HEREDITARY STROKE & CADASIL

Hereditary Stroke & CADASIL — NOTCH3 variants cause the most common genetic small vessel disease of the brain, where anticoagulation may be harmful and the correct diagnosis transforms management from stroke prevention to CADASIL-specific care.

Whole genome sequencing evaluates all hereditary stroke and cerebrovascular genes — NOTCH3 (CADASIL), COL4A1, COL4A2, HTRA1 (CARASIL), and additional small vessel disease genes — providing the molecular diagnosis that changes stroke prevention strategy.

NOTCH3
COL4A1
COL4A2
HTRA1
GLA
APP

About this condition

Stroke & CADASIL — Genetic Risk

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common hereditary cerebral small vessel disease, caused by NOTCH3 cysteine-altering variants. Prevalence is estimated at 2-5 per 100,000. CADASIL presents with migraine with aura (typically beginning in the 20s-30s), recurrent lacunar strokes (30s-50s), mood disturbance, and progressive vascular cognitive impairment leading to vascular dementia (50s-60s). The condition is autosomal dominant but frequently undiagnosed — many CADASIL patients carry diagnoses of 'MS,' 'migraine,' or 'early-onset dementia.'

CADASIL management differs fundamentally from typical ischemic stroke management. Anticoagulation and thrombolysis may increase intracerebral hemorrhage risk in CADASIL and are generally AVOIDED — directly contradicting standard stroke guidelines. Antiplatelet therapy is used cautiously. Aggressive blood pressure control is the cornerstone of CADASIL stroke prevention. This management distinction is critical — applying standard stroke protocols to a CADASIL patient may cause harm. Molecular NOTCH3 diagnosis is what triggers CADASIL-specific management.

Additional hereditary stroke genes include COL4A1 and COL4A2 (porencephaly, intracerebral hemorrhage, retinal arteriolar tortuosity — autosomal dominant), HTRA1 (CARASIL — autosomal recessive with alopecia and lumbar disc disease), and rare monogenic forms of cerebral amyloid angiopathy (APP, CST3, ITM2B). Fabry disease (GLA) causes both ischemic and hemorrhagic stroke through vascular endothelial glycolipid accumulation — and is treatable with enzyme replacement therapy. Identifying Fabry as the cause of young-onset stroke is one of the highest-impact genetic diagnoses in stroke neurology.

Anticoagulation and thrombolysis may HARM CADASIL patients — the opposite of standard stroke management. Untreated CADASIL patients receiving standard stroke protocols are at increased hemorrhage risk. Molecular diagnosis prevents iatrogenic harm.

Gene locus: NOTCH3 (19p13.12), COL4A1 (13q34), COL4A2 (13q34), HTRA1 (10q26.13), GLA (Xq22.1), APP (21q21.3)

Standard stroke protocols (anticoagulation, thrombolysis) may harm CADASIL patients. Molecular diagnosis is the only way to identify these patients and redirect their management to CADASIL-specific protocols.

CADASIL is frequently misdiagnosed as MS — years of ineffective MS therapy while the true stroke risk goes unmanaged

CADASIL produces white matter lesions on MRI that can satisfy McDonald MS criteria. Patients may receive disease-modifying MS therapies (interferon, natalizumab) for years — treatments that have no effect on CADASIL and carry significant side effects. Meanwhile, the CADASIL-specific interventions (aggressive BP control, avoiding anticoagulation) are not implemented. NOTCH3 testing should be considered in any adult with white matter disease, migraine with aura, and stroke — particularly with autosomal dominant family history.

Fabry disease causes young-onset stroke and is TREATABLE — missing the diagnosis means missing enzyme replacement therapy

GLA variants causing Fabry disease produce small vessel cerebrovascular disease leading to stroke — often the presenting feature in males and heterozygous females. Fabry disease is treatable with enzyme replacement therapy (agalsidase alfa/beta) and oral chaperone therapy (migalastat) — interventions that can prevent further strokes. Without molecular GLA testing, Fabry is never considered in the stroke workup. WGS evaluates GLA alongside NOTCH3 and all other hereditary stroke genes.

Hereditary Stroke & CADASIL — NOTCH3 variants cause the most common genetic small vessel disease of the brain, where anticoagulation may be harmful and the correct diagnosis transforms management from stroke prevention to CADASIL-specific care.

Stroke & CADASIL — Genetic Risk

Standard stroke protocols (anticoagulation, thrombolysis) may harm CADASIL patients. Molecular diagnosis is the only way to identify these patients and redirect their management to CADASIL-specific protocols.

CADASIL is frequently misdiagnosed as MS — years of ineffective MS therapy while the true stroke risk goes unmanaged

Fabry disease causes young-onset stroke and is TREATABLE — missing the diagnosis means missing enzyme replacement therapy

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