COL4A1 Mutation in a Patient With Sporadic, Recurrent
Intracerebral Hemorrhage
Katayoun Vahedi, MD; Nathalie Kubis, MD, PhD; Monique Boukobza, MD; Minh Arnoult, MD, PhD;
Pascale Massin, MD; Elisabeth Tournier-Lasserve, MD; Marie-Germaine Bousser, MD
Background and Purpose—Recently COL4A1, a gene encoding the type IV collagen ␣1 chain, has been found to be
involved in families with autosomal-dominant porencephaly and infantile hemiparesis. In addition to neonatal stroke,
some family members had experienced, during adulthood, spontaneous intracerebral hemorrhages (ICHs) and
leukoencephalopathy, suggestive of underlying small-vessel disease of the brain. We now report a patient with sporadic,
recurrent ICHs and a novel COL4A1 mutation.
Methods—We performed a clinical and genetic study of a 25-year-old-patient with an 8-year history of recurrent ICHs.
Results—This young, normotensive patient with a history of infantile hemiparesis had experienced, since the age of 17,
recurrent, spontaneous, deep ICHs occurring during sports activities. He became severely disabled. Brain magnetic
resonance imaging showed ventricular enlargement, diffuse white-matter abnormalities, and newly appearing, deep,
silent microbleeds. Extensive investigations found no cause. There was no family history of stroke or infantile
hemiparesis. A novel COL4A1 mutation (G805R) was identified.
Conclusions—The clinical spectrum of COL4A1 mutations includes recurrent ICHs in association with diffuse
leukoencephalopathy in young adults, even in the absence of a family history of infantile hemiparesis or ICH. In addition
to birth trauma, anticoagulant use, and head trauma previously reported, sports activities may be a precipitating factor
of ICHs in persons with COL4A1 mutations. (Stroke. 2007;38:1461-1464.)
Key Words: intracerebral hemorrhage 䡲 genetics 䡲 white matter 䡲 young adults

I

nfantile hemiparesis (congenital hemiplegia, or hemiparetic cerebral palsy) is considered the consequence of
perinatal stroke. The prevalence of perinatal stroke for infants
⬍30 days of age is estimated to be 1 in 4000 live births, with
approximately two thirds ischemic and one third hemorrhagic.1 The underlying mechanisms of infantile hemiparesis are
heterogeneous. Intrauterine growth restriction, preeclampsia,
chorioamnionitis, systemic infection, birth asphyxia, prolonged rupture of membranes, cord abnormalities, and cardiac and coagulation disorders have all been reported as risk
factors.1–3 However, infantile hemiparesis can occur after
normal pregnancy and normal birth. Families with infantile
hemiparesis and autosomal-dominant porencephaly have also
been reported.4 Recently, a new mouse mutant that develops
fatal perinatal hemorrhage and porencephaly has been identified with a mutation in Col4a1, a gene that encodes the type
IV collagen ␣1 chain.5 Mutant Col4a1 mice have structural
alterations of the vascular basement membrane in the brain
and other tissues. Recent studies have shown that mutations
in COL4A1 on chromosome 13q34 are involved in human

families with infantile hemiparesis and porencephaly.5–7 Interestingly, some mutant mice had, depending on their genetic background, a highly tortuous retinal vasculature in
addition to perinatal hemorrhage and porencephaly.8 This
retinal phenotype has been previously associated with familial infantile hemiparesis in a French family that was shown to
have a COL4A1 mutation.8,9 COL4A1 also plays a role in
intracranial hemorrhage (ICH) during adulthood in the mouse
and in humans.8,10
Herein we describe a novel COL4A1 mutation in a young
patient with a history of infantile hemiparesis who experienced, during adulthood, sporadic, recurrent ICHs associated
with diffuse white-matter abnormalities.

Subjects and Methods
A 25-year-old male with infantile hemiparesis and recurrent ICHs
and his 45-year-old mother were examined. Family history was
obtained from the mother. Genomic DNA was extracted from white
blood cells of the proband and his mother. Each of the 52 coding
exons of the COL4A1 gene was amplified (oligonucleotides and
conditions available on request from E.T.-L.). Direct sequencing of

Received October 10, 2006; final revision received October 24, 2006; accepted November 1, 2006.
From AP-HP, Service de Neurologie (K.V., N.K., M.G.B.), Centre de Référence pour les Maladies Vasculaires Rares du Système Nerveux Central et
de la Rétine (K.V., M.B., P.M., E.T.-L., M.G.B.), and Physiologie-Explorations Fonctionnelles (N.K.), Hôpital Lariboisière, Paris; INSERM U689 (N.K.),
Université Paris VII, Paris; AP-HP, Service de Neuroradiologie (M.B.), Hôpital Lariboisière; Paris; INSERM U740 (M.A., E.T.-L., M.G.B.), Université
Paris VII, Paris; and AP-HP, Service d’Ophthalmologie (P.M.) and Laboratoire de Cytogénétique (E.T.-L.), Hôpital Lariboisière, Paris, France.
Correspondence to Katayoun Vahedi, MD, AP-HP, Service de Neurologie, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France. E-mail
katayoun.vahedi@lrb.aphp.fr
© 2007 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

DOI: 10.1161/STROKEAHA.106.475194

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COL4A1 mutation in the proband.
Genomic DNA sequence analysis of
COL4A1 revealed a G805R mutation within
exon 31 (left panel). This mutation led to
the replacement of 1 of the highly conserved glycine residues of the triple-helix
domain of COL4A1 and was not present in
50 control DNA samples. Brain CT (right
panels) at age 23 shows bilateral ventricular dilatation, diffuse cortical and left skull
atrophy, diffuse white-matter abnormalities,
and multiple, deep, hypodense lesions surrounded by punctiform calcifications suggesting vascular cavities.

both strands was performed on an ABI3700 automated sequencing
apparatus. Informed consent was obtained from the mother. Fifty DNA
samples from healthy individuals were available as a control panel.

Results
Clinical Data
The proband is a 25-year-old man with no remarkable
perinatal event except for a postterm forceps delivery. At 3
months of age, the mother first noticed right-sided weakness.
Later he developed right-sided hemiatrophy and hand dystonia. Infantile hemiparesis was diagnosed, but he had normal
intellectual development. At the age of 17 years, he experienced his first episode of sudden dysarthria during jogging.
Brain CT and MRI showed a recent, right lenticular hemorrhage; diffuse, bilateral, white-matter abnormalities; and left
lateral ventricle enlargement. Blood pressure was 125/85.
Four-vessel cerebral angiography and transesophageal echocardiography disclosed no abnormalities. Extensive biologic
investigations, including complete blood count, serum electrolytes, creatinine, liver enzymes, serum and urinary homocysteine, coagulation tests, anticardiolipids, and lupus anticoagulant, were all in the normal range. In addition, albumin
urinary concentration was normal with no hematuria. Screening for all coding exons of KRIT1, the sole cerebral cavernous
malformation gene known at that time, was negative (oligonucleotides and screening conditions available on request
from E.T.-L.). At the age of 18, he had a left eye injury with
a posterior retinal hemorrhage and then developed a traumatic
cataract. Between the ages of 19 and 21, the patient had 3
recurrent episodes of a sudden worsening of dysarthria and
right-sided hemiparesis at each time during sports activities.
At each episode, a brain CT and MRI disclosed a new, deep
ICH located in the internal capsule or the basal ganglia,
multiple new microbleeds within the corpus callosum and
midbrain on gradient-echo imaging, and a diffuse leukoencephalopathy. At age 22, he had a generalized seizure when
swimming, leading to water inhalation and coma. Brain
imaging evidenced a large, deep hematoma in the right basal
ganglia with a mass effect and intraventricular hemorrhage.
After the last episode of ICH, the patient remained tetraparetic, totally bedridden, and dependent with pronounced
generalized spasticity, severe dysphagia, emotional lability,
and no verbal communication (modified Rankin scale⫽5).
His 45-year-old mother was clinically asymptomatic, and her
brain MRI examination was normal. She reported no family
history of infantile hemiparesis, stroke, or retinal hemorrhage

among the proband’s father (of Italian ascent), 18-year-old
sister, and grandparents.

COL4A1 Gene Screening
Genomic DNA sequence analysis revealed in this patient a
G2413A transition within exon 31 (the Figure). This mutation
changed a glycine amino acid to an arginine (G805R) within
the triple-helix domain of COL4A1. This mutation was not
detected in the control panel and was absent in his healthy
mother.

Discussion
Herein we report a patient with a novel COL4A1 mutation
who had experienced, since age 17, recurrent, sporadic, deep
ICHs leading to severe disability and total dependence at age
22. This COL4A1 mutation affects a highly conserved glycine
residue involved in repeated Gly-Pro-X motifs within the
triple helix, and their mutation has been shown to be
pathogenic both in COL4A1 and in various collagen genes.
There are several remarkable particularities in this patient:
(1) the early age of onset of ICH; (2) the deep locations of the
ICHs and asymptomatic microbleeds; (3) the high frequency
of recurrence over a short period of time; (4) the triggering of
ICH by sports activities without head trauma; (5) the absence
of any cause, including the absence of hypertension; (6) the
past history of infantile hemiparesis; and (7) the associated
diffuse leukoencephalopathy.
Among genetic vascular malformations that eventually
cause recurrent ICHs, cerebral cavernous angiomas were
ruled out in this patient on the basis of MRI, which did not
show the typical patterns of cerebral cavernous angiomas and
revealed diffuse, white-matter abnormalities not typically
encountered in cerebral cavernous angiomas. In addition,
screening of KRIT1 showed no mutation.
The clinical phenotype of deep, recurrent ICHs, leukoencephalopathy, and infantile hemiparesis led us to consider
COL4A1 as a candidate gene in this young, normotensive
patient. All 5 recently reported families with COL4A1 mutations had an autosomal-dominant porencephaly and infantile
hemiparesis but with incomplete penetrance, suggesting the
possibility of sporadic cases (Table 1).6,7,10 Among the
reported families, variations in the phenotypes of COL4A1
mutations were noted, including ICHs during adulthood,
diffuse leukoencephalopathy on brain imaging, and retinal
arteriolar tortuousities, even in the absence of infantile
hemiparesis or congenital porencephaly. There is so far no

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Vahedi et al
TABLE 1.

COL4A1 Mutation and Intracerebral Hemorrhage

1463

Reported Clinical and Imaging Data in 19 Patients With COL4A1 MUTATIONS5,7,9,10
No. of Patients/Total of Patients With Data

Neurologic manifestations

Neuroradiologic abnormalities

Porencephaly and infantile hemiparesis

13/19

Reported perinatal events

3/19 (postterm pregnancy in 2,
protracted duration of expulsion in 1)

Slight to moderate mental retardation

7/19

Seizures in childhood

4/19

ICH in adulthood

5/19

Migraine

5/19 (migraine with aura in 3)

Leukoencephalopathy on brain MRI or CT

16/19

Porencephaly without infantile hemiparesis

2/19

Silent microbleeds on gradient-echo MRI

2/4

Ophthalmologic manifestations

Retinal arteriolar tortuousities

5/8

Retinal hemorrhage

2/7 (traumatic in 1)

Cataract

3/19 (traumatic in 1)

Hematuria

1/19

Other clinical manifestations

pathology study of the cerebral vessels in patients with
COL4A1 mutations. Endothelial cell basement membrane
abnormalities of skin capillaries with focal interruptions or
increased thickness have been reported in a patient with
COL4A1 mutations and recurrent and disabling ICHs in
adulthood.10 Abnormalities of the basement membrane of
cerebral vessels have also been noted in col4a1-mutant mice
by electron microscopy.5 All of these data suggest that
COL4A1 mutations cause generalized small-vessel disease
with particular involvement of the brain vessels. Herein we
report the first sporadic patient with COL4A1 mutation and
enlarge the phenotypic spectrum of COL4A1 mutation to
early-onset sporadic, recurrent, and disabling deep ICHs. In
our patient, sports activity, in addition to birth trauma, brain
trauma, and use of oral anticoagulants previously reported,
may have been a precipitating factor of the ICHs associated
with the COL4A1 mutation.
Ophthalmologic manifestations of COL4A1 mutations include cataract, spontaneous or traumatic retinal hemorrhage,
and retinal arteriolar tortuousities present in 5 of 8 patients
previously reported with COL4A1 mutations who underwent
fundus examination.9,10 It is interesting to note that, depending on their genetic background, some but not all col4a1mutant mice had retinal vascular tortuousities.8 Retinal arteriolar tortuousities have also been found in a family without
porencephaly but with leukoencephalopathy, hematuria, and
renal insufficiency.11 Whether the COL4A1 gene is also
involved in this family is not yet known. Type IV collagen is
TABLE 2. Main Features of COL4A1 Mutations, CADASIL
(NOTCH3 Mutations), and Hereditary Amyloid Angiopathy (CAA)

Neonatal stroke (infantile
hemiparesis, porencephaly)
ICH
Cerebral infarcts
Leukoencephalopathy
Silent microbleeds

COL4A1

CADASIL (NOTCH3)

CAA

Yes

No

No

an essential component of the glomerular basement membrane. Hematuria has been rarely reported in patients with
COL4A1 mutations (Table 1) but was not found in our
patient.
Because of the lack of pathognomonic neurologic symptoms, specific brain MRI abnormalities, and the possibility of
asymptomatic gene carriers and sporadic cases, patients with
COL4A1 mutations may be underdiagnosed. Considering our
data and the previously reported families with COL4A1
mutations, at least 1 of the following arguments should
prompt COL4A1 genetic screening in young patients with
deep ICHs of undetermined etiology: (1) a personal or family
history of infantile hemiparesis or congenital porencephaly,
(2) leukoencephalopathy with silent microbleeds in the absence of hypertension, and (3) the presence of retinal arteriolar tortuousities. Genetic counseling of at-risk young women
planning to become pregnant is of major importance, because
cesarean delivery should be recommended to try to prevent
vascular injury attributable to birth trauma. In at-risk adults,
sustained physical activity or sports activities that may cause
head trauma should be avoided, and anticoagulant use should
be strictly monitored.
COL4A1 mutation features are distinct from those of other
known genetic small-vessel diseases of the brain, as congential hemiplegia and perinatal stroke are not features of
cerebral amyloid angiopathy or CADASIL, although silent
microbleeds on gradient-echo imaging have been frequently associated with both cerebral amyloid angiopathy
and CADASIL (Table 2).12–14
In conclusion, COL4A1 mutations have a wide clinical
spectrum, including recurrent and disabling ICHs in young
adults, even in the absence of any family history of infantile
hemiparesis or stroke. Further studies will be needed to
determine the frequency of COL4A1 mutations and the
mechanisms by which they lead to hemorrhagic strokes and
leukoencephalopathy.

Yes

Rare

Yes

Uncertain

Yes

Rare

Yes

Yes

Yes

Acknowledgment

Yes

The authors thank Stéphane Chabrier for the critical comments on
the manuscript.

Yes

Yes

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Disclosures
None.

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COL4A1 Mutation in a Patient With Sporadic, Recurrent Intracerebral Hemorrhage
Katayoun Vahedi, Nathalie Kubis, Monique Boukobza, Minh Arnoult, Pascale Massin,
Elisabeth Tournier-Lasserve and Marie-Germaine Bousser
Stroke. 2007;38:1461-1464; originally published online March 22, 2007;
doi: 10.1161/STROKEAHA.106.475194
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2007 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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