Response to Letter Regarding Article, "Cysteine-Sparing CADASIL Mutations in NOTCH3 Show Proaggregatory Properties In Vitro".

Abstract

We thank Rutten et al1 for their comments on our work on cysteine-sparing NOTCH3 mutations in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).2 We fully agree that the diagnostic workup of patients with atypical mutations requires an experienced CADASIL team and needs to incorporate all available information including medical and family history, clinical and neuropsychological examination, biopsy results, neuroimaging data, and sequencing of at least all NOTCH3 exons encoding EGF repeats. In that respect, the majority of previously published reports on cysteine-sparing mutations were incomplete. Hence, the CADASIL diagnosis in some of these studies can indeed be questioned. In accord with this, our in vitro aggregation assay suggests heterogeneity among previously reported cysteine-sparing …