A case report about CADASlL: mutation in the NOTCH 3 receptor.

Abstract

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a rare autosomal dominant genetic disease characterized with recurrent stroke, migrainous headache, cognitive deficits, and psychiatric symptoms associated with mutations in the NOTCH 3 gene on chromosome 19. Here, we report a case of CADASIL who presented with migrainous headache, behavioral disorder, and familial history of stroke and the diagnosis was established by the findings of head magnetic resonance images revealing characteristic white matter lesions and a mutation in the NOTCH 3 gene.

Full text

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Acta Neurologica Taiwanica Vol 18 No 4 December 2009
From the Diskapi Yildirim Beyazit Training and Research
Hospital, Neurology Department, Ankara, Turkey.
Received April 6, 2008. Revised May 1, 2009.
Accepted June 10, 2009.
Reprint requests and correspondence to: Sennur Delibas, MD.
Diskapi Yildirim Beyazit Training and Research Hospital,
Neurology Department, Ankara, Turkey.
E-mail: drsennurdelibas@yahoo.com
A Case Report About CADASIL: Mutation in the
NOTCH 3 Receptor
Sennur Delibas, Hayat Guven, and Selim Selcuk Comoglu
Abstract- CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and
Leukoencephalopathy) is a rare autosomal dominant genetic disease characterized with recurrent stroke,
migrainous headache, cognitive deficits, and psychiatric symptoms associated with mutations in the
NOTCH 3 gene on chromosome 19. Here, we report a case of CADASIL who presented with migrainous
headache, behavioral disorder, and familial history of stroke and the diagnosis was established by the find-
ings of head magnetic resonance images revealing characteristic white matter lesions and a mutation in the
NOTCH 3 gene.
Key Words: CADASIL, Migraine, Magnetic resonance image, Notch 3
Acta Neurol Taiwan 2009;18:262-266
INTRODUCTION
CADASIL is an autosomal dominant arteriopathy
associated with mutations in the NOTCH 3 gene on
chromosome 19(1-12). Clinical manifestations include
recurrent cerebral ischaemic episodes, progressive cog-
nitive deficit, migraine with aura, dementia, and psychi-
atric symptoms(2-12). The neurological symptoms often
develop between the 3rd and 6th decades. Head magnet-
ic resonance image (MRI) often discloses diffuse white
matter lesions, small subcortical lacunar infarcts, and
cerebral microhemorrhages(1,3-5,8,9,13). Electron microscopy
evaluations of skin or smooth muscle biopsy specimens
may show the characteristics of CADASIL, that are spe-
cific accumulation of granular osmophilic material
(GOM) in the basal lamina(5,6,9,10). The diagnosis of
CADASIL is established by the detection of mutations
in the NOTCH 3 gene. This report aimed to discuss neu-
rological and radiological characteristics of CADASIL
through evaluation of a patient diagnosed with this rare
disease.
CASE REPORT
A 43-year-old female patient presented with the
complaints of headache for 7 years with the frequency
of 1 to 2 episodes a year. The headache was severe and
throbbing in nature, generally located in the vertex, and
accompanied with nausea and vomiting. She had sus-
tained progressive mental deterioration since 10 years
ago and became more severe in the recent 2 years. The
patient also suffered from intermittent occasional numb-
Case Reports

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Acta Neurologica Taiwanica Vol 18 No 4 December 2009
ness of the left arm and leg, lasting shorter than 15 min-
utes.
According to the history obtained from her spouse,
the patient had suffered from behavioral changes, such
as extreme irritability and crying and laughing episodes,
in the last few years. Her personal history was non-spe-
cific otherwise, except smoking habit. She did not expe-
rience problem during pregnancy. Her family history
revealed that her father died at the age of 56 years and
her uncle died in his 50s from ischemic cerebrovascular
disease, and her brother had been bed-ridden after an
ischemic cerebrovascular attack in his 40s.
There was unremarkable for blood pressure and
physical examination, nor pathological focal neurologi-
cal deficit. Head computer tomography (CT) showed
hypodense lesions with undefined margins in bilateral
periventricular white matters, external capsules, centrum
semiovales, and left temporal lobe (Fig.). Head MRI
showed widespread lesions in bilateral periventricular
and subcortical white matters, external capsules, and the
white matter of both temporal lobes. Lesions close to the
temporal poles were more marked. The lesions were iso-
hypodense in the pons on T1-weighted sections and
hyperintense on T2-weighted and FLAIR sections. The
lesions did not have edematous changes and contrast
involvement. Head MRI of her brother, who also had
cerebrovascular disease, revealed hyperintense lesions in
the periventricular white matter on T2- weighted sections
(Figs.).
The results of routine hematological, biochemical,
hormonal, coagulopathy and vascularity studies were
normal. The levels of lysosomal enzymes, serum B12,
lactic acid, and pyruvic acid were also normal.
Brucellosis agglutination test and lyme screening results
Figure. (A) hyperintensity lesions in the
external capsule, the anterior and
posterior horns of the lateral ven-
tricules, and the white matter of
the subcortical right frontoparietal
lobe on the FLAIR axial images; (B)
subcortical widespread hyperin-
tensity lesions in bilateral anterior
temporal lobes on the FLAIR axial
images; (C) widespread hyperin-
tensity lesions in the subcortex of
the bilateral temporal lobes and
periventriculary area on the T2
coronal images; and (D) hyperin-
tensity lesions in bilateral periven-
triculary and deep white matter
areas on the T2 axial images.
AB
CD

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Acta Neurologica Taiwanica Vol 18 No 4 December 2009
were negative. No abnormality was detected in visual
evoked potential, electroencephalopathy, and electroneu-
romyography. Due to mental and behavioral changes in
the patient, cognitive and psychometric measurements
were performed. Short-term memory functions test
(SMFT), mini-mental state examination (MMSE) and
Benton tests showed the scores were at the lower thresh-
old of normal levels. The test results generally showed
deficiency in attention. Through the clinical observations
and neuropsychiatric inventory (NPI) studies, unmarked
behavioral changes of agitation, irritability, and disinhi-
bition in particular were detected. The genetic analysis
of the patient and her brother revealed a heterozygote
R153C mutation in the exon 4 of the NOTCH 3 gene.
The diagnosis of CADASIL was based on the presence
of family history of stroke, clinical and head MRI find-
ings, and the detection of NOTCH 3 gene mutation.
DISCUSSION
CADASIL is a hereditary vasculopathy affecting the
small arteries and arterioles of the brain and other
tissues(1). It was first described in 1977 in a case with
hereditary multiinfarct dementia syndrome, followed by
several reports of cases with autosomal dominant genetic
stroke and dementia(1-21). CADASIL syndrome is the first
detected form of vascular dementia with a genetic-ori-
gin(10). It is also one of the common hereditary forms of
stroke(4). The incidence of CADASIL in general popula-
tion is thought to be higher than estimated(4,10).
The onset of the disease is usually between the ages
of 30 and 60 years(8). Eighty-five per cent of the patients
experience recurrent strokes and transient ischemic
attacks(8). The first stroke usually occurs in the ages of
35-45 years(6). Recurrent strokes may result in motor dis-
ability, pseudobulbar palsy, and urinary incontinence(2,5,8).
The patient may become bed-ridden in time and has a
mean life expectancy of 65 years(9). Cognitive changes
may develop after 35 years of age. However, in 70-80%
of the patients, marked cognitive deficit develops paral-
lel to the increased burden of lesions at about 60 years of
age and is followed by dementia(3,13,15). Cognitive decline
may be progressive as well as stepwise with acute
episodes(2). In 30-50% of the patients, migraine attacks
occur and are usually with aura(2-11). Migraine attacks
generally present a few years before the first vascular
event(11). Patients with CADASIL may also show behav-
ioral anomalies and psychiatric disorders(2-5,7-10).
Psychiatric symptoms vary from mild personality disor-
ders to severe depression and mania(2-4). The onset of
migraine and psychiatric symptoms is usually in the
early phases of the disease(6,9)and in some families, they
are the dominant clinical findings(9). Ten per cent of
CADASIL patients suffer epileptic attacks, and in some,
subclinical polyneuroptahy has been reported(8-11,15,16). In a
series of 45 patients, the incidence rate for subcortical
events was 84%; for progressive or stepwise subcortical
dementia accompanied by pseudobulbar palsy, 31%; for
migraine with aura, 22%; and mood disorders accompa-
nied by severe depression attacks, 20%(20). Subclinical
retinal lesions(8)and rarely, hearing loss have been report-
ed in some cases(1). Our patient suffered from occasional
migraine attacks without aura. Occasional short-term
and transient numbness on her left side could not be
explained; however, it was attributed to the ischemic
attacks associated with the lesions detected on the head
MRI. The psychiatric evaluation of our patient revealed
impaired executive and concentration functions as well
as findings of increased agitation, irritability, and disin-
hibition.
Hyperintense areas are observed in the subcortical
white matter of CADASIL patients on T2-weighted sec-
tions of cranial magnetic resonance images(1,3-5,8,9,13). In
addition, 2/3 of the subcortical lacunar infarcts and
rarely microhemoorahges in the thalamus may be
observed(1-5,8,9,13,18,19). On head MRI, involvement of the
white matter of the anterior temporal lobe and external
capsule are characteristic(5,6,8,10,11). Hyperintensities in the
white matter of the anterior lobe have been reported to
provide high sensitivity (90%) and specificity (100%)
rates for the diagnosis of the disease(21). External capsule
involvement is less specific and may be observed in the
early phase of the disease(5). In some patients, the corpus
callosum was also involved(5). The frontal lobes have the
highest burden of lesions in the white matter, followed
by the temporal and parietal lobes(17). Characteristic MRI

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findings may be observed in asymptomatic individuals
with mutations in the NOTCH 3 gene(3,9), and in just
about all of the mutant gene carriers, pathologic MRI
findings are observed in the 3rd decade(1). Cerebral
angiography results are normal because of the small size
of the involved arteries, the images of which cannot be
obtained(11). Angiography has not been recommended for
CADASIL patients because of increased risk of compli-
cations(11). Similarly, in our patient, involvement of the
periventricular and subcortical white matter as well as
the temporal poles and bilateral external capsule was
observed. The head MRI findings of her brother were
compatible with CADASIL findings; however, they were
in the form of atypical widespread hyperintensities in the
periventricular white matter.
Because the disease systemically affects the vascular
structure, the result of the peripheric biopsy evaluation is
often positive. In the electron microscopy evaluation of
the smooth muscles and skin specimens, GOM may be
detected(5,6,9,10). Although evaluation of the skin biopsy is
a common procedure, the results of almost half of the
studies are false negative(11). Muscle biopsy studies, how-
ever, have a higher sensitivity(11). The disease develops
due to the mutations in the NOTCH 3 gene on chromo-
some 19. This gene codes a large transmembrane recep-
tor that is expressed in the arterial smooth muscle cells
and has a role in the arterial development(4,5,10,11). In our
patient and her brother, a heterozygote R153C mutation
in the exon 4 of the NOTCH 3 gene was detected.
NOTCH 3 gene is a long one and may have multiple
mutations. However, most of these mutations are seen in
exon 3 or exon 4(5,9,10). In Turkey Utku and his friends
found out R90C mutation in 12 individuals in four gen-
erations in the same family(22). Uyguner and his cowork-
ers presented 3 families with mutation in the Notch 3
receptor: two in the exon 3, and the one in the exon 4(23).
Although mutations in NOTCH 3 have commonly been
reported in patients with familial history of CADASIL,
there have also been recent reports of novo mutations(4).
This indicates that CADASIL is more common than
thought and suggests that even when there is no familial
history, investigations for possible NOTCH 3 gene muta-
tions may prove useful in patients with clinical findings
of CADASIL(4).
Lesions observed on the MRI of CADASIL patients
mimic lesions in sparodic arteriopathies, including
Binswanger disease. However, in such conditions, deep
perforating arteries are affected, while the external cap-
sule, corpus callosum, and anterior temporal lobes are
intact(11). Sparodic arteriopathies were ruled out in our
patient based on the absence of vascular risk factors
except smoking habit, presence of familial history for
stroke, specific lesions observed on MRI and detection
of the mutation in the NOTCH 3 gene. Multiple sclero-
sis, primary angitis of the central nervous system, mito-
chondrial cytopathies (MELAS), Fabry disease, leukody-
strophies, and CARASIL should be considered in differ-
ential diagnosis(10). These diseases were ruled out in the
light of clinical findings, hereditary transmission and its
form as well as the results of the laboratory studies and
imaging.
The treatment of CADASIL is symptomatic.
Literature presents no specific studies on the use of
acetilacidic acid in CADASIL patients. Nevertheless, it
has been recommended for the treatment of CADASIL
because it is a general antiaggregant agent used in cere-
brovascular disease prophylaxis(8). In addition, recom-
mendations have been made for CADASIL patients to
avoid risk factors for ischemic cerebrovascular
diseases(8).
In conclusion, particularly in young adult patients
with no vascular risk factors, mild clinical findings, but
a familial history of stroke and characteristic lesions on
MRI, CADASIL should be suspected, and mutations in
NOTCH 3 gene should be investigated.
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