Abstract 012: Decoding CADASIL: Genotype‐Phenotype Complexity and Extra‐Cerebral Manifestations

Introduction Cerebral Autosomal‐Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a systemic vascular disease caused by mutations in the NOTCH3 gene. It follows an autosomal dominant inheritance pattern and primarily affects small arterioles. Clinically, it presents with recurrent strokes, cognitive decline, and migraine. We present a case of a 38‐year‐old male with recurrent strokes and a heterozygous NOTCH3 mutation, in the setting of a family history of early‐onset end‐stage renal disease (ESRD). Methods and Results The patient initially presented with a right A2/A3 occlusion and an ACA/MCA borderzone infarct, followed by bilateral lenticulostriate ischemic strokes 2 months later. Stroke workup revealed a Factor V Leiden mutation and a slight protein S deficiency. Transthoracic echocardiogram (TTE) and cardiac monitoring were unremarkable. The patient reported a history of migraines with photophobia and phonophobia, and a recent change in personality marked by emotional lability.Family history was significant for the mother having hypertension and renal failure of unknown etiology, progressing to dialysis and kidney transplant at age 27. The father had no known renal or cognitive issues. Genetic testing revealed a heterozygous missense mutation in NOTCH3 and APP, both classified as variants of uncertain significance. However, the NOTCH3 variant has been reported in association with CADASIL and renal vascular involvement, particularly nephroangiosclerosis, leading to ESRD.Although the patient's initial stroke involved large vessel occlusion and spared the anterior temporal lobes—features atypical of CADASIL—the recurrence of strokes in lenticulostriate territories, migraines, and personality changes aligned with classical features. NOTCH3 mutations can result in toxic gain or loss of function, or hyperactivation, leading to small vessel disease with granular osmiophilic material (GOM) deposition.Literature review indicates that renal arteriopathy, including mesangial IgA deposits and juxtaglomerular GOM deposition, may occur in patients with NOTCH3 mutations. These vascular changes impair renal autoregulation and can lead to systemic hypertension. NOTCH3 transgenic mouse models also demonstrate vascular pathology in cerebral, cutaneous, and caudal vessels, paralleling human CADASIL pathology. Conclusion CADASIL is a systemic arteriopathy with underrecognized and underreported extra‐cerebral manifestations, including renal involvement. The genotype‐phenotype correlation of NOTCH3 mutations remains poorly understood, contributing to frequent misdiagnosis or delayed diagnosis. The highly variable clinical presentation—particularly in patients with early‐onset strokes—underscores the need for heightened clinical suspicion and broader awareness of non‐neurologic manifestations such as renal disease. image