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Year : 2021  |  Volume : 1  |  Issue : 1  |  Page : 14-17

Cerebral venous sinus thrombosis with heterozygous methylenetetrahydrofolate reductase mutation: Cause or chance association?

Department of Pediatrics, Tata Manipal Medical College, Jamshedpur, Jharkhand, India

Date of Submission18-Aug-2020
Date of Decision26-Oct-2020
Date of Acceptance19-Nov-2020
Date of Web Publication27-Feb-2021

Correspondence Address:
Dr. Prabir Maji
Department of Pediatrics, Tata Manipal Medical College, Baridih, Jamshedpur - 831 017, Jharkhand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_1_21

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Background: Cerebral venous sinus thrombosis (CSVT) in children is a rare, obscure, but potentially fatal problem. The clinical presentation is varied, as is the multiple underlying causes. CSVT can be seen in patients with inherited or acquired prothrombotic risk factors, even in the absence of an underlying condition. The respective etiological roles of methylenetetrahydrofolate reductase (MTHFR) CG677T mutation and hyperhomocysteinemia in CSVT is still not clear. We present a case of CSVT following a minor head injury, in whom an MTHFR mutation was identified, but with initial normal homocysteine levels. Clinical Description: A 9-year-old boy presented with nonaccidental fall followed by persistent headache, projectile vomiting, bradycardia and hypertension suggesting features of raised intracranial pressure. Brain imaging (magnetic resonance venography) showed extensive dural venous sinus thrombosis. Prothrombotic workup revealed heterozygous CG677T polymorphism of the MTHFR gene with normal serum homocysteine, B12 and folate levels. Management: The child was given supportive management. Low-molecular-weight heparin was initiated followed by long-term warfarin. There were no neurological deficits at discharge. Six months afterward, there is persistence of thrombosis with partial recanalization in the affected cerebral sinuses. The serum homocysteine level is now marginally elevated. Conclusion: Available neuroimaging should be promptly instituted to establish CSVT. A targeted search for prothombotic risk factors should be undertaken but within the proper timeframe. Genetic mutations may be identified accurately in the acute phase, but other factors should be done after 4–6 weeks. The relationship between MTHFR polymorphisms and hyperhomocysteinemia with venous thrombosis is yet to be defined.

Keywords: Cerebral venous sinus thrombosis, homocysteine, methylenetetrahydrofolate reductase

How to cite this article:
Maji P, Mishra S, Singh D. Cerebral venous sinus thrombosis with heterozygous methylenetetrahydrofolate reductase mutation: Cause or chance association?. Indian Pediatr Case Rep 2021;1:14-7

How to cite this URL:
Maji P, Mishra S, Singh D. Cerebral venous sinus thrombosis with heterozygous methylenetetrahydrofolate reductase mutation: Cause or chance association?. Indian Pediatr Case Rep [serial online] 2021 [cited 2023 Feb 3];1:14-7. Available from: http://www.ipcares.org/text.asp?2021/1/1/14/310207

Cerebral venous sinus (sinovenous) thrombosis (CSVT) in childhood is a rare, but obscure problem, with an estimated incidence of 0.67/100,000 children. A predisposing comorbid condition is recognized in up to 95% of cases,[1] i.e., fever, infection, dehydration, anemia, congenital heart disease, nephrotic syndrome, and systemic lupus erythematosus malignancy. There is a definite association with some hypercoagulable or thrombophilic states, but the status of hyperhomocysteinemia is uncertain.[2],[3] The proposed mechanism is that increased homocysteine levels result in oxidative stress due to increased reactive oxygen species (including superoxide). This causes inflammation and dysfunction of the endothelial cells resulting in atherosclerosis and thrombosis, and severe clinical outcomes such as coronary artery disease, deep-vein thrombosis, peripheral arterial occlusive disease, and cerebral infarction.

The conversion of homocysteine to methionine requires the donation of a methyl molecule by 5, methyl-tetrahydrofolate. This is obtained from the action of the enzyme methylenetetrahydrofolate reductase (MTHFR) on 5, 10 methylene-tetrahydrofolate. Hence, decreased enzyme activity will result in hyperhomocysteinemia. There are two common functional MTHFR genes (situated on chromosome 1p36.3) mutations that lead to impaired enzyme activity resulting in higher than normal plasma homocysteine level. The first occurs when cytosine (C) is replaced by thymidine (T) at the 677th position on exon 4, leading to valine being formed instead of alanine. This results in homozygous normal (CC), heterozygous (CT), or homozygous mutant (TT) genotypes. The second occurs when Adenosine is replaced by Cytosine at the 1298th position on exon 7 leading to alanine being formed instead of glutamate and is associated with lesser functional impact. Homozygous genotypes lead to more enzymatic impairment than heterozygotes. For example, homozygous (677 TT) and heterozygous (C677T) mutation result in approximately 30% and 65% of normal MTHFR enzyme activity, respectively.[4] Compound heterozygous genotypes A1298C/C677T have also been reported.

Case reports of CSVT with heterozygous MTHFR C677T and A1298C polymorphisms and hyperhomocysteinemia have been published.[5],[6] Although hyperhomocysteinemia is known to cause thrombosis, the evidence is still inconclusive whether the MTHFR gene mutations can directly cause thrombus formation, irrespective of homocysteine levels. Here, we report a child with heterozygous MTHFR C677T mutation who presented with CSVT despite a normal homocysteine level.

  Clinical Description Top

A 9-year-old previously healthy boy presented with the severe headache associated with episodes of projectile vomiting. There was a significant history of a preceding fall a few hours before the onset of symptoms. There was no history of loss of consciousness, seizures, discharge or bleeding from the ear or nose or any external injuries. There was no history of preceding fever or diarrhea. The child did not have a history of blurring of vision, ocular abnormality, slurring of speech, facial asymmetry, gait disturbance, sudden motor weakness, or loss of sensations. There was no similar history in the past. His medical and family histories were unremarkable. The child was not on any prolonged medication.

The child was afebrile with a pulse rate of 62 beats/min and blood pressure of 126/78 mmHg (>95th percentile, both systolic and diastolic). Anthropometric measurements and general physical examination were normal. There were no pallor, bruising, or rashes. The Glasgow coma score was 15/15 and he was oriented to time, place, and person. Eye movements were equal in all directions. Both pupils were central, normal in size, and displayed normal reflexes. No papilledema was found on examination of the fundi. No cranial nerve abnormalities were noted. There was no motor weakness or sensory loss. Deep-tendon reflexes were present with bilateral flexor plantar responses. There were no cerebellar or meningeal signs. All other systems including cardiovascular were within normal limits. In view of the acute severe headache, projectile vomiting, bradycardia, and hypertension, a clinical diagnosis of posttraumatic intracranial hemorrhage (ICH) with raised intracranial pressure (ICP) was kept.

Management and Outcome

Supportive management was started including measures to reduce ICP. The hemogram revealed hemoglobin 12.4 g/dl, total leukocyte counts 9200/mm3 with normal differentials, platelets 1,96,000/mm3 and a normal peripheral smear. Liver function and kidney function were normal. The coagulation profile was normal; prothrombin time 12.0 s (s), international normalized ratio (INR) 1.07, activated partial thromboplastin time 26 s against control of 24.1 s.

A plain computed tomography scan brain was done suspecting head injury resulting in ICH. This revealed hyperdensities in the region of superior sagittal sinus, left transverse and sigmoid sinus, suggesting a possible cerebral venous thrombosis (CVT). Magnetic resonance venography (MRV) confirmed complete thrombosis of the posterior half of superior sagittal sinus, straight sinus, bilateral transverse sinus and right sigmoid sinus with dilated superficial veins, prominent draining veins in ambient cisterns, left cerebellopontine angle cistern, left para medullary cistern causing mild compression over the brainstem. There was no evidence of parenchymal bleed or infarct [Figure 1a and b]. In view of CVT, subcutaneous low molecular weight heparin (LMWH) at the dose of 1 mg/kg over 12 h was started. Later, he was shifted to oral warfarin (0.1 mg/kg/day). Osmotherapy was stopped after 1 week when features of raised ICP subsided. The plan was to give LMWH for at least 7 days followed by warfarin according to the protocol of the British Committee for Standards in Hematology. Warfarin dosages were titrated with target INR values and the duration was to be decided as investigation reports and risk factors for thrombophilia emerged. At discharge, he had normal neurological examination.
Figure 1: (a) T2 axial magnetic resonance imaging brain showing normal brain parenchyma with thrombus (white closed arrow) in posterior part of superior sagittal sinus. (b) Magnetic resonance time-of-flight venography reformatted image showing thrombosis (white closed arrows) of both transverse sinuses

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Since trauma can be a triggering event for CVT, history and examination were reviewed for other predisposing conditions known in children, and investigations planned accordingly. Thyroid function test was normal with thyroid-stimulating hormone 0.59 μIU/mL (normal 0.3–0.65), CRP was not elevated (0.15 mg/dl). Sickling test and HIV serology were negative. Echocardiography was also unremarkable. Evidence of autoimmune disorders (antinuclear and anti-double-stranded deoxyribonucleic acid antibodies) was absent. The prothrombotic genetic mutation panel was sent.[7] No mutations were found for factor V Leiden (R506Q) or the prothrombin gene (G2021A). However, a heterozygous CG677T polymorphism of the MTHFR gene was identified. Suspecting hyperhomocysteinemia, we ordered serum homocysteine levels which were not increased; 9.10 μmol/L (normal 5.46–16.2 μmol/L). Other factors that are crucial to the homocysteine-methionine conversion cycle, i.e., serum folate and Vitamin B12 level were measured but found normal; serum folate 7.79 ng/mL (normal 3.56–20 ng/mL) and Vitamin B12 238 pg/mL (normal 180–914 pg/mL).

At 6 months follow-up, the child did not have any complaints of headache or any other neurological symptoms. A repeat MRV showed persistence of thrombosis in previously involved sinuses with prominent superficial and draining veins with collateral formation. Partial recanalization was noted in the ventral portion of the straight sinus [Figure 2]. Repeat fasting homocysteine level (on warfarin) showed marginally elevated level 16.80 μmol/L. A comprehensive evaluation of the thrombophilia profile will be considered after the stoppage of anticoagulation for 6 weeks in follow-up.[7] The clinical timeline for the entire sequence of events is depicted in [Figure 3]. Parents were advised for MTHFR polymorphism screening.
Figure 2: Time-of-flight magnetic resonance venography lateral view showing thrombosis in superior sagittal sinus (white closed arrow) and posterior part of straight sinus (black closed arrow) and partial recanalization of anterior segment (white open arrow) of straight sinus

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Figure 3: Clinical timeline of the described case with salient investigations and management

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  Discussion Top

CSVT in childhood is a rare, yet poorly understood problem. Prothrombotic risk factors promote CSVT in the presence of predisposing clinical conditions. Inherited prothrombotic risk factors primarily include homocysteinemia, factor V Leiden homozygous mutation, G20210A prothrombin gene and MTHFR 677TT mutations, protein C and S and anti-thrombin III deficiency.[1] The frequency of the MTHFR 677T allele varies according to country and ethnicity. It ranges from 20% to 55% in Europeans and from 4% to 38% in the Asian populations. Two Indian studies have reported the following prevalence: Devi et al. 10.12% in a south Indian population[8] and Rai et al. 12% in a population from Eastern Uttar Pradesh.[9]

A meta-analysis including 9 case–control studies, indicated a notable association (odds ratio 2.95 with 95% confidence interval 2.08–4.17) between hyperhomocysteinemia and thrombosis.[2] However, subsequent prospective studies refuted this claimed association.[3] Homozygous or heterozygous MTHFR mutations lead to hyperhomocysteinemia, but given the prevalence in normal populations, whether it is a definite cause or incidental finding in cases of thrombosis, is still unclear. The MEGA (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) study, on 4375 adults with deep vein thrombosis and pulmonary thromboembolism refuted MTHFR mutation as a risk factor for thrombosis. A similar conclusion was arrived at by Park and Chang in a study in 111 patients (19–91 years) with arterial (48) or venous (63) thrombosis.[10]

The occurrence of CSVT in cases with MTHFR CG677T polymorphism is uncommon. We cite two cases, a 45-year-old male with severe headache who had heterozygous MTHFR CG677T polymorphism and hyperhomocysteinemia[5] and; a 21-year adult presenting with seizures with heterozygous MTHFR A1298C mutation and hyperhomocysteinemia.[6] In contrast, heterozygous MTHFR 677CT mutation alone, in absence of elevated serum homocysteine, causing venous thrombosis, is not yet reported. Our case was a 9-year-old premorbid healthy child presented with acute onset raised ICP because of CSVT. His targeted prothrombotic workup revealed heterozygous MTHFR (C677T) mutation with normal homocysteine level. The possible reason for this was because sampling done in the acute phase, especially since the second sample was marginally elevated, although on warfarin. Ideally, this should be done after warfarin has been stopped.[7] Thus, a comprehensive thrombophilia screening will be repeated once this is stopped.

This case highlights the importance of prompt identification and management of CSVT because of its obscure and varied nature of the presentation. The role of MTHFR mutation as a prothrombotic risk factor is yet to be defined.


The authors would like to thank the patient and his family for their cooperation. We sincerely thank Dr. Nilanjjan Sarkar, Senior consultant, Department of Radiology, Tata Main Hospital for guiding us in imaging analysis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Dlamini N, Billinghurst L, Kirkham FJ. Cerebral venous sinus (sinovenous) thrombosis in children. Neurosurg Clin N Am 2010;21:511-27.  Back to cited text no. 1
Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998;158:2101-6.  Back to cited text no. 2
Mäkelburg AB, Lijfering WM, Middeldorp S, et al. Low absolute risk of venous and arterial thrombosis in hyperhomocysteinaemia – A prospective family cohort study in asymptomatic subjects. Thromb Haemost 2009;101:209-12.  Back to cited text no. 3
Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93:7-9.  Back to cited text no. 4
Jalal MJ, Menon MK. Headache presenting as cerebral venous thrombosis associated with heterozygous methylenetetrahydrofolate reductase gene mutation: A case report. Muller J Med Sci Res 2016;7:136-40.  Back to cited text no. 5
  [Full text]  
Shah JH, Salagre KD, Sahay RN, et al. Heterozygous MTHFR A1298C mutation causing cerebral venous sinus thrombosis. J Assoc Physicians India 2016;64:76-7.  Back to cited text no. 6
Nakashima MO, Rogers HJ. Hypercoagulable states: An algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants. Blood Res 2014;49:85-94.  Back to cited text no. 7
Devi AR, Govindaiah V, Ramakrishna G, et al. Prevalence of methylene tetrahydrofolate reductase polymorphism in South Indian population. Curr Sci 2004;86:440-3.  Back to cited text no. 8
Rai V, Yadav U, Kumar P. Prevalence of methylenetetrahydrofolate reductase C677T polymorphism in eastern Uttar Pradesh. Indian J Hum Genet 2012;18:43-6.  Back to cited text no. 9
  [Full text]  
Park WC, Chang JH. Clinical implications of methylenetetrahydrofolate reductase mutations and plasma homocysteine levels in patients with thromboembolic occlusion. Vasc Specialist Int 2014;30:113-9.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3]


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