A pathogenic mutation on exon 21 of the NOTCH3 gene causing CADASIL in an octogenarian paucisymptomatic patient

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is an inherited small vessel disease causing migraine, early strokes, cognitive impairment and premature death. The disease is caused by NOTCH3 gene puntiform mutations on one of the exons coding for the epidermal-growth factor (EGF)-like repeats of the extracellular domain of the NOTCH3 receptor. Mutations have been reported with higher frequency on some exons, and never on 6 out of a total of 23. We report for the first time a mutation (c.3471C>G) on exon 21 of the NOTCH3 gene that leads to a cysteine substitution (p.1131C>W) in the EGF-like repeat 29 of the NOTCH3 receptor extracellular domain, and that is responsible for CADASIL in a functionally independent elderly man who came to our attention at the age of 79 because of a minor stroke. CADASIL suspicion aroused only from the finding of severe white matter changes extended to the temporopolar region on cerebral magnetic resonance imaging. This case report underlines that, when CADASIL is suspected, molecular analysis should be performed on all the NOTCH3 exons coding for EGF-like repeats and not be limited to those where mutations have been found with higher frequency, and that the disease may be encountered also in mildly symptomatic elderly patients. The newly reported mutation might sustain a milder expressivity of the disease