CARASIL

CARASIL is cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a rare hereditary small vessel disease caused by biallelic variants in HTRA1. Heterozygous variants cause a milder, later onset form.

It is extremely rare and was first described in Japan; cases are mostly in East Asia, with sporadic reports worldwide. Onset is typically before age 40.

Genetics. HTRA1 encodes a serine protease that regulates transforming growth factor beta signalling. Autosomal recessive inheritance with consanguinity is common; heterozygous carriers have a risk of late onset small vessel disease.

Course. Stepwise strokes and progressive cognitive decline lead to severe disability and death over 10 to 20 years.

Pathophysiology.

Loss of HTRA1 activity increases signalling by transforming growth factor beta, causing arteriolar intimal thickening, smooth muscle loss and extracellular matrix change.

The same signalling defect affects spinal discs and hair follicles, explaining the extraneurological features.

• Early alopecia, often in adolescence, and acute severe low back pain with spondylosis deformans or disc herniation in the second to third decade.
• Recurrent lacunar strokes starting in early adulthood.
• Progressive cognitive decline, apathy, gait disorder, pseudobulbar signs and mood change.
• Heterozygous carriers present later with milder small vessel disease.

• MRI: diffuse confluent white matter hyperintensities, lacunes and microbleeds, with pontine hyperintensity (arc sign) in some.
• Spine imaging for degenerative change.
• HTRA1 sequencing confirms the diagnosis; biallelic pathogenic variants in CARASIL.
• Skin or brain biopsy shows arteriosclerosis without granular osmiophilic material or amyloid.

Differential diagnosis. CADASIL, other monogenic small vessel disease, sporadic small vessel disease, mitochondrial disease, multiple sclerosis and leukodystrophies.

• No proven disease modifying treatment.
• Control vascular risk factors: blood pressure under 130/80 mmHg, treat dyslipidaemia and diabetes, stop smoking.
• Aspirin 75 mg orally once daily after an ischaemic event, long term. Maximum 100 mg daily in this indication. Monitor bleeding and dyspepsia and check full blood count. Avoid in active peptic ulcer, bleeding disorders and aspirin sensitive asthma; use caution when eGFR is under 10; avoid in children under 16; benefit is not proven.
• Manage spinal disease with analgesia, physiotherapy and orthopaedic review; manage cognitive and mood symptoms with specialist care.
• Rehabilitation, falls prevention and supportive care.

Monitoring. Annual clinical review of function, cognition and mood; imaging only for clinical change.

Referral and escalation. Clinical genetics for counselling, carrier testing and family planning; neurology for confirmation and follow up.