المؤلفون: Tomoyuki Akiyama, Ichiro Kuki, Kiyohiro Kim, Naohiro Yamamoto, Yumi Yamada, Kazuya Igarashi, Tomohiko Ishihara, Yuya Hatano, Katsuhiro Kobayashi

المصدر: JIMD Reports, Vol 63, Iss 6, Pp 529-535 (2022)

مصطلحات موضوعية: 5‐formyltetrahydrofolic acid, cerebral folate deficiency, folate receptor 1, folinic acid, Kearns‐Sayre syndrome, methylenetetrahydrofolate reductase deficiency, Diseases of the endocrine glands. Clinical endocrinology, RC648-665, Genetics, QH426-470

الوصف: Abstract Objective The use of folic acid (FA) has been discouraged in cerebral folate deficiency (CFD) because, theoretically, it could inhibit the transport of 5‐methyltetrahydrofolic acid (5MTHF) across the blood–cerebrospinal fluid (CSF) barrier. We present the clinical biochemical data of two cases with CFD to support this hypothesis. Methods We measured CSF and serum 5MTHF concentrations in a patient with Kearns‐Sayre syndrome (KSS) and a patient homozygous for MTHFR C677T polymorphism before and during folate supplementation therapy. To evaluate these 5MTHF concentrations, we also analyzed CSF and serum samples in pediatric patients without folate supplementation. Results Both patients had low CSF 5MTHF before treatment and high‐dose FA therapy did not normalize CSF 5MTHF. There was a dissociation between serum total folate and 5MTHF concentrations during FA therapy, which was considered to be due to the appearance of unmetabolized FA. The addition of folinic acid did not improve low CSF 5MTHF in the KSS patient and the cessation of FA resulted in the normalization of CSF 5MTHF. In the patient homozygous for MTHFR C677T, minimization of the FA dosage resulted in the normalization of CSF 5MTHF and an increased CSF‐to‐serum 5MTHF ratio. Conclusions Our data suggest that excess supplementation of FA impaired 5MTHF transport across the blood–CSF barrier. In the treatment of CFD, supplementation of folinic acid or 5MTHF (in cases of impaired 5MTHF synthesis) is preferred over the use of FA. The reference values of CSF 5MTHF concentration based on 600 pediatric cases were also provided.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2192-8312Test

الوصول الحر: https://doaj.org/article/5777a91eae754e17a852a102daa09081Test

المؤلفون: Salam Massadeh, Muhammad Umair, Manal Alaamery, Majid Alfadhel

المصدر: Frontiers in Neurology, Vol 10 (2019)

مصطلحات موضوعية: MTHFR, non-sense mutation, white matter disease, microcephaly, severe methylenetetrahydrofolate reductase deficiency, Neurology. Diseases of the nervous system, RC346-429

الوصف: Background: Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a heterogeneous metabolic disorder inherited in an autosomal recessive manner. Pathogenic mutations in MTHFR gene have been associated with severe MTHFR deficiency. The clinical presentation of MTHFR deficiency is highly variable and associated with several neurological anomalies.Methods: Direct whole-exome sequencing (WES) was performed in all the five available individuals from the family, including the affected individual (III-7) using standard procedures.Results: We observed a proband (III-7) with an abnormality in the cerebral white matter, apnoea, and microcephaly. WES analysis identified a novel homozygous non-sense mutation (c.154C>T; p.Arg52*) in MTHFR gene that segregated with the disease phenotype within the family.Conclusion: We identified a novel non-sense mutation in MTHFR gene in a single Egyptian family with severe MTHFR deficiency. The present investigation is clinically important, as it adds to the growing list of MTHFR mutations, which might help in genetic counseling of families of affected children and proper genotype-phenotype correlation.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/article/10.3389/fneur.2019.00411/fullTest; https://doaj.org/toc/1664-2295Test

الوصول الحر: https://doaj.org/article/18241ca27f584c8e8d6fbce1b8684d2dTest

المؤلفون: AL-Eitan LN, Al-Dalalah IM, Mustafa MM, Alghamdi MA, Elshammari AK, Khreisat WH, Aljamal HA

المصدر: Pharmacogenomics and Personalized Medicine, Vol Volume 12, Pp 87-95 (2019)

مصطلحات موضوعية: Methylenetetrahydrofolate reductase deficiency, Epilepsy, Pharmacogenetics, Tonic- clonic epilepsy, Psychotic disorders, Therapeutics. Pharmacology, RM1-950

الوصف: Laith N AL-Eitan,1,2 Islam M Al-Dalalah,1 Mohamed M Mustafa,3 Mansour A Alghamdi,4 Afrah K Elshammari,5 Wael H Khreisat,5 Hanan A Aljamal11Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Neuroscience, Jordan University of Science and Technology, Irbid, Jordan; 4College of Medicine, King Khalid University, Abha, Saudi Arabia; 5Queen Rania Hospital for Children, King Hussein Medical Center, Royal Medical Services, Amman, JordanBackground: Epilepsy is one of the most common neurological diseases with unclear etiology where its genetic background and treatment regime still need further exploration.Objectives: This study designed to evaluate the pharmacogenomics of MTHFR and ABCC2 genes, and their association with epilepsy susceptibility among Jordanian population.Methods: A case-control study was conducted on Jordanian cohort of 296 epileptic patients and 299 healthy individuals. Custom platform array was used to genotype the genetic polymorphisms within MTHFR (rs1801133) and ABCC2 (rs717620, rs3740066, rs2273697) genes.Results: This study revealed a significant genetic association of MTHFR rs1801133 polymorphism with susceptibility to generalized in general and generalized tonic-clonic epilepsy (GTCE)(p=0.018 and 0.01, respectively). Regarding ABCC2 gene, rs717620 was of linkage with generalized and GTCE subtypes (p=0.045 and 0.048, respectively), while rs717620 was associated with poor responder patients (p=0.036) with no linkage of the ABCC2 haplotypes.Conclusions: MTHFR and ABCC2 polymorphisms showed an association with either epilepsy types in general or subtypes and treatment response among Jordanian population. This study also suggested that these gene polymorphisms have an important role in epilepsy development and drug effectiveness and could be of a great impact in the era of epilepsy diagnosis and treatment.Keywords: ...

العلاقة: https://www.dovepress.com/effects-of-mthfr-and-abcc2-gene-polymorphisms-on-antiepileptic-drug-re-peer-reviewed-article-PGPMTest; https://doaj.org/toc/1178-7066Test; https://doaj.org/article/ed2d54bb81c1482c877ef5f569e421f1Test

الإتاحة: https://doaj.org/article/ed2d54bb81c1482c877ef5f569e421f1Test

المؤلفون: Céline Bürer, Viktor Kozich, D. Sean Froese, Jochen Weile, Song Sun, Marinella Gebbia, Nishka Kishore, Robert L. Nussbaum, Iosifina Fotiadou, David Watkins, Alexander Holenstein, Ranim Maaieh, Roujia Li, Michael Garton, Rima Rozen, Linnea Blomgren, Shan Yang, Frederick P. Roth, Yingzhou Wu, Marta Verby, Julia Kitaygorodsky

المصدر: American Journal of Human Genetics

مصطلحات موضوعية: Genotype, Methylenetetrahydrofolate reductase deficiency, Folate Metabolism, DNA Mutational Analysis, Mutation, Missense, Homocystinuria, Saccharomyces cerevisiae, folate, Article, homocystinuria, 03 medical and health sciences, 0302 clinical medicine, deep mutational scanning, Dietary folate, Genetics, medicine, Humans, Missense mutation, variant effect mapping, Methylenetetrahydrofolate Reductase (NADPH2), Genetics (clinical), Gene Library, 030304 developmental biology, mthfr, 0303 health sciences, biology, clinical variant interpretation, cystathionine beta synthase, medicine.disease, Diploidy, methylenetetrahydrofolate reductase, Cystathionine beta synthase, Phenotype, molecular dynamics, digestive system diseases, Amino Acid Substitution, Methylenetetrahydrofolate reductase, gene- environment interaction, biology.protein, 030217 neurology & neurosurgery

الوصف: Summary Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8a1b7fb137ff7cfb59d628fe70d842d6Test
https://doi.org/10.1016/j.ajhg.2021.05.009Test

المؤلفون: Aydogan Aydogdu, Cem Haymana, Kamil Baskoy, Ali H Durukan, Gokhan Ozgur, Omer Azal

المصدر: Journal of Research in Medical Sciences, Vol 19, Iss 1, Pp 75-79 (2014)

مصطلحات موضوعية: Choroidal neovascularization, drug therapy, hypopituitarism, intravitreal injections, methylenetetrahydrofolate reductase deficiency, MTHFR, ranibizumab, vascular endothelial growth factor, Medicine

الوصف: We report a case of choroidal neovascularization (CNV) secondary to methylenetetrahydrofolate reductase (MTHFR) gene mutation in a 20-year-old male patient with hypopituitarism. Treatment with three consecutive injections of intravitreal ranibizumab (anti-vascular endothelial growth factor) resulted in significant improvement of the patient′s vision and the appearance of the macula. A search of the literature produced no previously reported case of MTHFR gene mutation associated both CNV and possibly hypopituitarism. With hormone replacement therapy of hypopituitarism, acetyl salicylic acid 100 mg/day also was started. The patient was clinically stable both for CNV and other thromboembolic disorders over a 6-month follow-up and also 1-year follow-up period.

وصف الملف: electronic resource

العلاقة: http://www.jmsjournal.net/article.asp?issn=1735-1995;year=2014;volume=19;issue=1;spage=75;epage=79;aulast=AydogduTest; https://doaj.org/toc/1735-1995Test; https://doaj.org/toc/1735-7136Test

الوصول الحر: https://doaj.org/article/7a9c2cc5609d4b42ad33f715a943e909Test

المؤلفون: Christian Lavigne, Christoph Kessler, Matthias R. Baumgartner, Patricie Burda, François Feillet, Martina Huemer, Viktor Kožich, Mirian C. H. Janssen, Fanny Mochel, Rebecca Schüle, Pavel Ješina, Karolina M. Stepien, Adeline Regnier, Isabelle Redonnet-Vernhet, Jean-François Benoist, Cecilia Marelli

المساهمون: Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)

المصدر: Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease, Springer Verlag, 2021, 44 (3), pp.777-786. ⟨10.1002/jimd.12323⟩
Journal of Inherited Metabolic Disease, 44, 777-786
Journal of Inherited Metabolic Disease 44(3), 777-786 (2021). doi:10.1002/jimd.12323
Journal of Inherited Metabolic Disease, 44, 3, pp. 777-786

مصطلحات موضوعية: Male, Delayed Diagnosis, Methylenetetrahydrofolate reductase deficiency, diagnosis [Muscle Spasticity], Gastroenterology, pathology [Epilepsy], Epilepsy, 0302 clinical medicine, late-onset, Medicine, Age of Onset, Cognitive decline, Child, Genetics (clinical), 0303 health sciences, biology, MTHFR deficiency, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Middle Aged, 3. Good health, Neurology, Muscle Spasticity, diagnosis [Psychotic Disorders], Homocystinuria, Female, medicine.symptom, pathology [Homocystinuria], Polyneuropathy, pathology [Muscle Spasticity], Adult, diagnosis [Seizures], medicine.medical_specialty, Adolescent, Late onset, Late-onset, Asymptomatic, pathology [Intellectual Disability], Young Adult, 03 medical and health sciences, Seizures, Intellectual Disability, Internal medicine, Genetics, Humans, pathology [Psychotic Disorders], deficiency [Methylenetetrahydrofolate Reductase (NADPH2)], Inherited metabolic disease, inherited metabolic disease, Methylenetetrahydrofolate Reductase (NADPH2), Retrospective Studies, 030304 developmental biology, pathology [Seizures], business.industry, neurology, diagnosis [Homocystinuria], medicine.disease, diagnosis [Epilepsy], Psychotic Disorders, diagnosis [Intellectual Disability], Methylenetetrahydrofolate reductase, biology.protein, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology

الوصف: Item does not contain fulltext 5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4d46842247db613f3948216a26335491Test
https://doi.org/10.1002/jimd.12323Test

المؤلفون: Xi Liu, Xiaojun Wang, Zhe Wang, Limin Zhang, Tao Peng, Wenping Liang, Yu Li, Menghan Wang, Hong Lu

المصدر: Aging (Albany NY)

مصطلحات موضوعية: Baclofen, Proteasome Endopeptidase Complex, Aging, Adolescent, Methylenetetrahydrofolate reductase deficiency, molecular mechanisms, Mutation, Missense, Neural Conduction, Single-nucleotide polymorphism, pathogenic mutation, medicine.disease_cause, Polymorphism, Single Nucleotide, Exon, Folic Acid, Methionine, single nucleotide polymophorism, Mutant protein, Muscle Hypertonia, medicine, Humans, SNP, Cognitive Dysfunction, Allele, Alleles, Methylenetetrahydrofolate Reductase (NADPH2), Genetics, Mutation, Reflex, Abnormal, biology, Muscle Relaxants, Central, MTHFR deficiency, Brain, Cell Biology, medicine.disease, proteasome degradation, Magnetic Resonance Imaging, Spine, digestive system diseases, Vitamin B 12, Psychotic Disorders, Muscle Spasticity, Methylenetetrahydrofolate reductase, Proteolysis, Vitamin B Complex, biology.protein, Ataxia, Female, Homocystinuria, Research Paper

الوصف: 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare hereditary disease characterized by defects in folate and homocysteine metabolism. Individuals with inherited MTHFR gene mutations have a higher tendency to develop neurodegeneration disease as Alzheimer’ disease and atherosclerosis. MTHFR is a rate-limiting enzyme catalyzing folate production, various SNPs/mutations in the MTHFR gene have been correlated to MTHFR deficiency. However, the molecular mechanisms underpinning the pathogenic effects of these SNPs/mutations have not been clearly understood. In the present study, we reported a severe MTHFR deficiency patient with late-onset motor dysfunction and sequenced MTHFR gene exons of the family. The patient carries an MD-associating SNP (rs748289202) in one MTHFR allele and the rs545086633 SNP with unknown disease relevance in the other. The rs545086633 SNP (p.Leu439Pro) results in an L439P substitution in MTHFR protein, and drastically decreases mutant protein expression by promoting proteasomal degradation. L439 in MTHFR is highly conserved in vertebrates. Our study demonstrated that p.Leu439Pro in MTHFR is the first mutation causing significant intracellular defects of MTHFR, and rs545086633 should be examined for the in-depth diagnosis and treatment of MD.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3ef7aa3a2cbb7f060c83cf3305ffb9b8Test
https://doi.org/10.18632/aging.202256Test

المؤلفون: Hongrui Shen, Kai-Jie Chang, Zhe Zhao, Qi Bing, Nan Li, Jing Hu, Xuan Guo

المصدر: Neurological Sciences. 42:1987-1993

مصطلحات موضوعية: Adult, medicine.medical_specialty, Neurology, Adolescent, Homocysteine, Methylenetetrahydrofolate reductase deficiency, Anemia, Dermatology, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, Cognitive Dysfunction, 030212 general & internal medicine, Cognitive decline, Psychiatry, Gait Disorders, Neurologic, Methylenetetrahydrofolate Reductase (NADPH2), biology, business.industry, Vitamin B 12 Deficiency, General Medicine, medicine.disease, MMACHC, Vitamin B 12, Psychiatry and Mental health, chemistry, Methylenetetrahydrofolate reductase, biology.protein, Homocystinuria, Neurology (clinical), CBLC, Oxidoreductases, business, 030217 neurology & neurosurgery

الوصف: Homocysteine remethylation disorders are rare inherited disorders caused by a deficient activity of the enzymes involved in the remethylation of homocysteine to methionine. The adolescent/adult-onset remethylation disorders are rarely reported. We analyzed the clinical and genetic characteristics of seven cases with adolescent/adult remethylation disorders, including 5 cases of the cobalamin C disease (cblC) and 2 cases of the methylenetetrahydrofolate reductase deficiency. The average onset age was 21.1 (range 14 to 40) years. All patients complained of gait disturbances. Other common symptoms included psychiatric symptoms (5/7) and cognitive decline (4/7). Acute encephalopathy, dysarthria, anorexia, vomiting, ketoacidosis, anemia, cataract, and hand tremor were also observed. The mean total homocysteine in serum when the patients were diagnosed was 94.6 (range 53.1-154.5) mol/L. Electrophysiological studies revealed neuropathy in the lower limbs (6/7). The brain MRI showed reversible altered signal from the dorsal portions of the cerebellar hemispheres (1/7), periventricular hyperintensity (2/7), and delayed/impaired myelination (2/7). The sural nerve biopsy performed in one case showed a modest loss of myelinated fibers. Five patients showed heterozygous mutations of the MMACHC gene, including c.482G>A (5/5), c.609G>A (2/5), and c.658-660delAAG (3/5). Two patients showed heterozygous mutations of the MTHFR gene, including c.698C>A (2/2), c.698C>G (1/2), and c.236+1G>A (1/2). The patients responded well to the treatments with significant improvements. Adolescent/adult-onset remethylation disorders are easily misdiagnosed. We recommend testing the serum homocysteine concentrations in young/adult patients with unexplained neuro-psychotic symptoms. Furthermore, individuals with significantly elevated serum homocysteine concentrations should be further tested by organic acid screening and genetic analysis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cfb18597c9c2ea6ae1228498d97d086fTest
https://doi.org/10.1007/s10072-020-04756-0Test

المؤلفون: Sheela Nampoothiri, Harikrishnan Ramachandran, Ramshekhar N. Menon, Santhakumar Senthilvelan, Chandrasekharan Kesavadas, Sathish Kandasamy, Bejoy Thomas

المصدر: Clinical Neuroradiology. 31:277-281

مصطلحات موضوعية: medicine.medical_specialty, Pediatrics, Neurology, Methylenetetrahydrofolate reductase deficiency, business.industry, medicine.disease, Leukoencephalopathy, Myelopathy, medicine, Radiology, Nuclear Medicine and imaging, Neurology (clinical), Neurosurgery, business, Neuroradiology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::7878f87cf08ec5b6fa76a1d18b29ceaaTest
https://doi.org/10.1007/s00062-020-00947-6Test

المؤلفون: Mayank Nilay, Deepti Saxena, Suzena Masih, Shubha R. Phadke, Arya Shambhavi, Amita Moirangthem

المصدر: Clinical dysmorphology. 31(2)

مصطلحات موضوعية: Infantile encephalopathy, medicine.medical_specialty, Methylenetetrahydrofolate reductase deficiency, Homocystinuria, Gastroenterology, Pathology and Forensic Medicine, Leukoencephalopathy, Internal medicine, Medicine, Humans, Genetics (clinical), Methylenetetrahydrofolate Reductase (NADPH2), biology, business.industry, Spastic paraparesis, General Medicine, medicine.disease, Phenotype, Betaine, Folic acid, Muscle Spasticity, Methylenetetrahydrofolate reductase, Pediatrics, Perinatology and Child Health, biology.protein, Anatomy, Nervous System Diseases, business

الوصف: Inherited methylenetetrahydrofolate reductase (MTHFR) deficiency is associated with a wide spectrum of disorders including homocystinuria. This study aims to describe the neurological phenotypes and molecular profiles of patients with homocystinuria caused by biallelic variants in MTHFR. We report six subjects with MTHFR deficiency who presented with variable neurological phenotypes which could be viewed as a continuous spectrum. Fatal infantile encephalopathy was observed in one family, whereas another patient presented at 27 years with acute leukoencephalopathy and recovered within 3 months. Intermediate forms presenting as complicated hereditary spastic paraparesis of variable severity were observed in four subjects. Clinical and molecular information of the 207 cases reported in literature were also retrieved and analyzed. We categorized all subjects into three categories - severe, intermediate and mild forms according to the clinical presentation. In addition, a total of 286 disease-causing variations reported to date were analyzed. These included seven disease-causing variants reported in this study of which one is novel. Some genotype-phenotype correlation could be seen which corroborated with previous observations. However, inter- and intrafamilial variability was also noted. Treatment with betaine, B12 and folic acid was started in four subjects with variable outcomes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::935db431112d9d120b7e23cd7a855b34Test
https://pubmed.ncbi.nlm.nih.gov/34845156Test