Cerebral small vessel disease

Monogenic CSVD predominantly affects the central nervous, cerebrovascular and neuropsychiatric systems. Clinical manifestations include recurrent transient ischaemic attacks and ischaemic strokes (the most frequent presentation in the prototypical CADASIL subtype, affecting approximately 85% of symptomatic individuals), cognitive decline, migraine with aura, mood disturbances and apathy. Mean age at first ischaemic event in is 47 years (range 20 to 70 years); cognitive decline may commence by age 35, and up to 75% of affected individuals develop dementia. Severe disability typically ensues, with median age at loss of independent ambulation around 60 years and median age at death around 68 years. Presentation and progression vary substantially within and between families, with paediatric onset possible in COL4A1-related disease.

The estimated prevalence is 1/25,000-1/50,000 (GeneReviews, 2019). This figure is anchored to CADASIL, the most common monogenic CSVD subtype; broader monogenic CSVD spectrum prevalence has not been separately estimated.

To date, pathogenic variants in at least 10 genes are known to cause monogenic CSVD, reflecting substantial genetic heterogeneity. The clinically most relevant causative genes include NOTCH3 (), HTRA1, COL4A1, COL4A2 and GLA (). Germline pathogenic variants act through heterogeneous mechanisms: toxic accumulation of mutant NOTCH3 ectodomain with granular osmiophilic material deposition, loss of HTRA1 serine protease activity, and abnormal assembly of type IV collagen alpha-1/alpha-2 chains in vascular basement membranes. These pathways converge on small-vessel arteriopathy with vascular smooth muscle cell degeneration, impaired cerebral vasoreactivity and progressive ischaemic white matter injury.

Inheritance is heterogeneous across the panel. (NOTCH3), COL4A1-/COL4A2-related disease and HTRA1-related CSVD type 2 are autosomal dominant; CARASIL (biallelic HTRA1) is autosomal recessive; (GLA) is X-linked. In autosomal dominant forms, recurrence risk for first-degree relatives is 50%. Predictive testing of at-risk adult relatives is possible once the familial pathogenic variant has been identified.

Brain MRI is the principal supportive investigation. Imaging demonstrates symmetric, progressive white matter hyperintensities (with characteristic involvement of the anterior temporal lobes and external capsules in ), lacunes of presumed vascular origin, recent subcortical infarcts, dilated perivascular spaces, brain atrophy and cerebral microbleeds. Skin biopsy with electron microscopy showing granular osmiophilic material is a supportive but variably sensitive finding for CADASIL. Definitive diagnosis rests on molecular genetic testing.

Main differential diagnoses include:

• Sporadic small vessel disease (including Binswanger’s disease): hypertension, typical onset >65 years, external-capsule and temporal-pole involvement less frequent than in ; no monogenic causative gene.
• Multiple sclerosis: optic neuritis, spinal cord involvement, Dawson fingers and CSF oligoclonal bands; non-genetic (autoimmune) aetiology.
• MELAS: paediatric onset, stroke-like lesions not conforming to arterial distributions, sensorineural hearing loss; maternal inheritance; MT-TL1, MT-ND5 (mitochondrial DNA).

• Establishing the diagnosis confirms the clinical suspicion, ends the diagnostic odyssey and enables genetic counselling for affected individuals and their families.
• A confirmed molecular diagnosis informs specific and individualised surveillance and clinical management, including control of vascular risk factors, and is a prerequisite for targeted medical care decided by the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant enables targeted predictive and carrier testing in at-risk relatives within the framework of genetic counselling.

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