Journal of the Neurological Sciences 238 (2005) 87 – 91
www.elsevier.com/locate/jns

CADASIL with NOTCH3 S180C presenting anticipation of onset age
and hallucinations
Tomohiko Nakamura a, Hirohisa Watanabe a, Masaaki Hirayama a, Akira Inukai a,
Hidehiro Kabasawa b, Michitaka Matsubara c, Shigehisa Mitake d, Masaaki Nakamura e,
Yukio Ando e, Makoto Uchino f, Gen Sobue a,*
a

Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
b
Department of Rehabilitation, Nagoya City Rehabilitation and Sports Center, Nagoya 467-8622, Japan
c
Department of Neurology, Nagoya City Rehabilitation and Sports Center, Nagoya 467-8622, Japan
d
Department of Neurology, Tosei General Hospital, Seto 489-8642, Japan
e
Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
f
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
Received 18 March 2005; received in revised form 6 June 2005; accepted 6 July 2005
Available online 18 August 2005

Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading
to strokes and vascular dementia. The average age of onset for stroke is 45 years with a range of about 30 to 70 years. We describe a Japanese
CADASIL family showing S180C in the exon 4 of NOTCH3, presenting an anticipation of the onset age for stroke. MRI demonstrated a
similar extent of white matter involvement in younger and older individuals, supporting the presence of anticipation. In addition,
hallucinations in 71% of affected patients, and delusions in 57% were also described. Our findings in this family suggest that a specific
NOTCH3 mutation was related to unique clinical features, although such correlations have seldom been encountered in CADASIL.
D 2005 Elsevier B.V. All rights reserved.
Keywords: CADASIL; Anticipation; Hallucination; NOTCH3; S180C; Vascular dementia

1. Introduction
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an
inherited vasculopathy resulting in stroke and vascular
dementia [1,2]. Although various mutations in the NOTCH3
gene cause the disease, mutation sites related to specific
clinical phenotypes have not been well recognized [3,4].
However, recent studies have shown that mutations such as
C455R [5] and C174Y [6] are associated with an earlier onset
of illness. We recently encountered a family presenting an
anticipation of the onset age for stroke. Gene analysis showed
an S180C mutation in NOTCH3, for which details of the
clinical phenotype have not been described. To our knowl* Corresponding author. Tel.: +81 52 744 2385; fax: +81 52 744 2384.
E-mail address: sobueg@med.nagoya-u.ac.jp (G. Sobue).
0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2005.07.001

edge, this is the first report of a CADASIL family presenting
with such a condition. In addition, a marked prevalence of
hallucinations and delusions was also presented, which
would be an unusual clinical feature in CADASIL. These
clinical features seem to indicate the possibility of phenotype –genotype correlations in CADASIL.

2. Patients and methods
2.1. Clinical and radiological evaluation
No consanguineous marriages had occurred in the family.
All living patients were examined by neurologists. Deceased
individuals were reevaluated by reviewing their medical
records, including CT and MRI [T1-weighted, T2-weighted,
and fluid-attenuated inversion recovery (FLAIR) images].

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T. Nakamura et al. / Journal of the Neurological Sciences 238 (2005) 87 – 91

Scheltens’ rating scale was used to rate hyperintensities in
T2-weighted images of white matter lesions in the subcortical region of frontal, parietal, occipital, temporal, and
periventricular areas, basal ganglia, insula and infratentorial
regions as follows: 0 (absent), 1 (< 3 mm; n < 5), 2 (< 3 mm;
n > 5), 3 (4 to 10 mm; n < 5), 4 (4 to 10 mm; n > 5), 5 (> 10
mm; n > 1), or 6 (confluent) [5,7].
2.2. Mutation analysis
After informed consent was obtained, total genomic
DNA was isolated from peripheral blood cells by using
the PUREGEN DNA Isolation Kit (Gentra Systems,
Minneapolis, MN). Exons 3 and 4 for the NOTCH3
gene were amplified by PCR using primers as follows: exon
3 , 5 V- AT C T T T G T G T C T G G G G C C AT- 3 V a n d 5 VACTGACCACACCCCCGACTA-3V; and exon 4, 5VTAGTCGGGGGTGTGGTCAGT-3V and 5V-CCTCTACTCCTGAGTAG-3V. After a sequencing reaction with
the amplified PCR products, a pair of primers, and the
BigDye Terminator v1.1 cycle sequencing kit (Applied
Biosystems, Foster City, CA), nucleotide sequences were
determined by an automated DNA sequencer (model 310;
Applied Biosystems).
2.3. Statistics
The Wilcoxon signed rank test was used for the analysis
of anticipation of age at onset for stroke, which was
defined as the age when an individual first presented
symptoms of apparent ischemic attacks and symptoms
lasting more than 24 h.

3. Results
3.1. Representative case
The proband was a 40-year-old man (Fig. 1: III-7) with
a 17-year history of migraine with aura, emotional lability

evident as weeping, and two episodes of stroke. He
showed dysarthria and right hemiparesis at age 23. Brain
CT demonstrated multiple, small low-density lesions
bilaterally in the subcortical cerebral white matter. After
admission to a hospital for about a month, his symptom
almost recovered. In the following year, he first suffered
migraine headaches with aura. At age 38, numbness
affected the right side of his body in the absence of
common cardiovascular risk factors and of any identifiable
vascular abnormalities in a cerebral angiogram. His
grandmother, father, four uncles, and a cousin were also
affected (Fig. 1). Neurologic examination revealed personality change, reports of hallucinations, mild dysarthria,
pseudobulbar palsy, right hemiparesis, diminished superficial touch sensation, and increased deep tendon reflexes
in all extremities. Hallucinations that first appeared at age
40 were visual, usually involving a human figure or
sometimes a few animals such as cats and dogs. These
suddenly appeared on the patient’s right side, crossing the
street. Figures were not clearly recognized, nor were their
color perceived. When the patient shifted his gaze, the
hallucinations disappeared. He experienced such hallucinations in the daytime with his eyes open, and was aware
that they were unreal. He had no auditory hallucinations.
No medication was used that might cause hallucinations,
and EEG showed no epileptic discharge. The revised
Wechsler Intelligence Scale (WAIS-R) showed intellectual
impairment (VIQ, 78; PIQ, 83; TIQ, 77). No laboratory
abnormalities for any known vascular risk factor, including
blood glucose, protein C and S, antinuclear/anti-DNA/
antiphospholipid antibodies, antithrombin III, or fibrinogen, were presented except for hypercholesterolemia (246
mg/dl, normal values <220). Lactic acid and pyruvic acid
were normal. Fundoscopic findings, visual acuity, and
visual fields were normal. Carotid ultrasonography and
MR angiography revealed no apparent arteriosclerotic
lesion. T2-weighted and FLAIR MRI demonstrated multiple hyperintense lesions in the subcortical cerebral white
matter, basal ganglia, midbrain, and anterior temporal lobe.
No infarction was found in the region of the posterior

Fig. 1. Pedigree in our CADASIL family. Squares represent men, and circles women. Filled symbols represent individuals with CADASIL. Oblique lines
indicate deceased family members. The proband is indicated by an arrow. Numbers in parentheses are age at onset for stroke. DNA, DNA examined; *,
hallucinations and delusions present; **, hallucinations present.

T. Nakamura et al. / Journal of the Neurological Sciences 238 (2005) 87 – 91

cerebral artery, including the occipital cortex or posterior
thalamus, except for periventricular lesions.
3.2. Clinical, radiologic, and genetic features of family
members
Clinical features are summarized in Table 1. Four of
seven patients in the family were deceased, and two were
bedridden from recurrent strokes. The initial symptoms were
apathy in one individual, bradykinesia with depression in
one, and ischemic episode in five. Stroke occurred at the age
of 65 years in the first generation, 33 to 48 years in the
second, and 23 years in the third. Thus, onset occurred
significantly earlier in patients of successive generations
( p = 0.027, Wilcoxon signed rank test). No patients had
either hypertension or diabetes. Hypercholesterolemia that
was evident in six of seven patients was below 260 mg/dl.
Most affected members of this family manifested sensory
and motor deficits, gait disturbance, increased tendon
reflexes, cognitive impairment, personality changes and
mood disorders. In addition, five of seven (71%) had
hallucinations, and four (57%) experienced delusions during
their disease. All hallucinations were visual, occurring
mostly in the daytime. The content of hallucinations varied
among patients, although humans and animals were most
common. No one had taken any drugs which might induce
hallucinations.
Although CT in patient II-3 and MRI in patients II-5, II7, and III-4 demonstrated severe periventricular subcortical
white matter lesions, no apparent infarction was observed in

89

the region of the posterior cerebral artery, including the
occipital cortex except for a periventricular lesion of the
posterior horn of lateral ventricle. Small lacunar infarction
in the cerebral peduncle was observed only in patient II-7 at
age 57, but no hallucination or delusion was observed in this
patient. According to Scheltens’ score, the extent of white
matter lesions revealed by MRI was similar, indicating
larger, more numerous lesions present at an earlier age in
patients belonging to younger generations (Table 1).
Direct DNA sequencing of the exon 4 PCR product from
the DNA of patients II-7 and III-7 showed both cytosine and
guanine at the second base of codon 180 of the NOTCH3
gene. Thus, the patients were heterozygous, with both a
normal TCC (serine) and a variant TGC (cysteine) codon
corresponding to amino acid position 180 of NOTCH3.
Brain autopsy was performed in patients I-1 and II-2.
Diffuse myelin pallor and numerous infarcts were observed
mainly in the cerebral white matter and basal ganglia with
the preservation of U-fiber. Atherosclerosis was generally
mild, and occlusion was rarely observed. No pathological
change of neuronal degeneration in the substantia nigra nor
the presence of Lewy bodies in the substantia nigra, locus
ceruleus and cerebral cortex was found. There were also no
plaques and tangle observed.

4. Discussion
To our knowledge, this is the first description of clinical
and radiologic findings of patients with CADASIL asso-

Table 1
Clinical and MRI features of affected CADASIL family members
Patient

I-2

II-2

II-3

II-5

II-7

III-4

III-7

Gender
Onset of stroke (years)
Onset of psychosis (years)
Disease duration (years)
Hypercholesterolemia
Migraine
Initial symptom
Psychiatric features
Depressive state
Affective incontinence
Change of personality
Hallucinations
Delusions
Status
MRI features
Age at examination (years)
Scheltens’ scores
PWM
SWM
BG
IT
In

F
65
67
7

M
48
45
5
+

M
39
43
21
+

M
33
42
15
+

M
42
35
22
+

M
23
NA
25
+

+
+
+
+
+
Deceased
NA

+
+
+
+
+
Deceased
NA

+
+
+
+
+
Deceased
NA

+
+
+
+
+
Deceased

+
+
+

+
+
+

+
+
+
+

Bedridden

Bedridden

Difficulties at work

48

39

31

40

6
24
10
1
6

6
24
5
1
5

6
24
9
1
6

5
24
4
4
6

M
23
24
17
+
+
Left hemiparesis Depression Left hemiparesis Left hemiparesis Bradykinesia Gait disturbance Right hemiparesis

NA, not available; +, present; , absent; PMW, periventricular white matter; SWM, subcortical white matter; BG, basal ganglia; IT, infratentorial structures; In,
insula. SWM, total of individual Scheltens’ scores from frontal, parietal, occipital, and temporal lobes. BG, total of individual scores from caudate, putamen,
globus pallidus, thalamus, and capsules. IT, total of individual scores from brainstem and cerebellum.

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T. Nakamura et al. / Journal of the Neurological Sciences 238 (2005) 87 – 91

ciated with a NOTCH3 S180C mutation in the literature.
The present family exhibited characteristic features in
several respects. First, the onset age for stroke occurred
earlier in patients of successive generations. Previous
studies reported that the mean onset age for stroke is about
45 years with a range of about 30 to 70 years in CADASIL
[3,8,9]. An association with transient ischemic attacks and a
history of smoking at the time of the stroke episode has been
reported in certain patients with CADASIL, particularly in
early-onset cases [4]. Such relationships were not found in
the present family. Arboleda-Velasquez et al. [5] reported
that CADASIL patients with a C455R mutation in NOTCH3
showed a significantly earlier onset of illness (median age,
31 years) than that seen with other mutations. Furthermore,
patients with the C174Y mutation showed a phenotype–
genotype correlation with an earlier age of onset [6].
However, no anticipation was seen concerning age of onset.
Van dem Boom et al. [10] demonstrated that the spectrum of
imaging abnormalities of hyperintensity of lacunar infarcts
revealed in a T2-weighted MRI increases with age in
CADASIL patients. However, younger patients in the most
recent generation of this family showed severe white matter
involvement, similar to findings in older patients of prior
generations. This finding would also support the presence of
anticipation. Anticipation has been reported mostly in
polyglutamine disease with an instability of CAG repeat
expansion, and has also been documented in association
with point mutations in several neurodegenerative diseases
such as familial amyloid polyneuropathy, Creutzfeldt –
Jakob disease, and familial amyotrophic lateral sclerosis,
although the mechanisms underlying such anticipation
remain unknown [11]. Indeed, it will be virtually impossible
to confirm that patients who were reported to be affected in
their 50s or 60s were free of migraine, stroke-like episodes
or psychiatric symptoms during younger ages since four
cases were already deceased. Thus, the presence of
anticipation of age onset must be discussed with caution.
In addition, the number of patients investigated in the study
is limited since we did not investigate the NOTCH3 S180C
mutation of the siblings for preclinical diagnosis because of
ethical reason. Further studies are needed to clarify whether
the S180C mutation causes anticipation, or whether different modulating genetic/environmental factors might be
involved.
The second characteristic feature in this family was the
presentation of hallucinations and delusion. About 15% of
the CADASIL population has been reported to demonstrate
psychiatric disturbances such as depression or mood change
as initial symptoms [12,13]. Almost one fourth of the
CADASIL patients present such symptoms in their disease
course, but the prevalence of hallucinations and delusions is
extremely low [8]. Although hallucinations are generally
related to cortical lesions [14], such lesions are rare in
patients with CADASIL [15]. There are several explanations for hallucination in our patients with CADASIL.
First, peduncular hallucinosis [14,16] is related with

hypoperfusion or infarction in the mesencephalon which
can occur in CADASIL. In this series, no family member
who presented hallucinations had obvious ischemic lesion in
the midbrain except for patient III-7. However, the existence
of hypoperfusion in the mesencephalon could not be denied
since no SPECT had been studied during the hallucinations.
In general, peduncular hallucinosis is characterized by vivid,
nonstereotypical-colored visual images of people and
animals of brief duration occurring at dusk [16], while
hallucinations in our patients, which were not vivid images
appearing in daytime, were not related to peduncular
hallucinosis. Second, ocular involvement may relate to
hallucinations (Charles Bonnet syndrome) [14] since retinal
lesions of the vascular origin [17] and retinal dysfunction
[18] have been described in CADASIL. Charles Bonnet
syndrome affects people with sight difficulties, usually only
people who have lost their sight later in life. But patient III-7
had normal retina. In addition, to our knowledge, no
CADASIL patient presenting Charles Bonnet syndrome
had been reported. Third, there might be concomitant
diseases. Hallucination and delusion have been also reported
in mitochondrial myopathy, encephalopathy, lactic acidosis
and stroke-like episodes (MELAS), in which hypoperfusion
in occipital cortex and thalamus or delirium due to strokelike episode is considered to be the cause of the symptom
[19]. However, our family member had no characteristic
features of MELAS represented by short stature, deafness,
and glucose intolerance, and there was also no maternal
inheritance in the third generation. Patients with Parkinson’s
disease and Alzheimer’s disease also had high prevalences
of visual hallucinations. Especially in Alzheimer’s disease,
they often presented with other psychotic symptoms such as
auditory hallucinations and delusions [20]. Pathologic
findings in I-2 and II-2 were different from those in
Parkinson’s disease and Alzheimer’s disease. Fourth,
periventricular white matter change in the temporal horn is
one of the other possible causes of the psychiatric symptoms
[21], or CADASIL patients with a vascular risk factors are
reported to show symptoms related to cortical involvement
[22].
Furthermore, no family member was treated with
hallucinogenic drugs [14]. On the other hand, Lagas and
Juvonen reported a patient with an R133C mutation in
NOTCH3 presenting psychiatric symptoms similar to those
of schizophrenia including auditory hallucinations [23].
Further studies will be needed to clarify whether NOTCH3
S180C is associated with the hallucinations and delusions
observed in this family.
Third, the occurrence of hypercholesterolemia was high
(86%) compared with that observed in a CADASIL
population (20%) [9,24]. Although hypercholesterolemia
is generally closely related with macroangiopathy, MRA
and ultrasonic echo in patient III-7 showed no atherosclerotic changes in the main arteries. A recent study reported
that hypercholesterolemia had no association with either the
MRI lesion volume or stroke in CADASIL [4]. Thus

T. Nakamura et al. / Journal of the Neurological Sciences 238 (2005) 87 – 91

hypercholesterolemia was an unlikely cause of stroke in this
series.
In conclusion, we found that a Japanese CADASIL
family showing S180C in NOTCH3 showed an anticipation
of the onset age for stroke and high rates of hallucination
and hypercholesterolemia. To our knowledge, mutations
associated with anticipation have not been reported in
CADASIL to date. Although specific phenotype – genotype
correlations have been considered rare in CADASIL, the
unique clinical features observed in our patients suggest the
possibility of certain phenotypes being associated with
specific NOTCH3 mutations.

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