Brief Communication

Ischemic Stroke in a 7-Month-Old Infant With
Antiphospholipid Antibody and Homozygous
C677T Methylenetetrahydrofolate Reductase
(MTHFR) Polymorphism

Journal of Child Neurology
25(8) 1047-1050
ª The Author(s) 2010
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0883073809356710
http://jcn.sagepub.com

Se Hee Kim, MD,1 Hee Hwang, MD,1 Jong Hee Chae, MD, PhD,1
Ki Joong Kim, MD, PhD,1 Yong Seung Hwang, MD, PhD,1 and
Byung Chan Lim, MD1

Abstract
Prothrombotic risk factors in children with ischemic stroke have been increasingly recognized with recent developments in
technology. Extensive evaluation including a detailed family history is required to identify various inherited or acquired
prothrombotic conditions. We report a 7-month-old male who presented with right hemiparesis. Acute cerebral infarction in
the area supplied by the left lenticulostriate artery was confirmed through magnetic resonance imaging. De novo synthesis of antiphospholipid antibodies and homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism were identified as presumed prothrombotic risk factors. His twin sister and mother were also positive for antiphospholipid antibodies. Multiple risk
factors for ischemic stroke should be considered, particularly in the perinatal and infancy period. This case also underlines the
rare familial occurrence of antiphospholipid antibodies and its relationship to ischemic stroke in infancy.
Keywords
infant, stroke, risk factor, antiphospholipid antibody, methylenetetrahydrofolate reductase
Received October 29, 2009. Received revised November 8, 2009. Accepted for publication November 9, 2009.

The risk factors of ischemic stroke in the pediatric age group
are poorly understood compared with those for adults, which
comprise atherosclerosis, hypertension, diabetes, hypercholesterolemia, and smoking. In addition to a few well-known risk
factors, such as congenital heart disease and arteriopathies
resulting from dissection or certain infections,1 various prothrombotic factors are increasingly being recognized as playing
an important role in ischemic stroke in children.2-4
Here, we report a 7-month-old male who presented with
right-sided hemiparesis. Two prothrombotic risk factors were
identified after extensive evaluation: native antiphospholipid
antibodies and homozygous methylenetetrahydrofolate
reductase (MTHFR) C677T polymorphism. His mother and
twin sister were also positive for antiphospholipid antibodies,
suggesting familial occurrence.

perinatal events. His developmental milestones were normal.
His mother had a history of 1 intrauterine fetal death at 8 weeks
of gestation. He had no history of chickenpox infection. Three
family members within 3 generations on the maternal side
(maternal grandfather and maternal great-grandparents) suffered from stroke. The maternal grandfather died of stroke in
his 30s. A neurological examination was conducted on his arrival and revealed a right-sided hemiparesis including facial
muscles with a decreased muscle strength of grade 3. Deeptendon reflexes were increased, and the Babinski reflex was
present on the right side. He was alert, and the remainder of
his neurological examination results was normal. No other
physical abnormalities were noted.

Case Report

Department of Pediatrics, Seoul National University College of Medicine,
Seoul, Korea

A 7-month-old male was admitted because of a right-sided
weakness, which had begun 2 hours before his admission. He
was a natural discordant twin born second at a gestational age
of 35 weeks and 3 days. He was born from an emergency
cesarean section because of placenta totalis and without any

Corresponding Author:
Byung Chan Lim, Department of Pediatrics, Seoul National University College
of Medicine, Seoul National University Hospital, 28 Yongon-Dong, Jongno-Gu,
Seoul, 110-744, Korea
Email: prabbit@medimail.co.kr

1047
Downloaded from jcn.sagepub.com at UNIV OF CONNECTICUT on May 27, 2015

1048

Journal of Child Neurology 25(8)

Figure 1. Magnetic resonance imaging of the patient at the onset. (A) Axial T2-weighted image demonstrating subtle high-signal intensity in
the left putaminal area and posterior limb of the internal capsule. Diffusion-weighted imaging (B) and apparent diffusion coefficient mapping
(C) demonstrating the presence of diffusion restriction in the same area.

Brain magnetic resonance imaging conducted on the day of
admission showed a subtle high-signal intensity in the left
putaminal area and the posterior limb of the internal capsule
on T2-weighted images (Figure 1A) and diffusion restriction
in the same area, as demonstrated by the presence of
hyperintensity on diffusion-weighted imaging (Figure 1B) and
depressed apparent diffusion coefficient mapping (Figure 1C).

These observations were compatible with acute lenticulostriate
artery infarction. No stenosis or occluded area was noted on
magnetic resonance angiography. An echocardiogram finding
was normal. Various prothrombotic risk factors were evaluated: anticardiolipin antibody, lupus anticoagulant, protein C,
protein S, antithrombin III, serum homocysteine, lipoprotein
(a), factor V Leiden mutation, MTHFR polymorphism

1048
Downloaded from jcn.sagepub.com at UNIV OF CONNECTICUT on May 27, 2015

Kim et al

1049

Table 1. Profile of Antiphospholipid Antibodies and Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism in Patient, Twin Sister, and
Mother
Patient
(7 mo, 10 mo)

Twin Sister
(10 mo)

Mother

Anticardiolipin IgG antibody (<15 IgG pospholipid or GPL)
Anticardiolipin IgM antibody (<12.5 IgM phospholipid or MPL)
Lupus anticoagulant
MTHFR C677T
MTHFR A1298C

21.8, 18.9
Negative, 12.6
Negative
TT homozygote
AA homozygote

34
32.1
Negative
CT heterozygote
AC heterozygote

Negative
Negative
Weakly positive
CT heterozygote
AC heterozygote

(C677T, A1298C), and prothrombin G20210A mutation. Two
prothrombotic risk factors were identified: anticardiolipin antibody IgG was mildly elevated, and anticardiolipin antibody
IgM was negative. MTHFR genotyping revealed homozygous
MTHFR C677T polymorphism. The anticardiolipin antibody
IgG remained elevated, and anticardiolipin antibody IgM was
detected at borderline levels when re-evaluated after 14 weeks.
The patient’s twin sister and mother were also evaluated. The
anticardiolipin antibody IgG and anticardiolipin antibody IgM
were elevated in the twin sister, and lupus anticoagulant was
positive in his mother. Specific data for the patient, his twin
sister, and mother are presented in Table 1.
Antithrombotic treatment was not started immediately
because there was a small acute hemorrhage around the infarction area. After the hemorrhage spontaneously resolved, the
patient was prescribed with aspirin and physical therapies.
After a 6-month follow-up period, his right-side muscle
strength had improved, and no further attacks had occurred.

was beyond the perinatal period. The abortion history of the
mother and several stroke episodes in 3 members on the maternal side of the family raise the suspicion that there might be an
inherited factor in addition to the passive transfer of antiphospholipid antibodies. The results of repeated testing of the
patient at 10 months of age plus the presence of prothrombotic
risk factors in the patient’s twin sister and mother favored the
de novo synthesis of antiphospholipid antibodies. The presence
of different antiphospholipid antibodies in the infants and
mother requires some speculation. One family study revealed
a high prevalence of various antiphospholipid antibodies in the
family members of patients with antiphospholipid syndrome,
which were not necessarily the same as those seen in patients.9
De novo synthesis of antiphospholipid antibodies in preterm
newborns from mothers with antiphospholipid syndrome has
also been demonstrated,10 which suggests that passive transfer
of antibodies across the placenta is not the only way fetuses and
neonates acquire antiphospholipid antibodies. Therefore, different antiphospholipid antibodies from the mothers can be
produced de novo, even during the fetal period. However, it
remains to be determined whether the current antibody status
of the patient and his twin sister resulted from inheritance of
genetic susceptibility to antiphospholipid syndrome or vertical
transmission of phospholipid antigens from the mother during
gestation. We plan to regularly follow-up the antiphospholipid
antibodies status of the patient and his twin sister. If the levels
of antiphospholipid antibodies in the patient and his twin sister
decrease over time, this would support the hypothesis that
a transient immune response might be caused by transient exposure to antigens from the mother during the gestational period.
It is interesting that the patient’s twin sister, despite higher
titers of antiphospholipid antibodies, remained asymptomatic.
She had heterozygous MTHFR C677T polymorphism. It would
be interesting to know whether this difference in genotype
generates a difference in clinical phenotype. The evidence is
insufficient to determine this at present because MTHFR polymorphisms showed an only modestly increased risk for ischemic
stroke.3 However, the concept that multiple prothrombotic factors
add to the risk of ischemic stroke is supported by our patient.
The presence of multiple prothrombotic risk factors required
the maintenance of antithrombotic treatment in our patient.
Although anticoagulation in patients with pediatric antiphospholipid antibody syndrome is associated with lower recurrence of thrombotic events, according to one report,11
a recent study of 121 patients reported that both anticoagulation

Discussion
Although the presence of antiphospholipid antibodies was
recognized as a risk factor for ischemic stroke in children in
a previous study,2 the evaluation of its clinical significance in
the context of pediatric ischemic stroke remains poor, mainly
because of the relatively low incidence of pediatric antiphospholipid syndrome and the lack of sufficient multicenter data.
Moreover, ischemic stroke accounts for only about 30% of
thrombotic events in pediatric antiphospholipid syndrome.5
The role of antiphospholipid antibodies in ischemic stroke has
been more actively studied in the perinatal-onset group because
these antibodies can be transferred transplacentally from the
mother with antiphospholipid antibodies, or antiphospholipid
syndrome, possibly affecting the prothrombotic status of the
fetus and neonate. A recent well-designed clinical study,6
review,7 and case report8 support the related risk of antiphospholipid antibodies. However, these studies also point out that
other comorbid prothrombotic conditions are usually required
for ischemic stroke to occur. The clinical presentation of our
patient with homozygous MTHFR C677T polymorphism in
addition to antiphospholipid antibodies supports this concept
that multiple prothrombotic risk factors are required for
ischemic stroke. However, it is not clear whether the antiphospholipid antibodies were transferred from his mother or
synthesized de novo, considering that the onset of the stroke

1049
Downloaded from jcn.sagepub.com at UNIV OF CONNECTICUT on May 27, 2015

1050

Journal of Child Neurology 25(8)

and antiaggregation therapy were used similarly in patients
with arterial thrombosis.5 The MTHFR C677T homozygous
state may also require the maintenance of antithrombotic
treatment and folate supplementation. Based on the clinical
evidence described above, we selected aspirin as the antithrombotic treatment. As the repeated serum homocystein levels
were normal (6.2 and 5.2 mmol/L; reference, 5-15 mmol/L),
we decided not to supplement with folate.
In conclusion, our 7-month-old patient with ischemic stroke
highlights the importance of conducting a thorough evaluation
of prothrombotic risk factors and family history, with specific
emphasis on the familial occurrence of antiphospholipid antibodies in infancy. It would be useful to pay more attention to
this age group, although hampered by low prevalence, because
infancy may have overlapping clinical features and risk factors
with perinatal and later childhood periods.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the authorship and/or publication of this article.

Funding
The authors disclosed receipt of the following financial support for the
research and/or authorship of this article: This study was supported by
a grant of the Korea healthcare technology R&D project, Ministry for
Health, Welfare and Family Affairs, Republic of Korea (A080588).

References
1. Bernard TJ, Goldenberg NA. Pediatric arterial ischemic stroke.
Pediatr Clin North Am. 2008;55:323-338, viii.

2. Kenet G, Sadetzki S, Murad H, et al. Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic
stroke in children. Stroke. 2000;31:1283-1288.
3. Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and
first arterial ischaemic stroke: a systematic review. Arch Dis
Child. 2005;90:402-405.
4. Herak DC, Antolic MR, Krleza JL, et al. Inherited prothrombotic
risk factors in children with stroke, transient ischemic attack, or
migraine. Pediatrics. 2009;123:e653-660.
5. Avcin T, Cimaz R, Silverman ED, et al. Pediatric antiphospholipid syndrome: clinical and immunologic features of 121 patients
in an international registry. Pediatrics. 2008;122:e1100-1107.
6. Simchen MJ, Goldstein G, Lubetsky A, et al. Factor V Leiden and
antiphospholipid antibodies in either mothers or infants increase
the risk for perinatal arterial ischemic stroke. Stroke. 2009;40:
65-70.
7. Boffa MC, Lachassinne E. Infant perinatal thrombosis and antiphospholipid antibodies: a review. Lupus. 2007;16:634-641.
8. Paro-Panjan D, Kitanovski L, Avcin T. Neonatal antiphospholipid
syndrome associated with heterozygous methylenetetrahydrofolate reductase C677T and prothrombin G20210A gene mutations.
Rheumatology (Oxford). 2007;46:720-721.
9. Goldberg SN, Conti-Kelly AM, Greco TP. A family study of
anticardiolipin antibodies and associated clinical conditions. Am
J Med. 1995;99:473-479.
10. Soares Rolim AM, Castro M, Santiago MB. Neonatal antiphospholipid syndrome. Lupus. 2006;15:301-303.
11. Berkun Y, Padeh S, Barash J, et al. Antiphospholipid syndrome
and recurrent thrombosis in children. Arthritis Rheum. 2006;55:
850-855.

1050
Downloaded from jcn.sagepub.com at UNIV OF CONNECTICUT on May 27, 2015