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Neurology India, Vol. 57, No. 5, September-October, 2009, pp. 659-660 Invited Commentary Invited Commentary M. V. Padma Srivastava Department of Neurology, AIIMS, New Delhi - 110 029, India Date of Acceptance: 02-Jul-2009 Code Number: ni09184 DOI: 10.4103/0028-3886.57807 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
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