (23 pregnant while 21 non pregnant) were included in the study. Mean age of theparticipants was 27.6 ± 5.9years and mean BMI was 23.9 ± 4.1kg/m2 respectively. The meanvalues of Red blood cells folate at baseline and at 24 weeks were 623.6 ± 406.6 and 861.9 ±432.4respectively. Paired sample t-test results showed that there was no significant difference.Thirty-two (70.4%) women showed an increase in RBC folate status while 13 (29.6%) womenhad steady or decreased levels of folate after taking folic acid for 24 weekswhich may be dueto RBS enzyme methylenetetrahydrofolate reductase (MTHFR) deficiency. Conclusion: Simplefolic acid supplementation is not very helpful in improving folate status in female Pakistanipatients. Resistant to improvement may be due to MTHFR deficiency in our study subjects.

Manifestations of neurological symptoms and thromboembolism in adults with MTHFR-deficiency

BackgroundMethylenetetrahydrofolate-reductase (MTHFR) deficiency is a rare autosomal recessive disorder affecting intracellular folate metabolism with affection of different organ systems and clinical manifestation usually in childhood. ObjectiveWe report on four adult members of a family with MTHFR deficiency presenting with neurological and thromboembolic complications in adulthood. MethodsExtensive diagnostic work-up including genetic testing was performed in four adult members. ResultsThe male siblings aged 42 and 32years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135μmol/L and 231μmol/L. and compound heterozygosity for two novel MTHFR gene mutations in exon 2 (c.202C>G, p.Arg68Gly) and intron 10 (c.1632+2T>G), and the known polymorphic variant MTHFR c.665C>T (p.Ala222Val, MTHFR 677C>T). Their mother was heterozygous for MTHFR c.1632+2T>G and c.665C>T, and a paternal relative was heterozygous for MTHFR c.202.C>G and MTHFR c.665C>T mutation. Both brothers showed partial response to therapy with betaine and multivitamins with clinical improvement. MTHFR activity was determined in fibroblast extracts and was around 4% of the mean control. Cell culture analysis indicated a re-methylation defect due to MTHFR deficiency. ConclusionSevere hyperhomocysteinemia due to two mutations of the MTHFR gene resulted in severe neurological symptoms in adulthood. Vitamin and methionine supplementation stabilize tHcy plasma levels. Severity of clinical manifestation varied greatly between the siblings. Damages to the nervous system may be present for years before becoming clinically manifest.

Methylene Tetrahydrofolate Reductase Deficiency: the Hidden Risk in Paediatric Anaesthesia.

Methylene tetrahydrofolate reductase (MTHFR) deficiency is an autosomal recessive disorder that results in increased homocysteine levels in the body. Hyperhomocysteinemia causes a predisposition to venous and arterial thrombosis and ischaemic insults. The incidence of the deficiency is around 40% in some countries. In this study, we aimed to evaluate the effects of anaesthetic agents in children with MTHFR deficiency. Twelve paediatric patients with an MTHFR enzyme deficiency who underwent surgery in a ten-month period in a single centre were retrospectively evaluated. Demographic data, homocysteine levels before and after surgery, anaesthesia management and postoperative complications were recorded. In four patients, propofol was used both for anaesthesia induction and total intravenous anaesthesia (TIVA). Eight patients received sevoflurane for both induction and maintenance of anaesthesia. Nitrous oxide (N2O) was not used in any patients. There was not a significant difference between the preoperative and postoperative homocysteine levels (p>0.05). Twenty-four hours after the surgery, the homocysteine levels were within normal limits. No complications were observed. Sevoflurane and propofol have no deleterious effects on homocysteine levels in patients with MTHFR deficiency. Avoidance of N2O is the key point for anaesthetic consideration regarding these patients.

メチレンテトラヒドロ葉酸還元酵素(MTHFR)の共通遺伝子多型677C>TがAla222Valである理由

メチレンテトラヒドロ葉酸還元酵素(MTHFR)の共通遺伝子多型677C>TがAla222Valである理由

MTHFR, TSER and DPYD gene mutation is associated with toxicity and response in pre-operative chemo-radiotherapy for local advanced rectal cancer

Background: Radiotherapy and 5 FU based chemotherapy is the most common pre-operative regimen used for cT3-T4, N1 rectal cancer (RC). Evaluation of predictive markers of response and toxicity to radio-chemotherapy is a challenging approach for patients (pts) and drug selection. in the present experience we have analyzed the predictive role of the genetic polymorfisms (MTHFR, TSER and DPYD) on toxicity and response to pre-operative radio-chemotherapy. Materials and methods: We HAVE enrolled sixteen patients with locally advanced RC treated with pre-operative radiotherapy and fluoropyrimidines base chemotherapy. Genetic polymorphisms of MTHFR C677T, MTHFRA 1298C, DPYD IVS 14 + 1G>A, DPYDA 2846T, DPYD T 1679 G, TSER 28 bp VNTR were analyzed by PCR and pyrosequensing of genomic DNA extracted from peripheral blood samples. Genetics markers were correlated with toxicity to treatment (chemotherapy and radio-chemotherapy) and clinical response. Results: Patients characteristics were: male 13 pts, female 3 pts, median age 66 years, ECOG PS 0-1 all pts. We found DPYD IVS 14 + 1 G>A G/G homozygous wilde type, DPYD A2846T, T/T homozygous wilde type and DPYD T1679 g, T/T homozygous wilde type in 100% of pts, homozygous wilde type MTHFR C677T in 10% of pts, MTHFR C677T homozygous mutated in 50% of pts, heterozygous MTHFR A1298C in 60% of pts and homozygous wilde type MTHFR A 1298C in 40% of pts. G3-G4 advers events (diarrhea, neutropenia, asthenia, mucositis) were observed in 60% of pts with heterozygous MTHFR A 1298C and in 10% of pts with homozygous mutated MTHFR C 677t. treated with chemo-radiotherapy combination. DPYD homozygous wilde type was not associated with severe toxicity. Rectal surgery with TME will be performed 8 weeks after the end of pre-operative chemo-radiotherapy. We obtained 7 patological complete response and nine partial patological response. Adjuvant chemotherapy was well tolerated without G3-G4 adverse events. Three pts with patological complete respose were treated with Transanal Endoscopic Microsurgery (TEM) and they are alive without recurrence to twelve months after surgery. Conclusion: Concomitant assesment of genetic polymorphisms of MTHFR and DPYD is promising to predict severe toxicity during preoperative chemo-radioterapy approach for pts with locally advanced rectal cancer. This result does not exclude the need to consider other non-genetic factors that might influence the individual enzyme activities.

Asymptomatic Duodenal Penetration by Inferior Vena Cava Filter: 3-Year Follow-up

INTRODUCTION: Inferior vena cava (IVC) filters are used to reduce the risk of thromboembolic events in subjects who are either not a candidate for anticoagulant therapy (ACT) or have failed ACT. Complications of IVC filters could be either early (bleeding, infection, acute venous thrombosis, hematoma and arteriovenous fistula formation) or late (filter migration and chronic thrombosis/recurrent thromboembolism). IVC filter penetration of the surrounding structures including bowel (duodenum), is a known although rare complication which can manifest as abdominal pain, gastrointestinal bleeding, cava-duodenal fistula, or small bowel obstruction. We present a rare case of asymptomatic duodenal penetration by IVC filter which was managed conservatively. CASE REPORT A 64-year-old male with history of multiple, recurrent DVTs and pulmonary embolism secondary to heterozygous MTHFR gene mutation presented to our facility 3 years ago for progressively worsening dysphagia. He had Greenfield IVC filter placed a few years back and was on long term ACT. Esophagogastroduodenoscopy(EGD) incidentally revealed a piece of metal protruding from the second portion of the duodenal wall, as shown in figure 1.CT scan of the abdomen and pelvis showed multiple IVC filter struts extending beyond the IVC wall with one of the struts extending anteriorly to penetrate the duodenal wall, as in figure 2. IVC venography confirmed CT scan findings, showing four struts of a patent IVC filter extending beyond the IVC wall. Vascular surgery (VS) and interventional radiology (IR) recommended conservative management in the absence of any symptoms. He remained asymptomatic for the next three years. Repeat EGD performed 3 years later revealed unchanged IVC filter strut in the duodenum, as shown in figure 3.Figure: EGD performed in 2013 showing IVC filter strut in duodenum.Figure: CT scan of the abdomen and pelvis showing multiple IVC filter struts extending beyond the IVC wall, with one of the struts penetrating duodenal wall.Figure: EGD performed in 2016 showing IVC filter strut at the same location in duodenum.DISCUSSION IVC filter migration into the GI tract is extremely rare and patients are usually symptomatic. Duodenum is the most common extra-caval involved organ. Current literature directs surgical treatment of patients with symptomatic duodenal perforation, however, there are no consensus guidelines for management of asymptomatic IVC filter penetrations in GI tract. Such cases should be managed by a multidisciplinary team of IR, VS and gastroenterologist. CONCLUSION Our patient was managed successfully with a non-surgical approach and remained asymptomatic during next 3 years.

A case with MTHFR gene mutation after secondary cirrhosis to portal vein thrombosis

Portal ven trombusu; portal hipertansiyonun sebeplerinden bir tanesidir. Portal venin tikanmasi, yavas ve iyi tolere edilebilen bir durum olabilecegi gibi, siddetli ve potansiyel olarak olumcul bir durumda olabilir. Trombofili, tromboza egilim olusturan durumlari tanimlayan bir terimdir. Trombofili cok yaygin bir fenomen degildir ve edinsel ve konjenital sebepleri vardir. Kalitimsal trombofilik anormallikler, portal ven trombusu gelisiminde rol oynarlar. Bunlar arasinda Faktor V Leiden mutasyonu, Protrombin 20210A mutasyonu, protein S ve C eksiklikleri ve antitrombin 3 eksikligi en sik bilinen ve trombofilik hastalarda en sik etiyolojik faktor olarak sorgulanan faktorlerdir. Bu olgu sunumu ile portal ven trombusu bulunan ve karaciger sirozu ile klinigimize basvuran, etiyolojik arastirmalar neticesinde MTHFR geni homozigot mutasyonu tespit edilen 37 yasindaki bayan hastayi sunmayi amacladik.

RE: Methylenetetrahydrofolate Reductase Deficiency: Rare but Considerable.

RE: Methylenetetrahydrofolate Reductase Deficiency: Rare but Considerable.