Focal Seizures as the First Manifestation of CADASIL; Novel Mutation Detected by Next Generation Exome Sequencing (P4.361)

Objective:To report a case of atypical CADASIL clinical presentation with seizures, and describe a new mutation in the NOTCH 3 gene Background:CADASIL is an arteriopathy with subcortical infarcts and leukoencephalopathy caused by mutations in the NOTCH3 gene on chromosome 19p13. Migraine, cognitive impairment and lacunar strokes are main clinical features. Seizures occur in about 5-10[percnt] of patients, but were rarely reported as an initial symptom. Methods: A 54-year-old woman experienced two episodes of focal seizures. Brain Magnetic Resonance Imaging (MRI) showed diffuse subcortical white matter hyperintensity (T2-wheighted images and FLAIR). A similar pattern was found on her father´s brain MRI, who died due to an unknown condition. Differential diagnoses of autosomal dominant adult leukoencephalopathies (ADAL) were considered. Nerve conduction velocities, very long chain fatty acids, plasmatic cortisol, fundoscopy, and CSF oligoclonal bands were normal. Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS) was excluded after sequencing the CSF1R coding sequence. Results:Full exome sequencing was performed, identifying heterozygous c.719G>T; p. (Cys240Phe) missense variant in exon 5 of NOTCH3. This variant causes the loss of a cysteine of an EGF-like domain of NOTCH3 gene. It was neither found in NOTCH3 specific databases (HGMD and LOVD), nor in population databases (ExAC-Exome Variant server) and 1000Genomes). The c.719G>C mutation at the same position, p.(Cys240Ser), was reported by Opherk et al. in 2004. Conclusions:We describe a novel mutation in exon 5 of NOTCH3 gene, causing CADASIL. Even without vascular events but seizures as a main symptom, CADASIL should be considered a differential diagnosis of ADAL. The use of NGS is a tool of high diagnostic yield in phenotypically similar but genotypically heterogeneous diseases. Disclosure: Dr. Emanuel has nothing to disclose. Dr. Alvarez has nothing to disclose. Dr. Serebrinsky has nothing to disclose. Dr. Salutto has nothing to disclose. Dr. Mazia has nothing to disclose.