Heritable Connective Tissue Disorders and Stroke

Stroke is a heterogeneous syndrome caused by multiple etiologies. Heritable defects in connective tissue cause a small fraction of ischemic and hemorrhagic stroke. They are the consequence of mutations in genes encoding extracellular matrix constituents such as collagens and proteoglycans. Ehlers-Danlos syndrome, Marfan's syndrome, osteogenesis imperfecta, and pseudoxantoma elasticum are the most common disorders responsible for cerebrovascular manifestations. Neurofibromatosis and polycystic kidney disease, although not connective tissue disorders, are hereditary diseases with a high prevalence of vascular complications. Ehlers-Danlos syndrome type IV is the most frequent and most life-threatening form due to the presence of intracranial aneurysms, carotid-cavernous fistulas, and arterial dissections. Marfan's syndrome has a typical phenotype associated with arterial dissections and intracranial aneurysms. Osteogenesis imperfecta, although infrequent, can present with aneurysms, dissections, fistulas, and stenosis of cerebral vessels. Pseudoxanthoma elasticum is commonly associated with occlusive disease of small vessels and other complications such as aneurysms or arteriovenous malformations. Autosomal-dominant polycystic kidney disease is a common cause of multiple intracranial aneurysms. Neurofibromatosis type 1 is characterized by multiple neurofibromas; it is responsible for stenosis or occlusions of intracranial arteries and vascular malformations. These vasculopathies are associated with a relatively high prevalence of cerebrovascular disease; their early recognition should help in the investigation of asymptomatic carriers, and to provide genetic counseling. The growing knowledge of molecular biology could help in the understanding of the underlying mechanism of these complex disorders as well as identify future therapeutic interventions.