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of Child Neurology

Inaugural Cerebral Sinovenous Thrombosis Revealing Homocystinuria in a 2-Year-Old Boy
Cécile Saboul, Stéphane Darteyre, Cécile Ged, Christine Fichtner, Claire Gay and Jean-Louis Stephan
J Child Neurol published online 5 March 2014
DOI: 10.1177/0883073813520502
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Brief Communication

Inaugural Cerebral Sinovenous
Thrombosis Revealing Homocystinuria
in a 2-Year-Old Boy

Journal of Child Neurology
1-6
ª The Author(s) 2014
Reprints and permission:
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DOI: 10.1177/0883073813520502
jcn.sagepub.com

Cécile Saboul, MSc1, Stéphane Darteyre, MD, MSc2,3, Cécile Ged, MD, PhD4,
Christine Fichtner, MD2, Claire Gay, MD1, and Jean-Louis Stephan, MD, PhD1

Abstract
Cerebral sinovenous thrombosis is unusual during childhood and requires early and accurate management because of its detrimental consequences. We report on the case of a 2-year-old boy with mild psychomotor delay, who presented with nonfebrile
acute ataxia. A brain computed tomographic (CT) scan showed complete thrombosis of the superior sagittal sinus, confirmed by
magnetic resonance angiography and associated with a right frontal hemorrhagic infarction. Systematic screening for thrombophilia revealed homocystinuria linked to cystathionine b-synthase deficiency with underlying compound heterozygosity. The
evolution was favorable after anticoagulant therapy, specific diet, and vitamin supplementation. This case is of interest because
of the unusual clinical presentation as a pediatric cerebral sinovenous thrombosis. Furthermore, homocystinuria is rarely revealed
by cerebral sinovenous thrombosis at the onset of the disease and should systematically be ruled out in pediatric stroke.
Keywords
cerebral sinovenous thrombosis, childhood, homocystinuria
Received November 03, 2013. Received revised December 03, 2013. Accepted for publication December 03, 2013.

Pediatric stroke is rare: the estimated incidence rate for children
is approximately 2.3 to 2.7 per 100 000 per year.1-3 Among all
forms of pediatric stroke, cerebral sinovenous thrombosis is
uncommon with an incidence of 0.3 per 100 000 children per
year.4 It is frequently associated with head infection, trauma,
or dehydration.5 Because of its rather nonspecific presentation,
the diagnosis of cerebral sinovenous thrombosis is often delayed,
which can lead to death and/or serious neurologic impairment.6
Classical homocystinuria is a rare inborn error of methionine
metabolism causing an accumulation of sulfur amino acids in
blood and urine due to cystathionine b-synthase deficiency.7
In this condition, markedly high plasmatic concentrations of
homocysteine lead to arterial and/or venous thrombotic disease.7
Homocystinuria presenting as cerebral sinovenous thrombosis is
unusual and has been reported mostly in older children or adults
at an advanced stage of the disease.5,8-11 In this paper, we report
on a rare case of cerebral sinovenous thrombosis in a 2-year-old
boy revealing cystathionine b-synthase deficiency and discuss
diagnostic and therapeutic implications.

Case Summary
Clinical Presentation
A 2-year-old boy was admitted to the pediatric emergency room for
tremor of the lower limbs, unsteady gait, and behavioral changes

that began abruptly about 8 hours before admission. His parents,
of Caucasian origin, were not related and presented with no
unusual medical history. Neither did his brother. Pregnancy and
birth had been unremarkable. He started walking at twenty months,
with a marked tendency to stumble, and language development
was delayed. The parents reported transient clonic movements of
his left arm but no loss of contact. He had no reported fever.
On physical examination, temperature was normal and he had
a normal blood pressure (88/56 mm Hg). He presented with asthenia and normal consciousness. No signs of raised intracranial
pressure or meningeal syndrome were noted. The upper limb
movements were dysmetric and he presented with Romberg negative ataxia and left hemiparesis. Tendinous and cutaneo-plantar
reflexes were normal. Further examination did not reveal any

1

Department of Pediatrics, CHU Saint-Etienne, Saint-Etienne, France
Department of Pediatric Rehabilitation, CHU Saint-Etienne, Saint-Etienne,
France
3
Research Group on Thrombosis–EA 3065, Université Jean Monnet, SaintEtienne, France
4
Department of Biology and Pathology, CHU Bordeaux, Bordeaux, France
2

Corresponding Author:
Cécile Saboul, MSc, CHU Saint-Etienne, Pédiatrie C, 42055 Saint-Etienne,
France.
Email: cecile.saboul@gmail.com

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Journal of Child Neurology

Figure 1. (A) Contrast-enhanced brain computed tomographic (CT) scan showing spontaneous hyperdensity of the superior sagittal sinus.
(B) After contrast injection, delta-shaped endoluminal defect, suggesting cerebral sinovenous thrombosis.

lack of sensitivity nor cranial nerves abnormality. Pupils were
symmetric and normally reactive to light. We also noticed fair
thin hair and an absence of any skeletal deformity.

Laboratory Tests
Routine laboratory blood tests showed normal blood cell count
and hemoglobin level, normal glycemia and an absence of
inflammation. Lactacidemia and ammonemia were within the
normal range and urine drug screen was negative.
Cerebrospinal fluid was clear with normal cell count and
biochemical parameters. Cerebrospinal fluid microbiology
and herpes simplex virus type 1 and 2 analyses were also
negative.

Neuroimaging and Electroencephalography (EEG)
Contrast-enhanced brain CT scan showed a spontaneous hyperdensity of the superior sagittal sinus (Figure 1a) and a classical
delta-shaped endoluminal defect after contrast injection, which
suggested cerebral sinovenous thrombosis (Figure 1b). The
presence of ataxia suggested venous thrombosis potentially
secondary to a brain tumor located in the posterior fossa.
We therefore decided to perform a brain magnetic resonance
angiography before starting anticoagulation. However, the
clinical status of the patient started to deteriorate, with altered
consciousness, hyperthermia and partial motor seizures of the
left upper limb. The EEG showed slow background activity
without paroxysmal abnormalities.
The brain magnetic resonance angiography evidenced an
extensive thrombotic lesion of the superior sagittal sinus
(Figure 2a and Figure 2b) with subarachnoid hemorrhage and
hemorrhagic infarction of the right frontal lobe (Figure 2c),
whereas posterior fossa imaging was normal.

Specific Testing
Hemostasis parameters were within the normal range, whereas
massive elevation of total plasma homocysteine (219.40 mmol/
L, normal concentration N < 15 mmol/L) suggested congenital
homocystinuria. Plasma amino acid profile showed increased
homocystine (36 mmol/L, N < 1) and methionine (41 mmol/L,
N ¼ 15-29), and low cysteine (7 mmol/L, N ¼ 11-30) concentrations. Urine amino acid profile showed massive accumulation of free homocystine (465 mmol/mol creatinine, N < 1).
Serum folic acid and vitamin B12 were within normal range.
The diagnosis of congenital homocystinuria revealed by cerebral sinovenous thrombosis was further confirmed by the
genetic analysis: the cystathionine b-synthase gene sequencing
revealed 2 missense mutations: p.Met126Val (c.376 A>G) and
p.His232Arg (c.695 A>G). Each variant was present at the
heteroallelic state in the mother and the father, respectively,
confirming compound heteroallelism in the affected child. The
clinical relevance of these mutations is discussed later. The
common MTHFR gene variant (c.677 C>T, associated with
thrombophilia) was not present in the child.

Treatment and Evolution
The partial seizures were rapidly controlled with intravenous
clonazepam and the antiepileptic treatment was maintained
(oral levetiracetam). Anticoagulation was initiated with a 50
IU/kg bolus of intravenous heparin followed by continuous
infusion (20 IU/kg/h) on a right femoral venous catheter. The
evolution was favorable, albeit thrombosis of the central catheter occurred. Intravenous heparin was discontinued after 1
week and replaced with oral vitamin K antagonists. The patient
was prescribed a low methionine diet and oral supplementation
with anhydrous betaine citrate (170 mg/kg/d), pyridoxine (20
mg/kg/d), vitamin B12 (1 mg/mo), and folic acid (5 mg/wk).

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Saboul et al

3

Figure 2. (A) Magnetic resonance angiography, gadolinium-enhanced sagittal T1-weighted images showing superior sagittal sinus endoluminal
defect. (B) Delta-shaped defect in the superior sagittal sinus on gadolinium enhanced coronal T1-weighted images. (C) Right frontal lobe
hemorrhagic infarct as a spontaneous hyperintensity on axial T1-weighted images.

After 3 months of anticoagulation and low methionine diet,
gait ataxia and hemiparesis had almost disappeared. Brain CT
angiogram showed nearly complete resolution of the thrombus
and no more hemorrhagic infarct. Vitamin K antagonists were
discontinued and relayed with oral aspirin. The antiepileptic
treatment was stopped after a normal control EEG. The
ophthalmic examination was normal, thereby ruling out pseudotumor cerebri and ectopia lentis. The evolution of metabolic
parameters is shown in Table 1.
Presently, the child has a mild psychomotor delay, discrete
gait ataxia, speech and behavioral disorders with reduced
attention span, normal stature, no skeletal deformities, and no
abnormal joint flexibility.

Discussion
The striking features of this case are the unusual presentation as
early pediatric cerebral sinovenous thrombosis, the novel genotype associated with cystathionine b-synthase deficiency, and
the therapeutic implications. Indeed, this is the first published
case of nonfebrile acute ataxia revealing childhood cerebral
sinovenous thrombosis due to homocystinuria. The accurate
diagnosis relied on systematic screening for thrombophilia, and
anticoagulant treatment was beneficial despite the presence of
a hemorrhagic infarct.
Only few published observations report cerebral sinovenous
thrombosis associated with homocystinuria at the onset of the
disease. Cardo et al published the case of a 6-month-old boy
who died of massive cerebral edema and hemorrhagic infarct
due to a thrombosis of the inferior sagittal sinus 6 days after
admission.5 The cause was diagnosed as the classical form of
homocystinuria based on postmortem analyses. In our case,
cystathionine b-synthase deficiency evidenced in the context
of a systematic screening for thrombophilia prompted an early,
specific treatment. Otherwise, authors diagnosed cystathionine
b-synthase deficiency in young children who presented with
inaugural arterial ischemic stroke.12,13

We also had to rule out the presence of a hemorrhagic lesion
with brain MRI before starting anticoagulation. Intriguingly in the
present case, the neurologic onset was poorly consistent with the
diagnosis of cerebral sinovenous thrombosis. Usual symptoms
such as fever and signs of raised intracranial pressure (headaches,
vomiting, photophobia, etc) were lacking.14 Besides, the presence
of ataxia and dysmetric upper limb movements raised concerns of
a lesion of the posterior fossa.15 This suggested the presence of
venous thrombosis adjacent to a brainstem tumor that could have
been missed with CT. This hypothesis could be corroborated by
our patient’s history of difficulties walking over obstacles and frequent stumbling, a gait development disorder observed in the
course of slowly expanding lesions located in the posterior
fossa.16 However, unlike adults, few children develop cerebral
sinovenous thrombosis secondary to a brain tumor.17 Moreover,
the clonic paroxysmal movements oriented toward cortical
lesions, probably because of small venous infarcts not seen on
conventional CT. Thus, the apparently paradoxical association
of cortical involvement and ‘‘pseudo-cerebellar’’ syndrome in our
patient could be understood if considering a frontal lobe origin for
ataxia. Erasmus et al18 have described 3 such cases in children
with unilateral frontal lesions (right frontal cavernoma and right
frontal abscesses), which disappeared after specific treatment.
Systematic screening for blood homocysteine led us to suspect
homocystinuria, which was confirmed by typical blood and urine
amino acid profiles. This screening is nowadays recommended
not only in cerebral sinovenous thrombosis but during the course
of any unusual thrombotic event in children.19 Homocystinuria
due to cystathionine b-synthase deficiency is an autosomal recessive disorder of the sulfur metabolism pathway showing 2 main
phenotypes: a mild pyridoxine-responsive form, often limited to
vascular thrombosis, and a severe pyridoxine-nonresponsive
form, including musculoskeletal and neuropsychological involvement.20 The normal cystathionine b-synthase enzyme
(EC 4.2.1.22) converts homocysteine to cystathionine in the
methionine transsulfuration pathway, and requires pyridoxal 5phosphate as a cofactor. The other 2 cofactors involved in methionine remethylation are vitamin B12 and folic acid (see Figure 3).21

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Journal of Child Neurology

Table 1. Metabolic Parameters Over a 12-Month Period After Diagnosis.

Plasma amino acids (mmol/L)
Total homocysteinea (N < 15)
Methionine (15 < N < 29)
Cystine (11 < N < 30)
Methionine diet (mg/d)

Diagnosis

1 mo

2 mo

3 mo

4 mo

6 mo

12 mo

219.4
41
7
300

3.34
18
23
300

6.03
45
19
>> 300

135.8
435
8
>> 300

42.9
78
12
250

4.27
29
6
250

31.8
97
23
250

a

Therapeutic target < 50 mmol/L.

Figure 3. Methionine metabolism: transsulfuration and remethylation pathway.

CBS gene analysis confirmed the diagnosis identifying a novel
genotype while excluding less frequent causes of homocystinuria,
notably defects in the remethylation pathway: methylene tetrahydrofolate reductase (MTHFR) and cobalamin deficiencies.19
According to the most recent review, at least 150 mutant alleles
of the CBS gene have been associated with homocystinuria.22
Genetic analysis identified 2 missense variants located in the third
and sixth coding exons of the CBS gene: p.Met126Val and
p.His232Arg (Human Genome Variation Society nomenclature,
reference sequence NM_000071.2). The former variant (reference CM99034 in the Human Genome Variation in Disease database) has been described in a single patient.23 The enzymatic
activity of the corresponding mutant enzyme expressed in
Escherichia coli was greatly diminished and Western blot analysis showed protein instability, confirming the pathogenicity of
the variant. The patient, an Italian male child diagnosed at age
4 years, reportedly had a severe pyridoxine-nonresponsive
form, including lens dislocation, mild mental retardation,
osteoporosis, and arterial disease revealed by ultrasonography.
The severity was explained by the molecular defect present on
the second allele, which carried 2 variants associated in cis:

p.Arg58Trp and Ala114Val variants were responsible for a
drastic overall reduction of cystathionine b-synthase enzymatic activity (1.3% of control) and stability.
Our patient’s second variant (p.His232Arg, c.695 A>G),
associated in trans with p.Met126Val, as shown by CBS gene
analysis in the parents, has not been previously described and
is not recorded in any available database (CBS mutation database
and HGVD database). A very close variant due to the c.694 C>G
substitution affects the same amino acid, p.His232Asp (referenced CM062492 in HGVD), and has been detected in 3 alleles
(CBS mutation database, no clinical history). No enzymatic data
are available for either variant, whereas the ALAMUT prediction software indicates a potentially pathogenic variant, located
on a highly conserved amino acid common to 15 species (ALAMUT version 2.2, Interactive Biosoftware, Rouen, France). The
analysis of 50 control chromosomes from the general population
did not identify either variant (position c.694 C>G and c.695
A>G), thus eliminating a rare polymorphism.
As stated in the latest review, the prediction of vitamin B6
responsiveness associated with novel missense CBS mutations
is not firmly based.22

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Saboul et al

5

To treat cerebral sinovenous thrombosis in our patient, we
used the recently published European guidelines, which
recommend anticoagulation even in the presence of hemorrhagic infarct. Prolonged treatment over 3 to 6 months could be
justified on the basis of individual factors.6
After biological confirmation of cystathionine b-synthase deficiency, we provided our patient with a low protein diet, anhydrous
betaine citrate, folic acid, vitamin B12, and pyridoxine supplementation. Sufficient available data now indicate that such a regimen
decreases the risk of thromboembolic events and poor neuropsychological outcome in patients diagnosed early.22 Usually pyridoxine, in combination with folic acid and vitamin B12, is sufficient to
control hyperhomocysteinemia in so-called B6-responder patients,
as opposed to B6-nonresponders, who require a low-methionine
diet as first-line treatment and who may require supplementation
with betaine citrate as a methyl provider.7,22,24 In our case, we
started with a combination of diet and a full vitamin regimen in
order to reduce the risk of life-threatening cerebral sinovenous
thrombosis extension. Then the rapid and favorable metabolic
response allowed us to reduce the diet. However, this resulted in
increased homocysteinemia and methioninemia (see Table 1), suggesting that the patient would benefit from full treatment, including
a controlled diet and vitamin supplementation.

Conclusion
This atypical case of congenital homocystinuria is of importance because it underlines the need for systematic blood
homocysteine screening in cerebral sinovenous thrombosis
occurring during childhood, and more generally in pediatric
stroke, in order to provide the patient with the appropriate treatment right away and to reduce the risk of long-term detrimental
neurologic consequences.
Author Contributions
CS, SD, and CG contributed to the drafting and writing of this article.
SD, CF, CG, and JLS contributed to the revision of this paper.

Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.

Funding
The author(s) disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: Genetic analysis
was performed, thanks to PNMR2011-14 funding (technical assistance).

Ethical Approval
This case report was reviewed and approved by the ethics committee of
the Saint-Etienne hospital. Written informed consent was obtained from
the parents of the affected child before performing the genetic analyses.

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