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CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts & leukoencephalopathy)

Epidemiology: - affects relatively young adults of both sexes Pathology: 1) notch-3 deposits in blood vessel walls 2) ischemic infarcts, lacunes & diffuse leukoencephalopathy a) periventricular white matter b) basal ganglia c) thalamus d) internal capsule e) pons Genetics: - autosomal dominant - linked to chromosome 19q12 [2], notch-3 homolog gene on chromosome 9p13.2-p13.1. (?) - > 200 NOTCH3 mutations have been described - most involve point mutations leading to gain or loss of Cys - R141C mutation in exon 4 in the NOTCH3 gene (case report) [3] - mutations affect highly conserved Cys within EGF-like repeat domains in the extracellular part of the receptor Clinical manifestations: 1) migraine with aura [3] generally 1st manifestation - 5X more common than in general population [3] 2) subcortical ischemic events - transient ischemic attack - lacunar infarcts [3] 3) vascular dementia 4) mood changes - severe depression, apathy, occasional manic episodes [3] Radiology: - MRI abonormalities present by age 35 (100%) a) white matter & microangiopathic changes b) temporal pole most characteristic Differential diagnosis: - CARASIL - symptom onset in CARASIL ~ 10-15 years earlier than in CADASIL - memory dysfunction appears to be more severe than CADASIL Complications: - increased risk for hemorrhage Management: - no specific treatment is available for CADASIL [3] - avoid vasoconstrictor agents - triptans may be safe - anticonvulsant & beta-blocker may be used for migraine prophylaxis - treat cardiovascular risk factors - statin, antiplatelet agents - avoid anticoagulants because of increased risk for hemorrhage [3] - acetazolamide 250 mg BID + aspirin 300 mg QD - escitalopram 10 mg QD (case report [3])

Interactions

disease interactions

Related

CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts & leukoencephalopathy) notch-3 (Drosophila) homolog protein (NOTCH3)

General

genetic disease of the central nervous system multi-infarct dementia

Database Correlations

OMIM correlations MORBIDMAP 600276

References

  1. Joutel et al. Nature 383:707-10 1996 Tournier-Lasserve et al. Nature Genetics 3:256-9 1993
  2. Kalaria RN, Viitanen M, Kalimo H, Dichgans M, Tabira T; The CADASIL Group of Vas-Cog. The pathogenesis of CADASIL: an update. J Neurol Sci. 2004 Nov 15;226(1-2):35-9. PMID: 15537516
  3. Toro J, Duque A, Reyes S, Patino J. Case Challenge: A Man with Migraine and Behavioral Changes. NEJM Journal Watch. Sept 12, 2017 Case Conclusion: A Man with Migraine and Behavioral Changes. NEJM Journal Watch. Sept 26, 2017 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
  4. Di Donato I, Bianchi S, De Stefano N et al Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC Med. 2017 Feb 24;15(1):41. Review. PMID: 28231783 Free PMC Article