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An italian kindred with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

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An Itahan Kmdred with Cerebral Autosomal
Dominant Arteriopathy with Subcortical
Infarcts and kdsoencephalopathy
(CADASIL)
Michele Ragno, MD," Elisabeth Tournier-Lasserve, MD,? Mario G. Fiori, MD,S Antonio Manca, MD,$
Maria Cristina Patrosso, PhD,n Alessandra Ferlini, MD," Giovanna Sirocchi, MD," Luigi Trojano, MD,"*
Hugues Chabriat, M D , t t and Fabrizio Salvi, MDSS
Vascular dementia is usually sporadic and associated with definite risk factors. Several cases also occur in a familial
fashion, and may affect middle-aged or even younger subjects. Recently, an autosomal dominant inheritance was
demonstrated in two unrelated French families, the members of which were affected by stroke-like episodes culminating in progressive dementia. Genetic linkage analysis assigned the disease locus to chromosome 19q12. We report an
additional kindred of Italian origin in which at least 16subjects presented leukoencephalopathic alterations. Recurrent
strokes, psychiatric disturbances, dementia, and in 2 members, tetraplegia and pseudobulbar palsy were the hallmarks
of this syndrome. Notably, 5 asymptomatic individuals had neuroradiological signs of leukoencephalopathy. Pathological examination of 1 subject revealed a widespread vasculopathy of the perforating arterioles, characterized by deposition of eosinophilic-congophilicmaterial that did not immunostain with antibodies against prion protein, P-amyloid,
cystatin C , transthyretin, or heat-shock protein 70 and was similar to that described in the French families. Based on
the maximum lod score, the most likely location for the disease locus was also mapped to chromosome 19q12, and
found to coincide with the CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) locus. The present results confirm the existence of a nosologically distinct, autosomal dominant
cerebrovascular disease, presenting with recurrent subcortical ischemic strokes independent of vascular risk factors.
Ragno M, Tournier-Lasserve E, Fiori MG, Manca A, Patrosso MC, Ferlini A, Sirocchi G , Trojano L,
Chabriat H, Salvi F. An Italian kindred with cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy(CADASIL).Ann Neurol 1995;38:231-236
In the last two decades the importance of genetic factors in the etiopathogenesis of some cerebrovascular
disorders has received increasing attention, although
only recently have genetic markers become available
to define the mode of inheritance and to map diseases
to specific chromosomal loci. An autosomal dominant
mode of transmission, traced through several generations, has been identified in syndromes that had been
usually termed according to either the organs involved
or their most typical features (e.g., MELAS; deposition
of mutated cystatin C; hereditary cerebral hemorrhage,
Dutch type; homozygous homocystinuria; deficiency of
proteins C and S). One syndrome in particular recently
was reported in two unrelated French families; this
dominantly inherited disorder is characterized by recurrent stroke episodes, dementia, and pseudobulbar
palsy (so-called CADASIL syndrome [l, 2)). The clinicopathological features of such a syndrome overlap
those of a number of other familial cerebrovascular
disorders that so far have received limited attention
because genetic details were unavailable when they
were first described {3]. O n the contrary, a recent
genetic linkage study succeeded in assigning the
CADASIL disease locus to chromosome 19q12 141.
Here we report an Italian kindred, the affected
members of which presented with similar clinical fea-
From the "Division of Neurology, "C. & G. Mazzoni" Hospital,
Ascoli Piceno, Italy; t Laboratory of Immunopathology, Necker Children's Hospital, Paris, France; $Postgraduate Program in Nerve Regeneration, Department of Orthopedics, University of Brescia
School of Medicine, Brescia, Italy; $Department of Radiology, National Institute for Research and Treatment of Aging, Ancona, Italy;
'Institute of Advanced Biomedical Technologies, National Research
Council, Milano, Italy; """Clinica del Lavoro" Foundation, Campoli
del Monte Taburno (BN), Italy; ttDivision of Neurology, St. Antoine Hospital, Paris, France; and $$Department of Neurology, Universiry of Bologna School of Medicine, Bologna, Italy.
Received Dec 15, 1994, and in revised form Apr 18, 1995. Accepted
for publication Apr 19, 1995.
Address correspondence to Dr Fiori, International Scientific Board,
ExPharma s.r.1.. Riviera Francia 3/A, 1-35127 Padova, Italy.
Copyright 0 1995 by the American Neurological Association
231
tures (cerebral arteriopathy, subcortical infarcts, and
leukoencephalopathy). Linkage analysis in these patients suggested that t h e syndrome was located to t h e
same chromosome locus as that of t h e two French families, hence emphasizing the need for a harmonized
nomenclature that would reconcile under the same
heading cerebrovascular disorders that are currently
termed or regarded as diverse.
Materials and Methods
Subjects
This study was based on 38 subjects belonging to a kindred
whose pedigree is shown in Figure 1. Eight subjects were
already dead when the present investigation started; data concerning their medical history and causes of death were
gathered from clinical records or interviews with surviving
relatives or both (Table). Postmortem examination was performed o n a single patient (III:3) who died of acute pulmonary edema and septic shock in the hospital.
The remaining 30 subjects underwent comprehensive
medical, neurological, psychiatric. genetic, neuroradiological,
and laboratory examinations. To assess the possible presence
of the most common vascu!ar risk factors and other causes
of familial strokes or inherited neurological disorders, laboratory examinations were performed, including investigations
o n mitochondria1 and genomic DNA.
By these means, 8 subjects were finally identified, 5 of
whom were clinically unremarkable yet had neuroradiological signs of white matter lesions, whereas the other 3 showed
Fig 1 . Pedigree of the Italian kindred with hereditay cerebroi fasculardisease. The Roman numbers o n the lgt represent the
generations; the Arabic numerals under each symbol identifv the
indioidwals in the relei,ant generation. Filled symbols represent
affected persons (squares, men; circles, women) in whom the disease uias assessed by direct clinical examination. A diagonal
line through square or circle represents a deceased person,
u&dr a bar crossing the connecting line above the symbols
denotes the swbjeits u5o undemwt clinical, genetic. and neuroimaging examinations. Half-filled symbols (left side) represent
n o m l persons uaith abnormal MRl findings, while those
filled in the right half indicate subjects who were considered as
affected on the basis of available medical o r historical data.
I
Ill
IV
232
Annals of Neurology
Vol 38 N o 2
August 1995
variable degrees of neurological impairment (see Table,
Fig 1).
Genetics
Genomic D N A was extracted from peripheral blood leukocytes of all the individuals who were regarded as potentially affected. Three markers spanning the D N A interval
containing the CADASIL locus on chromosome 1')
(AFM256yc9 for the D19S226 locus, AFM224ye9 for the
DlOS221 locus, and AFM164za7 for the Dl9S21S locus)
were selected for their informative potential [ S ] . Genetic
linkage analysis was performed as previously described [4]
on the 8 subjects who had been found to be either clinically
abnormal or still asymptomatic but with abnormal findings on
brain magnetic resonance imaging (MRI), and on 9 healthy
subjects with normal-appearing cerebral MRI (see Fig 1).
Pairwise and multipoint linkage analysis was carried out on
the basis of the allele frequencies observed for the selected
markers in 8 white reference Families of the Centre &Etude
du Polymorphisme Humain (CEPH) in which Gknkthon
marker information was available for chromosome 19 [ S ] .
Lod scores were calculated at various recombination fractions
for each marker, as previously reported [4], assuming no
differences in male and female recombination rates.
Neu roradiology
Brain computed tomography (CT) was performed in 4 subjects (119, 11:15, II:20, and I K 3 ) while the remaining subjects underwent brain MRI. Images were obtained along
sagittal, axial, and coronal planes.
Three main types of changes were considered in MRIs:
(1 ) focal, well-delineated areas in the white matter, characterized by either signal decrease in T1-weighted sequences or
increase in proton-density and T2-weighted images; (2)larger
areas involving the subcortical white matter, basal ganglia,
and internal and external capsule; and (3) confluent, periventricular areas in both hemispheres, with or without brainstem
or cerebellar involvement. In CT scans, white matter changes
were considered of clinicopathological significance when
meeting the definition as focal, diffuse, or extensive lowdensity areas in subcortical white matter and basal ganglia.
Neuropathology
Brain and spinal cord were dissected out during the postmortem examination offamily member III:3. Specimens from several regions of the central nervous system were immersionfixed in formol saline solution, embedded in paraffin,
and stained with hematoxylin-eosin. Additional serial sections, 7 km thick, were alternately stained with either Congo
red or thioflavin S to detect amyloid deposits.
Sections were also irnrnunostained using the peroxidaseantiperoxidase method with the following antisera: 4G8 (a
mouse monoclonal antibody [MAb) against the 17-24amino acid sequence of arnyloid PCA4) protein; dilution
1 :4,000);6ElO (a mouse MAb against the 1-17-amino acid
sequence of amyloid P(A4) protein; 1 : 10,000); antiprion
protein (1 :250); A84-5 (a MAb against gelsolin protein characterizing type IV [Finnish type) familial amyloidotic polyneuropathy [FAP); 1 : 500- 1 : 1,000); antihuman transthyretin (1 : 500-1 : 1,000); GT11 (a MAb against cystatin C;
1: 1,000); and C92 (an antibody against the heat-shock protein 70 Chsp701; 1:500). Preimmune sera or antisera absorbed with the corresponding antigens were used as controls.
Results
All the affected members had suffered from recurrent
subcortical ischemic strokes or transient ischemic attacks (TIAs), beginning usually in the sixth decade (age
range, 39-61 years; mean age at onset, 51.3 years).
Most patients developed severe motor disability (conducive, in 2, to pseudobulbar palsy) and showed mild
to severe mental deterioration (see Table) characterized by abrupt onset, stepwise progression, and impairment of one or more of the following functions: nonverbal intelligence, auditory language comprehension,
short-term as well as long-term verbal and spatial memory, controlled word association, and constructional
praxis.
No association with particular vascular risk factors
was detected; only 1 family member (III:3) showed
hypertension responsive to diuretic treatment. Hypercholesterolemia, when present, was mild and controllable by diet. Only 1 (III:4) of the 8 subjects dealt with in
the present study had neurophysiologically detectable
abnormalities in the form of bilateral carpal tunnel syndrome; however, both sensory evoked potentials and
brainstem auditory evoked potentials were within normal ranges.
Genetics
Linkage analysis with the marker for the D19S226 locus at a recombination fraction (genetic distance, 8)
equal to 0.05 resulted in a maximum lod score of
3.660. The two closely linked markers DI9S221 and
D19S215 also showed positive lod scores (2.900 at
8 = 0.03, and 2.189 at 8 = 0.15, respectively). These
results strongly indicated that the pathology affecting
the members of the present kindred is linked t o
CADASIL locus on chromosome 19q12.
Neu roradiology
CT and MRI demonstrated that all the subjects,
whether clinically affected or asymptomatic, had white
matter alterations. However, MRI abnormalities were
more severe in the affected patients, appearing as
T1-hypointense or T2-hyperintense multiple areas in
the periventricular white matter, internal and external
capsule, corona radiata, basal ganglia, and brainscem.
O n the contrary, MRI changes detected in clinically
asymptomatic subjects were modest, usually in the
form of small, nodule-like foci or slightly larger, welldelineated areas scattered in the white matter of both
hemispheres. Notably, the external capsule, basal ganglia, and brainstem were spared in these subjects, with
one exception-family member II:23 who also presented with slight enlargement of bilateral trigone and
cerebrospinal fluid (CSF) spaces over the temporal
lobe. Actually, a distinctive feature between clinically
asymptomatic subjects and affected patients was represented by the involvement of CSF spaces, which appeared normal in the former and more or less severely
enlarged in the latter. In any event, cortical lesions
were found in neither one of the kindred members
examined for this study.
Neuropathology
Sections from both parietal and temporal lobes of the
single family member subjected to necropsy showed
recently infarcted areas with typical appearance of coagulative necrosis, pallor of myelin staining, and axonal
swellings.
Small and medium-sized perforating arterioles were
characterized by features similar to those reported in patients with hypertensive encephalopathy, namely duplication and splitting of internal elastic lamina, hypertrophy of the media, and adventitial hyalinosis and fibrosis
(Fig 2). In addition, quite a distinctive feature was represented by eosinophilic granular deposits in the media;
these were not confined to the muscular cell layer, but
extended into the adventitia in the form of coarse, occasionally coalescing masses (see Fig 2). Although the
granules were slightly congophilic, use of polarized light
and epifluorescence did not demonstrate the typical biophysical reactivity of anisotropic structures. Since granular deposits were negative for the most common markers
of familial cerebrovascular diseases, corresponding sections from the brains of other patients with confirmed
diagnosis of Alzheimer’s disease, FAP, CreutzfeldtJakob disease, cerebral amyloid angiopathy, and Gerstmann-Straussler-Scheinker disease were used as internal
controls. As expected, these specimens were positive for
one or more of the above markers, demonstrating that
the lack of immunostaining in the CADASIL patient was
genuine and not attributable to technical faults. It is
worth noting that a thorough examination of other organs (lung, heart, liver, kidney) from this patient was un-
Fbgno et al: CADASIL Syndrome in Italy
233
Clinical ChavacteviJ.tics of Subjects uith Conjmed OY Suspected CADASlL Syndrome
Family
Member
Age at
Onset
Sex (yr)
Age at
Death
(yr)
Vascular Risk
Factors
1:2
M
61
64
NA
I:4
11:l
M
F
NA
52
NA
60
68
None
Two sudden episodes of right hemiplegia
with poor recovery and progressive mental deterioration
II:3
F
51
hi
Multiple stroke-like episodes leading to
pseudobulbar palsy; progressive mental
deterioration ending in dementia
II:5
F
58
66
Plasma total
cholesterol:
260 mgidl
Cholesterol:
250 mgidl
11%
F
58
64
Obesity
119
F
52
Living
Cholesterol:
220 mgldl
1I:lj
F
49
56
Cholesterol:
300 mg/dl
II:23
F
55
Living
Cholesterol:
240 mg/dl;
triglycerides
190 mg/dI;
cigarette
smoker
111: 1
M
50
Living
Cholesterol:
226 mgidl;
rriglycerides
194 mgidl
Clinical Features
~-
Neuroradiology
Three stroke episodes conducive to hemiplegia and death
Dead of stroke
Manic-depressive syndrome, accompanied
by migraine, vomiting and dizziness; transient ischemic attack followed by personality and cognitive disturbances; two further stroke-like episodes leading to
dementia, global incontinence, and spastic retraparesis
Progressive memory loss; two stroke-like
episodes followed by poor recovery,
right hemiplegia, dysphagia, and aphasia;
mental deterioration ending in dementia;
bedridden; dead of pneumonia
Bilateral white matter hypodensity (deThree episodes of left hemiplegia over a
tected by CT) and well-defined lesions
decade, with good recovery; now 70 yr
in the capsulonuclear regions, corona
old, she is unable to walk after two
radiata and cenrrum semiovale, with arromore episodes; complete right hemiplegia, bilateral pyramidal signs, axial rigidphic enlargement of CSF spaces
ity. neck dystonia, dysarrhria, moderate
dysphagia, and urinary incontinence;
however, she has normal pupils and ocular movements, active glabellar response,
and is capable of signing, copying simple
geometrical drawings, and responding to
simple verbal orders
Two smoke-like episodes followed by complete recovery; right hemiplegia and
death after the third stroke
Slight dysphagia for solid food; osteotendi- Multiple focal lesions in the basal ganglia,
nous hyperrellexia and bilateral indiffermore evident in the left thalamus and exent plantar reflex; otherwise asympternal capsule; other MRI T2-weighted
hyperintense foci in the periventricular
tomatic
white matter, corona radiata, and pons; a
small, T1-hypointense, well-delineated
(lacunar?) lesion in the left frontal lobe
white matter; slight enlargement of bilatcral trigone
Diffuse, confluent T2-hyperintense areas i n
Onset as mood changes (depression, abuthe white matter of both hemispheres
lia, irritability) followed by a further epiand well-delineated, hyperintense foci in
sode with severe headache, disorientathe basal ganglia and brainstem (pons);
tion, gait disturbance, and urinary
focal (cystic? signal identical to that of
inconrinence which subsided in a few
CSF) lesions in the perivenrricular white
days; a further episode gave rise to right
matter; atrophic enlargement of ventricuherniplegia, dysarthria, dysphagia, and
progressive cognitive deficit; currently
lar system
unable to walk, uncooperative, and
mute; pseudobulbar palsy, bilateral pyramidal and extrapyramidal signs, axial rigidity, neck dystonia, urinary incontinence, and severe dementia; ocular
movements and pupillary reactivity
within normal ranges
234 Annals of N e u r o l o g y 'Vol 38 No 2 August 1995
Clinical Charac.teristlcs of Subjects with Coilfirmedor Suspected CADASIL Syndrome (Continued)
Family
Member
Age at
Onset
Sex (yr)
Age at
Death
(yr)
Vascular Risk
Factors
111:3
44
44
1II:l
50
Living
Hypertension;
obesity;
cholesteroi:
277 mgidl
Overweight
111:16
52"
Living
None
II1:LG
46"
Living
Overweight
Ilk33
45J
Living
Cholesterol:
238 mgidl
11135
3Y
Lving
Cigarette
smoker
Neuroradiology
Clinical Features
Sudden episode of left herniplegia, followed by coma and death in a few days
C T revealed diffuse lowdensity bilateral lesions in the white matter, right capsulolenticular region, and ipsilareral corona
radiata
Mood changes and depression progressing Small, partially confluent foci in prriventricto cognitive deficits over 8 yr; no history
uiar white matter, centrum semiovale, inof stroke-like episodes or motor/sensory
ternal and external capsule, and pons as
impairment; bilateral carpal tunnel synhyperintense (T2 sequences) or slightly
hypointense (T 1-weighted) areas; moderdrome
ate enlargement of CSF spaces
Clinically normal
Slight T2-hyperintense areas in the internal
capsule; m;my focal hyperintense lesions
in the bilateral corona radiata and centrum semiovale
Clinically normal
Multiple, bilateral focal lesions in remporoparietal periventricular white matter and
corona radiara, visible as hyperintensities
in proton-density and TZ-weighted sequences
Anxiety and migrainous attacks; C6-C? ra- Multiple, well-delineated hyperintense ardiculopathy with hyporeflexia of triceps
eas in the bilateral corona radiata and
brachii; altered thyroid function
right internal capsule
Hyperreflexia in the lower limbs; otherMultiple focal hyperintensities in frontowise asymptomatic
parietal deep white matter
"Age at MRI examination.
NA
=
not assessed or otherwise unavailable; CT
=
computed tomography; CSF
successful in finding similar alterations in blood vessels
of any kind.
Discussion
We reported here some related family members who
were initially diagnosed as having a rare, possibly hereditary cerebrovascular disease. However, their syndrome may not be as unccmmon as supposed. In this
Fig 2 . Cross section of an unobliterated penetrating arteriole.
Granular material is deposited among the smooth muscle cells of
the tunica media (arrowheads). The iriternal elastic lamina appears reduplicated and fragmented. (Congo red, x 400 before
48% reduction.)
=
cerebrospinal fluid; MRI
=
magnetic resonance imaging.
connection, the association of CADASIL syndrome
with chromosome 19 is intriguing. For instance, linkage to this chromosome was recently demonstrated in
families with late-onset Alzheimer's disease 161, perhaps correlated to the presence of the ~4 allele of apolipoprotein E, a component of both neuritic plaques and
tangles that is also localized on chromosome 19 17J, as
well as in familial hemiplegic migraine, an autosomal
dominant disorder of unknown pathogenesis in which
the migrainous attacks are characterized by transient
hemiplegia during the aura 183.
Since CADASIL syndrome shares a number of features in common with other cerebrovascular disorders,
differential diagnosis may be difficult and elude clinicians and pathologists alike. The possibility to underestimate the actual frequency of CADASIL-like cases
suggests that neuroimaging investigations be performed in all the relatives (whether asymptomatic or
not) of individuals presenting with repeated strokes,
TIAs, or brain infarctions unrelated to vascular risk
factors. Unfortunately, this approach would also constitute a formidable challenge to the current health care
systems. Indeed, it is unlikely that white matter lesions
are seen by chance in the absence of neurological signs
symptoms.
MRI
studies
have shown that UP to 30%' of asymptomatic individuals may show patchy white matter abnormalities 191,
these lesions usually have been described in association
Or
Ragno et al: CADASIL Syndrome in Italy
235
with increased age as well as with risk factors such as
hypertension, TIAs, and coronary artery disease [lo].
In addition, more than 20% of patients with TIAs have
neuroradiologically detectable brain infarcts in spite of
the complete disappearance of neurological deficits
within 24 hours from the ischemic episode Ell]. As a
consequence, the finding of subcortical changes in a
young or middle-aged subject who is undergoing routine neuroradiological examination might be dismissed
as clinically irrelevant, while it should always elicit specific questioning about the occurrence of neurological
disorders in relatives and other family members and,
whenever possible, be followed by genetic analysis.
Histologically, the diagnosis has to rely on the negativity for a number of markers that characterize other clinical entities occurring as stroke. In particular, notably absent is the fibrohyaline thickening of the arteriolar walls
with luminal narrowing that is regarded as a distinctive
feature of Binswanger’s disease, even when occurring in
normotensive subjects 112). O n the other hand, differential diagnosis between cerebral amyloid angiopathy
(CAA) and CADASIL syndrome might be achieved
even without special staining, on the basis of the different distribution of microvascular lesions. In fact, CAA
can occur in a very patchy and asymmetrical distribution
throughout the neocortex, sometimes producing intraparenchymal hemorrhages, while CADASIL is characterized by recurrent subcortical ischemic strokes due to
angiopathic changes affecting mainly the small penetrating arteries of the subcortical white matter and basal
ganglia. Under this respect, the recent report of characteristic vascular changes in the sural nerve biopsy specimen of a CADASIL patient is particularly interesting
1131, because it may afford a fast and reliable way to
detect this syndrome in vivo, and suggests that the
deposition of granular material is probably a more
widespread phenomenon than that assumable from the
postmortem brain specimens.
In any event, the linkage analysis aimed at establishing an association with the 19q12 locus represents an
outstanding tool for the recognition of all CADASIL
families, and consequently, for the identification of
the defective gene underscoring a number of familial
cerebrovascular disorders that, in spite of differences in
the phenotype, prevalence, and prognosis, have been
commonly classified under the generalized name of
“progressive vascular subcortical leukoencephalopathy.” Such a conclusion is emphasized by the neuroradiological differences between the Italian kindred reported here and the French cases recently described
[ I , 2); interpretation of MRI, when used to score lesions of possible significance, may vary considerably,
so that a number of asymptomatic subjects could go
undetected because they have rather modest involvement of white matter and lack atrophic enlargement
of CSF spaces. O n the contrary, through the linkage
236 Annals of Neurology Vol 38 No 2
August 1995
analysis, even clinically normal or “presymptomatic”
subjects could be genetically identified as at risk of
becoming stroke prone at a relatively late age, regardless of their neuroradiological pattern.
This work was supported in part by grants from Telethon-Italy and
“Legato Enzo e Dino Ferrari,” Modena, Italy (to Dr Ferlini).
We thank D r Pierluigi Gambetri (Division of Neuropathology, Case
Western Reserve University, Cleveland, OH) and D r Maria Grazia
Nunzi (Laboratory of Neuromorphology, Department of Biobehavioral Sciences, University of Connecticut, Storrs, CT) for their helpful comments on the autopsy case and expert immunohistochemistry.
D r Gambetti and Dr Reinhold P. Linke (Max Planck Institute of
Biochemistry, Marrinsried-Munich, Germany) kindly provided some
of the antibodies. D r Massimo Zeviani (“C. Besta” Neurological
Institute, Milano, Italy) was responsible for mitochondrial D N A
analysis. D r G. V. Coppa (Department of Pediatrics, University of
Ancona, Italy) evaluated the levels of lysosomal enzymes. Yvonne
Dietz, Diane Kowski, and Renzo Zanoni provided excellent technical assistance.
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