Methylenetetrahydrofolate Reductase Deficiency Research Articles

METHYLATION-ASSOCIATED PATHWAYS IN MACULAR TELANGIECTASIA TYPE 2 AND OPHTHALMOLOGIC FINDINGS IN PATIENTS WITH GENETIC METHYLATION DISORDERS.

Serine (Ser) and glycine (Gly) levels were reported to differ between patients with macular telangiectasia type 2 (MacTel) compared with healthy controls. Because they are closely related to methylation metabolism, this report investigates methylation-associated metabolite levels in patients with MacTel and retinal changes in monogenetic methylation disorders. Prospective, monocentric study on patients with MacTel and healthy controls underwent a standardized protocol including a blood draw. Methylation-associated metabolite levels in plasma were determined using targeted quantitative metabolomics. Furthermore, patient records of cystathionine beta-synthase, methylenetetrahydrofolate reductase, and methylmalonic aciduria and homocystinuria type C protein (MMACHC) deficiency were screened for reported retinal changes. In total, 29 patients with MacTel and 27 healthy controls were included. Patients with MacTel showed lower plasma Ser ( P = 0.02 and P = 0.01) and Gly ( P = 0.11 and P = 0.11) levels than controls. Principal component analyses revealed that methylation-associated metabolite, especially homocysteine, contributed to a distinct clustering of patients with MacTel. No retinal changes were seen in cystathionine beta-synthase (n = 1) and methylenetetrahydrofolate reductase (n = 2) deficiency, while two patients with MMACHC (n = 4) deficiency displayed extensive macular dystrophy. Patients with MacTel show distinct clustering of methylation-associated metabolite compared with controls. Of the three homocystinurias, only MMACHC resulted in macular dystrophy, possibly due to distinct compensatory pathways.

TAKOTSUBO SYNDROME AND SMALL BOWEL OBSTRUCTION: WHEN THE HEART–GUT AXIS GOES HAYWIRE

Abstract Case Report A 66 years old woman was admitted to our emergency department for the onset of intense epigastric pain, nausea and asthenia after breakfast. She had a history of hypertension, dyslipidemia, COPD and deep venous thrombosis with MTHFR gene mutation. Moreover, she had a positive family history for coronary artery disease (CAD). On arrival, she was apyretic, hemodynamically stable, complaining chest and persisting epigastric pain. A mild and diffuse abdominal tenderness was noted without peritoneal signs. The ECG showed sinus tachycardia, ST elevation (STE) in leads D1, aVL, V2 and V3 and ST depression in leads D3, aVR and V1. Blood test revealed a marked increase of PCR with leukocytosis and elevation of Hs–cTnI (840 ng/L) while serum electrolytes were normal. Bed–side echocardiography revealed apical and mid–ventricular akinesia with a severe reduction of left ventricular ejection fraction (LVEF). InterTAK score was 62 (62,6% probability of Takotsubo syndrome – TTS). An urgent coronary angiography (CA) revealed non– obstructive CAD, while ventriculography showed a typical apical ballooning and hyperkinetic base of the LV suggestive of TTS. Subsequently, the CT abdomen showed extra–luminal free fluid and a dilated proximal small bowel (SB) with air–fluid levels and a bubbly pattern of gas in the wall. These radiological findings were consistent with a mechanical SB obstruction, complicated by mesenteric venous thrombosis and intestinal pneumatosis. Exploratory laparotomy revealed SB necrosis as consequence of bridle–mediated obstruction and therefore an ileum resection was performed. The patient clinically improved post–operatively with a complete recovery of the LVEF. Discussion We described a rare presentation of SB obstruction which induced a TTS in a setting of severe psychophysical stress. The management of this emergency situation in which cardiac injury and acute abdomen occurred simultaneously can be challenging. The consulting cardiologist needs to quickly decide whether to prioritize the heart with urgent CA or the gastroenteric condition with surgery. Despite the likelihood of TTS can be high (even calculating InterTak score), new STE and positive troponins can’t be disregarded especially in patients with significant risk factors as seen in our case. Therefore, the strong evidence of a possible acute coronary syndrome may trump a life–saving treatment for SB obstruction.

Correlation between common mutations of MTHFR gene and missed abortion cases, during the first trimester of pregnancy, at American Hospital, International Hospital and Cambridge clinical laboratories in Albania

Correlation between common mutations of MTHFR gene and missed abortion cases, during the first trimester of pregnancy, at American Hospital, International Hospital and Cambridge clinical laboratories in Albania

Discovery of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency in Individuals With Common Psychiatric Comorbidities: A Retrospective Case Review.

A retrospective analysis was conducted of a data set collected in an outpatient behavioral health clinic to assess medication metabolism and methylenetetrahydrofolate reductase (MTHFR) and to see if there was a correlation with certain diagnoses and/or gender. The outpatient routine completed genetic testing on their patients and the test results were later collected through a third-party company, which completed the pharmacogenomic test analyzing genetic variations in DNA, medication metabolism, and an MTHFR deficiency. This study reviewed 186 patients seen in an outpatient setting who were tested for an MTHFR deficiency and compared their psychiatric diagnoses and the number of failed medication attempts. Of those 186 patients, 77 had normal MTHFR enzyme function, 85 were found to have a moderate MTHFR deficiency, and 24 had a severe MTHFR deficiency. Those with a severe MTHFR deficiency had a higher number of medication trials as compared to those without the deficiency and there were overall more patients with a moderate MTHFR deficiency in this data set. Currently, MTHFR deficiency is not commonly tested due to lack of insurance coverage and provider knowledge, and due to the cost of the test itself. Thus, the diagnosis can often be missed.

Skin disorders in women with poor obstetric history: MTHFR polymorphisms and importance of preconceptional counseling

Objectives This study focused on the link between skin disorders and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Methods Study cases were taken from a pre-conceptional care program where patients with poor obstetric history were evaluated in terms of systemic disorders including skin diseases. This retrospective cohort (n = 472) consisted of 110 (23.3%) and 362 (76.7%) women with or without skin disorders, respectively. For ease of analysis, the history of skin diseases was classified into seven categories: (1) acne/rosacea/other acneiform disorders; (2) fungal disease; (3) pruritis/xerosis; (4) psoriasis vulgaris; (5) acrochordons and other benign skin growths; (6) urticaria/dermatitis; and (7) viral diseases. Results In this retrospective cohort of 472 women, we explored the impact of MTHFR A1298C and C677T polymorphisms on skin disorders. Despite similar allelic frequencies, our findings revealed a statistically significant association between the presence of MTHFR polymorphisms and skin disorders (p = .027). Subgroup analysis indicated significantly higher rates of MTHFR polymorphisms in patients with psoriasis vulgaris (p = .033) and acrochordons (p = .030), highlighting their potential relevance in specific skin disorder subtypes. Conclusions The increased prevalence of psoriasis and acrochordons among women with MTHFR deficiency underscores the complex relationship between genetic factors and dermatological health. Our findings emphasized the critical role of MTHFR polymorphisms not only in poor obstetric history but also as significant contributors to skin disorders. This dual association highlights the importance of comprehensive preconception counseling, especially customized for women affected by skin disorders.

Analysis of 9 patients with adolescence-onset methylenetetrahydrofolate reductase deficiency

Objective: To explore the diagnosis and treatment of adolescence-onset methylenetetrahydrofolate reductase (MTHFR) deficiency. Methods: This was a retrospective case study. Nine patients with adolescence-onset MTHFR deficiency were diagnosed at Peking University First Hospital from January 2016 to December 2022, and followed up for more than 1 year. Their general information, clinical manifestations, laboratory tests, cranial images, MTHFR gene variants, diagnosis, treatment, and outcome were analyzed retrospectively. Results: The 9 patients came from 8 families. They had symptoms at age of 8.0 years to 17.0 years and diagnosed at 9.0 years to 17.5 years. Eight were male and 1 was female. Two patients were brothers, the elder brother developed abnormal gait at 17.0 years; and the younger brother was then diagnosed at 15.0 years of age and treated at the asymptomatic stage, who was 18.0 years old with normal condition during this study. The main manifestations of the 8 symptomatic patients included progressive dyskinesia and spastic paralysis of the lower limbs, with or without intellectual decline, cognitive impairment and behavioral abnormalities. Totally, 15 variants of MTHFR gene were identified in the 9 patients, including 8 novel variants. Five patients had brain image abnormalities. Increased plasma total homocysteine level (65-221 μmol/L) was found in all patients, and decreased to 20-70 μmol/L after treatment with betaine and calcium folinate. Besides, the 8 symptomatic patients had their behavior and cognitive problems significantly improved, with a legacy of lower limb motor disorders. Conclusions: Late-onset MTHFR deficiency can occur in adolescence. The diagnosis is usually delayed because of non-specific clinical symptoms. The test of blood total homocysteine could be used as a selective screening test. Eight novel varients of MTHFR gene were identified. Timely treatment can improve clinical condition significantly, and pre-symptomatic treatment may prevent brain damage.

Sperm DNA methylation defects in a new mouse model of the 5,10-methylenetetrahydrofolate reductase 677C>T variant and correction with moderate dose folic acid supplementation.

5,10-Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays a key role in providing methyl groups for DNA methylation, including during spermatogenesis. A common genetic variant in humans (MTHFR 677C>T) results in reduced enzyme activity and has been linked to various disorders, including male infertility. A new animal model has been created by reproducing the human equivalent of the polymorphism in mice using CRISPR/Cas9. Biochemical parameters in the Mthfr 677TT mice recapitulate alterations found in MTHFR 677TT men. Our aims were to characterize the sperm DNA methylome of the Mthfr 677CC and TT mice on a control diet (2 mg folic acid/kg diet) and assess the effects of folic acid supplementation (10 mg/kg diet) on the sperm DNA methylome. Body and reproductive organ weights, testicular sperm counts, and histology were examined. DNA methylation in sperm was assessed using bisulfite pyrosequencing and whole-genome bisulfite sequencing (WGBS). Reproductive parameters and locus-specific imprinted gene methylation were unaffected by genotype or diet. Using WGBS, sperm from 677TT mice had 360 differentially methylated tiles as compared to 677CC mice, predominantly hypomethylation (60% of tiles). Folic acid supplementation mostly caused hypermethylation in sperm of males of both genotypes and was found to partially correct the DNA methylation alterations in sperm associated with the TT genotype. The new mouse model will be useful in understanding the role of MTHFR deficiency in male fertility and in designing folate supplementation regimens for the clinic.

Incidence of thrombophilic gene polymorphism (MTHFR C677T) in Egyptian COVID-19 patients and its clinical implications

BackgroundCOVID-19 has an important component of organ damage which is COVID-19-associated coagulopathy. It is necessary to assess the risk in patients to develop a thrombophylaxis plan. The higher prevalence of key thrombophilic genetic variants, such as mutation of the C677T-methylenetetrahydrofolate reductase (MTHFR) gene in Eastern Mediterranean countries, makes it challenging to use the same criteria in other world countries with differing thrombophilic panels.ObjectiveTo find the incidence of MTHFR gene polymorphism in a cohort of Egyptian patients with COVID-19, and its association with thromboembolic events.Subjects and methodsThis was a prospective observational cohort study, done at Ain-Shams University isolation Hospitals, Cairo, Egypt. It included 33 patients with COVID-19 and 13 healthy controls. The patients underwent lab investigations: HRCT chest in which the extent of radiological affection was described in terms of severe form (> 50% of lungs are affected) and non-severe form (< 50% of lungs are affected) and assessment of MTHFR-C677T genotypes. Then follow-up for 28 days for vascular thrombotic manifestations.ResultsOut of 33 patients, MTHFR-gene mutation was found in 10 (incidence rate 30.3%). Severe form of affection in the HRCT chest was significantly related to mutation of the MTHFR gene (P value = 0.009). Patient cure and discharge were significantly related to the absence of mutation of MTHFR-gene (P value = 0.025), whereas death and radiological evidence of thrombosis were significantly related to the presence of MTHFR-gene mutation (P value = 0.027 and 0.022 respectively). Age > 55 years (60% sensitivity, 100% specificity, PPV 100%), albumin ≤ 3.2 gm/dl (50% sensitivity, 95.65% specificity, PPV83.3%), and ferritin > 453 ng/L (70% sensitivity, 82.61% specificity, PPV 63.6%) were predictors of mutation of MTHFR-gene.ConclusionIncidence of mutation of MTHFR-gene was 30.3% in COVID-19 patients. Results suggest a potential association between inherited MTHFR gene mutation and severe form of COVID-19, thromboembolic events, and mortality.Trial registrationClinicalTrials.gov ID: NCT05679414. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000CU2V&selectaction=Edit&uid=U00056R5&ts=2&cx=lrrb7q. Retrospectively registered. 9th Jan 2023.

Ischemic cerebrovascular disease caused by genetic mutation and patent foramen ovale

Abstract Objectives The search for genetic mutations is very important in younger patients and other age groups with a history of recurrent cerebrovascular diseases (CVD) and a family history of other causes to be excluded. The aim of this study is to define the characteristics of genetic mutations in the etiology of ischemic stroke. Methods Twenty-three patients with acute CVD in the last 1 year and only genetic mutations acknowledged in the etiology were retrospectively analyzed. We determined the frequency of the genetic mutations that are observed in cerebral arterial events (CAE) and cerebral venous thrombosis (CVT). Results All patients had at least one genetic mutation and 19 of them had arterial events and 4 had venous thrombosis. MTHFR mutation was the most common mutation and PAI-1 mutation was the second in line for the arterial events. PAI 4G/5G, MTHFR A1298 and FV mutations were most frequently observed in venous events. Patent foramen ovale (PFO) was detected in 14 patients (%74) with CAE. Conclusions We concluded that multiple gene mutations may significantly increase the development of CVD. CVD is most commonly associated with MTHFR, PAI-1 or FV gene mutations and is most commonly seen in CAE. MTHFR mutations showed moderate linear correlation in the development of arterial events and FXII and FXIII mutations in venous events. The association of thrombophilia and PFO is high in patients who have undergone CAE, especially responsible for recurrent events. This study will need to be confirmed by prospective studies with larger sample and control group.

Characteristics, differential diagnosis, individualized treatment, and prevention of hyperhomocysteinemia in newborns

ObjectivesThis study aimed to investigate the incidence rate, clinical phenotype, gene variation spectrum, and prognosis of neonatal hyperhomocysteinemia (HHcy) and explore its diagnosis, individualised treatment, and prevention strategies. MethodsWe screened 84722 neonates for HHcy using liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with biochemical detection, urine gas chromatography-mass spectrometry (GC-MS), and next-generation sequencing (NGS) for gene analysis to comprehensively differentiate and diagnose diseases. Results18 children (P1–P18) were diagnosed with methylmalonic acidemia (MMA) and HHcy, and fourteen known and one new variant of the MMACHC gene were found. Five children showed poor mental reactions, brain dysplasia, lethargy, hyperbilirubinemia, and jaundice, whereas the other 13 children had no evident abnormalities. These children were all cobalamin- and folic acid-reactive types, and they were mainly supplemented with cobalamin, L-carnitine, betaine, and folic acid. The mother of P12 had a prenatal diagnosis at the next pregnancy; the results showed that MMACHC gene was not pathogenic and she gave birth to a healthy baby. One child (P19) was diagnosed with methylenetetrahydrofolate reductase (MTHFR) deficiency, and one new mutation was detected in the MTHFR gene. Patient P19 showed congenital brain dysplasia, neonatal anaemia, and hyperbilirubinemia, and treatment consisted mainly of betaine and cobalamin supplementation. One child (P20) was confirmed to have methionine adenosyltransferase I (MAT I) deficiency but had no clinical manifestations. After treatment, all the children had a good prognosis. ConclusionThe incidence of neonatal HHcy in the Zibo area was 1/4236, and the common pathogenic variants were c.609G>A, c.80A>G, and c.482G>A in the MMACHC gene. Patients with HHcy can achieve a good prognosis if pathogenic factors and targeted treatment are identified. Gene analysis and prenatal diagnosis contribute to the early prevention of HHcy.

A 13-Month-Old Iranian Boy with Thrombosis of the Left Transverse and Superior Sagittal Sinuses Due to Homozygous Mutations in MTHFR A1298C: A Case Report &amp; Review of Literature

Background and Aims: Cerebral sinus venous thrombosis (CSVT) is a rare stroke subtype in children, with limited data on its clinical presentation, etiology, and outcomes. This case report aims to describe a case of CSVT in a child, including their clinical presentation, imaging findings, and management, to increase awareness of this rare but serious condition. Case presentation: A 13-month-old boy presented with swelling and deviation of the left eye after being hospitalized for left periorbital cellulitis. The patient was diagnosed with thrombosis of the left transverse and superior sagittal sinuses and underwent treatment with levetiracetam, folinic acid, rosuvastatin and enoxaparin followed by warfarin. Genetic testing was also performed to identify the underlying genetic basis of thrombophilia. Results: Laboratory tests showed that there was one heterozygous mutation in the β-Fibrinogen gene and three homozygous mutations in MTHFR A1298C, PAI-I-675 4G/5G, and PAI-I-844 G/A genes. Additionally, Lipoprotein (a) was measured at 89.3 nmol/L and the patient's mother had two homozygous mutations in PAI-I-675 4G/5G and PAI-I-844 G/A genes. Conclusions: It appears that the mutation in MTHFR gene is more prevalent in our region, which may be a contributing factor to the increased incidence of stroke in children and adolescents in the country. Further research is needed to determine the prevalence of this mutation and its impact on thrombophilia in the population. This case highlights the importance of prompt diagnosis and treatment of CSVT in children, as well as the need for genetic counselling and testing to identify underlying risk factors.

Evaluation of the clinical, biochemical, and genetic presentation of neonatal and adult-onset 5,10-methylene tetrahydrofolate reductase (MTHFR) deficiency in patients from Pakistan.

To study the biochemical, clinical and molecular characteristics of 5,10- methylenetetrahydrofolate reductase (MTHFR) deficiency in Pakistani patients from a single center. Medical charts, urine organic acid chromatograms, plasma methionine and Hcys levels, and molecular testing results of MTHFR gene of patients presenting at the Biochemical Genetics Clinic, AKUH from 2016 to 2022 were reviewed. Neonatal MTHFR deficiency was found in five patients. The median (IQR) age of symptom onset and diagnosis were 18 (8.5-22) and 26 (16.5-31) days. The median lag between symptom onset and diagnosis was 8 (4.5-12.5) days. The median age of treatment initiation and duration of treatment were 26 (16.5-49) and 32 (25.5-54) days. The most common clinical features were lethargy, poor feeding, and seizures. The MTHFR gene sequencing revealed homozygous variants p.K510K, p.R567*, and p.R157W. Renal insufficiency manifesting as elevated serum creatinine and responding to betaine therapy was noted in one patient. This has not been previously reported in neonatal MTHFR deficiency and may reflect engagement of alternate pathways of remethylation. Adult onset MTHFR deficiency was found in six patients, with a heterogeneous neurological presentation. The median lag between symptoms onset and diagnosis was 7 (3-11) years. MTHFR gene sequencing revealed homozygous variant p.A195V in five patients from one family and p.G261V in the other. Two of the five reported variants are novel that include p.R157W and p.G261V. Eleven patients of this rare disorder from a single center indicate the need for clinical awareness and appropriate biochemical evaluation to ensure optimal outcomes.

Genetic impairment of folate metabolism regulates cortical interneurons and social behavior.

The implications of folate deficiency in neuropsychiatric disorders were demonstrated in numerous studies. Genetic deficiency in a key folate metabolism enzyme, MTHFR, is an example of the interaction between genetic and environmental risk factors: the maternal MTHFR deficiency governs in-utero nutrient availability, and the embryo's Mthfr genotype influences its ability to metabolize folates. Here, we explore how the maternal and offspring Mthfr genotypes affect cortical interneuron densities and distributions, mouse social outcome, and the relation of the different interneuron patterns to cortical excitability. Two experiments were conducted to examine the effects of maternal and offspring Mthfr-KO heterozygosity. Mice were tested for direct social interactions (DSIs), repetitive behavior and cortical laminar distribution of interneuron populations expressing glutamate-decarboxylase-65, parvalbumin and somatostatin. Susceptibility to seizure was tested by exposure to pentylenetetrazole (PTZ). Maternal Mthfr+/- genotype was associated with suppressed social activities and reduced interneuron densities in all layers of the retrosplenial cortex (RSC). Somatostatin density and the somatostatin/parvalbumin ratio in the RSC and frontal cortex positively correlated with social behavior in the mice. An interaction between maternal and offspring Mthfr genotypes resulted in higher susceptibility of wild-type offspring to PTZ induced seizure. Maternal folate metabolism was shown to be critical to interneuron ontogenesis. Our results demonstrate that interneurons have a specific susceptibility to folate deficiency that may mediate folate's involvement in neuropsychiatric disease. The relations between cortical somatostatin interneuron patterns and social behavior highlight this subpopulation of interneurons as a target for further research.

0992 Reversible Pediatric Central Sleep Apnea in Hyperhomocysteinemia and Cerebral Sinus Venous Thrombosis

Abstract Introduction Pediatric central sleep apnea (CSA) rarely initially presents in adolescent age groups, being more commonly diagnosed in infants. CSA may result from a multitude of neurological insults, such as stroke and brain masses. It may also less often present in metabolic and non-ischemic thrombotic disorders. Report of case(s) A 12-year-old female with history of global developmental delay of unclear etiology, chronic headaches, insulin resistance, and early morning tremors was referred for initial evaluation of possible narcolepsy. Severe daytime sleepiness had acutely worsened over the previous month. She was unable to stay awake during school, despite sleeping 13 hours per 24 hours. Central hypersomnia was suspected and polysomnogram with MSLT was scheduled. The patient presented to the Emergency Department 10 days later for worsening headaches and new oral aversion with 12-pound weight loss. Examination showed ataxic gait and dysarthria. Brain MRI revealed non-occlusive cerebral sinus venous thrombosis (CSVT) involving the superior sagittal sinus, right transverse sinus, right sigmoid sinus, right jugular bulb/vein, and cortical veins overlying both cerebral hemispheres with no stroke. Anticoagulation with enoxaparin was initiated and thrombophilia work-up commenced. Polysomnogram demonstrated a central AHI of 49.9/hr with significant periodic breathing and no obstructive sleep apnea. Oxygen titration sleep study failed to significantly improve CSA and BPAP was initiated. Thrombophilia work-up revealed severe hyperhomocysteinemia. Genetic analysis was consistent with autosomal recessive severe methylenetetrahydrofolate reductase (MTHFR) deficiency. The patient was begun on metabolic treatment with betaine, pyridoxine, hydroxocobalamin, and vitamin C, and transitioned to oral rivaroxaban. At 4 months, blood levels had normalized, and MRI demonstrated resolution of CSVT. Family endorsed BPAP compliance and complete resolution of all sleep symptoms. In addition, there was significant improvement in cognition, interpersonal skills, and abstract thought. Follow up polysomnogram 10 months after presentation demonstrated no CSA nor periodic breathing. Conclusion To our knowledge, this is the first report of MTHFR deficiency and CSVT resulting in severe CSA. While it is difficult to ascertain which entity ultimately caused the CSA, MTHFR deficiency can produce significant neurologic impairment through white matter disease and defective myelination, while CSVT can provoke venous hypertension, venous stasis, or hypoxia. Support (if any)

A RARE TREATABLE CAUSE OF ADULT ONSET SPASTIC PARAPARESIS

pastic paraparesis refers to weakness and stiffness of both lower limbs caused by lesions affecting the Pyramidal tract. It could be due to genetic or acquired etiology. Genetic causes include leukodystophies, Heriditary Spastic Paraplegia (HSP), metabolic disorders etc,. Acquired causes include B12 and folate deficiency , infections like HTLV-1 virus, HIV, neurosyphilis , vascular malformations and so on. Here we encounter a rare treatable cause of spastic paraparesis. A 28 year old male born out of 3o Consanguinous parents with normal developmental history came with insidious onset slowly progressive spastic paraparesis for the past 4 years. Initially at onset he noticed difficulty in getting up from squatting position, which was associated with stiffness of lower limbs. Then he noticed there was slippage of slippers while walking and he was aware about it. Physical examination revealed marfanoid Habitus ,increased tone and exaggerated reflexes involving both lower limbs .Motor power was MRC Grade 4/5 in both lower limbs in both proximal and distal muscles. Ocular Examination revealed Ectopia Lentis. MRI Spine screening was normal. MRI Brain revealed symmetric T2/FLAIR hyperintensities involving periventricular and deep white matter of bilateral frontoparietal region. Possibilities of Primary demyelinating diseases and genetic/degenerative leukoencephalopathies were considered. CSF examination was normal and oligoclonal bands were absent. Clinical Exome sequence testing was done in suspicion of Adult onset leukodystrophy which showed Homozygous MTHFR gene mutation on exon4. Plasma Homocysteine levels were elevated ( 60 µmol/L).Patient was started on Oral Vitamin B12 1500mcg/day, Folic acid and pyridoxine supplementation. Patient showed symptomatic improvement and is under follow up. MTHFR deficiency in adults is a mimicker of leukodystrophies and other white matter disease. It is a potentially treatable disease. Before considering degenerative diseases like HSP, treatable diseases should be considered.

Contribution of Genetic Test to Early Diagnosis of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency: The Experience of a Reference Center in Southern Italy

the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.

Hyperhomocysteinemia due to Vitamin B12 Deficiency with MTHFR Gene Mutation, an Atypical Metabolic Cause of Young Ischemic Stroke: A Case Report

Background: Vitamin B12 deficiency can impair the metabolism of homocysteine, leading to hyperhomocysteinemia that can cause thrombosis in the intracranial blood vessels resulting in a stroke. Case Presentation: A 15-year-old Muslim young boy initially presented with pallor, slurred speech, right facial weakness, and right-sided hemiplegia. On examination, he was found moderately anemic, nonicteric, and with right-sided stroke evidenced by hypertonia, reduced muscle power jerk exaggerated with extensor plantar response. There was no lymphadenopathy, bony tenderness, intellectual impairment, or organomegaly, and normal vital parameters with the unremarkable cardiovascular examination. Laboratory investigations revealed pancytopenia, with reduced Vit B12, folic acid, and moderately increased homocysteine level. Bone marrow study suggestive of megaloblastic anemia. Immunological, infectious screens; and prothrombotic markers were found negative. CT scan of the head revealed a hypodense lesion in the left parieto-occipital region, DWI sequence on MRI Brain revealed diffusion restriction in the same area while an MR angiogram of the Brain revealed occlusion of the left middle cerebral artery due to thrombus sparing a small segment after its origin. In addition, he had MTHFR c677 C&gt;T (Methyl tetrahydrofolate reductase) gene mutation and responded both clinically and biochemically after vitamin B12, folic supplementation along with aspirin in 5 months. Conclusion: Vitamin B12 deficiency along with MTHFR c677 C&gt;T gene mutation has increased the chance of thrombotic stroke. Vitamin B12 supplementation might be beneficial for patients with an MTHFR gene mutation positive. J MEDICINE 2023; 24: 51-55

A Rare Case of Deep Vein Thrombosis Secondary to Protein S Deficiency and Antithrombin III Deficiency with MTHFR (C677T) Heterozygous Mutation, and Crohn’s Disease

Deep vein thrombosis is a condition wherein a thrombus develops in the deep veins of the body, most commonly in the legs, due to increasing tendency of the blood to coagulate. One such reason is the MTHFR gene mutation, wherein an increase in homocysteine levels causes irritation of the blood vessel endothelium, causing a disturbance in Virchow’s triad, hence triggering clot formation. [1]

X-linked genodermatoses from diagnosis to tailored therapy.

Genodermatoses are rare heterogeneous genetic skin diseases with multiorgan involvement. They severely impair an individual's well-being and can also lead to early death. During the progress of this review, we have implemented a targeted research approach, diligently choosing the most relevant and exemplary articles within the subject matter. Our method entailed a systematic exploration of the scientific literature to ensure a compre-hensive and accurate compilation of the available sources. Among genodermatoses, X-linked ones are of particular importance and should always be considered when pediatric males are affected. Regardless of other syndromic forms without prevalence of skin symptoms, X-linked genodermatoses can be classified in three main groups: keratinization defects, pigmentation defects, and inflammatory skin diseases. Typical examples are dyskeratosis congenita, keratosis follicularis spinulosa decalvans, hypohidrotic ectodermal dysplasia, chondrodysplasia punctata, hypohidrotic ectodermal dysplasia, incontinentia pigmenti, chronic granulomatous disease, CHILD syndrome and ichthyosis. In this field, genetic diagnosis of the specific disease is important, also considering that numerous clinical trials of orphan drugs and genetic therapies are being proposed for these rare genetic diseases. Thus, this chapter starts from clinical to molecular testing and ends with a review of all clinical trials on orphan drugs and gene therapy for genodermatoses.

Methylenetetrahydrofolate reductase deficiency and high-dose FA supplementation disrupt embryonic development of energy balance and metabolic homeostasis in zebrafish.

Folic acid (synthetic folate, FA) is consumed in excess in North America and may interact with common pathogenic variants in methylenetetrahydrofolate reductase (MTHFR); the most prevalent inborn error of folate metabolism with wide-ranging obesity-related comorbidities. While preclinical murine models have been valuable to inform on diet-gene interactions, a recent Folate Expert panel has encouraged validation of new animal models. In this study, we characterized a novel zebrafish model of mthfr deficiency and evaluated the effects of genetic loss of mthfr function and FA supplementation during embryonic development on energy homeostasis and metabolism. mthfr-deficient zebrafish were generated using CRISPR mutagenesis and supplemented with no FA (control, 0FA) or 100μm FA (100FA) throughout embryonic development (0-5days postfertilization). We show that the genetic loss of mthfr function in zebrafish recapitulates key biochemical hallmarks reported in MTHFR deficiency in humans and leads to greater lipid accumulation and aberrant cholesterol metabolism as reported in the Mthfr murine model. In mthfr-deficient zebrafish, energy homeostasis was also impaired as indicated by altered food intake, reduced metabolic rate and lower expression of central energy-regulatory genes. Microglia abundance, involved in healthy neuronal development, was also reduced. FA supplementation to control zebrafish mimicked many of the adverse effects of mthfr deficiency, some of which were also exacerbated in mthfr-deficient zebrafish. Together, these findings support the translatability of the mthfr-deficient zebrafish as a preclinical model in folate research.