| EPIDEMIOLOGY |
CHARACTERIZATION |
| SYNONYMS |
Hereditary multi-infarct dementia
Chronic familial vascular encephalopathy
Familial disorder with subcortical ischemic strokes
Agnogenic medial arteriopathy
Familial Binswanger's disease |
| AGE RANGE-MEDIAN |
30-40 years
Death usually occurs 12-23 years after onset of symptoms |
|
CADASIL in a North American family: clinical, pathologic, and radiologic
findings.
Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Shungu DC, Naini
AB, Mohr JP.
Department of Neurology, Columbia University, College of Physicians
and Surgeons, New York, NY, USA.
|
Neurology 1998 Sep;51(3):844-9 Abstract quote
OBJECTIVE: To expand the reported phenotypic range of cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL).
BACKGROUND: Despite numerous patient reports, our knowledge of the
phenotypic range of CADASIL remains incomplete.
METHOD: We performed clinical, pathologic, and radiologic examinations
on members of a family with CADASIL.
RESULTS: The proband is a 61-year-old man with a history of migraine
and depression who has experienced multiple subcortical infarctions
resulting in a stepwise decline. Neuropsychological testing documented
a dementia syndrome with frontal lobe features and neurologic examination
noted a left hemiparesis and a right-sided palmomental reflex. Brain
biopsy with light microscopy revealed a nonatherosclerotic small-vessel
angiopathy with periodic acid-Schiff positive granular changes in the
media and white matter gliosis, with unremarkable cortex. Genetic testing
confirmed a Notch3 mutation. The proband's first cousin has a history
of depression, one seizure possibly resulting from an acute stroke,
and a learning disorder. Neuropsychological testing demonstrated deficits
in executive function and neurologic examination noted persistent extraneous
adventitial movements, poor coordination, and primitive reflexes. Skin
biopsy with electron microscopy demonstrated granular osmiophilic material
within the basement membrane of vascular smooth muscle cells, which
is considered to be pathognomonic of CADASIL. The proband's older son
and younger son have histories of migraine and depression, respectively,
and both also had learning disorders. MRI revealed diffuse white matter
disease extending into the temporal lobes, and lacunar infarctions in
these four nonhypertensive patients. Other family members have experienced
migraine, recurrent stroke, dementia, and depression.
CONCLUSIONS: CADASIL is a genetic basis for vascular dementia that
may be manifest earlier in life than previously reported.
|
| DISEASE ASSOCIATIONS |
CHARACTERIZATION |
|
Mitochondrial dysfunction associated with a mutation in the Notch3
gene in a CADASIL family.
de la Pena P, Bornstein B, del Hoyo P, Fernandez-Moreno MA, Martin
MA, Campos Y, Gomez-Escalonilla C, Molina JA, Cabello A, Arenas J, Garesse
R.
Departamento de Bioquimica, Instituto de Investigaciones Biomedicas
"Alberto Sols" CSIC-UAM, Facultad de Medicina, Universidad Autonoma
de Madrid, Spain.
|
Neurology 2001 Oct 9;57(7):1235-8 Abstract quote
BACKGROUND: Cerebral autosomal arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) is characterized by recurrent subcortical
ischemic strokes and dementia caused by mutations in the Notch3 gene.
In Drosophila melanogaster, Notch signaling has a pleiotropic effect,
affecting most tissues of the organism during development.
OBJECTIVE: To characterize a potential mitochondrial dysfunction associated
with mutations in the Notch3 gene.
METHODS: Biochemical, histochemical, molecular, and genetic analyses
were performed on muscle biopsy specimens and fibroblasts obtained from
patients of a Spanish family with CADASIL. Additional biochemical and
molecular analyses of the N(55e11) mutant of D. melanogaster were performed.
RESULTS: In muscle biopsy specimens, a significant decrease was found
in the activity of complex I (NADH [reduced form of nicotinamide adenine
dinucleotide] dehydrogenase), and in one patient, histochemical analysis
showed the presence of ragged-red fibers with abnormal cytochrome c
oxidase staining. Reduced fibroblast activity of complex V (ATP synthase)
was found. Supporting data on patients with CADASIL, it was found that
the mutation N(55e11) in Drosophila decreases the activity of mitochondrial
respiratory complexes I and V.
CONCLUSIONS: Mitochondrial respiratory chain activity responds, directly
or indirectly, to the Notch signaling pathway. Mitochondrial dysfunction
in patients with CADASIL may be an epiphenomenon, but results of this
study suggest that the pathophysiology of the disease could include
a defect in oxidative phosphorylation.
|
| PATHOGENESIS |
CHARACTERIZATION |
| NOTCH3 MUTATIONS |
Short arm of chromosome 19
The function is largely unknown although a gene involved in the Notch
signaling pathway has homology to the presenilin 1 gene altered in some
cases of premature Alzheimer's disease |
|
Mouse Notch 3 expression in the pre- and postnatal brain: relationship
to the stroke and dementia syndrome CADASIL.
Prakash N, Hansson E, Betsholtz C, Mitsiadis T, Lendahl U.
Department of Cell and Molecular Biology, Medical Nobel Institute,
Karolinska Institute, SE-171 77, Stockholm, Sweden.
|
Exp Cell Res 2002 Aug 1;278(1):31-44 Abstract quote
Mutations in the human Notch 3 gene cause the vascular stroke and dementia
syndrome CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical
Infarcts and Leukoencephalopathy) characterized by degeneration of vascular
smooth muscle cells and multiple small infarcts in the white and deep
gray matter of the brain.
Here we have analyzed the expression pattern of the Notch 3 gene in
the pre- and postnatal mouse brain. Prenatal Notch 3 expression is restricted
to a scattered population of cells within the vessel wall of all major
blood vessels in the developing embryo, including those that form the
perineural vascular plexus.
Expression in the postnatal brain is confined to a scattered cell population
within the vessel wall of small to medium-sized penetrating arteries,
which are the vessel type primarily affected in CADASIL patients. In
contrast, no expression was observed in capillaries and veins. Notch
3 is most likely expressed in a subset of vascular smooth muscle cells,
and the expression pattern of one of the Notch ligands, Serrate 1, was
very similar to that observed for Notch 3.
The Notch 3 expressing pattern was not significantly altered in platelet-derived
growth factor B- (PDGF-B) deficient mouse embryos, demonstrating that
Notch 3 expression is not under direct control of PDGF-B. These data
show that Notch 3 expression is conserved between mouse and human and
suggest that the mouse is a valid system for analysis of CADASIL.
|
C455R notch3 mutation in a Colombian CADASIL kindred with
early onset of stroke.
Arboleda-Velasquez JF, Lopera F, Lopez E, Frosch MP, Sepulveda-Falla
D, Gutierrez JE, Vargas S, Medina M, Martinez De Arrieta C, Lebo RV,
Slaugenhaupt SA, Betensky RA, Villegas A, Arcos-Burgos M, Rivera D,
Restrepo JC, Kosik KS.
Center for Neurological Diseases, Brigham and Women's Hospital-Harvard
Medical School, Boston, MA, USA. |
Neurology 2002 Jul 23;59(2):277-9 Abstract quote Cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) is caused by mutations in the notch3 epidermal growth factor-like
repeats. A Colombian kindred carries a novel C455R mutation located
in the predicted ligand-binding domain.
Stroke occurred in the patients at an unusually early age (median age:
31 years) in comparison to the more frequent onset in the fourth decade
of life in other CADASIL populations, including a second Colombian kindred
with an R1031C mutation. |
|
Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy. Phenotypic and mutational spectrum.
Dichgans M.
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-Universitat,
Marchioninistrasse 15, D-81377, Munich, Germany
|
J Neurol Sci 2002 Nov 15;203-204(C):77-80 Abstract quote Mutations
in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL) an inherited
small vessel disease leading to subcortical strokes and dementia.
Since the vascular pathology is clearly defined, CADASIL may provide
important insights into the mechanisms underlying lacunar infarcts,
ischemic white matter changes, and vascular dementia. Evidence from
different sources suggests a central role for vascular smooth muscle
cells (VSMC) in the pathophysiology of the disease.
This article gives a brief overview on the phenotypic spectrum of the
disease and discusses some of the relevant disease mechanisms that lead
from Notch3 mutations to ischemic infarcts.
|
| VASCULAR DAMAGE |
|
Primary damage to vascular smooth
muscle cells (VSMC) |
Damaged cells leak or extrude material which forms GOM
GOM may impede the delivery of nutrients leading to damage of the surrounding
tissue
GOM progressively impedes contact between astrocytic foot processes
and VSMC |
Primary damage to the endothelial
cells |
Endothelial cell alterations including condensation
of cytoplasm with progressive packing of microfilaments in skin arterioles
and capillaries
May have altered pinocytosis |
Primary proliferation of elastic lamina
and basement membrane material |
Could inhibit nutrient passage |
LABORATORY/
RADIOLOGIC/
OTHER TESTS |
CHARACTERIZATION |
| MRI |
Lesions usually symmetrically situated within the white
matter and deep gray nuclei-periventricular white matter is preferentially
involved
Usually in the frontal lobe, temporal lobe, subinsular white matter,
and internal and external capsules with relative sparing of the inferior
frontal and occipital white matter in the early stages
Brainstem affected in 45% of cases |
Subcortical lacunar lesions: an MR imaging finding in patients with cerebral
autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
van Den Boom R, Lesnik Oberstein SA, van Duinen SG,
Bornebroek M, Ferrari MD, Haan J, van Buchem MA.
Department of Radiology, Leiden University Medical Center,
Albinusdreef 2, C2S, the Netherlands |
Radiology 2002 Sep;224(3):791-6 Abstract quote PURPOSE: To assess
the prevalence and distribution of subcortical lacunar lesions (SLLs)
in patients with cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL), to determine whether SLLs
are an abnormal finding by studying their prevalence in healthy subjects,
and to assess whether SLLs occur in other conditions associated with
small vessel disease and white matter areas of high signal intensity
(WMH).
MATERIALS AND METHODS: The presence of SLLs, their location, and their
relation to other abnormalities were assessed on magnetic resonance
(MR) images (T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery)
obtained in 34 CADASIL patients and 20 healthy family members. Three
additional control groups of healthy volunteers, elderly patients with
vascular risk factors, and patients with another hereditary small vessel
disease were also screened for the presence and location of SLLs. Sensitivity
and specificity of the presence of SLLs for the diagnosis of CADASIL
were assessed.
RESULTS: SLLs were found in 20 (59%) of CADASIL patients. Incidence
of SLLs increased with age (20%, <30 years; 50%, 30-50 years; 80%,
>50 years). SLLs invariably occurred in the anterior temporal lobes
and in areas where diffuse WMH expanded into arcuate fibers. From the
anterior temporal lobe, the lesions could extend dorsally into the temporal
lobes and rostrally into the frontal lobes. Lesions were not found in
the parietal and occipital lobes. None of the control subjects had SLLs.
Specificity and sensitivity of SLLs for CADASIL were 100% and 59%, respectively.
CONCLUSION: SLLs are an abnormal finding at MR imaging that frequently
occur in CADASIL patients. Copyright |
|
CADASIL imitating multiple sclerosis: the importance of MRI markers.
O'Riordan S, Nor AM, Hutchinson M.
Department of Neurology, St Vincent's University Hospital,
Dublin, Ireland. |
Mult Scler 2002 Oct;8(5):430-2 Abstract quote Cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) can mimic multiple sclerosis (MS), leading to diagnostic confusion.
We report a family with CADASIL in which the index case and the daughter
of the index case were initially erroneously diagnosed with MS.
Relatively specific magnetic resonance imaging (MPI) markers of CADASIL
include involvement of the anterior temporal lobes and external capsules
and, as illustrated in this report, these MRI findings may aid in the
differentiation of the two conditions.
|
| PET and SPECT scanning |
May identify regions of hypoperfusion correlating with MRI
findings |
| ULTRASOUND |
|
Prolonged cerebral transit time in CADASIL: a transcranial ultrasound
study.
Liebetrau M, Herzog J, Kloss CU, Hamann GF, Dichgans M.
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians
University, Munchen, Germany.
|
Stroke 2002 Feb;33(2):509-12 Abstract quote
BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary
angiopathy caused by mutations in Notch3. Cerebral microvessels show
an accumulation of granular osmophilic material in the vicinity of degenerating
vascular smooth muscle cells. In this study, we measured the arteriovenous
cerebral transit time (CTT) to identify changes related to the microangiopathy
in CADASIL.
METHODS: CTT is the time that a contrast agent needs to pass from a
cerebral artery to its corresponding vein. CTT was measured in 17 CADASIL
individuals (mean age, 50.2+/-12.3 years) and an equal number of age-
and sex-matched control subjects (mean age, 48.9+/-13.0 years) with
transcranial color-coded duplex sonography. The intensity curves were
recorded in the P2 segment of the posterior cerebral artery and the
vein of Galen after injection of the ultrasound contrast agent Levovist.
RESULTS: CTT was significantly prolonged in individuals with CADASIL
(4.4+/-1.9 seconds) compared with control subjects (1.3+/-0.5 seconds,
P<0.0001). This difference was also significant when only nondisabled
CADASIL individuals (Rankin score=0, n=9) were analyzed (P<0.0001).
There was a nonsignificant trend for a correlation between Rankin score
and CTT (r=0.39, P=0.11).
CONCLUSIONS: The prolonged CTT likely reflects microvascular changes
in CADASIL. Measurements of the CTT may be used clinically to disclose
small-vessel disease. Studies comparing CADASIL subjects with other
patient populations seem warranted to determine possible differences
in CTT between different types of small-vessel disease. |
| SCREENING FOR GENETIC MUTATIONS |
|
Diagnostic strategies in CADASIL.
Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH,
Powell JF.
Department of Clinical Neuroscience, St. George's Hospital
Medical School, London, UK. |
Neurology 2002 Oct 22;59(8):1134-8 Abstract quote BACKGROUND: Cerebral
autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) is an inherited autosomal dominant condition characterized
by migraine, recurrent stroke, and dementia. It results from mutations
in the notch3 gene but mutations may occur at multiple sites making
molecular diagnosis time consuming. It has been suggested that the presence
of granular osmiophilic material (GOM) on skin biopsy and involvement
of the anterior temporal lobe and external capsule on MRI may help in
diagnosis.
METHODS: The authors identified 83 potential index cases from the British
population and screened exons 2 to 23 of notch3. MRI scans were scored
using a modified Scheltens scale. Skin biopsy was performed in a subgroup.
RESULTS: Fifteen different point mutations were identified in 48 families,
73% of which were in exon 4, 8% in exon 3, and 6% in each of exons 5
and 6. Moderate or severe involvement of the anterior temporal pole
on MRI had a sensitivity of 89% and specificity of 86% for diagnosis
of CADASIL, whereas external capsule involvement had a high sensitivity
of 93% but a low specificity of 45%. Skin biopsy, performed in 18 cases,
had a sensitivity of 45% and specificity of 100%.
CONCLUSIONS: The spectrum of mutations in this study can be used to
plan appropriate screening protocols; a suggested protocol is to screen
exon 4, and proceed to exons 3, 5, and 6 where indicated. GOM on skin
biopsy is diagnostic but can be negative. Anterior temporal pole involvement
on MRI is a useful diagnostic marker. |
GROSS APPEARANCE/
CLINICAL VARIANTS |
CHARACTERIZATION |
| BRAIN |
May have mild generalized brain atrophy with enlargement
of the ventricular spaces and widening of the perivascular spaces
White matter shows areas of patchy demyelination
Lacunar infarcts |
CADASIL: a common form of hereditary arteriopathy causing brain infarcts
and dementia.
Kalimo H, Ruchoux MM, Viitanen M, Kalaria RN.
Department of Pathology, Turku University Hospital, Finland.
|
Brain Pathol 2002 Jul;12(3):371-84 Abstract quote
Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease
leading to cognitive decline and dementia. CADASIL usually begins with
migraine in about one third of the patients.
More severe manifestations, transient ischemic attacks or recurrent
strokes, appear between 30 and 50 years of age. CADASIL, however, may
be diagnosed well before the first stroke on the basis of characteristic
white matter hyperintensities upon magnetic resonance imaging and presence
of pathognomonic granular osmiophilic material in arterial walls, including
dermal arteries, since the arteriopathy is generalized.
Gradual destruction of vascular smooth muscle cells (VSMC) leads to
progressive wall thickening and fibrosis and luminal narrowing in small
and medium-sized penetrating arteries. The reduced cerebral blood flow
finally causes lacunar infarcts, mainly in the basal ganglia and fronto-temporal
white matter, which lead to cognitive deficits and dementia of the subcortical
vascular type. CADASIL is caused by single missense mutations or small
deletions in Notch3 gene encoding a transmembrane receptor Notch3, of
which upon ligand binding a nuclear signaling protein is generated by
regulated intramembrane proteolysis. Notch signaling is essential during
development, regulating cellular differentiation.
In adults Notch3 is expressed only in VSMCs and it may promote cell
survival by inhibiting apoptosis, but its exact function is unknown.
Mutations result in either a gain or loss of one (or rarely, 3) cysteine
residue(s) in one of the 34 epidermal growth factor-like repeats in
the extracellular amino-terminal region of Notch3. It is as yet unclear
which disturbance in the Notch signaling pathway leads to the characteristic
vascular pathology of CADASIL. |
| VARIANTS |
|
| The phenotypic spectrum of CADASIL: clinical findings
in 102 cases.
Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger
G, Ebke M, Klockgether T, Gasser T.
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-Universitat,
Munich, Germany. |
Ann Neurol 1998 Nov;44(5):731-9 Abstract quote
Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) is an increasingly recognized autosomal
dominant disorder that leads to cerebrovascular manifestations in early
adulthood.
This study delineates the phenotypic spectrum and the natural history
of the disease in 102 affected individuals from 29 families with biopsy-proven
CADASIL. Recurrent ischemic episodes (transient ischemic attack [TIA]
or stroke) were the most frequent presentation found in 71% of the cases
(mean age at onset, 46.1 years; range, 30-66 years; SD, 9.0 years).
Forty-eight percent of the cases had developed cognitive deficits. Dementia
(28%) was frequently accompanied by gait disturbance (90%), urinary
incontinence (86%), and pseudobulbar palsy (52%). Thirty-nine patients
(38%) had a history of migraine (mean age at onset, 26.0 years; SD,
8.2 years), which was classified as migraine with aura in 87% of the
cases. Psychiatric disturbances were present in 30% of the cases, with
adjustment disorder (24%) being the most frequent diagnosis. Ten patients
(10%) had a history of epileptic seizures. To delineate the functional
consequences of ischemic deficits, we studied the extent of disability
in different age groups.
The full spectrum of disability was seen in all groups older than age
45. Fifty-five percent of the patients older than age 60 were unable
to walk without assistance. However, 14% in this age group exhibited
no disability at all. Kaplan-Meier analysis disclosed median survival
times of 64 years (males) and 69 years (females). An investigation of
the 18 multiplex families revealed marked intrafamilial variations. |
| HISTOLOGICAL TYPES |
CHARACTERIZATION |
| GENERAL |
Small to medium sized arteries are affected but smaller
arteries, arterioles,a and capillaries may be affected
Degeneration of the arterial wall with deposition in the media of the
vessels of a nonatheromatous, nonamyloidotic substance
Destruction of the media is accompanied with loss of vascular smooth
muscle cells
Under the electron microscope, it is a granular osmiophilic material
(GOM), which is pathognomonic for the disease |
| BRAIN |
Most severely affected vessels are accompanied by lacunar
infarcts |
Arterial changes in cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) in relation to pathogenesis
of diffuse myelin loss of cerebral white matter: examination of cerebral
medullary arteries by reconstruction of serial sections of an autopsy
case.
Okeda R, Arima K, Kawai M.
Department of Neuropathology, Medical Research Institute, Tokyo
Medical and Dental University, Tokyo, Japan. |
Stroke 2002 Nov;33(11):2565-9 Abstract quote BACKGROUND AND PURPOSE:
There is little information regarding the pathogenesis underlying diffuse
myelin loss in the cerebral white matter and sparing of the U fibers
in cerebral autosomal-dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL), in which the medial smooth muscle
cells of systemic arteries are characteristically involved. We sought
to examine the precise extent and severity of changes in the cerebral
arteries in an autopsy case of CADASIL in relation to pathogenesis of
the diffuse myelin loss.
METHODS: We reconstructed 1000 serial sections of the frontal cerebral
medullary arteries of an autopsy subject, which was the first identified
Japanese case of CADASIL, as confirmed by the presence of ultrastructural
deposits of granular osmiophilic material in the media of some visceral
arteries and by genetic analysis.
RESULTS: We reconstructed 11 medullary arteries of the frontal lobe
showing diffuse myelin loss and atrophy of the white matter with sparing
of the U fibers. All of these showed complete loss of medial smooth
muscle cells over their entire length and severe adventitial fibrosis.
Although intimal fibrosis or hyalinosis was present, luminal occlusion
was scarce. These changes were also observed in the small and large
arachnoidal arteries but were relatively mild in the latter and in the
cortical and subcortical medullary arteries.
CONCLUSIONS: These arterial changes resulted in transformation of the
cerebral arteries, in particular almost all the medullary arteries,
to a so-called earthen pipe state. This supports the reported findings
of a reduction in vascular reactivity to fluctuations in CO2 levels
and systemic blood pressure in CADASIL. |
| SKIN |
J Am Acad Dermatol 2000;43:1125-7
Electron microscopy shows numerous areas, granular, electron-dense,
osmiophilic material abutted vascular smooth muscle cells |
-
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephaloapthy (CADASIL): a hereditary cerebrovascular disease, which can be diagnosed by skin biopsy electron microscopy.
Ishiko A, Shimizu A, Nagata E, Ohta K, Tanaka M.
Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
|
-
| Am J Dermatopathol. 2005 Apr;27(2):131-4. Abstract quote |
|
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease characterized by recurrent subcortical ischemic strokes starting in the third or fourth decade as a result of mutations in the Notch3 gene. Granular osmiophilic material (GOM) deposition around the vascular smooth muscle cells is a specific feature and electron microscopic observations of skin biopsies are useful for this diagnosis.
A 39-year-old female with dizziness, abnormal visual fields, and hemiplegia, and a 42-year-old male with tinnitus and dizziness, were suspected of suffering from CADASIL based on MRI findings. Both cases were shown to have characteristic deposits of GOM, 200 to 800 nm in diameter, around the vascular smooth muscle cells of small arteries in the deep dermis, and thus the diagnoses of CADASIL were made, although there was no family history of cerebrovascular disorders or dementia.
Dermatologists should be aware of these ultra-structural findings because this disease may occur sporadically and might be more common than initially thought.
|
Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL
diagnosis.
Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux
F, Domenga V, Cecillon M, Vahedi K, Ducros A, Cave-Riant F, Bousser
MG, Tournier-Lasserve E.
INSERM EPI 99-21, Faculte de Medecine Lariboisiere, 10 Avenue
de Verdun, 75010, Paris, France
|
Lancet 2001 Dec 15;358(9298):2049-51 Abstract quote
CADASIL (cerebral autosomal dominant arteriopathy with subcortical
infarcts and leucoencephalopathy) is a small-artery disease of the brain
caused by NOTCH3 mutations that lead to an abnormal accumulation of
NOTCH3 within the vasculature.
We aimed to establish whether immunostaining skin biopsy samples with
a monoclonal antibody specific for NOTCH3 could form the basis of a
reliable and easy diagnostic test. We compared the sensitivity and specificity
of this method in two groups of patients suspected of having CADASIL
with complete scanning of mutation-causing exons of NOTCH3 (in a retrospective
series of 39 patients) and with limited scanning of four exons that
are mutation hotspots (prospective series of 42 patients).
In the retrospective series skin biopsy was positive in 21 (96%) of
the 22 CADASIL patients examined and negative in all others; in the
prospective series, seven of the 42 patients had a positive skin biopsy
whereas only four had a mutation detected by limited NOTCH3 scanning.
Our immunostaining technique is highly sensitive (96%) and specific
(100%) for diagnosis of CADASIL.
|
| A CADASIL case with normal skin biopsy and without
mutations in exons 3 and 4 of the Notch3 gene.
de Freitas GR, Miklossy J, Christen-Zach S, Reichhart M, Bogousslavsky
J.
Department of Neurology, Centre Hospitalier Universitaire Vaudois,
CH1011, Lausanne, Switzerland |
J Neurol Sci 2001 Dec 15;193(1):43-7 Abstract quote
The diagnosis of cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) is usually confirmed by genetic
testing or skin biopsy.
We here report the case of a 69-year-old woman with recurrent transient
ischemic attacks (TIAs) and strokes, seizures, and dementia without
any mutations in exons 3 and 4 of the Notch3 gene and with a normal
skin biopsy, but who showed characteristic CADASIL abnormalities on
brain pathological examination.
Our findings suggest that negative results in these two tests do not
exclude the disease and a leptomeningeal biopsy or a second skin biopsy
should be considered in such cases. |
|
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy): a neurovascular disease diagnosed by ultrastructural
examination of the skin.
Kanitakis J, Thobois S, Claudy A, Broussolle E.
Department of Dermatology, Hopital Ed. Herriot, and Department of
Neurology (U401-402), Hopital Neurologique Pierre Wertheimer, Lyon,
France. |
J Cutan Pathol 2002 Sep;29(8):498-501 Abstract quote
BACKGROUND: CADASIL (cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy) is a recently recognized
neurovascular disease due to mutations of the Notch3 gene, manifesting
with strokes or stroke-like episodes, major psychiatric symptoms and
dementia. The diagnosis can be confirmed either by molecular analysis
or by ultrastructural examination of the brain or more simply the skin.
METHODS: The skin of a patient with a suspected diagnosis of CADASIL
was studied by electron microscopy.
RESULTS: Characteristic granular osmiophilic material within the basement
membrane surrounding pericytes and smooth muscle cells of small and
medium-sized vessels of the skin were found, confirming the diagnosis
of CADASIL.
CONCLUSIONS: CADASIL is an additional example of a neurologic disease
that can be diagnosed thanks to electron microscopic examination of
the skin. Dermatopathologists should be aware of these ultrastructural
findings, all the more so since the disease could be more common than
originally thought. |
SPECIAL STAINS/
IMMUNOPEROXIDASE |
CHARACTERIZATION |
| Granular material |
PAS positive but staining is lost following acetylation
Negative for amyloid stains |
| Antibodies to aB crystallin |
Protein in the heat shock protein superfamily
Positive in the granular material |
| Electron microscopy |
This is diagnostic
Pathognomonic finding of GOM in the arterial walls
These findings are found throughout the systemic circulation allowing
for potential diagnosis through skin biopsies |
Morphometric analysis of ultrastructural vascular changes in CADASIL:
analysis of 50 skin biopsy specimens and pathogenic implications.
Brulin P, Godfraind C, Leteurtre E, Ruchoux MM.
EA 2691 MENRT, Faculte de Medecine de Lille, 59037 Lille, France.
|
Acta Neuropathol (Berl) 2002 Sep;104(3):241-8 Abstract quote
Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) is a systemic vascular disease caused
by Notch 3 gene mutations.
On electron microscopy a specific granular osmiophilic material (GOM)
is found surrounding the vascular smooth muscle cells. In 1993, we first
proposed the use of skin biopsy to diagnose patients and to identify
relatives of patients with CADASIL.
We analyze here our experience with skin biopsies from 50 patients
with CADASIL and compare the findings with those of 20 normal skin biopsy
specimens. A morphometric analysis of skin vessel morphology on electron
microscopy was performed by systematic measurements of several blood
vessel diameters, as well as of areas of lumen, endothelial cell and
smooth muscle cell cross-sectional areas, vessel wall area, arterial
media and extracellular matrix areas.
We found relative absence of stenosis but marked destruction of smooth
muscle cells, resulting in decrease of vessel wall thickness and loss
of extracellular matrix area, producing vessel wall weakness. Similar
changes were also observed in brain arterioles from 5 patients with
CADASIL. Our results suggest that hypotonicity of the arteriolar tree
may constitute an important pathogenetic mechanism in CADASIL. Other
than hypotonicity, the early and severe destruction of smooth muscle
cells may potentially result in decreased secretion of vascular endothelial
growth factor, loss of vascular permeability and damaging hemodynamic
consequences. Blood vessel morphology of skin vessels correlated well
with changes in brain arterioles.
Vascular morphology in skin biopsy samples contributes to our understanding
of the pathogenesis of CADASIL. It could be important to perform skin
biopsies in future therapeutic trials of CADASIL as a direct measure
of therapeutic effectiveness. |
| DIFFERENTIAL DIAGNOSIS |
KEY DIFFERENTIATING FEATURES |
| MULTIPLE SCLEROSIS |
|
| PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM |
|
|
CADASIL mimicking primary angiitis of the central nervous system.
Engelter ST, Rueegg S, Kirsch EC, Fluri F, Probst A, Steck
AJ, Lyrer PA.
Neurological Clinic and Stroke Unit, University Hospital Basle,
Petersgraben 4, CH-4031 Basel, Switzerland. |
Arch Neurol 2002 Sep;59(9):1480-3 Abstract quote BACKGROUND: Cerebral
autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) and primary angiitis of the central nervous system (PACNS)
share several clinical and radiological features. However, digital subtraction
angiogram (DSA) is generally reported as normal in CADASIL, whereas
lumen irregularities in distal cerebral arteries indicate PACNS.
OBJECTIVE: To describe a potential pitfall of DSA interpretation, which
led to the tentative diagnosis of PACNS in a CADASIL patient.
PATIENT AND METHODS: Single case observation.
RESULTS: A 47-year-old man sustained recurrent subcortical infarcts.
He had mild hypercholesterolemia and migraine. His family history was
unremarkable. The underlying cause of stroke could not be elucidated.
Transcranial Doppler sonography revealed decreased intracranial blood
flow velocities compatible with CADASIL. Lumen irregularities of several
peripheral intracranial arteries were seen on DSA, which suggested PACNS.
CADASIL was confirmed by results from skin biopsy and genetic testing.
CONCLUSIONS: First, in patients with CADASIL, DSA can show segmental
lumen irregularities in distal cerebral arteries suggestive of PACNS.
Second, the potential role of transcranial Doppler sonography to distinguish
CADASIL from PACNS deserves further testing. |
