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CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. Maiya Geddes, R2 February 28 th 2008. Questions this lecture will tackle. 1) When should I suspect CADASIL? 2) Where is the lesion (in Notch3)?

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CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

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  1. CADASIL:Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Maiya Geddes, R2 February 28th 2008

  2. 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?

  3. 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

  4. 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)

  5. 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

  6. Mapping(Joutel Nature 1996) • 19p13.1-13.2 • NOTCH3 • Gain of function mutation

  7. Predicted Protein Structure of Notch3 • Transmembrane Protein • 33 Exons • 2321 Amino Acids Federico Neurol Sci 2005

  8. Predicted Protein Structure of Notch3 Transmembrane Region Federico Neurol Sci 2005

  9. Predicted Protein Structure of Notch3 Intracellular Domain Extracellular Domain Federico Neurol Sci 2005

  10. Where is the Lesion? 58% of Missense Point mutations are in Exon 4 (Peters 2005) Joutel Lancet 1997

  11. Haplotype Analysis • Joutel et al. Lancet 1997 • Unpaired reactive cysteine residue • Inappropriate disulfide bonding? • Change in three-dimentional structure

  12. Disulphide Bridge

  13. 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

  14. Skin Biopsy in CADASIL • Generalized arteriopathy • Skin biopsy 96% sensitive 100% specific (Joutel 2001) • Granular Osmiophilic Material deposits

  15. Small vessel arteriopathy

  16. Gross Pathology Kalimo 1999

  17. Notch Signaling CBF 1

  18. 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

  19. Binding of Notch to ligand triggers proteolytic cleavage 1 2 3 Hayward 2008

  20. 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

  21. 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

  22. Physician and Patient Resources • OMIM Pubmed • CADASIL foundation website: • http://home.earthlink.net/~cadasil/ • Leukodystrophy foundation: • http://www.ulf.org/types/Cadasil.html • CADASIL support group: • http://www.cadasil.pwp.blueyonder.co.uk/

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