CADASIL/CARASIL

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and classic CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) are progressive cerebral small-vessel arteriopathies. CADASIL is characterised by five cardinal manifestations: transient ischaemic attacks and recurrent ischaemic strokes, cognitive decline progressing to vascular dementia, migraine with aura, mood disturbance, and apathy. Ischaemic events have a mean age at onset of 47 years (range 20-70 years), with stepwise neurological deterioration and progressive disability over decades. Classic CARASIL typically begins with slowly progressive gait disturbance from spasticity and pyramidal signs between ages 20 and 40 years; spondylosis deformans with lumbago and lower-limb pain may emerge from age 10 to 30 years, and alopecia is frequent before age 30 years. Presentation across the HTRA1 spectrum is highly variable, ranging from minimally symptomatic individuals to severe classic CARASIL with emotional incontinence, abulia and akinetic mutism in advanced stages.

The estimated prevalence of CADASIL is 1/25,000-1/50,000 (GeneReviews, 2019). For CARASIL, due to insufficient data, no reliable statement on prevalence can currently be made.

95% of CADASIL pathogenic variants are cysteine-altering missense changes in in one of the 34 epidermal growth factor-like repeat (EGFr) domains of NOTCH3 (19p13.12). These missense variants create an uneven number of cysteine residues, disrupting disulphide-bridge formation and causing aggregation of the mutant NOTCH3 extracellular domain in vascular smooth muscle cells, with
sequestration of extracellular matrix proteins. Classic CARASIL results from biallelic pathogenic variants in HTRA1 (10q26.13); heterozygous HTRA1 variants underlie HTRA1-related cerebral small-vessel disease and may exert dominant-negative effects. Pathogenic HTRA1 variants reduce serine-protease activity and impair repression of TGF-β family signalling.

CADASIL and HTRA1-related cerebral small-vessel disease are inherited in an autosomal dominant manner; classic CARASIL is inherited in an autosomal recessive manner. For the dominant forms, each child of an affected individual has a 50% risk of inheriting the pathogenic variant; in recessive CARASIL, each child of two carriers has a 25% recurrence risk.

Diagnosis is established by molecular genetic testing identifying a germline pathogenic variant in NOTCH3 (CADASIL) or HTRA1 (CARASIL and HTRA1-related cerebral small-vessel disease). Brain MRI supports diagnosis with characteristic white-matter hyperintensities, lacunes and microbleeds in CADASIL, and early-onset leukoaraiosis with an external-capsule signal change and brain-stem arc sign in classic CARASIL. Skin biopsy showing granular osmiophilic material in vessel walls is considered pathognomonic for CADASIL.

Main differential diagnoses include:

• COL4A1/COL4A2-related cerebral small-vessel disease: intracerebral haemorrhage, porencephaly, intracranial aneurysms, retinal arteriolar tortuosity, renal/cardiovascular abnormalities; COL4A1, COL4A2
• : periodic severe extremity pain, angiokeratoma, renal insufficiency, corneal opacities, cardiomyopathy with vertebrobasilar strokes; GLA
• CARASAL: therapy-resistant hypertension, intracerebral haemorrhage, muscle cramps, xerostomia, keratoconjunctivitis sicca; CTSA

• Genetic testing establishes the diagnosis, ending the diagnostic odyssey, and providing aetiological clarity for the affected individual and family.
• A confirmed molecular diagnosis is a prerequisite for targeted, individualised surveillance and clinical management, which are determined by the treating physicians in consultation with the affected individual.
• Identification of a familial pathogenic variant enables predictive testing of at-risk relatives, who may then access tailored surveillance or, where appropriate, reproductive counselling.

• Hack RJ, Rutten J, Lesnik Oberstein SAJ. CADASIL. 2000 Mar 15 [Updated 2019 Mar 14]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:20301673.
• Onodera O, Nozaki H, Fukutake T. HTRA1 disorder. 2019 Nov 7. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:20437615.
• Guyler SK, Tsai J, Maksemous N, Smith RA, Sutherland HG, Harvey E, et al. The spectrum of NOTCH3 variants in an Australian CADASIL cohort. Genes (Basel). 2025;16(11):1353. doi:10.3390/genes16111353. PMID:; PMCID: PMC12651956. 
• Hu Y, Sun Q, Zhou Y, Yi F, Tang H, Yao L, et al. NOTCH3 variants and genotype-phenotype features in Chinese CADASIL patients. Front Genet. 2021;12:705284. doi:10.3389/fgene.2021.705284. PMID:; PMCID: PMC8320595