Figure 1: Diffusion-weighted magnetic resonance imaging of brain showing restricted diffusion involving posterior limb of internal capsule and occipital lobe.

Considering the above findings, a routine blood investigation was sent which was normal. An autoimmune panel was sent which was also normal. His echocardiography, doppler ultrasonography of bilateral lower limbs and electrocardiogram was also normal. Furthermore, a thrombotic panel was also sent.

He was initially initiated on tablet aspirin and tablet rosuvastatin. Later, his thrombotic panel revealed MTHFR-C677T heterozygous mutation (heterozygous C>T substitution at nucleotide position 677 in MTHFR gene resulting in replacement of alanine with valine at amino acid 222) and Factor V-R506Q heterozygous mutation (heterozygous G>A substitution was observed at nucleotide position 1691 in Factor V gene resulting in replacement of arginine with glutamine at amino acid 506). Thus, he was initiated with tablet rivaroxaban, a direct oral anti-coagulation drug. Subsequent follow up revealed no progression of his symptoms.

Thrombophilia, as genetic inheritance, is one of the causes for young onset ischemic stroke. Factor V is one of the most important factors responsible for dual role for the regulation of the coagulation cascade.⁶ Factor V Leiden mutation trait shows autosomal dominant inheritance.¹ The single point mutation in factor V gene (guanine to adenine at nucleotide 1691) would lead to replacement of arginine with glutamine at amino acid 506. This abolishes the Arg506 cleavage site for activated protein C (APC) in factor V and factor Va. This enhances the procoagulant role of factor Va and reduction in anticoagulant role of factor V.⁷ This also potentiates the effect of MTHFR. Heterozygous inheritance usually doesn’t have clinical thrombotic complications unless a convergence with other inherited predisposition or an acquired thrombogenic stimulus to thrombosis is present.⁸ MTHFR, a folate dependent enzyme, plays an important role in regulating plasma homocysteine level. A C677T point mutation has been linked to an increased risk of ischemic stroke. This variant contributes to decreased enzyme activity, leading to increased hyperhomocysteinemia which ultimately leads to ischemic stroke.⁹ Although the homozygous factor V Leiden mutation incidence predominates by higher degree, the heterozygous factor V Leiden mutation is also somehow the cause for thrombosis.⁶ The prevalence of heterozygous Factor V R506Q mutation has been reported to be less than 5% and that of heterozygous MTHFR mutation being less than 50% individually.⁴ Interestingly, the mutations of both of them occurring simultaneously in a symptomatic patient with a median age of 65.5 years has been seen is 0.02% cases.⁴ The genetic predisposition for the combined heterozygous factor V Leiden R506Q and MTHFRC677T suggested reason for the young onset ischemic stroke along with other risk factor like smoking. The management of patients with dual genetic mutation depends on recurrence of thromboembolic events, family history and associated risk factors like smoking, obesity, etc. The prophylactic anticoagulant therapy is indicated in patients who have developed a thrombotic event. The duration of treatment depends on unprovoked or provoked reasons of thrombosis, site of thrombosis, family history, risk factors involved and type of thrombophilia, ranging from six months to lifelong treatment.¹⁰

Our case report has its own limitations to find the association of ischemic stroke with other possibilities due to the very low frequency of young onset ischemic stroke. However, the evidence of this case report will warrant for further study of genetic mutation in detail for young onset ischemic stroke and also advice clinicians to maintain a high index of suspicion for genetic screening and genetic predisposition in such a situation.

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