Navigating Thrombotic Terrain: Unveiling a Novel Homocystinuria Mutation Associated with Thrombophilia in a 16-Year-Old: A Case Report

Navigating Thrombotic Terrain: Unveiling a Novel Homocystinuria Mutation Associated with Thrombophilia in a 16-Year-Old: A 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 Research Article Navigating Thrombotic Terrain: Unveiling a Novel Homocystinuria Mutation Associated with Thrombophilia in a 16-Year-Old: A Case Report POOJITHA TULASI, Amulya Veeramachaneni, Niranjan Kamble, Darshan Rajatadri Rangaswamy This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3997075/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Background: Thrombophilia is characterised by an abnormality of blood coagulation that increases thrombosis. Homocystinuria, encompasses a group of disorders marked by increased levels of homocysteine and other amino acids detectable in the bloodstream and urine. Conversely, homocystinuria due to Methylenetetrahydrofolatereductase (MTHFR) deficiency, a rarer disorder, stems from impaired folate metabolism due to deficient MTHFR enzyme. Case presentation: A 16-year-old presented with walking difficulties, headaches, and thrombotic events, thrombophilia workup led to a diagnosis of Homocystinuria due to a novel mutation in MTHFR gene. Anticoagulant therapy was initiated which showed clinical imrpovement, but financial constraints hindered follow-up. Conclusions: This case highlights the complexities of diagnosing and treating pediatric thrombophilia, particularly in resource-limited settings. Notably, the identified homozygous Autosomal Recessive (AR) missense variation in the MTHFR gene (Exon 4 – c582C>G) represents a novel mutation, suggesting the ongoing significance of genetic research in elucidating the underlying mechanisms of thrombotic disorders. Anticoagulation Methylcobalamin MTHFR Thrombophilia Thrombosis BACKGROUND Thrombophilia is characterised by an abnormality of blood coagulation that increases thrombosis. Homocystinuria, encompasses a group of disorders marked by increased levels of homocysteine and other amino acids detectable in the bloodstream and urine. They present with diverse symptoms, including neurological manifestations, premature arteriosclerosis, and venous and arterial thrombotic events. 1 The primary genetic form arises from the deficiency of the Cystathionine beta-synthase (CBS) enzyme. Conversely, homocystinuria due to Methylenetetrahydrofolatereductase (MTHFR) deficiency, a rarer disorder, stems from impaired folate metabolism due to deficient MTHFR enzyme. This study highlights a novelgenetic variant of Homocystinuria, in the MTHFR gene. CASE PRESENTATION A 16-year-old boy, born to a non-consanguineous couple with an unremarkable birth and development history, presented with a one-year history of walking difficulties and antalgic gait. Additionally, he had experienced past episodes of intermittent lower limb swelling and headache. Notably, he experienced paraparesis following a fall in the past. He was evaluated outside for the same, and imaging studies (computed tomography of brain and magnetic resonance imaging (MRI) of spine) were performed to exclude any central nervous system (CNS) pathology and revealed no significant findings. Following this, as his symptoms persisted he presented to us. The clinical examination indicated findings consistent with an upper motor neuron lesion. It was noted that the mother also had paraplegia and was wheel chair bound due to Schwannoma. During his hospitalisation, an MRI of the brain revealed a bleed in the bi-thalamic regions and venous thrombosis involving the superior sagittal sinus and deep cerebral veins. Prompted by the history of intermittent lower limb swelling, venous doppler of lower limbs revealed bilateral deep vein thrombosis (DVT). Consequently, the coagulation profile indicated an elevated activated partial thromboplastin time (aPTT) and international normalised ratio (INR), leading to the initiation of Warfarin therapy with dose adjustment based on INR values. Considering deranged coagulation profile with evidence of thrombosis, a detailed thrombophilia-based etiological workup was planned; however, considering cost-effectiveness, whole exome sequencing was performed. The results unveiled a homozygous AR missense variation in the MTHFR gene (Exon 4 – c582C > G), affirming a diagnosis of Homocystinuria due to MTHFR deficiency with AR inheritance. The child was started on vitamin supplements and anticoagulation with warfarin was continued and was doing well for two months but failed to follow up. CONCLUSIONS The incidence of childhood thrombosis is 0.07–0.14 per 10,000. 2 Children with thrombophilia,s have a elevated risk of developing complications like deep vein thrombosis, pulmonary embolism and other clot related complications. Thrombophilia involves multiple factors, comprising both congenital and acquired risk factors. MTHFR plays a crucial role in synthesising 5-methyltetrahydrofolate, a key methyl donor for remethylating homocysteine to methionine. Severe MTHFR deficiency manifests as an autosomal recessive disorder associated with severe hyperhomocysteinemia and homocystinuria, leading to various neurological and vascular complications such as developmental delay, mental retardation, seizures, motor and gait abnormalities, and thromboses. 3 Milder forms of the condition have been described and are associated with higher residual enzyme activity, later symptom onset, and predominantly psychiatric symptoms, intellectual disability, and movement disturbances. 4 Exome sequencing of our case demonstratedhomocysteinuria due to MTHFR deficiency, caused by a mutation on Exon 4, identified as a Homozygous Autosomal Recessive variant c.582C > G (p.lle194Met), a novel finding, not previously reported. Our case demonstrated MTHFR deficiency contributing to thrombophilia, necessitating anticoagulation therapy. As per the American College of Chest Physician guidelines, anticoagulation therapy is recommended for at least three months in children with provoked venous thromboembolism (VTE), with an extension to 12 months or lifelong if the underlying risk factor persists. 5 The primary conventional anticoagulants include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and vitamin K antagonists (VKA). UFH is typically reserved due to concerns over long-term osteoporosis risk. LMWHs, such as enoxaparin, have emerged as the preferred choice over UFH, demonstrating greater inhibitory activity on factor Xa, administered via subcutaneous injection, with lower risks of heparin-induced thrombocytopenia and osteoporosis[ 5 ].Warfarin, a VKA, inhibits vitamin K-dependent clotting factor carboxylation and is orally administered at 0.1-0.2mg/kg (max 5mg). Monitoring and adjusting warfarin dosage are crucial, requiring INR testing to maintain the therapeutic range between 2 and 3. 5 A significant concern is its narrow therapeutic range, its interactions with various drugs and dietary components, which can lead to elevated drug levels and an increased risk of bleeding. Considering our child's risk factors and due to financial limitations, warfarin was chosen. Furthermore, Homocystinuria with an MTHFR mutation can be treated with a combination of dietary adjustments and supplements like a methionine-restricted diet to mitigate homocysteine production. 6 Various other treatments attempted are a combination of folic acid, vitamin B6, vitamin B12, methionine supplementation, and betaine. 7 Early intervention with betaine yields favourable outcomes by reducing homocysteine levels in bodily fluids by remethylatinghomocysteine into methionine. 7 Furthermore, enzyme replacement therapy (ERT), orally administered enzyme CDX-6512, has demonstrated favourable outcomes. However, it remains at an experimental stage and is challenging to obtain. 8,9 Liver transplantation has served as a curative measure in rare instances. 10 The range of phenotypical outcomes associated with MTHFR gene mutations spans from severe neurological decline and premature death to asymptomatic adults. Unfortunately, our ability to follow up with our child was hindered by financial constraints and through subsequent phone conversations, we learned of the child's demise. This case underscores the intricate interplay between genetic disorders, diagnostic challenges, and therapeutic complexities in pediatric thrombosis. The influence of financial constraints on diagnostic pathways and treatment decisions highlights the need for accessible healthcare resources. Despite limitations, insights gained contribute to understanding rare genetic variants and their clinical implications in thrombotic disorders. Abbreviations AR Autosomal Recessive CBS Cystathionine beta-synthase MTHFR Methylenetetrahydrofolatereductase CNS central nervous system DVT deep vein thrombosis aPTT activated partial thromboplastin time INR international normalised ratio VTE venous thromboembolism UFH unfractionated heparin LMWH low-molecular-weight heparin VKA vitamin K antagonists ERT enzyme replacement therapy Declarations ETHICS APPROVAL AND CONSENT TO PARTICIPATE: As per institutional policy, case reports do not need ethics approval however the committee was intimated regarding this submission. CONSENT FOR PUBLICATION: Written informed consent was obtained from the patient’s parents/legal guardians for publication of this case report. A copy of the written consent is available for the review by the Editor-in-Chief of this journal. Contact author for the form. AVAILABILITY OF DATA AND MATERIAL: Data will be shared on request COMPETING INTERESTS: The authors declare that they have no competing interests. FUNDING: No funding. AUTHORS’ CONTRIBUTIONS: PT analysed patient data and contributed in writing the manuscript. AV analysed patient data and contributed in writing the manuscript. NK analysed and interpreted the patient data, managed the case and contributed in writing the manuscript. DRR analysed and interpreted the patient data, managed the case and contributed in writing the manuscript. All authors read and approved the final manuscript. ACKNOWLEDGEMENTS: We thank Dr Vinayaka G and Dr Vikram S Kumar for their support. References Shay H, Frumento RJ, Bastien A (2007) General anesthesia and methylenetetrahydrofolatereductase deficiency. J Anesth 21:493–496. https://doi.org/10.1007/s00540-007-0544-8 Celkan T, Dikme G (2018) Thrombosis in children: Which test to whom, when and how much necessary? Turk PediatriArs 53:1–9. https://doi.org/10.5152/TurkPediatriArs.2018.2586 Sibani S, Leclerc D, Weisberg IS, O’Ferrall E, Watkins D, Artigas C, Rosenblatt DS, Rozen R (2003) Characterization of mutations in severe methylenetetrahydrofolatereductase deficiency reveals an FAD-responsive mutation. Hum Mutat 21:509–520. https://doi.org/10.1002/humu.10193 Goyette P, Frosst P, Rosenblatt DS, Rozen R (1995) Seven novel mutations in the methylenetetrahydrofolatereductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolatereductase deficiency. Am J Hum Genet 56:1052–1059 Monagle P, Newall F (2018) Management of thrombosis in children and neonates: practical use of anticoagulants in children. Hematology 399–404. https://doi.org/10.1182%2Fasheducation-2018.1.399 Majtan T, Park I, Cox A, Branchford BR, Paola J, Bublil EM, Kraus JP (2019) Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine-restricted diet or enzyme replacement therapy. FASEB j 33:12477–12486. https://doi.org/10.1096/fj.201901203r Kliegman RM (2019) Nelson textbook of pediatrics, 21st edn. Elsevier, Philadelphia, MO Majtan T, Jones W, Krijt J, Park I, Kruger WD, Kožich V, Bassnett S, Bublil EM, Kraus JP (2018) Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria. Mol Ther 26:834–844. https://doi.org/10.1016%2Fj.ymthe.2017.12.014 Skvorak K, Mitchell V, Teadt L et al (2023) An orally administered enzyme therapeutic for homocystinuria that suppresses homocysteine by metabolizing methionine in the gastrointestinal tract. Mol Genet Metab 139:107653. https://doi.org/10.1016/j.ymgme.2023.107653 Kerkvliet SP, Rheault MN, Berry SA (2021) Liver transplant as a curative treatment in a pediatric patient with classic homocystinuria: A case report. Am J Med Genet PtA 185:1247–1250. https://doi.org/10.1002/ajmg.a.62076 Supplementary Files CAREchecklistEnglish2013.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 03 Mar, 2024 Editor assigned by journal 28 Feb, 2024 First submitted to journal 27 Feb, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3997075","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276077257,"identity":"e718308e-b5f4-4086-bce0-6afc1b0e3994","order_by":0,"name":"POOJITHA TULASI","email":"","orcid":"","institution":"Subbaiah Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"POOJITHA","middleName":"","lastName":"TULASI","suffix":""},{"id":276077258,"identity":"218a4f12-6143-40e9-a6af-b99ce298cffd","order_by":1,"name":"Amulya Veeramachaneni","email":"","orcid":"","institution":"Subbaiah Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Amulya","middleName":"","lastName":"Veeramachaneni","suffix":""},{"id":276077259,"identity":"f2b8fe8c-4508-4db8-9d16-0d09981a4e33","order_by":2,"name":"Niranjan Kamble","email":"","orcid":"","institution":"Subbaiah Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Niranjan","middleName":"","lastName":"Kamble","suffix":""},{"id":276077260,"identity":"0af0bdba-f1f1-4e20-8825-3ce7b797fe5f","order_by":3,"name":"Darshan Rajatadri Rangaswamy","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYHCCBCBmZmBjbz/4AMji4SNKywGQFp4zyQYgLWxE2QPSwiCRYCYB4hDUYt5+4OHnDzXW+XwSCWmVX3PsZNgYmB8+uoFHi8yZhGSJA8fSLdt4Hh67LbstGegwNmPjHDxaJBgSEiQOsB02YGNPSLstuY0ZqIWHTRqvFv4HyT8O/ANqYUgwK5bcVk+EFqAXJA62AbVwJJgxftx2mBgtD9IszvalG4ACWZpx23EeNmZCfuHPSb5R8c3aQL69/eDHn9uq7fnZmx8+xqcFGHcJcCYzD5jEqxwE2A/AmYw/CKoeBaNgFIyCkQgACdNFf2sIX5QAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-8485-6073","institution":"Subbaiah Institute of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Darshan","middleName":"Rajatadri","lastName":"Rangaswamy","suffix":""}],"badges":[],"createdAt":"2024-02-28 15:25:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3997075/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3997075/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52074665,"identity":"6c68bb65-df64-44b9-9103-bcefea979f27","added_by":"auto","created_at":"2024-03-06 09:13:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":163606,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3997075/v1/a39db176-758c-4257-afcb-9c44fe8c91de.pdf"},{"id":52074207,"identity":"a56eacc8-08b0-4122-9dd9-cc61c48a85dd","added_by":"auto","created_at":"2024-03-06 09:05:40","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":88517,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklistEnglish2013.docx","url":"https://assets-eu.researchsquare.com/files/rs-3997075/v1/371058d1492a88c448cb19a9.docx"}],"financialInterests":"","formattedTitle":"Navigating Thrombotic Terrain: Unveiling a Novel Homocystinuria Mutation Associated with Thrombophilia in a 16-Year-Old: A Case Report","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eThrombophilia is characterised by an abnormality of blood coagulation that increases thrombosis. Homocystinuria, encompasses a group of disorders marked by increased levels of homocysteine and other amino acids detectable in the bloodstream and urine. They present with diverse symptoms, including neurological manifestations, premature arteriosclerosis, and venous and arterial thrombotic events.\u003csup\u003e1\u003c/sup\u003e The primary genetic form arises from the deficiency of the Cystathionine beta-synthase (CBS) enzyme. Conversely, homocystinuria due to Methylenetetrahydrofolatereductase (MTHFR) deficiency, a rarer disorder, stems from impaired folate metabolism due to deficient MTHFR enzyme. This study highlights a novelgenetic variant of Homocystinuria, in the MTHFR gene.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003eA 16-year-old boy, born to a non-consanguineous couple with an unremarkable birth and development history, presented with a one-year history of walking difficulties and antalgic gait. Additionally, he had experienced past episodes of intermittent lower limb swelling and headache. Notably, he experienced paraparesis following a fall in the past. He was evaluated outside for the same, and imaging studies (computed tomography of brain and magnetic resonance imaging (MRI) of spine) were performed to exclude any central nervous system (CNS) pathology and revealed no significant findings. Following this, as his symptoms persisted he presented to us. The clinical examination indicated findings consistent with an upper motor neuron lesion. It was noted that the mother also had paraplegia and was wheel chair bound due to Schwannoma.\u003c/p\u003e \u003cp\u003eDuring his hospitalisation, an MRI of the brain revealed a bleed in the bi-thalamic regions and venous thrombosis involving the superior sagittal sinus and deep cerebral veins. Prompted by the history of intermittent lower limb swelling, venous doppler of lower limbs revealed bilateral deep vein thrombosis (DVT). Consequently, the coagulation profile indicated an elevated activated partial thromboplastin time (aPTT) and international normalised ratio (INR), leading to the initiation of Warfarin therapy with dose adjustment based on INR values.\u003c/p\u003e \u003cp\u003eConsidering deranged coagulation profile with evidence of thrombosis, a detailed thrombophilia-based etiological workup was planned; however, considering cost-effectiveness, whole exome sequencing was performed. The results unveiled a homozygous AR missense variation in the MTHFR gene (Exon 4 \u0026ndash; c582C\u0026thinsp;\u0026gt;\u0026thinsp;G), affirming a diagnosis of Homocystinuria due to MTHFR deficiency with AR inheritance. The child was started on vitamin supplements and anticoagulation with warfarin was continued and was doing well for two months but failed to follow up.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThe incidence of childhood thrombosis is 0.07\u0026ndash;0.14 per 10,000.\u003csup\u003e2\u003c/sup\u003e Children with thrombophilia,s have a elevated risk of developing complications like deep vein thrombosis, pulmonary embolism and other clot related complications. Thrombophilia involves multiple factors, comprising both congenital and acquired risk factors. MTHFR plays a crucial role in synthesising 5-methyltetrahydrofolate, a key methyl donor for remethylating homocysteine to methionine. Severe MTHFR deficiency manifests as an autosomal recessive disorder associated with severe hyperhomocysteinemia and homocystinuria, leading to various neurological and vascular complications such as developmental delay, mental retardation, seizures, motor and gait abnormalities, and thromboses.\u003csup\u003e3\u003c/sup\u003eMilder forms of the condition have been described and are associated with higher residual enzyme activity, later symptom onset, and predominantly psychiatric symptoms, intellectual disability, and movement disturbances.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eExome sequencing of our case demonstratedhomocysteinuria due to MTHFR deficiency, caused by a mutation on Exon 4, identified as a Homozygous Autosomal Recessive variant c.582C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.lle194Met), a novel finding, not previously reported. Our case demonstrated MTHFR deficiency contributing to thrombophilia, necessitating anticoagulation therapy.\u003c/p\u003e \u003cp\u003eAs per the American College of Chest Physician guidelines, anticoagulation therapy is recommended for at least three months in children with provoked venous thromboembolism (VTE), with an extension to 12 months or lifelong if the underlying risk factor persists.\u003csup\u003e5\u003c/sup\u003e The primary conventional anticoagulants include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and vitamin K antagonists (VKA). UFH is typically reserved due to concerns over long-term osteoporosis risk. LMWHs, such as enoxaparin, have emerged as the preferred choice over UFH, demonstrating greater inhibitory activity on factor Xa, administered via subcutaneous injection, with lower risks of heparin-induced thrombocytopenia and osteoporosis[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].Warfarin, a VKA, inhibits vitamin K-dependent clotting factor carboxylation and is orally administered at 0.1-0.2mg/kg (max 5mg). Monitoring and adjusting warfarin dosage are crucial, requiring INR testing to maintain the therapeutic range between 2 and 3.\u003csup\u003e5\u003c/sup\u003eA significant concern is its narrow therapeutic range, its interactions with various drugs and dietary components, which can lead to elevated drug levels and an increased risk of bleeding. Considering our child's risk factors and due to financial limitations, warfarin was chosen.\u003c/p\u003e \u003cp\u003eFurthermore, Homocystinuria with an MTHFR mutation can be treated with a combination of dietary adjustments and supplements like a methionine-restricted diet to mitigate homocysteine production.\u003csup\u003e6\u003c/sup\u003eVarious other treatments attempted are a combination of folic acid, vitamin B6, vitamin B12, methionine supplementation, and betaine.\u003csup\u003e7\u003c/sup\u003e Early intervention with betaine yields favourable outcomes by reducing homocysteine levels in bodily fluids by remethylatinghomocysteine into methionine.\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFurthermore, enzyme replacement therapy (ERT), orally administered enzyme CDX-6512, has demonstrated favourable outcomes. However, it remains at an experimental stage and is challenging to obtain.\u003csup\u003e8,9\u003c/sup\u003e Liver transplantation has served as a curative measure in rare instances.\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe range of phenotypical outcomes associated with MTHFR gene mutations spans from severe neurological decline and premature death to asymptomatic adults. Unfortunately, our ability to follow up with our child was hindered by financial constraints and through subsequent phone conversations, we learned of the child's demise.\u003c/p\u003e \u003cp\u003eThis case underscores the intricate interplay between genetic disorders, diagnostic challenges, and therapeutic complexities in pediatric thrombosis. The influence of financial constraints on diagnostic pathways and treatment decisions highlights the need for accessible healthcare resources. Despite limitations, insights gained contribute to understanding rare genetic variants and their clinical implications in thrombotic disorders.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAutosomal Recessive\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCBS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCystathionine beta-synthase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMTHFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMethylenetetrahydrofolatereductase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecentral nervous system\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDVT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edeep vein thrombosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eaPTT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eactivated partial thromboplastin time\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eINR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einternational normalised ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVTE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evenous thromboembolism\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUFH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eunfractionated heparin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLMWH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elow-molecular-weight heparin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVKA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evitamin K antagonists\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eERT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eenzyme replacement therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE:\u0026nbsp;As per institutional policy, case reports do not need ethics approval however the committee was intimated regarding this submission.\u003c/p\u003e\n\u003cp\u003eCONSENT FOR PUBLICATION:\u0026nbsp;Written informed consent was obtained from the patient\u0026rsquo;s parents/legal guardians for publication of this case report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA copy of the written consent is available for the review by the Editor-in-Chief of this journal.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eContact author for the form.\u003c/p\u003e\n\u003cp\u003eAVAILABILITY OF DATA AND MATERIAL: Data will be shared on request\u003c/p\u003e\n\u003cp\u003eCOMPETING INTERESTS: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFUNDING: No funding.\u003c/p\u003e\n\u003cp\u003eAUTHORS\u0026rsquo; CONTRIBUTIONS: PT analysed patient data and contributed in writing the manuscript. AV analysed patient data and contributed in writing the manuscript. NK analysed and interpreted the patient data, managed the case and contributed in writing the manuscript. DRR analysed and interpreted the patient data, managed the case and contributed in writing the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eACKNOWLEDGEMENTS: We thank\u0026nbsp;Dr Vinayaka G and Dr Vikram S Kumar for their support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShay H, Frumento RJ, Bastien A (2007) General anesthesia and methylenetetrahydrofolatereductase deficiency. J Anesth 21:493\u0026ndash;496. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00540-007-0544-8\u003c/span\u003e\u003cspan address=\"10.1007/s00540-007-0544-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCelkan T, Dikme G (2018) Thrombosis in children: Which test to whom, when and how much necessary? Turk PediatriArs 53:1\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.5152/TurkPediatriArs.2018.2586\u003c/span\u003e\u003cspan address=\"10.5152/TurkPediatriArs.2018.2586\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSibani S, Leclerc D, Weisberg IS, O\u0026rsquo;Ferrall E, Watkins D, Artigas C, Rosenblatt DS, Rozen R (2003) Characterization of mutations in severe methylenetetrahydrofolatereductase deficiency reveals an FAD-responsive mutation. Hum Mutat 21:509\u0026ndash;520. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/humu.10193\u003c/span\u003e\u003cspan address=\"10.1002/humu.10193\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoyette P, Frosst P, Rosenblatt DS, Rozen R (1995) Seven novel mutations in the methylenetetrahydrofolatereductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolatereductase deficiency. Am J Hum Genet 56:1052\u0026ndash;1059\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonagle P, Newall F (2018) Management of thrombosis in children and neonates: practical use of anticoagulants in children. Hematology 399\u0026ndash;404. https://doi.org/10.1182%2Fasheducation-2018.1.399\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMajtan T, Park I, Cox A, Branchford BR, Paola J, Bublil EM, Kraus JP (2019) Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine-restricted diet or enzyme replacement therapy. FASEB j 33:12477\u0026ndash;12486. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1096/fj.201901203r\u003c/span\u003e\u003cspan address=\"10.1096/fj.201901203r\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKliegman RM (2019) Nelson textbook of pediatrics, 21st edn. Elsevier, Philadelphia, MO\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMajtan T, Jones W, Krijt J, Park I, Kruger WD, Kožich V, Bassnett S, Bublil EM, Kraus JP (2018) Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria. Mol Ther 26:834\u0026ndash;844. https://doi.org/10.1016%2Fj.ymthe.2017.12.014\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSkvorak K, Mitchell V, Teadt L et al (2023) An orally administered enzyme therapeutic for homocystinuria that suppresses homocysteine by metabolizing methionine in the gastrointestinal tract. Mol Genet Metab 139:107653. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ymgme.2023.107653\u003c/span\u003e\u003cspan address=\"10.1016/j.ymgme.2023.107653\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKerkvliet SP, Rheault MN, Berry SA (2021) Liver transplant as a curative treatment in a pediatric patient with classic homocystinuria: A case report. Am J Med Genet PtA 185:1247\u0026ndash;1250. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/ajmg.a.62076\u003c/span\u003e\u003cspan address=\"10.1002/ajmg.a.62076\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bulletin-of-the-national-research-centre","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnrc","sideBox":"Learn more about [Bulletin of the National Research Centre](https://BNRC.springeropen.com)","snPcode":"42269","submissionUrl":"https://submission.springernature.com/new-submission/42269/3","title":"Bulletin of the National Research Centre","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Anticoagulation, Methylcobalamin, MTHFR, Thrombophilia, Thrombosis","lastPublishedDoi":"10.21203/rs.3.rs-3997075/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3997075/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003e\u003cem\u003eThrombophilia is characterised by an abnormality of blood coagulation that increases thrombosis. \u003c/em\u003eHomocystinuria, encompasses a group of disorders marked by increased levels of homocysteine and other amino acids detectable in the bloodstream and urine. Conversely, homocystinuria due to Methylenetetrahydrofolatereductase (MTHFR) deficiency, a rarer disorder, stems from impaired folate metabolism due to deficient MTHFR enzyme.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eA 16-year-old presented with walking difficulties, headaches, and thrombotic events, thrombophilia workup led to a diagnosis of Homocystinuria due to a novel mutation in MTHFR gene. Anticoagulant therapy was initiated which showed clinical imrpovement, but financial constraints hindered follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThis case highlights the complexities of diagnosing and treating pediatric thrombophilia, particularly in resource-limited settings. Notably, the identified homozygous Autosomal Recessive (AR) missense variation in the MTHFR gene (Exon 4 – c582C\u0026gt;G) represents a novel mutation, suggesting the ongoing significance of genetic research in elucidating the underlying mechanisms of thrombotic disorders.\u003c/p\u003e","manuscriptTitle":"Navigating Thrombotic Terrain: Unveiling a Novel Homocystinuria Mutation Associated with Thrombophilia in a 16-Year-Old: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-06 09:05:36","doi":"10.21203/rs.3.rs-3997075/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-03-03T17:56:52+00:00","index":0,"fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-28T12:36:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bulletin of the National Research Centre","date":"2024-02-28T03:47:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bulletin-of-the-national-research-centre","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnrc","sideBox":"Learn more about [Bulletin of the National Research Centre](https://BNRC.springeropen.com)","snPcode":"42269","submissionUrl":"https://submission.springernature.com/new-submission/42269/3","title":"Bulletin of the National Research Centre","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"46226a31-331f-4513-bb58-2bfdf3d099a5","owner":[],"postedDate":"March 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-04-16T10:28:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-06 09:05:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3997075","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3997075","identity":"rs-3997075","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}