Response to letter regarding article, "Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism".

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HomeStrokeVol. 45, No. 7Response to Letter Regarding Article, “Archetypal Arg169Cys Mutation in NOTCH3 Does Not Drive the Pathogenesis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leucoencephalopathy via a Loss-of-Function Mechanism” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letter Regarding Article, “Archetypal Arg169Cys Mutation in NOTCH3 Does Not Drive the Pathogenesis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leucoencephalopathy via a Loss-of-Function Mechanism” Emmanuel Cognat, MD Dominique Hervé, MD Anne Joutel, MD, PhD Emmanuel CognatEmmanuel Cognat INSERM, U1161, Paris, France Search for more papers by this author Dominique HervéDominique Hervé CERVCO, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique – Hôpitaux de Paris, Paris, France Search for more papers by this author Anne JoutelAnne Joutel INSERM, U1161, Paris, France Search for more papers by this author Originally published27 May 2014https://doi.org/10.1161/STROKEAHA.114.005616Stroke. 2014;45:e129Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 We thank Moccia et al1 for their interest in our recently published study on the functionality of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) mutations.2 We are grateful for the opportunity to respond to their comments about a nonsense mutation in NOTCH3.In our study, we investigated the in vivo functionality of an archetypal CADASIL mutation. By CADASIL mutation, we mean a mutation leading to an uneven number of cysteine residues in 1 of the 34 epidermal growth factor repeats (EGFR) constituting the extracellular domain of the NOTCH3 receptor. These so-called “cysteine mutations” are the only mutations, which can be unambiguously classified as pathogenic. Using Notch3 null mice as well as knock-in and transgenic mouse models of the archetypal Arg169Cys CADASIL-associated NOTCH3 mutation, we presented several lines of evidence arguing against the general conclusion that all CADASIL mutations reflect hypomorphic NOTCH3 activity and that reduction in NOTCH3 activity is a major driving force of the brain manifestations of CADASIL.Although Moccia et al1 do not question the results of our experimental studies, they raise the possibility that hypomorphic NOTCH3 alleles could be responsible for a CADASIL-like syndrome. They refer to their recent work describing a nonsense mutation (p.R103X, in the EGFR2 of NOTCH3) in a 76-year-old hypertensive patient with a recent history of a progressive parkinsonian syndrome and an MRI consistent with a small vessel disease (SVD) of the brain.3 It was further concluded that this mutation was likely pathogenic based on the finding that (1) this mutation was present in the patient’s sister who had a history of recurrent strokes in her 40s and (2) this mutation was absent in another 3 relatives, reported as unaffected. We think that such an assertion may be extremely premature for several reasons. First, too few controls (100 subjects) have been analyzed to exclude with certainty that this mutation is a rare polymorphism. Second, cosegregation of the mutation with a disease, although suggestive, is not a clear-cut proof of its pathogenicity. Moreover, clinical and MRI records of the patient’s relatives are lacking to ensure that the brother and her sister have the same disease, and the relatives are actually unaffected. Third, and more importantly, the same nonsense mutation was identified by Rutten et al4 in 2 siblings, namely a 55-year-old patient with a polyneuropathy, migraine with aura, recurrent strokes, and a brain MRI consistent with large vessel strokes and his 50-year-old brother who had normal neurological examination and brain MRI. Finally, what would be intriguing for a disease-causing mutation is the lack of any clinical or MRI similarities between the index cases of these 2 families. Hence, we think that the p.R103X should in no way be interpreted as a disease-causing mutation, unless there is additional evidence.What these 2 case reports3,4 illustrate well is the fact that the significance of nonsense mutations, frameshift deletions or insertions with predicted loss of NOTCH3 function, remains unclear. Those mutations could be simply rare neutral polymorphisms or, alternatively, rare variants conferring a risk of developing a cerebrovascular disease that may be not necessarily a SVD. Indeed, the brain MRI of the 55-year-old patient reported by Rutten et al4 is clearly not compatible with a SVD, and one might ask whether the parkinsonian syndrome of the 76-year-old patient reported by Erro et al is attributable to a SVD.For both clinicians and patients, CADASIL refers to an autosomal dominant cerebral SVD, with well-defined clinical and neuroradiological features, pathognomonic lesions of the small vessels, and an increasingly appreciated toxic mechanism of mutant NOTCH3.5 Hence, we think inappropriate and even confusing the suggestion of Moccia et al1 to use the term CADASIL-like syndrome to describe neurological manifestations associated with loss-of-function mutations in NOTCH3, which are yet of unknown significance. Having said that, we agree that such mutations are an important area that deserves further investigation.Emmanuel Cognat, MDINSERM, U1161Paris, FranceDominique Hervé, MDCERVCO, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique – Hôpitaux de ParisParis, FranceAnne Joutel, MD, PhDINSERM, U1161Paris, FranceDisclosuresNone.FootnotesStroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. Letters must reference a Stroke published-ahead-of-print article or an article printed within the past 3 weeks. The maximum length is 750 words including no more than 5 references and 3 authors. Please submit letters typed double-spaced. Letters may be shortened or edited.