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062 Cadasil presenting with focal and generalised epilepsy due to a novel NOTCH3 mutation

Introduction Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations of the NOTCH3 gene. Clinical manifestations include migraine, recurrent ischaemic strokes, and cognitive decline. Seizures are an uncommon early symptom and usually occur after the onset of stroke. We report a CADASIL family with epilepsy as an early clinical symptom due to a novel NOTCH3 mutation. Methods The clinical histories of three family members from two generations are reported, alongside para-clinical details including results of magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic testing. Results The proband developed focal and generalised seizures at age 51. She had a preceding history of cognitive impairment and migraines. The proband’s son developed focal seizures at age 25 involving his left arm and then generalised seizures. He experienced intermittent headaches, without history of stroke or cognitive impairment. His sister (the proband’s daughter) had epilepsy from age 12, characterised by blank spells and generalised seizures. Cognitive decline was noted from age 38, without history of stroke. There was no family history of epilepsy in those without CADASIL. MRI in all three family members showed multifocal T2 FLAIR hyperintensities within the supratentorial white matter, particularly the temporal lobes. EEG was abnormal only in the proband’s son, with paroxysmal bursts of poorly organised 3–4 Hz spike-wave activity. Genetic testing in all three family members found a novel NOTCH3 mutation, c.1337G>A p.(Cys446Tyr). Conclusion We have identified a novel NOTCH3 mutation in a kindred with epilepsy as an early manifestation of CADASIL without prior history of strokes. The association with epilepsy is unlikely to be coincidental given the strong segregation of epilepsy and CADASIL in this kindred and the clear focal seizure semiology noted in all family members. Whether this mutation represents a distinct new phenotype requires further investigation.