Transcript A Breath, Beat and Belief

CADASIL:
Cerebral Autosomal Dominant Arteriopathy with
Subcortical Infarcts and Leukoencephalopathy
Maiya Geddes, R2
February 28th 2008
Questions this lecture will tackle
1) When should I suspect CADASIL?
 2) Where is the lesion (in Notch3)?
 3) What is the role of Notch3 in vascular
smooth-muscle cells?
 4) How can a skin biopsy be useful in a
disorder exclusive to the CNS?
 5) Does Notch play a role in other disorders?

When to suspect CADASIL

Symptoms
1) Migraine with aura (38% Caucasian and 8.3%
Korean)
 2) Stroke-like episodes age 30-50
 3) Early cognitive impairment (Peters 2005) and
dementia (80% over 65 years)
 4) Affective disorders (20%), Psychosis
 Seizures (10%)
 Pregnancy complications (Roine 2005)
 Gait disorder
 Parkinsonism

Clinical Spectrum

Mean age of onset 26-38 years (Kalimo 1999)

Peak of first stroke 40-50 years

Death age 53 males, 59 females (Dichgans 1998)

Many ethnic groups affected

Differential Diagnosis


Binswanger’s disease (HTN)
MELAS (cortical/occipital infarcts)
Radiologic Correlation

Lacunes in white matter and deep gray

Periventricular (96%), brainstem, external capsule, corpus callosum,
frontal, spinal cord

Increased T2 white matter hyperintensities in asymptomatic

Microbleeds in 31% of symptomatic (Oberstein 2001)

Cerebral Angiography contraindicated

Disability associated with (Viswanathan 2007)

volume of lacunar lesions, cerebral microhemorrhages, bp
Mapping
(Joutel Nature 1996)
19p13.1-13.2
 NOTCH3
Gain
of function mutation
Predicted Protein Structure of
Notch3



Transmembrane Protein
33 Exons
2321 Amino Acids
Federico Neurol Sci 2005
Predicted Protein Structure of
Notch3
Transmembrane Region
Federico Neurol Sci 2005
Predicted Protein Structure of
Notch3
Extracellular Domain
Intracellular Domain
Federico Neurol Sci 2005
Where is the Lesion?
58% of Missense Point mutations are in Exon 4 (Peters 2005)
Joutel Lancet 1997
Haplotype Analysis

Joutel et al. Lancet 1997
Unpaired
reactive cysteine residue
Inappropriate
 Change
disulfide bonding?
in three-dimentional structure
Disulphide Bridge
Notch3 in vascular smooth-muscle




Abnormal accumulation in eosinophilic deposits
Thickened tunica media
Infarcts from thickened and fibrotic wall of
small and medium penetrating arteries
Notch3 required for differentiation and
maturation of VSMC (Domenga 2004)

Impaired cerebral blood flow reactivity and
cerebrovascular resistance in knockout mice
Skin Biopsy in CADASIL

Generalized arteriopathy

Skin biopsy 96% sensitive 100% specific (Joutel 2001)

Granular Osmiophilic Material deposits
Small vessel arteriopathy
Gross Pathology
Kalimo 1999
Notch Signaling
CBF 1
Notch3

Mutations show differential Jagged1 binding and
RBP/JK transcriptional activity (Joutel 2004)

Notch3 important during development


Highly conserved

Cell fate (astroglia), organogensis, vasculogenesis

Notch active in mature astroglia and prevents neurite
outgrowth (Sestan Science 1999)
Same signaling pathway as Presenillin 1

PS 1 mediated proteolytic cleavage of Notch 1
Binding of Notch to ligand
triggers proteolytic cleavage
1
2
3
Hayward 2008
Other Notch Signaling Disorders
(Gridley 2003)

Notch1 in adult T-cell leukemia

Alagille syndrome



Mutation in Jagged-1 or Notch2
hepatic ductular hypoplasia, pulmonic valvular stenosis,
neonatal jaundice, butterfly vertebrae, retinal changes, absent
reflexes
Spondylocostal Dysostosis


DLL3 gene mutation at 19q13
Rib and vertebral anomalies “crab-like” spine
In Summary

Mutation in extracellular domain of NOTCH3
(chromosome 19)

Lone cysteine prevents disulphide bonding and dimerization

Accumulation in VSMC

Obliteration of small and medium arteries

Lacunes in white matter and deep gray

1) Migraine with aura 2) Stroke 3) Depression 4) Dementia
Physician and Patient Resources

OMIM Pubmed

CADASIL foundation website:


Leukodystrophy foundation:


http://home.earthlink.net/~cadasil/
http://www.ulf.org/types/Cadasil.html
CADASIL support group:

http://www.cadasil.pwp.blueyonder.co.uk/