Case Report: Inflammatory CADASIL phenotype associated with a rare NOTCH3 variant of uncertain significance

Abraham Madjidov¹Mary-Alice Abbott¹Katherine M Mullen¹Richard Hicks¹Gottfried Schlaug^1,2*

• ¹Neurology, UMass Chan Medical School - Baystate Campus, Springfield, MA, United States
• ²University of Massachusetts Amherst, Amherst, Massachusetts, United States

We present a 50-year-old female who has a longstanding history of migraine with aura. She experienced one episode of partial visual field loss associated with a small acute/subacute lesion involving the cortex and subcortical white matter (showing contrast enhancement), alongside extensive white matter hyperintensities. Given these findings, CADASIL was suspected. Genetic testing identified a rare heterozygous NOTCH3 variant (c.6102dup, p.Gly2035Argfs*60), currently classified as a variant of uncertain significance. Concurrent cerebrospinal fluid analysis revealed elevated myelin basic protein, an elevated IgG index, and 4 oligoclonal bands, indicating an inflammatory process. Her visual evoked potentials showed no evidence of optic nerve or tract impairment. Approximately 9 months later, the occipital lesion evolved into encephalomalacia and gliosis without enhancement, while the extensive white matter hyperintensities remained stable. A repeat lumbar puncture 1 year later showed persistently elevated myelin basic protein and IgG index, now with 7 oligoclonal bands (some shared with serum). Currently, her neurological examination is normal. She is managed on dual antiplatelet therapy, and her migraines are effectively controlled with calcium-channel blocker prophylaxis. Notably, her mother, diagnosed with multiple sclerosis for several decades despite imaging findings suggestive of CADASIL, shares the same NOTCH3 variant. One of her two children tested negative for the variant and had normal imaging, while the other minor child has a significant history of migraines with aura. Our patient's clinical presentation and comprehensive findings raise the possibility of an inflammatory phenotype potentially associated with the rare NOTCH3 c.6102dup variant, though causation remains unclear. Coexistence with another demyelinating central nervous system disease is possible, and further research is needed to clarify this relationship. If inflammatory variants of CADASIL exist, alternative treatments targeting inflammation may need consideration.