Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small-vessel disease caused by NOTCH3 variants. Clinical overlap with epilepsy and multiple sclerosis (MS) can delay diagnosis. Characteristic MRI patterns, particularly anterior temporal pole T2/FLAIR hyperintensities, together with gene testing, aid recognition. 

Case 1: 43-year-old man with new headache, dysarthria, left facial droop, confusion, and a family history of early strokes. MRI showed acute diffusion-positive infarcts in the right frontal lobe and thalamus and confluent white-matter hyperintensities with anterior temporal pole involvement. Sequencing identified NOTCH3 c.1268A>G (p.Tyr423Cys).  

Case 2: 51-year-old man previously diagnosed with MS presented with early-onset dementia and hallucinations without a family history of stroke or migraine. MRI demonstrated diffuse white-matter disease. Sequencing identified NOTCH3 c.545G>A (p.Arg182His) and COL4A2 c.610G>A (p.Val204Met).  

Two cysteine-altering NOTCH3 variants (p.Tyr423Cys and p.Cys82Phe) were concordant with CADASIL in cases showing anterior temporal pole involvement, whereas a non-cysteine NOTCH3 variant (p.Arg182His) co-occurred with a rare COL4A2 missense change. These cases illustrate common diagnostic pitfalls, including Seizure-like or Multiple Sclerosis-like presentations. Emphasizing MRI “red flags,” cautious variant interpretation, and early genetic counseling may reduce misdiagnosis and guide family screening and vascular risk management.