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Year : 2009  |  Volume : 57  |  Issue : 5  |  Page : 659-660

Invited Commentary

Department of Neurology, AIIMS, New Delhi - 110 029, India

Date of Acceptance02-Jul-2009
Date of Web Publication20-Nov-2009

Correspondence Address:
M V Padma Srivastava
Department of Neurology, AIIMS, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.57807

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How to cite this article:
Padma Srivastava M V. Invited Commentary. Neurol India 2009;57:659-60

How to cite this URL:
Padma Srivastava M V. Invited Commentary. Neurol India [serial online] 2009 [cited 2021 Apr 15];57:659-60. Available from:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), first described by van Bogaert in 1955, [1] is an autosomal dominant disease whose typical clinical features are migraine like headaches, recurrent lacunar strokes or transient ischemic attacks (TIAs), cognitive decline, psychiatric manifestations, and epilepsy. [2],[3],[4] From a pathological point of view, CADASIL patients have a systemic nonamyloid, nonarteriosclerotic disease that affects the wall of small vessels. [5] The disease is caused by a mutation (mainly missense) of the NOTCH3 gene located on chromosome 19q12. [6],[7] Most mutations in the NOTCH3 gene in individuals with CADASIL are located in exon 4. NOTCH3 receptor located on the surface of the smooth muscle cells of arteries, contain a large number of epidermal growth factor (EGF)-like repeats in their external domains. More than 50 mutations have been reported till date, which largely result in the insertion or deletion of a cysteine residue in the EGF repeats of the NOTCH3 protein. [2] As a consequence of these changes, an accumulation of granular osmiophilic material is observed in the area surrounding vascular smooth muscle cells of small and medium-sized arteries. [3],[4],[8] It is hypothesized that the accumulation of this pathologic NOTCH3 receptor protein in small and medium-sized cerebral arteries is responsible for the pathogenesis and phenotypic presentation of CADASIL.

It is interesting to hypothesize that other vascular risk factors which may alter the thrombogenecity, hemorrheology, platelet aggregability or adhesion may enhance the clinical expression of this inherited disease. Recent observations suggest that exogenous factors (other vascular risk factors) may modulate the phenotype, anticipating or aggravating the disease process and consequently its clinical expression. [9] There have been reports of CADASIL patients, who in addition to hypertension and hyperlipidemia, also had thrombophilic risk factors such as hyperhomocysteinemia, elevated levels of lipoprotein(a), and antiphospholipid antibodies. [9] The first Greek family with CADASIL, caused by the R153C mutation at exon 4 of the NOTCH3 gene was reported recently. [10] A member of this family carrying this mutation was also found to be heterozygotic for the methylenetetrahydrofolate reductase (MTHFR) mutation, factor V Leiden mutation and had low serum levels of antithrombin III, thus resulting in the appearance of recurrent strokes and thombotic episodes since his early childhood. [10] The coexistence of these thrombophilic disorders with CADASIL in the same individual may pose therapeutic dilemmas, as the administration of anticoagulant agents may predispose to intracranial hemorrhage. The identification of these cofactors may open up important preventative perspectives. [9],[10] There is meager but burgeoning literature on these "co-habiting" inherited/acquired vascular risk factors which may coexist and potentiate the clinical expression of CADASIL. Factor XII deficiency has not been reported till date and the report by Nadezda et al., [11] is exciting in this regard. This interesting observation needs further research. It may be possible to unravel many more of these coinherited vascular risk factors, coagulopathies and angiopathies which may explain the protean possibilities of disease expression in CADASIL.

  References Top

1.Van Bogaert L. Encephalopathie sous-corticale progressive (Binswanger) a evolution rapide chez duex seurs. Med Hellen 1955;24:961.  Back to cited text no. 1      
2.Chabriat H, Vahedi K, Iba-Zizen MT, Joutel A, Nibbio A, Nagy TG, et al. Clinical spectrum of CADASIL: A study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical iinfarcts and leukoencephalopathy. Lancet; 346:934-9.  Back to cited text no. 2      
3.Dichigans M, Mayer M, Uttner I, Brüning R, Müller-Höcker J, Rungger G, et al. The phenotypic spectrum of CADASIL: Clinical findings in 102 cases. Ann Neurol 1998;44:731-9.  Back to cited text no. 3      
4.Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain 2004;127:2031-8.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Ruchoux MM, Guerrouaou D, Vandenhaute B, Pruvo JP, Vermersch P, Leys D. Systemic vascular smooth muscle cell impairement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Acta Neuropahtol 1995;89:500-12.  Back to cited text no. 5      
6.Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707-10.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
7.Mazzei R, Conforti FL, Lanza PL, Sprovieri T, Lupo MR, Gallo O, et al. A novel Notch3 gene mutation not involving cysteine residue in an Intalian family with CADASIL. Neurology 2004;63:561-4.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]  
8.Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, et al. Tournier-Lasserve E. Stron clustering and stereotyped nature of Natch3 mutations in CADASIL patients. Lancet 1997;350:1511-5.  Back to cited text no. 8      
9.Pantoni L, Sarti C, Pescini F, Bianchi S, Bartolini L, Nencini P, et al. Thrombophilic risk factors and unusual clinical features in three Italian CADASIL patients. Eur J Neurol 2004;11:782-7.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.Mandellos D, Limbitaki G, Papadimitriou A, Anastasopoulos D. Cerebral autosomal domianat arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a Greek family. Neurol Sci 2005;26:278-81.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Nadezda S, Aleksandra P, Predrag M, Milos B, Maja L, Vesna L. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with severe factor XII deficiency. Neurol India 2009;57:657-60.  Back to cited text no. 11    Medknow Journal  


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