Download ARCD

The defining cerebral vascular pathology of the new clinical
histopathologic entity ACTA2-related cerebrovascular disease (ARCD)
Maria-Magdalena Georgescu
Smooth muscle cell (SMC) contractility is essential for the function of vessels and
viscera and relies on the integrity of the actin-myosin apparatus. Two tissue-specific actin
isoforms, 2-smooth muscle actin (SMA), encoded by the ACTA2 gene, and -SMA are
predominantly expressed in vascular and visceral SM, respectively. ACTA2 mutations
induce vascular abnormalities that lead, among other manifestations, to aortic aneurysms,
coronary artery and cerebrovascular disease. A distinct variant of cerebrovascular disease
has been proposed for patients with the 2-SMA R179H mutation. We present here an
integrated analysis of a severely compromised adult patient succumbing from massive
stroke and carrying the R179H mutation that defines the new entity of ACTA2-related
cerebrovascular disease (ARCD). A second infant patient carrying this disease
succumbed of pulmonary hypertension. The presence of aortic aneurysms, persistence of
patent ductus arteriosus, congenital absence of iris and characteristic radiologic
appearance of the internal carotid artery and its major branches are confirmed as defining
clinical features. The striking underlying histologic abnormalities in both patients
involved arteries of all sizes and included massive intimal SMC proliferation, elastic
lamina dissection/fragmentation, disorganized media and prominent increase in vessel
wall extracellular matrix, suggesting impaired function of arterial SMCs. Actin threedimensional molecular modeling revealed critical positioning of R179 at the interface
between the two strands of filamentous (F)-actin and destabilization of interstrand
bundling by the R179H mutation, thus explaining the severe associated phenotype. In
conclusion, these characteristic clinical and pathologic findings establish ARCD as a new
syndrome for which therapeutic implications are discussed.