The chart says: 44-year-old with a second lacunar stroke, blood pressure normal on every reading, no diabetes, never smoked. The history says: migraines with aura since her twenties, a mother who "had strokes and then dementia in her fifties," an uncle with a psychiatric admission nobody explains. The MRI says: white matter disease far beyond her age — reaching into the anterior temporal poles.

That is not three separate problems. That is one diagnosis announcing itself in sequence, and the sequence has a name: CADASIL — cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

What it is

CADASIL is the most common inherited cause of stroke and vascular dementia — an autosomal dominant arteriopathy caused by mutations in NOTCH3, nearly always altering a cysteine residue in the receptor's extracellular domain.1 The mutant protein accumulates around vascular smooth muscle cells (the granular osmiophilic material of the pathology literature), degenerating the small penetrating arteries that sporadic hypertension takes decades longer to injure. The result is small vessel disease on an accelerated clock: lacunar infarcts, confluent white matter change, microbleeds, and ultimately the subcortical cognitive decline we cover from the sporadic side in vascular cognitive impairment.2

The tetrad, in order of appearance

  • Migraine with aura — in roughly a third to a half of patients, typically beginning in the 20s–30s, often years before anything else and sometimes with atypical, prolonged, or confusional auras.2
  • Ischemic events — TIAs and lacunar strokes, classically starting in the 40s–50s, recurring, and conspicuously unaccompanied by the usual risk-factor résumé.
  • Mood and behavior — depression and apathy are common and under-attributed; screen for them deliberately (PHQ-9) rather than reading them as reaction alone.
  • Cognitive decline — executive-and-processing-speed first, the subcortical signature, progressing toward dementia over years.

Penetrance is high but expression varies widely — even within one family, one sibling strokes at 45 while another mostly has migraines into their 60s. That variability is exactly why the family history question must be asked as "strokes, early dementia, or psychiatric illness in a parent's fifties," not just "did anyone have a stroke."

The MRI signature: look at the temporal poles

White matter hyperintensities are universal by mid-adulthood in mutation carriers and precede symptoms. What separates CADASIL from garden-variety small vessel disease is distribution: involvement of the anterior temporal poles and external capsules is characteristic and unusual in sporadic hypertensive disease.2 Add lacunes, prominent perivascular spaces, and — relevant to every antithrombotic conversation — cerebral microbleeds in a substantial minority. In a young patient, that combination should stop the "nonspecific white matter changes, likely migraine" read in its tracks.

"Too much white matter disease for age" plus temporal-pole involvement is a phenotype, not an incidental finding.

Who earns the test — and what to say before sending it

NOTCH3 sequencing confirms the diagnosis; skin biopsy is now rarely needed. Test the phenotype: young-lacunar-stroke-without-cause (part of the tier-three workup in stroke in young adults), the suggestive MRI, the compatible family story — ideally all discussed with genetic counseling first. Before the blood draw, say out loud what a positive result means: a 50% risk to each sibling and child, presymptomatic testing dilemmas for relatives, and implications for insurance and family planning that the patient should walk into with eyes open. What a positive result changes clinically is honest but real: it ends the diagnostic odyssey, retires the vasculitis workups and repeat lumbar punctures, sharpens prevention, and reframes the migraines and the mood disorder as part of one disease rather than three.

Management: no magic, real housekeeping

There is no disease-modifying therapy for CADASIL. What remains is not nothing:

  • Vascular risk control — blood pressure treated to standard secondary-prevention targets, smoking cessation non-negotiable (smoking associates with earlier stroke in carriers), diabetes and lipids managed conventionally.
  • Antithrombotics with respect for the substrate — a single antiplatelet is common practice after ischemic events; anticoagulation has no role for the arteriopathy itself and the microbleed-prone vessels argue for restraint unless a separate compelling indication (like atrial fibrillation) forces the discussion.
  • Migraine care — standard preventives; individualized judgment on vasoconstrictive abortives.
  • The rest of the disease — treat the depression, follow cognition with an executive-weighted instrument, and plan supports early rather than after the crisis.

The wider family of genetic small vessel disease

CARASIL is the rare recessive cousin (HTRA1): earlier onset, alopecia, and spondylosis alongside the leukoencephalopathy — worth knowing mostly so the "CADASIL-negative but looks hereditary" patient gets a second gene considered. Heterozygous HTRA1 variants, COL4A1/A2 disease (small vessel disease with hemorrhage, retinal arteriolar tortuosity, porencephaly), and Fabry disease round out the list a genetics referral will cover. The unifying clinical move is the same: recognize that small vessel disease has arrived too early and too florid, and let the phenotype route the gene test.

The bottom line

Think of CADASIL whenever lacunar strokes arrive without their usual causes — young patient, clean risk profile, migraine with aura in the backstory, psychiatric or early-dementia shadows in the family tree — and look at the temporal poles yourself. Test the right phenotype with counseling, manage the vessels aggressively while promising no cure honestly, and treat the mood and the migraines as part of the disease. The diagnosis will not change the infarcts already on the scan; it changes everything about how the next twenty years are planned.