Phenotypic characterization of CADASIL patients with the Arg332Cys mutation in the NOTCH3

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary vascular disease caused by mutations in NOTCH3, that are primarily localized in exons 4, 3, and 11. The Arg332Cys mutation in exon 6 has been rarely reported in patients with CADASIL.

A case study and the results of a comprehensive systemic search of the PubMed database, using the keywords "CADASIL", "Arg332Cys", "R332C", and "exon 6", are reported. The results obtained, combined with the data obtained from the largest published case series on CADASIL, the clinical and imaging characteristics of patients with the Arg332Cys mutation, were compared and analyzed.

A 48-year-old woman with a rare Arg332Cys mutation in exon 6 of NOTCH3, who presented with rapidly developing dementia and recurrent ischemic stroke, was investigated herein. Magnetic resonance imaging (MRI) revealed abnormal signals in the cerebral white matter, bilateral thalamus, internal and external capsules, basal ganglia, corpus callosum, and brainstem. Literature review identified an additional 21 individuals, comprising 11 Europeans and 10 Asians, with the Arg332Cys mutation; of these identified individuals, clinical data was available for 2 Italian and 9 Asian patients. Analysis of the clinical characteristics of the 11 patients and the patient we reported showed that their mean age at disease onset was 
37.82±9.36 years, much earlier than 57.0±9.36 years reported in literature. The most frequent manifestations were transient ischemic stroke or stroke (83.3%), followed by cognitive impairment (58.3%), psychiatric symptoms (50%), and migraine (33.3%). Among the 10 Asian patients with available imaging data, the characteristic high signals for the external capsule and brainstem accounted for 90% and 71.43% respectively, and anterior temporal high signal took proportion of 60% (higher than 34.5% reported for Asian patients in literature). None of the 6 patients with available gradient echo imaging data had cerebral microbleeding.

CADASIL patients with the Arg332Cys mutation in exon 6 have been reported in Europe and Asia. The majority of patients had early disease onset. Diffuse high signals involving the external capsule, brainstem, and bilateral temporal pole are the main neuroimaging characteristics.