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COL4A1 mutation in AxenfeldЦRieger anomaly with leukoencephalopathy and stroke.

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COL4A1 Mutation in Axenfeld–Rieger
Anomaly with Leukoencephalopathy
and Stroke
Igor Sibon, MD, PhD,1 Isabelle Coupry, PhD,2 Patrice Menegon, MD,3 Jean-Pierre Bouchet, MD,4
Philippe Gorry, MD, PhD,2,5 Ingrid Burgelin, LT,2 Patrick Calvas, MD, PhD,6 Isabelle Orignac, MS,7
Vincent Dousset, MD, PhD,3 Didier Lacombe, MD,2,5 Jean-Marc Orgogozo, MD,1
Benoı̂t Arveiler, PharmD, PhD,2,5 and Cyril Goizet, MD, PhD1,2,5
Objective: Several hereditary ischemic small-vessel diseases of the brain have been reported during the last decade. Some of them
have ophthalmological, mainly retinal, manifestations. Herein, we report on a family affected by vascular leukoencephalopathy
and variable abnormalities of the anterior chamber of the eye.
Methods: After the occurrence of a small, deep infarct associated with white matter lesions in a patient with a medical history
of congenital cataract and amblyopia, we conducted clinical and neuroradiological investigations in 10 of her relatives.
Results: Diffuse leukoencephalopathy associated with ocular malformations of the Axenfeld–Rieger type was observed in five
individuals. Familial genetic analyses led to the identification of a novel missense mutation in the COL4A1 gene, p.G720D,
which cosegregates with the disease.
Interpretation: Our data corroborate previous observations demonstrating the role of COL4A1 in cerebral microangiopathy and
expand the phenotypic spectrum associated with mutations in this gene. We delineate a novel association between the Axenfeld–
Rieger anomaly and leukoencephalopathy and stroke.
Ann Neurol 2007;62:177–184
Several hereditary disorders that affect small blood vessels of the brain recently have been individualized: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
(MIM125310), caused by mutations in the gene
NOTCH3 located on chromosome 19p131; cerebroretinal vasculopathy (CRV); hereditary endotheliopathy
with retinopathy, nephropathy, and stroke (HERNS);
hereditary vascular retinopathy (HVR) (CRV,
HERNS, and HVR are linked to the same locus on
chromosome 3p21) (MIM192315)2; cerebral autosomal recessive arteriopathy with subcortical infarcts and
leukoencephalopathy (CARASIL) (MIM600142)3;
Fabry’s disease (MIM301500)4; and familial variants of
cerebral amyloid angiopathies.5 More recently, the role
of mutations in the gene COL4A1 encoding collagen
IVA1 has been highlighted as a cause of cerebral
microangiopathy (MIM607595) and porencephaly
(MIM175780) in several reports of animal and human
studies.6 –9
Ocular manifestations are common in most of these
conditions.10 Funduscopic examination and retinal angiograms may show different types of lesions associated
with cerebral small-vessel diseases. For example, retinal
infarcts, with vascular occlusions, microaneurysms, and
capillary leakage, were described in patients with CRV/
HERNS2; nerve fiber loss, cotton-wool spots, sheathed
arteries, and tortuous arteries were reported in patients
with CADASIL11; and retinal arteriolar tortuosity with
prominent enlargement of perivascular spaces was
found in patients with mutations in the gene
COL4A1.8
Other ophthalmological anomalies appear to be extremely rare and have been reported in few cases. Involvement of the anterior chamber of the eye was described in the context of cerebral small-artery disease. A
From the 1Centre Hospitalier Universitaire Bordeaux, Fédération
des Neurosciences Cliniques, Hôpital Pellegrin; 2Université Victor
Segalen Bordeaux 2, Laboratoire de Génétique Humaine, Développement et Cancer; 3Centre Hospitalier Universitaire Bordeaux,
Service de Neuroradiologie, Hôpital Pellegrin, Bordeaux; 4Cabinet
d’Ophtalmologie, Mont de Marsan; 5Centre Hospitalier Universitaire Bordeaux, Service de Génétique Médicale, Hôpital Pellegrinenfants, Bordeaux; 6Centre Hospitalier Universitaire Toulouse, Service de Génétique Médicale, Hôpital Purpan, Toulouse; and
7
Centre Hospitalier Universitaire Bordeaux, Département
d’Ophtalmologie, Hôpital Pellegrin, Bordeaux, France.
Received Feb 9, 2007, and in revised form Apr 23. Accepted for
publication Jun 15, 2007.
I.S. and I.C. contributed equally to this work.
Published online August 14, 2007, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21191
Address correspondence to Dr Sibon, Department of Neurology,
CHU Bordeaux, 33076 Bordeaux Cedex, France.
E-mail: igor.sibon@chu-bordeaux.fr
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
177
cataract was noted in three patients with hereditary
porencephaly and adult stroke related to a mutation in
COL4A1.9
We describe here an autosomal dominant syndrome
related to a novel COL4A1 mutation, and characterized
by cerebral vasculopathy and variable congenital defects
of the anterior segment of the eye that belong to the
clinical spectrum of Axenfeld–Rieger anomaly (ARA).
This term is used for a variety of overlapping phenotypes, including anomalies of the anterior chamber angle and aqueous drainage structures (iridogoniodysgenesis), iris hypoplasia, eccentric pupil, iris tears, and
iridocorneal tissue adhesions traversing the anterior
chamber.12,13 ARA appears to be genetically heterogeneous. It has been associated with mutations in three
genes: PITX2 (on chromosome 4q25), FOXC1 (also
named FKHL7) (6p25), and PAX6 (11p13).12 An additional locus has been identified on chromosome
13q14.14
Subjects and Methods
Subjects
Eleven members of a four-generation family gave informed
consent and underwent systematic ophthalmological examination. In addition, the proband (Case III.2) underwent cerebral angiography; cerebral magnetic resonance angiography;
cervical and transcranial ultrasound examination; transthoracic and transesophageal echocardiography; Holter electrocardiography; arterial lower limb and renal Doppler echography;
hematological, clotting, biochemical, and immunological laboratory analysis of serum and cerebrospinal fluid; skin biopsy
to study cutaneous vessels; muscle biopsy to study the mitochondrial respiratory chain; measurement of sensory- and
visual-evoked potentials; and electromyography.
Magnetic Resonance Imaging
Neuroimaging was performed in nine subjects (all subjects
except Subjects I.1 and I.2) at 1 to 1.5 Tesla. T1-weighted
images were obtained from axial and/or sagittal planes, and
T2-weighted images or fluid-attenuated inversion recovery
(FLAIR) images were obtained from axial planes. In addition, diffusion-weighted images and T2-weighted gradientecho images were obtained in the axial plane in Case III.2. A
neuroradiologist (P.M.) blinded to the clinical status of subjects reviewed the magnetic resonance images for evidence of
anomalies.
Genetic Studies
After informed consent was obtained, blood samples were
collected from 10 examined subjects (all subjects except Subject I.1). Genomic DNA was extracted from peripheral blood
cells following standard procedures. Microsatellite markers
were selected from published data and used for genetic linkage analyses directed toward three loci associated with hereditary vasculopathies: three microsatellite markers (D19S841,
D19S226, and D19S199) were used for testing the CADASIL locus on 19p13 (NOTCH3 gene)15; four markers
(D3S3685, D3S3582, D3S1289, and D3S3616) were used
178
Annals of Neurology
Vol 62
No 2
August 2007
for testing the CRV/HERNS/HVR locus on 3p212; and
three markers (D13S1315, D13S148, and D13S261) were
used for testing the COL4A1 gene locus on chromosome
13q34. We also performed linkage on the four loci known to
be associated with ARA. The markers used for testing these
loci were as follows: D6S1600, D6S344, 27919-TG, and
27919-GT (FOXC1) on 6p25; D4S2301, D4S2945,
D4S193, and D4S2940 on 4q25 (PITX2); D13S1293,
D13S218, and D13S263 on locus 13q14; and Z23802/
D11S1322, Z66772, and Z67040 on 11p13 (PAX6). In addition, direct sequencing of the entire coding region and
intron-exon boundaries of PITX2 and COL4A1, as well as
indirect analysis by denaturing high-performance liquid
chromatography of the coding region and intron-exon
boundaries of PAX6, was performed in the proband. The designed primer sequences and conditions used for amplification, denaturing high-performance liquid chromatography,
and sequencing are available on request.
Results
Case Reports
The main clinical and MRI features of five study cases
are summarized in the Table.
The proband, a 37-year-old woman, was
born after an uneventful pregnancy; delivery was also
uneventful. A bilateral congenital cataract with congenital chronic glaucoma, bilateral microcornea, peripheral
opacities, and amblyopia of the left eye were diagnosed
early (Figs 1A, B). The cataract was surgically treated at
age 12 years. She was treated by hypotensive eyedrops
since age 23. The patient was hospitalized for sudden
right hemiplegia at age 35. Clinical examination
showed right hemiplegia with a Babinski sign, without
sensory disturbance, and right central facial palsy. The
Mini-Mental State Examination (MMSE) score was 27
of 30. Cardiovascular examination findings were normal. Computed tomography showed a diffuse leukoencephalopathy. Brain MRI demonstrated a left small
deep infarct of the centrum ovale on diffusionweighted images (Fig 2A). FLAIR images showed bilateral periventricular diffuse hyperintensities of the
white matter (see Fig 2B) but a normal brainstem. T2weighted gradient-echo images showed microbleeds located mainly in the basal ganglia and the cerebellum
(see Fig 2C). Angiography and magnetic resonance angiography demonstrated an asymptomatic aneurysm of
the top of the basilar artery. Ophthalmological examination showed decreased visual acuity in both eyes.
Fundus examination findings were normal, without
retinal hemorrhages or arteriolar tortuosity and with
normal veins in both eyes. Visual field of the right eye
was normal. All results of serum and cerebrospinal
fluid analysis, including anticardiolipin antibodies, lupus anticoagulant, antinuclear factor, creatinine clearance, lysosomal enzyme activity, and very long chain
fatty acids, were normal. There was no microalbumin-
CASE III.2.
Table. Main Clinical and Brain Magnetic Resonance Imaging Features
Features
Clinical Data
Sex
Age (yr)
Neurological
Pyramidal syndrome
Cranial nerve palsy
Sensory disturbance
Cerebellar syndrome
Extrapyramidal
syndrome
MMSE score (out
of 30)
Ophthalmological
Axenfeld–Rieger
anomaly
Congenital cataract
Microcornea
High intraocular
pressure
Optic nerve
excavation
Retinal arteriolar
tortuosity
MRI Data
Leukoencephalopathy
Small deep infarct
Porencephaly
Microbleeds
Case No.
II.2
III.2
III.3
III.4
IV.1
F
58
F
37
M
32
F
29
F
8
⫹
⫺
⫺
⫺
⫺
⫹
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
28
27
27
27
NA
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫺
NA
⫹
⫹
⫺
⫹
⫹
⫺
⫺
NA
⫹
⫺
⫺
NA
⫹
⫺
⫹
NA
MMSE ⫽ Mini-Mental State Examination; NA ⫽ not available.
uria. The karyotype of lymphocytes was normal
(46,XX). Transthoracic and transesophageal echocardiography, cervical and transcranial ultrasonography,
measurement of evoked potentials, and electromyography all yielded normal findings. Light microscopy of a
skin biopsy, including several arterioles, capillaries, and
venules, did not disclose vessel wall lesions; no abnormal deposits were stained by periodic acid–Schiff or
Congo Red, or shown by antiubiquitin immunohistochemistry. Biopsy for ultrastructural study included
only capillaries and some very small venules, and there
were no detectable abnormalities. Muscle biopsy findings were also normal, without ragged red fibers or abnormalities of mitochondrial enzymes. A diagnosis of
small deep infarct of unknown cause was established.
During the 2 years after this stroke, the patient had no
additional cerebrovascular events, but a left detachment
of the retina occurred. At age 37, examination showed
a right spastic hemiparesis with pyramidal signs and
central facial palsy. There was no sensory or cerebellar
disturbance. The MMSE score was 27 of 30, and she
experienced development of severe depression that required antidepressive and anxiolytic drugs.
CASE IV.1.
This 8-year-old girl is the proband’s
daughter. She was born after an uneventful pregnancy;
delivery was normal. No fetal distress was reported. At
birth, malformations of the eyes were obvious. Her
ophthalmological abnormalities included a bilateral
congenital cataract, iris hypoplasia, microcornea (see
Fig 1C), and left amblyopia with normal intraocular
pressure. Infantile hemiparesis was noted during the
neonatal period. Brain MRI performed at age 11
months showed a left paraventricular porencephaly
without other anomalies. No further neurological event
was reported after this date. At age 8 years, neurological examination showed a right spastic hemiparesis.
Blood pressure and cardiovascular examination findings
were normal. Visual acuity was low in both eyes. Fundus examination did not show retinal arteriolar tortuosity or any retinal hemorrhages or exudates in either
eye. Fluorescein angiography showed no abnormality;
Sibon et al: ARA, Leukoencephalopathy, and Stroke
179
Fig 1. Ophthalmological features of some affected family members. (A, B) Case III.2 (proband): Contact lens is worn on the right
eye (A) to correct aphakia caused by congenital cataract surgery (arrow). Note microcornea, corectopia (arrow 1), and peripheral
corneal opacity (arrow 2). On the left eye (B), note microcornea, peripheral corneal opacities (arrow 2), and irregular pupil (arrow
3). (C) Case IV.1: Right eye presents only microcornea; the congenital cataract cannot be seen in this photograph. The corectopia is
shown by arrow 1.
arteriolar caliber was normal, and there was no leakage
of fluorescein or capillary dropout. Brain MRI showed
widespread, asymmetric, periventricular white matter
hyperintensities on FLAIR images, associated with
poststroke dilatation of the posterior horn of the left
lateral ventricle (see Fig 2D). No brainstem lesion was
observed.
This 32-year-old man is the proband’s
brother. He had had bilateral amblyopia since birth.
Ophthalmological examination showed bilateral high
myopia, polycoria on the left eye, and a bilateral congenital cataract. Bilateral juvenile glaucoma was treated
by glaucoma drainage implant surgery on the right side
and by hypotensive eyedrops on the left one. The patient had no history of neurological manifestations or
headache. Neurological examination disclosed generalized brisk tendon reflexes, and the MMSE score was 27
of 30. Blood pressure was normal, and no vascular risk
factors were recorded. Fundus examination showed an
excavation of the optic disc caused by glaucoma. T2weighted images of the brain showed a diffuse hyperintensity of the periventricular white matter (see Fig
2E). No brainstem lesion was observed. The first pregnancy of the patient’s wife ended in spontaneous abortion in the third trimester. Later, the couple had one
unaffected child with normal ophthalmological findings.
CASE III.3.
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This woman, sister of the proband, was 29
years old. She also had bilateral amblyopia, predominating in the left eye. Ophthalmological examination
showed a microcornea and an unoperated bilateral cataract, with normal intraocular pressure. Neurological
examination results and blood pressure (120/80mm
Hg) were normal. The MMSE score was 27 of 30. She
did not report headache or other neurological symptoms. Brain MRI showed a diffuse periventricular leukoencephalopathy (see Fig 2F). No brainstem lesion
was observed. Fundus examination showed no anomalies of retinal vessels.
CASE III.4.
This 58-year-old woman is the mother of
the proband. She had bilateral high myopia, iridogoniodysgenesis, iris hypoplasia, microcornea, and congenital cataract. At age 55, high intraocular pressure
was observed (26mm Hg on both sides) requiring
treatment using hypotensive eyedrops. She had no history of diabetes or hypertension. She did not report
any neurological symptoms or headaches. Neurological
examination showed generalized brisk tendon reflexes
without sensorimotor deficit and a rest tremor of the
head without akinesia or hypertonia. The MMSE score
was 28 of 30. Fundus examination was normal without
retinal arteriolar tortuosity. Brain T1-weighted images
and FLAIR MRI showed a diffuse leukoencephalopathy with two large holes (see Figs 2G, H) compatible
CASE II.2.
Fig 2. Magnetic resonance imaging data from some affected family members. (A–C) Case III.2 (proband): Diffusion-weighted image (A) showing a left small deep infarct of the posterior limb of the internal capsule, fluid-attenuated inversion recovery (FLAIR)
image (B) demonstrating a widespread leukoencephalopathy, and T2* (C) showing microbleeds (arrowhead). (D) Case IV.1: FLAIR
image showing a periventricular leukoencephalopathy and poststroke dilatation of the posterior horn of the left lateral ventricle (porencephaly) (arrow). (E) Case III.3: T2-weighted image showing a periventricular leukoencephalopathy. (F) Case III.4: T2-weighted image
showing a periventricular leukoencephalopathy. (G, H) Case II.2: T1-weighted image (G) demonstrating two hypointense lesions suggestive of ischemic lesions (small arrows); FLAIR image (H) showing a marked periventricular leukoencephalopathy.
with ancient asymptomatic small deep infarct or small
hemorrhages. No brainstem lesion was observed.
Subjects I.1, I.2, and
II.4 had normal neurological findings. Subject II.3 had
a 10-year history of hypertension and showed bilateral
Babinski signs with generalized brisk tendon reflexes
and a moderate right kinetic cerebellar syndrome on
examination. Brain MRI showed asymmetric, slight
periventricular leukoencephalopathy on T2-weighted
images and few small deep infarcts of the basal ganglia
in this subject. Brain MRI was normal in Subject II.4.
SUBJECTS I.1, I.2, II.3, AND II.4.
Subjects I.1 and I.2 each had a senile cataract surgically
treated after age 70 years. Subject I.1 refused to give
blood samples for genetic analysis or to undergo cerebral MRI. Neurological examination findings at age 78
years were normal. Because some data could not be
obtained, she was considered to be probably healthy.
Genetic Studies
Direct sequencing of the coding region of PITX2 was
performed in the proband (Case III.2) and detected no
deleterious mutation. Genetic linkage analyses with
markers located on chromosomes 19p13 (NOTCH3),
Sibon et al: ARA, Leukoencephalopathy, and Stroke
181
Fig 3. COL4A1 mutation in a family with Axenfeld–Rieger anomaly, leukoencephalopathy, and stroke. Pedigree of the family is
presented. All affected members of the family (black symbols) had ocular malformations of the Axenfeld–Rieger type and leukoencephalopathy. Subject I.1 refused to undergo genetic analysis. Haplotypes obtained on locus 13q34 are indicated on the right of each
individual’s symbol. The sequence analysis of COL4A1 demonstrated a G2159A transition in exon 29, leading to the replacement
of glycine with aspartic acid at position 720 (p.G720D) in affected members. The genotype (normal [A/A] or mutant [G/G]) is
indicated for each family member. Wt ⫽ wild-type.
3p21, 6p25 (FOXC1), 4q25 (PITX2), and 13q14
showed that for each of the fully informative markers
tested, affected individuals did not share the haplotype
transmitted by the obligate affected founder (Case II.2)
to the definitely affected offspring. These data strongly
suggest that this disorder is not linked to these different loci.
Genetic linkage with markers located on chromosomes 11p13 (PAX6) and 13q34 (COL4A1) showed
the transmission of a common haplotype to all definitely affected subjects. Because linkage to these two
loci remained possible, we also performed in the proband a genomic DNA search for mutation in the entire
coding region and exon-intron boundaries of PAX6 using denaturing high-performance liquid chromatography techniques and of COL4A1 by direct sequencing.
No mutation was detected in PAX6. A heterozygous G
to A transition at position 2159 (c.2159G⬎A) was
identified in exon 29 of COL4A1 (Fig 3), leading to
the replacement of a highly conserved (Fig 4) glycine
residue at position 720 with aspartic acid (p.G720D)
within the triple-helix domain. This missense mutation
cosegregated with the disease in the family (see Fig 3)
and was not present in 200 control chromosomes.
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August 2007
Discussion
We report on a French Caucasian kindred affected over
at least three generations by a white matter disease consistent with cerebral vasculopathy in the context of familial autosomal dominant malformations of the anterior chamber of the eye and missense mutation in the
COL4A1 gene. After clinical examination, 5 of the 11
family members were diagnosed as being definitely affected. These five cases had ocular anterior chamber
abnormalities of the Axenfeld–Rieger type, of variable
severity, and cerebral MRI showed diffuse leukoen-
Fig 4. Sequence alignment of COL4A1 orthologs in nine species. Conservation of the glycine residue at position 720 of
exon 29, mutated in the study family to an aspartic acid residue, is shown in dark gray.
cephalopathy. Stroke had occurred in two family members; a neonatal episode led to infantile hemiparesis.
Regarding cerebral involvement, several clinical and
neuroimaging findings suggest a chronic small-vessel
vascular disease: the occurrence of infantile hemiparesis
in one case (Case IV.1); the occurrence of young adult
stroke unrelated to cardiovascular risk factors or hypercoagulability in one other case, in association with microbleeds discovered on T2* images (Case III.2); and
the existence of two asymptomatic small deep infarcts
in a third case (Case II.2).
The deleterious effect of the p.G720D mutation and
its role in the cerebrovascular and ophthalmological
phenotypes observed in the study family are supported
by several arguments. First, the mutation affects a
highly conserved glycine of Gly-X-Y repeats within the
collagenous domain of the protein that is known to
interact with COL4A2 to form a collagen IV triple helix.16 Second, glycine residues are highly conserved
within the triple-helix domain of collagen type IV ␣1,
and mutations in codons encoding glycine are pathogenic in multiple species.6,16,17 These amino acid
changes are predicted to result in severe detrimental effects on collagen triple-helix formation and stability.18
Third, dominant mutations in the procollagen type IV
␣1 gene (Col4a1) have been shown to predispose mice
to porencephaly, renal vascular defects, newborn and
adult intracerebral hemorrhages,6,7 and ocular anterior
segment dysgenesis consistent with ARA.18 –20 Fourth,
recent studies have demonstrated that mutations in
COL4A1 in humans can lead to microangiopathy, with
late-onset leukoencephalopathy, ischemic and hemorrhagic strokes, and retinal arteriolar tortuosity,7–9 and
also to hereditary porencephaly, with probable predisposition to environmental stress–induced hemorrhage.6,9,16 Five of the six mutations previously described in humans, as well as the one observed in the
family presented here, affect such a glycine residue in
the triple-helix domain: p.G1236R, p.G749S,
p.G1130D, and G1423R were reported to segregate
with porencephaly,6,7,16 whereas p.G562E was associated with small-vessel disease.7,9
In reference to previous MRI findings for patients
with COL4A1 mutations,6 –9,16 our observations confirm that this leukoencephalopathy predominates in
the supratentorial posterior periventricular areas and
can be observed in subjects with and without focal
neurological symptoms. Intracranial hemorrhages after
minor or major brain trauma in adults have also been
reported previously.7 Such an event was not observed
among the adults of the family described here. However, the case with infantile hemiparesis and porencephaly (Case IV.1) is in accordance with the increased
risk, described in humans and mouse models, of cerebrovascular complications related to the stress of delivery.6,7 In contrast, a relatively low MMSE score was
noted among all adult subjects affected by the disease
(Cases III.2, III.3, III.4, and II.2). Mild-to-moderate
mental retardation has been reported in patients with
infantile hemiparesis and the COL4A1 mutation8;
however, no cognitive impairment was described in the
absence of neurological symptoms among patients with
the COL4A1 mutation. Complementary neuropsychological evaluation and follow-up will be mandatory to
clearly identify a cognitive impairment related to the
pathology, as has been described in CADASIL.21
Type IV collagens are ubiquitous basement membrane proteins, including the vascular basement membrane. Six different ␣ chains belong to the family of
the type IV collagen molecules, which can form three
distinguishable networks.22 Collagens IV A1 and A2
are the most abundant type IV collagens and confer
strength to basement membranes. Gould and colleagues7 showed that mutations in Col4a1 lead to focal
disruptions of the vascular basement membrane and
swelling of vascular endothelial cells with prominent
vesicles. van der Knaap and coworkers9 also found focal disruptions and a major increase in thickness of the
vascular basement membrane of human skin capillaries.
Therefore, it has been suggested that focal disruptions
of the vascular basement membrane may predispose to
hemorrhage, whereas the swelling of vascular endothelial cells and the increased thickness of the basement
membrane may lead to narrowing of vessels and may
predispose to ischemic damage.9 We failed to find any
anomaly in our skin biopsy samples. This result may
be related to the wide phenotypic variability of the disease or to chance.
The main differences between the family described
here and other cases previously described are represented by the presence of ARA. Although the eye’s anterior chamber abnormalities have never been described
in humans with COL4A1 mutations before now, a polar cataract was reported in the clinical description of
three patients with neonatal porencephaly and adult
stroke.9 Conversely, we did not observe retinal vascular
tortuosity as Vahedi and colleagues8 described. Only
one case combining cataract and retinal vascular tortuosity has been reported to date.9 All these data demonstrate a wide variability in the ocular and cerebrovascular phenotypic spectrum and strongly suggest a
phenotype–genotype correlation in COL4A1 mutations
in humans, as suggested by previous studies in Col4a1mutated mice.6,18 Indeed, several Col4a1-mutated mice
have recently been shown to express variable defects in
the eye, brain, and kidney, vascular stability, and viability. ARA has been observed in 11 mouse strains: 10
strains carrying different Col4a1 missense mutations18,20 and, recently, in the model Gould and colleagues6,7 previously reported, 1 strain carrying a deletion of exon 40.19 Of particular interest is that mice of
four of these strains also have hemorrhagic stroke and
Sibon et al: ARA, Leukoencephalopathy, and Stroke
183
small-vessel disease,19,20 similar to the cases observed in
our study.
Several rare hereditary conditions are known to affect cerebral and retinal vessels, such as CADASIL,15,23,24 cerebroretinal hereditary conditions recently linked to 3p21,2 and other causes of cerebral
vascular leukoencephalopathy, such as Fabry’s disease
or CARASIL.3,25,26 Our study indicates that careful examination of the anterior segment of the eye, in addition to fundus examination, is recommended in the
context of cerebral microangiopathy because it may
suggest a possible mutation in COL4A1.
This work was supported by the Ministère de l’Enseignement Supérieur et de la Recherche and the Ministère de la Santé. The experimental work was performed on the Plateforme Génotypage Séquençage (PGS) of Bordeaux. The Plateforme Génotypage
Séquençage was constituted through support from the Conseil Régional d’Aquitaine (20030304002FA, 20040305003FA) and the
Fonds Européen de Développement Régional (FEDER; 2003227).
We are grateful to the family members who agreed to participate.
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