Pediatric Cerebral Infarction Unraveled: A Case of MTHFR Mutation and Hyperhomocysteinemia-Case Report

Pediatric Cerebral Infarction Unraveled: A Case of MTHFR Mutation and Hyperhomocysteinemia-Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Pediatric Cerebral Infarction Unraveled: A Case of MTHFR Mutation and Hyperhomocysteinemia-Case Report Diao Yu, Yuran Huang, Chengyuan Hu, Xiaohu Xian, Jinlin Liu, Lan Hu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5212213/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Cerebral infarction in children without underlying diseases is rare, and its causes are complex. Case presentation We present a case of a 14-year-old boy who experienced left limb weakness and slurred speech for 5 days. MRI revealed cerebral infarction in the bilateral occipital lobes and right centrum semiovale, with high homocysteine levels. He was diagnosed with cerebral infarction due to hyperhomocysteinemia and treated with anticoagulation. While his symptoms resolved, homocysteine levels remained elevated after 3 months. Genetic testing identified an MTHFR mutation, leading to a treatment adjustment that included betaine, riboflavin, pyridoxine, folate, and hydroxocobalamin. Following 3 months of this new regimen, the patient fully recovered, with normalized homocysteine levels. Conclusions Hyperhomocysteinemia caused by MTHFR mutations should be considered in young patients with unexplained cerebral infarction. The supplementation with betaine, riboflavin, pyridoxine, folate, and hydroxocobalamin was beneficial in decreasing homocysteine levels. Cerebral infarction Hyperhomocysteinemia Pyridoxine Figures Figure 1 Background Cerebral infarction is a clinical syndrome caused by various disorders of the brain blood supply that result in local brain tissue ischemia, hypoxic necrosis, and corresponding neurological function defects. Most patients are over 50 years old and often have a long history of hypertension, arteriosclerosis, and heart disease. Cerebral infarction in young adults is rare, and its causes are complex. Gao et al. [ 1 ] reported that the incidence rate of all cerebral infarctions in young patients was 2.09 per 100,000 person-years. Therefore, the etiology of the disease should be actively delineated in young patients with cerebral infarction to improve treatment outcomes. Herein, we report a case of pediatric cerebral infarction accompanied by hyperhomocysteinemia caused by MTHFR mutation. Case report A 14-year-old boy was transferred to our hospital after he experienced weakness in the left upper and lower limbs and slurred speech for 5 days. Physical examination revealed mild dysarthria, a shallow right labial groove, mouth deviation to the left, and left deviation in tongue extension. Cranial computed tomography revealed a low-density shadow in the right cerebellum and brainstem. Subsequent magnetic resonance imaging confirmed that the right cerebellar hemisphere and pons had deviated to the right. Multiple lacunar cerebral infarctions in the bilateral occipital lobes and right centrum semiovale were also observed in the acute and subacute phases. Magnetic resonance angiography revealed a significant narrowing of the anterior communicating segment of the right anterior cerebral artery compared with the left ( Fig. 1 ). Transcranial Doppler ultrasonography revealed decreased blood flow velocity in the bilateral middle cerebral arteries. Other tests, including cervical vascular ultrasonography, echocardiography, contrast echocardiography of the right heart, computed tomography cerebral artery imaging, computed tomography cervical large-vessel imaging, and electrocardiography yielded normal results. The results of routine blood analysis, urine analysis, and biochemical laboratory tests (including electrolytes, glucose, lipid levels, and liver and kidney function) were unremarkable except for homocysteine, the serum level of which was significantly elevated at 96.83 µmol/L (reference interval: 5–15 µmol/L). However, lupus anticoagulant, anti-cardiolipin antibodies, and anti-nuclear antibody profile were negative. Levels of folate, vitamin B 12 , interleukin-6, procalcitonin, C-reactive protein, and coagulation factors (including C and S proteins and antithrombin III) were normal. The patient was diagnosed with cerebral infarction and was treated with enteric-coated aspirin tablets. Because the folate and vitamin B 12 levels were both normal, the clinician speculated that the increased level of homocysteine might be due to dietary effects or test errors and recommended a review after 3 months. When the patient returned to the hospital for reexamination 3 months later, he had made a full recovery; however, the serum level of homocysteine remained high at 87.14 µmol/L. This condition led the healthcare team to suspect a genetic disorder, possibly causing hyperhomocysteinemia, which may have led to the cerebral infarction. Analyses of the serum levels of amino acids and organic acids, as well as whole-exome genetic testing were performed to identify the cause of persistent hyperhomocysteinemia. One month later, genetic testing results showed that the patient was heterozygous for the MTHFR c.742A > G (p.Ile248Val) variant; however, the serum levels of amino acids and organic acids were normal. The patient was finally diagnosed with a cerebral infarction caused by an MTHFR mutation. The patient’s treatment regimen was modified to include folate, hydroxocobalamin, betaine, riboflavin, and pyridoxine. When the patient returned to the hospital for reexamination 3 months later, he had fully recovered, having normal serum levels of homocysteine. After 1 year of follow-up, cerebral infarction had not recurred, and the homocysteine level remained within the normal range. Discussion Cerebral infarction is relatively rare in young adults, and its causes are more diverse than those in older individuals. [ 2 ] These causes can be divided into two main categories. First, cerebral infarction can stem from cardiogenic causes such as atrial fibrillation, structural cardiac diseases such as patent foramen ovale, or infective endocarditis. [ 2 ] Second, it can stem from large- and small-vessel diseases, including trauma (e.g., cervical artery dissection), inherited disorders, congenital conditions, metabolic issues, autoimmune disorders, infectious diseases, and neoplastic factors. [ 2 ] In our patient, the results of echocardiography, contrast echocardiography of the right heart, and electrocardiography were all normal, ruling out a cardiac cause of cerebral infarction. Additionally, the results of cerebral and cervical angiography were normal. The results of further tests for autoimmune antibodies, coagulopathy, and inflammatory markers were all within normal ranges, ruling out cerebral infarction due to vasculopathy. The lack of response to treatment for hyperhomocysteinemia led the healthcare team to consider cerebral infarction caused by an MTHFR mutation. The MTHFR gene, which is located on chromosome 1, is the gene encoding methylenetetrahydrofolate reductase. The main function of methylenetetrahydrofolate reductase is to provide methyl for the recycling process of homocysteine to methionine. MTHFR gene mutations may lead to a decrease in enzyme activity and affect the homocysteine​metabolism pathway, leading to the accumulation of homocysteine in the body. [ 3 , 4 ] Homocysteine is a toxic intermediate in methionine metabolism, and typically, low levels are maintained in the plasma. [ 5 ] Hyperhomocysteinemia causes endothelial dysfunction, oxidative stress, and abnormal blood clotting due to decreased tissue plasminogen activator activity and increased plasminogen activator inhibitor-1 activation. [ 6 – 8 ] Prolonged hyperhomocysteinemia contributes to the development of cerebral infarction. [ 6 ] In this case, the homocysteine level returned to normal 3 months later when the treatment regimen was changed to include supplementations of betaine, riboflavin, pyridoxine, folate, and hydroxocobalamin. After 1 year of follow-up, symptoms of cerebral infarction had not recurred, and the homocysteine level remained within the normal range. One reason for this may be that pyridoxal supplementation improves the activity of cystathionine β-synthase that promotes homocysteine metabolism through the transsulfuration pathway. Betaine supplementation aids in the remethylation of homocysteine to generate methionine through an alternative pathway in the liver and kidney. Riboflavin supplementation enhances residual activities and further improves remethylation, which facilitates homocysteine degradation. [ 3 ] However, the efficacy of B vitamin supplementation in cerebral infarction caused by hyperhomocysteinemia due to MTHFR mutations is controversial. A randomized controlled trial showed that decreasing homocysteine levels with vitamin B supplementation did not reduce the risk of stroke. [ 9 ] Another recent randomized controlled trial revealed that lowering homocysteine levels with vitamin supplementation could reduce the risk and progress of stroke, which was inconsistent with the results of the previous study. [ 10 ] Owing to the low cost and safety of this treatment, supplementation with vitamins is recommended for patients with cerebral infarction. Conclusions Hyperhomocysteinemia caused by MTHFR mutations should be considered in young patients with unexplained cerebral infarction. The supplementation with betaine, riboflavin, pyridoxine, folate, and hydroxocobalamin is beneficial in decreasing homocysteine levels. Declarations Acknowledgments We sincerely thank the patient in this study and the pediatric team of Zhejiang Provincial People’s Hospital, Bijie Hospital. Author Contributions Diao Yu: Conceptualization; writing—original draft. Xiaohu Xian: Data curation; investigation. Jinlin Liu: Validation; supervision. Chengyuan Hu: Formal analysis; visualization; resources. Lan Hu: writing—review and editing. Funding No funding. Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate This study was approved by the ethical committee of Zhejiang Provincial People’s Hospital Bijie Hospital, China. Consent for publication The legal guardians of the study participant provided informed consent for publication. Competing interests The authors declare that they have no competing interests. References Gao L, Lim M, Nguyen D, et al. The incidence of pediatric ischemic stroke: A systematic review and meta-analysis. Int J Stroke 2023;18(7):765-772. Narayanan D, Luvai A, Barski R, Sharma R. Stroke in a young man. BMJ 2013;347:f4484. Sahai I, Mochida GH, Grabowski EF, Caruso PA. Case records of the Massachusetts General Hospital. Case 27-2014. A 10-month-old boy with microcephaly and episodic cyanosis. N Engl J Med 2014;371(9):847-858. Collaboration HS. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288(16):2015-2022. Kumar A, Palfrey HA, Pathak R, Kadowitz PJ, Gettys TW, Murthy SN. The metabolism and significance of homocysteine in nutrition and health. Nutr Metab 2017;14:78. van Guldener C, Stehouwer CD. Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction. Semin Thromb Hemost. 2000;26(3):281-289. Kristensen B, Malm J, Nilsson TK, et al. Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke. Stroke. 1999;30(5):974-980. Furie KL, Kelly PJ. Homocyst(e)ine and stroke. Semin Neurol 2006;26(1):24-32. Bønaa KH, Njølstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354(15):1578-1588. Cao Y, Su N, Zhang D, et al. Correlation between total homocysteine and cerebral small vessel disease: A Mendelian randomization study. Eur J Neurol 2021;28(6):1931-1938. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 04 Nov, 2024 Reviews received at journal 03 Nov, 2024 Reviews received at journal 02 Nov, 2024 Reviewers agreed at journal 02 Nov, 2024 Reviewers agreed at journal 31 Oct, 2024 Reviewers agreed at journal 30 Oct, 2024 Reviewers invited by journal 25 Oct, 2024 Editor assigned by journal 21 Oct, 2024 Submission checks completed at journal 18 Oct, 2024 First submitted to journal 06 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5212213","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":373984411,"identity":"5bce9291-0d5f-4fc5-b86a-d61586acdc52","order_by":0,"name":"Diao Yu","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital, Bijie Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Diao","middleName":"","lastName":"Yu","suffix":""},{"id":373984413,"identity":"cfae6a84-ae28-418f-956e-44e6238c2066","order_by":1,"name":"Yuran Huang","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital, Bijie Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuran","middleName":"","lastName":"Huang","suffix":""},{"id":373984415,"identity":"dc0d3aa1-a616-4e11-8eea-2a401a850d03","order_by":2,"name":"Chengyuan Hu","email":"","orcid":"","institution":"Wusheng County Hospital of Traditional Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chengyuan","middleName":"","lastName":"Hu","suffix":""},{"id":373984420,"identity":"222d59c4-fcd9-49a8-830d-f4c875f60bf6","order_by":3,"name":"Xiaohu Xian","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital, Bijie Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaohu","middleName":"","lastName":"Xian","suffix":""},{"id":373984422,"identity":"2a11d718-293c-45f4-960f-029a9bacfe85","order_by":4,"name":"Jinlin Liu","email":"","orcid":"","institution":"Shenzhen University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jinlin","middleName":"","lastName":"Liu","suffix":""},{"id":373984425,"identity":"ec8da430-ce00-416e-909d-ff31b2bcb9e1","order_by":5,"name":"Lan Hu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIie3RMUvDQBTA8QuBxOEkjq8E8g2EJwfWItSvkiOii0iKSyabEHhd+gHSb5HJORIwDvkAli4NgnOgo4M9swkmxc3h/vP9eHfvGNPp/mHIzJixEOZXi7TctvjlWXaSNO0gMRTBCx/5y81ZFpnC4WUq4DCJfIQ7dI9qU66yWzrhA2QMMtmFCPdjRYRBlpGvG2LApt5p/DuZZDJ1M4SHyfIjfJ8RN3EjaRuyQJwXPRd7k7HLEYy4CnKxIrAUWSCwQj71k/SzI4WP7jEhx/UzAR8m9D1F5q/X6PLah1FmHCB1Q5eKiNGyW3KBDpdqyTjwliooNzx69By7+8piTnbVNG009fpIX/i34zqdTqf72R4B22PtoFzTiAAAAABJRU5ErkJggg==","orcid":"","institution":"Zhejiang Provincial People's Hospital, Bijie Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Lan","middleName":"","lastName":"Hu","suffix":""}],"badges":[],"createdAt":"2024-10-06 09:38:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5212213/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5212213/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71000381,"identity":"681c2355-8c70-40f7-8374-dbfb1df00adb","added_by":"auto","created_at":"2024-12-10 05:36:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":169502,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5212213/v1/4f0f1cd80d43387323cb29a8.png"},{"id":71000382,"identity":"b12b73d4-8ff5-4e1e-bfa7-04b88a89b558","added_by":"auto","created_at":"2024-12-10 05:36:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":445026,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5212213/v1/3851f213-2208-4b04-ae04-4bf73444630a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pediatric Cerebral Infarction Unraveled: A Case of MTHFR Mutation and Hyperhomocysteinemia-Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eCerebral infarction is a clinical syndrome caused by various disorders of the brain blood supply that result in local brain tissue ischemia, hypoxic necrosis, and corresponding neurological function defects. Most patients are over 50 years old and often have a long history of hypertension, arteriosclerosis, and heart disease. Cerebral infarction in young adults is rare, and its causes are complex. Gao et al.\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e reported that the incidence rate of all cerebral infarctions in young patients was 2.09 per 100,000 person-years. Therefore, the etiology of the disease should be actively delineated in young patients with cerebral infarction to improve treatment outcomes. Herein, we report a case of pediatric cerebral infarction accompanied by hyperhomocysteinemia caused by \u003cem\u003eMTHFR\u003c/em\u003e mutation.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eA 14-year-old boy was transferred to our hospital after he experienced weakness in the left upper and lower limbs and slurred speech for 5 days.\u003c/p\u003e \u003cp\u003ePhysical examination revealed mild dysarthria, a shallow right labial groove, mouth deviation to the left, and left deviation in tongue extension. Cranial computed tomography revealed a low-density shadow in the right cerebellum and brainstem. Subsequent magnetic resonance imaging confirmed that the right cerebellar hemisphere and pons had deviated to the right. Multiple lacunar cerebral infarctions in the bilateral occipital lobes and right centrum semiovale were also observed in the acute and subacute phases. Magnetic resonance angiography revealed a significant narrowing of the anterior communicating segment of the right anterior cerebral artery compared with the left (\u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e). Transcranial Doppler ultrasonography revealed decreased blood flow velocity in the bilateral middle cerebral arteries. Other tests, including cervical vascular ultrasonography, echocardiography, contrast echocardiography of the right heart, computed tomography cerebral artery imaging, computed tomography cervical large-vessel imaging, and electrocardiography yielded normal results. The results of routine blood analysis, urine analysis, and biochemical laboratory tests (including electrolytes, glucose, lipid levels, and liver and kidney function) were unremarkable except for homocysteine, the serum level of which was significantly elevated at 96.83 \u0026micro;mol/L (reference interval: 5\u0026ndash;15 \u0026micro;mol/L). However, lupus anticoagulant, anti-cardiolipin antibodies, and anti-nuclear antibody profile were negative. Levels of folate, vitamin B\u003csub\u003e12\u003c/sub\u003e, interleukin-6, procalcitonin, C-reactive protein, and coagulation factors (including C and S proteins and antithrombin III) were normal.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient was diagnosed with cerebral infarction and was treated with enteric-coated aspirin tablets. Because the folate and vitamin B\u003csub\u003e12\u003c/sub\u003e levels were both normal, the clinician speculated that the increased level of homocysteine might be due to dietary effects or test errors and recommended a review after 3 months. When the patient returned to the hospital for reexamination 3 months later, he had made a full recovery; however, the serum level of homocysteine remained high at 87.14 \u0026micro;mol/L. This condition led the healthcare team to suspect a genetic disorder, possibly causing hyperhomocysteinemia, which may have led to the cerebral infarction. Analyses of the serum levels of amino acids and organic acids, as well as whole-exome genetic testing were performed to identify the cause of persistent hyperhomocysteinemia.\u003c/p\u003e \u003cp\u003eOne month later, genetic testing results showed that the patient was heterozygous for the \u003cem\u003eMTHFR\u003c/em\u003e c.742A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Ile248Val) variant; however, the serum levels of amino acids and organic acids were normal. The patient was finally diagnosed with a cerebral infarction caused by an \u003cem\u003eMTHFR\u003c/em\u003e mutation. The patient\u0026rsquo;s treatment regimen was modified to include folate, hydroxocobalamin, betaine, riboflavin, and pyridoxine. When the patient returned to the hospital for reexamination 3 months later, he had fully recovered, having normal serum levels of homocysteine. After 1 year of follow-up, cerebral infarction had not recurred, and the homocysteine level remained within the normal range.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCerebral infarction is relatively rare in young adults, and its causes are more diverse than those in older individuals.\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e These causes can be divided into two main categories. First, cerebral infarction can stem from cardiogenic causes such as atrial fibrillation, structural cardiac diseases such as patent foramen ovale, or infective endocarditis.\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e Second, it can stem from large- and small-vessel diseases, including trauma (e.g., cervical artery dissection), inherited disorders, congenital conditions, metabolic issues, autoimmune disorders, infectious diseases, and neoplastic factors.\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn our patient, the results of echocardiography, contrast echocardiography of the right heart, and electrocardiography were all normal, ruling out a cardiac cause of cerebral infarction. Additionally, the results of cerebral and cervical angiography were normal. The results of further tests for autoimmune antibodies, coagulopathy, and inflammatory markers were all within normal ranges, ruling out cerebral infarction due to vasculopathy. The lack of response to treatment for hyperhomocysteinemia led the healthcare team to consider cerebral infarction caused by an \u003cem\u003eMTHFR\u003c/em\u003e mutation.\u003c/p\u003e \u003cp\u003eThe \u003cem\u003eMTHFR\u003c/em\u003e gene, which is located on chromosome 1, is the gene encoding methylenetetrahydrofolate reductase. The main function of methylenetetrahydrofolate reductase is to provide methyl for the recycling process of homocysteine to methionine. \u003cem\u003eMTHFR\u003c/em\u003e gene mutations may lead to a decrease in enzyme activity and affect the homocysteine​metabolism pathway, leading to the accumulation of homocysteine in the body.\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e Homocysteine is a toxic intermediate in methionine metabolism, and typically, low levels are maintained in the plasma.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e Hyperhomocysteinemia causes endothelial dysfunction, oxidative stress, and abnormal blood clotting due to decreased tissue plasminogen activator activity and increased plasminogen activator inhibitor-1 activation.\u003csup\u003e[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e Prolonged hyperhomocysteinemia contributes to the development of cerebral infarction.\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this case, the homocysteine level returned to normal 3 months later when the treatment regimen was changed to include supplementations of betaine, riboflavin, pyridoxine, folate, and hydroxocobalamin. After 1 year of follow-up, symptoms of cerebral infarction had not recurred, and the homocysteine level remained within the normal range. One reason for this may be that pyridoxal supplementation improves the activity of cystathionine β-synthase that promotes homocysteine metabolism through the transsulfuration pathway. Betaine supplementation aids in the remethylation of homocysteine to generate methionine through an alternative pathway in the liver and kidney. Riboflavin supplementation enhances residual activities and further improves remethylation, which facilitates homocysteine degradation.\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e However, the efficacy of B vitamin supplementation in cerebral infarction caused by hyperhomocysteinemia due to \u003cem\u003eMTHFR\u003c/em\u003e mutations is controversial. A randomized controlled trial showed that decreasing homocysteine levels with vitamin B supplementation did not reduce the risk of stroke.\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e Another recent randomized controlled trial revealed that lowering homocysteine levels with vitamin supplementation could reduce the risk and progress of stroke, which was inconsistent with the results of the previous study.\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e Owing to the low cost and safety of this treatment, supplementation with vitamins is recommended for patients with cerebral infarction.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eHyperhomocysteinemia caused by \u003cem\u003eMTHFR\u003c/em\u003e mutations should be considered in young patients with unexplained cerebral infarction. The supplementation with betaine, riboflavin, pyridoxine, folate, and hydroxocobalamin is beneficial in decreasing homocysteine levels.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank the patient in this study and the pediatric team of Zhejiang Provincial People\u0026rsquo;s Hospital, Bijie Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDiao Yu:\u0026nbsp;Conceptualization; writing\u0026mdash;original draft. Xiaohu Xian: Data curation; investigation. Jinlin Liu: Validation; supervision. Chengyuan Hu: Formal analysis; visualization; resources. Lan Hu: writing\u0026mdash;review and editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethical committee of Zhejiang Provincial People\u0026rsquo;s Hospital Bijie Hospital, China.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe legal guardians of the study participant provided informed consent for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGao L, Lim M, Nguyen D, et al. The incidence of pediatric ischemic stroke: A systematic review and meta-analysis. \u003cem\u003eInt J Stroke \u003c/em\u003e2023;18(7):765-772.\u003c/li\u003e\n\u003cli\u003eNarayanan D, Luvai A, Barski R, Sharma R. Stroke in a young man. \u003cem\u003eBMJ \u003c/em\u003e2013;347:f4484.\u003c/li\u003e\n\u003cli\u003eSahai I, Mochida GH, Grabowski EF, Caruso PA. Case records of the Massachusetts General Hospital. Case 27-2014. A 10-month-old boy with microcephaly and episodic cyanosis. \u003cem\u003eN Engl J Med \u003c/em\u003e2014;371(9):847-858.\u003c/li\u003e\n\u003cli\u003eCollaboration HS. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. \u003cem\u003eJAMA \u003c/em\u003e2002;288(16):2015-2022.\u003c/li\u003e\n\u003cli\u003eKumar A, Palfrey HA, Pathak R, Kadowitz PJ, Gettys TW, Murthy SN. The metabolism and significance of homocysteine in nutrition and health. \u003cem\u003eNutr Metab \u003c/em\u003e2017;14:78.\u003c/li\u003e\n\u003cli\u003evan Guldener C, Stehouwer CD. Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction. \u003cem\u003eSemin Thromb Hemost. \u003c/em\u003e2000;26(3):281-289.\u003c/li\u003e\n\u003cli\u003eKristensen B, Malm J, Nilsson TK, et al. Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke. \u003cem\u003eStroke. \u003c/em\u003e1999;30(5):974-980.\u003c/li\u003e\n\u003cli\u003eFurie KL, Kelly PJ. Homocyst(e)ine and stroke. \u003cem\u003eSemin Neurol \u003c/em\u003e2006;26(1):24-32.\u003c/li\u003e\n\u003cli\u003eB\u0026oslash;naa KH, Nj\u0026oslash;lstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. \u003cem\u003eN Engl J Med \u003c/em\u003e2006;354(15):1578-1588.\u003c/li\u003e\n\u003cli\u003eCao Y, Su N, Zhang D, et al. Correlation between total homocysteine and cerebral small vessel disease: A Mendelian randomization study. \u003cem\u003eEur J Neurol \u003c/em\u003e2021;28(6):1931-1938.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cerebral infarction, Hyperhomocysteinemia, Pyridoxine","lastPublishedDoi":"10.21203/rs.3.rs-5212213/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5212213/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCerebral infarction in children without underlying diseases is rare, and its causes are complex.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe present a case of a 14-year-old boy who experienced left limb weakness and slurred speech for 5 days. MRI revealed cerebral infarction in the bilateral occipital lobes and right centrum semiovale, with high homocysteine levels. He was diagnosed with cerebral infarction due to hyperhomocysteinemia and treated with anticoagulation. While his symptoms resolved, homocysteine levels remained elevated after 3 months. Genetic testing identified an \u003cem\u003eMTHFR\u003c/em\u003e mutation, leading to a treatment adjustment that included betaine, riboflavin, pyridoxine, folate, and hydroxocobalamin. Following 3 months of this new regimen, the patient fully recovered, with normalized homocysteine levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHyperhomocysteinemia caused by \u003cem\u003eMTHFR\u003c/em\u003emutations should be considered in young patients with unexplained cerebral infarction. The supplementation with betaine, riboflavin, pyridoxine, folate, and hydroxocobalamin was beneficial in decreasing homocysteine levels.\u003c/p\u003e","manuscriptTitle":"Pediatric Cerebral Infarction Unraveled: A Case of MTHFR Mutation and Hyperhomocysteinemia-Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-10 05:36:18","doi":"10.21203/rs.3.rs-5212213/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-04T16:39:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-04T02:30:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-02T08:53:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"282645042249453749145616061451163725407","date":"2024-11-02T08:46:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237640635243506203806712884744659048949","date":"2024-10-31T21:39:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"680949412171331912052980245974097307","date":"2024-10-31T03:41:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-25T09:52:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-21T04:09:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-18T05:07:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Medicine","date":"2024-10-06T09:24:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a1afd309-7e78-404b-8995-434c2487a9f4","owner":[],"postedDate":"December 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-03-26T08:38:36+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-10 05:36:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5212213","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5212213","identity":"rs-5212213","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}