To describe a previously unreported NOTCH3 mutation in a case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), initially misdiagnosed as a demyelinating disease.

CADASIL is a rare autosomal dominant disorder characterized by progressive cognitive decline, recurrent strokes, and headaches. Due to its rarity and the non-specificity of its symptoms, it is frequently misdiagnosed or overlooked in favor of other neurological conditions.

We present the case of a 56-year-old male who was initially diagnosed with multiple sclerosis 14 years prior following an evaluation for progressive cognitive decline, vertigo, and gait instability. His initial MRI revealed extensive white matter changes, which were attributed to demyelinating disease. Despite initiating multiple disease-modifying therapies, his symptoms continued to worsen and his leukodystrophy burden increased, leading to a referral to Behavioral Neurology for further diagnostic evaluation.

Genetic testing confirmed the presence of a novel p.Cys395Tyr mutation in the NOTCH3 gene, confirming a diagnosis of CADASIL.  PolyPhen-2, an in-silico model predicting the functional effects of human nsSNPs, predicts this substitution to be damaging to NOTCH3 function. 

CADASIL can present with a wide range of symptoms, and due to its non-specific clinical features, it is frequently misdiagnosed as other conditions, such as demyelinating diseases. Key aspects of this case—including a strong family history, lack of response to disease-modifying therapies, progressively worsening largely symmetric bilateral white matter disease and lacunar strokes—strongly indicated CADASIL rather than a demyelinating disorder. Genetic testing confirmed the presence of a novel p.Cys395Tyr mutation in the NOTCH3 gene. This case highlights the importance of considering leukodystrophies in the differential when evaluating young patients with progressive cognitive decline, particularly when standard treatments fail.