Hereditary cerebral small vessel disease: from phenotype to management

Hereditary cerebral small vessel disease (cSVD) comprises a heterogeneous group of monogenic disorders affecting small cerebral arteries, arterioles, capillaries, and venules, leading to stroke, intracerebral hemorrhage, and vascular cognitive impairment, often at a young age. Despite their rarity, these conditions offer critical insights into the molecular mechanisms underlying microvascular brain injury and are frequently underdiagnosed due to phenotypic overlap with sporadic cSVD. Key diagnostic clues include early onset, disproportionate MRI burden, positive family history, and systemic manifestations. Distinct genetic entities, such as CADASIL, HTRA1-related arteriopathies, COL4A1/2-associated microangiopathies, RVCL-S, Fabry disease, and hereditary cerebral amyloid angiopathies, exhibit characteristic clinical, radiological, and extracerebral features. Accurate recognition is essential to guide genetic testing, avoid inappropriate treatments, enable targeted monitoring, and identify the few conditions with disease-modifying therapies. Early diagnosis also allows appropriate genetic counseling and risk stratification for affected families.