ACTA2 mutation with childhood cardiovascular, autonomic and brain anomalies and severe outcome

Abstract

Thoracic aortic aneurysm and dissection (TAAD) are associated with connective tissue disorders like Marfan syndrome and Loeys-Dietz syndrome, caused by mutations in the fibrillin-1, the TGFβ-receptor 1- and -2 genes, the SMAD3 and TGFβ2 genes, but have also been ascribed to ACTA2 gene mutations in adults, spread throughout the gene. We report on a novel de novo c.535C>T in exon 6 leading to p.R179C aminoacid substitution in ACTA2 in a toddler girl with primary pulmonary hypertension, persistent ductus arteriosus, extensive cerebral white matter lesions, fixed dilated pupils, intestinal malrotation, and hypotonic bladder. Recently, de novo ACTA2 R179H substitutions have been associated with a similar phenotype and additional cerebral developmental defects including underdeveloped corpus callosum and vermis hypoplasia in a single patient. The patient here shows previously undescribed abnormal lobulation of the frontal lobes and position of the gyrus cinguli and rostral dysplasis of the corpus callosum; she died at the age of 3 years during surgery due to vascular fragility and rupture of the ductus arteriosus. Altogether these observations support a role of ACTA2 in brain development, especially related to the arginine at position 179. Although all previously reported patients with R179H substitution successfully underwent the same surgery at younger ages, the severe outcome of our patient warns against the devastating effects of the R179C substitution on vasculature.

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

“…Compensatory increases in the skeletal alpha actin isoform (ACTA1), as well as the dominant expression of the gamma isoform of smooth muscle actin (ACTG2) in visceral smooth muscle (45), likely compensate for loss of ACTA2 in the gastrointestinal and urinary tracts. However, there are some de novo mutations in human ACTA2 (R179H and R179C) that associate with hypotonic bladder, malrotation, and intestinal hypoperistalsis (46,47). Notably, the Actg2 knockout mouse has yet to be reported.…”

Progressive Aortic Dilation Associated With ACTA2 Mutations Presenting in Infancy

“…Intermittent seizures persisted, and at age 6 years cerebral Previous deaths occurred in a 2-year-old from fulminant liver failure, a 3-year-old from PDA rupture, an 11-year-old from unknown causes (autopsy not revealing), and a 17-year-old after aortic dissection. [2][3][4] angiography revealed moderate narrowing of the cavernous and supraclinoid portions of the right internal carotid artery with narrowing extending into the anterior and middle cerebral arteries as well as aneurysmal dilation of the base of the left internal carotid artery with moderate narrowing distally. Tortuosity of distal vessels was noted.…”

“…2 This pediatric form of the disease, known as multisystemic smooth muscle dysfunction syndrome, affects smooth muscle in the eyes, lungs, gastrointestinal tract, genitourinary tract, central nervous system, and cardiovascular system. 2,3 Although vascular disease has been well described in adults with other ACTA2 mutations, no data are available on the progression of vascular involvement in patients with the diffuse smooth muscle form of the disease. We report on 3 patients with an Arg179His mutation in ACTA2, further delineating the clinical manifestations of this newly reported disease (Table 1), and provide a detailed review of the progression of vascular involvement.…”

Twins With Progressive Thoracic Aortic Aneurysm, Recurrent Dissection and ACTA2 Mutation

“…The p.Arg179His mutation has been associated with global smooth muscle dysfunction and diverse vasculopathies, including congenital mydriasis, hypotonic bladder, malrotation, gut hypoperistalsis, pulmonary hypertension, patent ductus arteriosus, and central nervous system anomalies. [9][10][11][12] Cerebrovascular occlusive disease is a common complication associated with ACTA2 mutations. Analysis of mutations that have been identified in more than 15 individuals indicate that p.Arg258Cys and p.Arg258His mutations confer a 6.5-fold increased risk of stroke as compared with other mutations, but are not associated with coronary artery disease.…”