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Anovel hereditary small vessel disease of the brain.

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A Novel Hereditary Small Vessel Disease of
the Brain
Steve Verreault, MD,1 Anne Joutel, MD, PhD,2 Florence Riant, MD,2 Georgina Neves, MD,3
Mario Rui Silva, MD,3 Jacqueline Maciazek,2 Elizabeth Tournier-Lasserve, MD,2
Marie-Germaine Bousser, MD,1 and Hugues Chabriat, MD, PhD1
Objective: Only few hereditary ischemic small vessel diseases of the brain (SVDB) have been reported so far. Cerebral
autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent of
them. Herein, we report a family affected by a SVDB distinct from CADASIL. Methods: After the occurrence of a small
deep infarct associated with white matter lesions both in a 46-year-old man and in his 52-year-old sister, clinical and
neuroimaging investigations were conducted in 13 of their relatives originating from Portugal. Other investigations
included (1) skin biopsy immunostaining with a Notch3 monoclonal antibody, (2) sequencing of the 23 exons encoding
the epidermal growth factor–like domains of the NOTCH3 gene, and (3) a NOTCH3 locus haplotype analysis. Results:
Diffuse white matter hyperintensities were observed on T2-weighted magnetic resonance imaging (MRI) in six individuals. In contrast with MRI results in the father and paternal uncle of the proband who were hypertensive, white matter
lesions were extensive in the mother who had no vascular risk factor. MRI data in four asymptomatic family members
together with the results in the two initial cases were suggestive of an underlying hereditary small vessel disease of the
brain. Skin biopsy and NOTCH3 gene mutation screening were negative. Haplotype analysis excluded the NOTCH3
locus. Interpretation: These data strongly suggest that this family is affected by a novel hereditary small vessel disease of
the brainand that the mutated gene is distinct from NOTCH3.
Ann Neurol 2006;59:353–357
Various hereditary small vessel diseases of the brain
(SVDB) have been identified recently as potential
sources of lacunar infarcts associated with leukoaraiosis.1 The most common familial SVDB, cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL), is caused by
mutations in the NOTCH3 gene.2,3 CADASIL is a
systemic arteriopathy responsible for recurrent ischemic
strokes and progressive subcortical dementia in middleaged adults. Prominent clinical manifestations also include migraine with aura and mood disorders.3,4 Other
rare genetic causes of ischemic SVDB have been reported: cerebral autosomal recessive arteriopathy with
subcortical infarcts and leukoencephalopathy (CARASIL),5 cerebroretinal vasculopathy,6 hereditary endotheliopathy with retinopathy, nephropathy and stroke
syndrome (HERNS),7 and familial amyloid angiopathies.8
We report a SVDB affecting a large family originating from Portugal with features resembling those ob-
From 1Service de Neurologie, Laboratoire de génétique, Hôpital
Lariboisière, Assistance Publique des Hôpitaux de Paris and 2Institut
National de la Sante et de la Recherche Médicale, U740, Faculté de
Médecine Lariboisière Saint-Louis, Paris, France; and 3Department
of Neurology, Hospital San Pedro, Vila Real, Portugal.
Received Jun 18, 2005, and in revised form Oct 28. Accepted for
publication Nov 2, 2005.
served in CADASIL without NOTCH3 gene mutations.
Subjects and Methods
Two patients originating from Portugal were seen after the
occurrence of a small deep infarct with leukoencephalopathy.
We examined consenting adult members of their large family
(Fig 1).
Magnetic Resonance Imaging Investigations
Neuroimaging studies were performed using a 1.5-Tesla
magnetic resonance (MR) scanner and included standard
T1-weighted (T1WI), T2-weighted (T2WI), fluid-attenuated
inversion recovery (FLAIR), and T2*-weighted gradient-echo
images as well as cerebral MR angiography (MRA).
Skin Biopsy Immunostaining and Electron Microscopy
A skin biopsy immunostaining with the 1E4 Notch3 monoclonal antibody was performed in Patient III-17 as previously
reported.9 For electron microscopy, tissues were fixed in
CARSON solution and embedded in Epon E812 resin; ul-
Published online Jan 10, 2006, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20775
Address correspondence to Dr Chabriat, Department of Neurology,
Hopital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France.
E-mail: hugues.chabriat@lrb.ap-hop-paris.fr
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
353
trathin sections were stained with lead citrate and uranyl acetate as described.10
Mutation Screening and Genetic Linkage Analysis
DNA of the index patient (Patient III-17) was selected for
NOTCH3 mutation screening. Each of the 23 exons encoding for epidermal growth factor (EGF) motifs were sequenced as previously described.11
NOTCH3 haplotype analysis was conducted as previously
described.12 A partial map of the NOTCH3 locus with the
indication of the markers and their respective distances is
shown in Figure 1.
In addition, genomic DNA of Patient III-17 has been sequenced to check for mutations in the APP, Cystatin C,
Transthyretin, Gelsolin and Bri genes (oligonucleotides and
sequencing conditions available upon request).
Results
Thirteen family members participated in this study
(Fig 1) after evaluation of Patients III-17 and III-19.
Clinical Data in Patients III-17 and III-19
PATIENT III-17. Patient III-17 was 50-year-old man
(proband) without cardiovascular risk factors who had
a single episode of acute left-sided hemiplegia at age 46
years. He had no history of headache but reported
memory deficits with emotional lability 2 years after
the episode. His blood pressure was 120/80mm Hg,
and his neurological examination showed a residual
hemiparesis. An extensive neuropsychological evaluation showed a reduction in memory performances as-
sociated with alterations in executive functions. The
patient was not demented.
The routine laboratory workup including blood cell
count, urea, creatinine, glucose, cholesterol, sedimentation rate was normal. Electrocardiogram, cervical and
transcranial Doppler, transthoracic and transoesophageal echocardiography, and fluorescein retinal angiography were normal. The cerebrospinal fluid examination (protein, glucose, and cell count) was normal.
Electromyography and nerve conduction studies were
normal.
PATIENT III-19. Patient III-19 was a 54-year-old
woman who had no cardiovascular risk factors and no
history of migraine, mood disorders, or cognitive dysfunction. She had an acute right hemiplegia at age 52
years. Examination showed hemiplegia involving the
face, arm, and leg with an associated sensory deficit
and moderate dysarthria. Blood pressure at admission
was 175/95mm Hg but it normalized within a week
(130/85mm Hg). The routine laboratory workup was
normal. Electrocardiogram, and cervical and transcranial Doppler were normal. Transthoracic and transoesophageal echocardiography showed an atrial septal aneurysm without patent foramen ovale.
Clinical Data in the 13 Relatives of Patients III-17
and III-19
Patients II-13 and II-14 were the parents of the proband. Detailed questioning did not suggest consan-
Fig 1. Family tree and NOTCH3 locus haplotyping data. The status used for genetic linkage analysis is indicated: (black filled
symbols) affected individual with clinical symptoms and typical magnetic resonance imaging (MRI) white matter changes; (half
blackened symbol) affected individual without clinical symptoms but with typical MRI white matter changes; (gray symbol) individuals with MRI white matter changes possibly related to chronic hypertension; (question mark) individual with an unknown
status, including (1) individuals without clinical symptoms and punctate nonspecific MRI white matter changes and (2) individuals
for whom no clinical and MRI data were available.
354
Annals of Neurology
Vol 59
No 2
February 2006
guinity. Patient II-13 was a 78-year-old man with a
longstanding history of alcohol abuse. His blood pressure was 165/80mm Hg at time of investigation and
170/90mm Hg 1 year later. Patient II-14 was a 73year-old woman without vascular risk factors. Both
cases were asymptomatic and had a normal examination.
In the same generation, Patient II-6 was a 75-yearold man with hypertension and hypercholesterolemia.
At age 73 years, he had an acute left-sided pure motor
hemiplegia related to a small deep infarct in the right
internal capsule. Clinical examination showed a leftsided motor deficit. Blood pressure was 180/100mm
Hg.
Patient II-12 was a 59-year-old woman who presented with a progressive paraparesis associated with a
complete anesthesia under the T-12 level at age 53
years. A thorough diagnostic workup including lumbar puncture and MRI of the spinal cord was normal.
No angiography was performed. Her medical history
was otherwise negative. Blood pressure was 140/
90mm Hg.
Patient II-15 was a 65-year-old woman without vascular risk factors. Decades before, she had a right peripheral facial palsy and a major depressive episode.
Clinical examination showed a mild residual right facial palsy. Blood pressure was 140/80mm Hg.
Investigations were also performed in six sisters and
two brothers of the proband. Blood pressure was normal in all subjects except in Patient II-18 who was
treated for hypertension by diuretics. His blood pressure was 150/90mm Hg. Four subjects had a history of
attacks of migraine without aura (Patients III-18, III21, III-23, and III-27). There was no history of stroke,
mood disorders, or cognitive dysfunction and neurological examination was normal in all of them. The
routine laboratory workup was normal in all cases except in Patient III-18 who had hypercholesterolemia.
Other Laboratory Tests
Additional blood tests were obtained in Patients III-17
and III-19: protein C and S, antithrombin III, prothrombin (G20210A), factor V (Leiden) and methylenetetrahydrofolate reductase gene (C677T) mutations,
anticardiolipid antibodies, anti-␤-2 GP1 antibodies,
antinuclear antibodies, homocysteinemia, human immunodeficiency virus serology, Venereal Disease Research Laboratory test, and Treponema pallidum hemagglutination test. All these tests were negative or in
the reference range.
Magnetic Resonance Imaging Data
MRI data obtained in Patients III-17 and III-19 are
presented in Figure 2. FLAIR images obtained in their
relatives are presented in Figure 3.
Based on MRI data, Patients II-14, III-20, III-23,
Fig 2. Magnetic resonance imaging (MRI)/MR angiography
(MRA) data obtained in Patients III-17 and III-19. Note in
Patient III-17 the widespread white matter hyperintensities the
presence of a lacunar infarction in the posterior limb of the
internal capsule on the right side and in the head of the left
caudate nucleus, and the presence of an hyperintense lesion
corresponding to the degeneration of the pyramidal tract
within the pons. Note in Patient III-19, the acute ischemic
lesion in the deep white matter on a diffusion-weighted image
(image C) and the presence of a discrete hyperintensity in the
white matter within the temporal lobe on fluid-attenuated
inversion recovery (FLAIR). On FLAIR images, a typical “état
criblé” was also detected within the lentiform nuclei.
and III-25 who were asymptomatic were considered
to be affected by the same disorder as detected in Patients III-17 and III-19. Asymptomatic Subjects III18, III-24, and II-15 (aged 30, 38, and 52 respectively) who had a strictly normal MRI were
considered healthy subjects. Individuals III-21, III-26,
III-27 who were asymptomatic and II-12 who had a
sudden paraparesis had subtle MRI signal abnormalities and were considered as having an unknown status. Chronic uncontrolled hypertension was most
likely involved in the white matter lesions detected in
Subjects II-13 and II-6 who were also considered as
having an unknown status.
Skin Biopsy
Immunostaining with a Notch3-specific monoclonal
antibody in Patient III-17 did not detect any accumulation of the Notch3 extracellular domain and therefore was considered normal. Ultrastructural analysis of
skin arterioles showed that smooth muscle cells were
poorly cohesive with nonspecific marked alterations in
shape but without any granular osmiophilic material
(GOM) deposits.
Verreault et al: Hereditary Small Vessel Disease
355
Fig 3. Magnetic resonance imaging data obtained in all other family members included in the study (FLAIR images, two cuts in
each subject). Flair images were normal in Patients II-15, III-18, III-24, and III-27 (no frame). Diffuse or patchy hyperintensities
were detected in the periventricular as well as in the subcortical white matter at distance from the ventricles in Patients II-14, III20, III-23, and III-25 (white frames). Hyperintense lesions predominate in the periventricular white matter in Patients II-6 and
II-13 and were very few and punctate in cases II-12, III-21 and III-26 (dotted white frame).
Genetic Studies
Sequencing of the genomic DNA to screen for mutations in the 23 exons encoding the EGF motifs located
in the extra cellular domain of Notch3 was performed
in Patient II-17. We did not detect any mutation affecting the number of cysteine residues.
To definitely exclude the role of the NOTCH3 gene,
we conducted a genetic linkage analysis in the family
using microsatellite markers bracketing the NOTCH3
locus. NOTCH3 haplotypes analysis showed that the
two clinically affected Patients III-17 and III-19 did
not share any paternal or maternal haplotype. In addition, Patient III-24 who was clinically healthy and had
a normal MRI shared both the maternal and the paternal haplotypes of Patient III-17 who is affected. The
same is true for Patient III-18 who is healthy and
shared both the maternal and paternal haplotypes of
Patient III-19 who is affected. These data establish that
the NOTCH3 locus is not involved in the disease
which segregates in this family.
Discussion
Two family members in this pedigree had a motor
hemiplegia related to a small deep infarct and MRI
features suggestive of a SVDB in the absence of vascular risk factors. Among their eight brothers and sis-
356
Annals of Neurology
Vol 59
No 2
February 2006
ters, three (ages range, 36 – 47 years) had similar MRI
white matter lesions. Their 73-year-old mother who
was normotensive also had extensive white matter hyperintensities on FLAIR images associated with multiple microbleeds. All of them were asymptomatic.
These data suggest a hereditary SVDB whose pattern
of inheritance cannot yet be firmly established, although an autosomal dominant inheritance with incomplete penetrance appears most likely involved.
The involvement of the NOTCH3 gene has been
ruled out in this kindred based on (1) skin biopsy data,
(2) the absence of mutation in the 23 exons of
NOTCH3 encoding EGF-like motifs in the index patient, and (3) Notch3 haplotype analysis which excluded the NOTCH3 locus.
Other hereditary SVDBs causing ischemic cerebral
white matter lesions also differ from the present disorder. CARASIL has been reported in Japanese families.5,13 The disease, which starts at a younger age, is
associated with alopecia, degenerative arthropathy,
and modifications of bony structures not present in
this family.5 The clinical presentation is distinct from
that reported in cerebroretinal vasculopathy6 or in
HERNS syndrome,14 both associated with visual loss,
brain mass lesions, or renal insufficiency.5 Finally,
mutations in genes involved in hereditary cerebral
amyloid angiopathies8 mostly responsible for dementia and cerebral hemorrhages also have been excluded.
In conclusion, the family reported herein is affected
by a novel hereditary SVDB. Investigation of additional family members and new pedigrees are now
needed to establish the pattern of inheritance and to
identify the mutated gene in this disorder.
We thank all of the family members from Portugal and France who
participated in this study. We also thank Dr C. Levy and D. Reizine
for their support in MRI investigations of different family members
and Dr A. Viswanathan for corrections to the manuscript.
References
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Verreault et al: Hereditary Small Vessel Disease
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