CYSTEINE-SPARING NOTCH3 MUTATIONS: CADASIL OR CADASIL VARIANTS?

Abstract

Mutations in the Notch3 gene in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) usually involve cysteine residues.1 We report a cysteine-sparing mutation (A1020P) in association with a CADASIL-compatible phenotype in two German families. ### Case histories. The index patient 1 is a 49-year-old woman with a medical history of sensorineural hearing loss of adolescent onset. At the age of 34, arterial hypertension was diagnosed. Since her 40s she reported episodes of unilateral headache, vertigo, and nausea. In addition, the patient had intermittent paresthesias and weakness of the left extremities, reduced fine motor skills, cognitive slowing, and impaired memory. MRI in 2003 revealed widespread T2-hyperintense white matter lesions (WMLs) (figure, A). Electron microscopic examination of a skin biopsy showed deposits of osmiophilic material between the smooth-muscle cells of small arteries (figure e-1 on the Neurology ® Web site at www.neurology.org), and immunostaining with a Notch3 monoclonal antibody showed granular labeling of vascular smooth-muscle cells (figure e-2). Figure Axial T2-weighted (A, C, E) and fluid-attenuated inversion recovery MRIs (B, D) of the index patient (A), the index patient’s mother (B), and patient 2 (D), compatible with widespread ischemic leukoaraiosis Note especially the absence of white matter lesions (WMLs) in the anterior temporal lobes in all three individuals. The MRI of the index patient’s uncle (C), although characterized as a mutation carrier, only showed a slight pallor of the white matter and dilated Virchow Robin spaces. (E) MRI of the father of the …