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.
3
DISCUSSION
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
4
CONCLUSION
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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