High-resolution iris and retinal imaging in multisystemic smooth muscle dysfunction syndrome due to a novel Asn117Lys substitution in ACTA2: a case report

Abstract

Background: Congenital mydriasis and retinal arteriolar tortuosity are associated with the life-threatening multisystemic smooth muscle dysfunction syndrome (MSMDS) due to mutations in the gene, ACTA2, which encodes alpha-smooth muscle actin (α-SMA). Previous reports attributed MSMDS-related congenital mydriasis to the absence of iris sphincter muscle. Similarly, it has been hypothesized that abnormal proliferation of the vascular smooth muscle cells causes the marked tortuosity of retinal arterioles in MSMDS. In this report, high-resolution ocular imaging reveals unexpected findings that reject previous hypotheses. Case presentation: The proband is a 37-year-old female with a history of neonatal patent ductus arteriosus (PDA) ligation, left-sided choreiform movements at the age of 11 and a transient aphasia with right-sided weakness at the age of 30. Her older sister also had PDA ligation and congenital mydriasis but no neurological deficit up to age 41. Magnetic resonance angiogram demonstrated cerebrovascular lesions resembling but distinct from Moyamoya disease, characterised by internal carotid artery dilatation, terminal segment stenosis and absent basal collaterals. Their mother had poorly reactive pupils with asymptomatic cerebral arteriopathy resembling her daughters. All three had prominent retinal arteriolar tortuosity. The daughters were heterozygous and the mother was a somatic mosaic for a novel c.351C > G (p.Asn117Lys) transversion in ACTA2. Iris optical coherence tomography (OCT) showed a hyporeflective band anterior to the pigment epithelium indicating the presence of dysfunctional sphincter muscle. Adaptive optics retinal imaging showed no thickening of the arteriolar vessel wall whilst OCT angiography showed extreme corkscrew course of arterioles suggesting vessel elongation. Conclusions: In addition to the known association between Met46, Arg179 and Arg258 substitutions and ACTA2related arteriopathy, this case illustrates the possibility that Asn117 also plays an important role in α-SMA function within the cerebrovascular smooth muscle cell. MSMDS-related congenital mydriasis is due to reduced iris sphincter contractility rather than its absence. Retinal arteriolar tortuosity might be due to longitudinal proliferation of arteriolar smooth muscle cells. The described cerebrovascular and ocular signs are consistent with predicted effects of the novel Asn117Lys substitution in ACTA2.

Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

“…In total, 8 individuals were asymptomatic, which is defined as the absence of an aortic event and/or an aortic aneurysm. The mean diameter in asymptomatic individuals was 30.6 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) mm (1.20 [0.79-1.5] inches) and the mean age was 37.0 (± 17.0) years. One individual was a post mortem diagnosed heterozygote; no information about aortic diameters was present.…”

Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome

“…A family with the ACTA2 p.Asn117Lys variant had MMD‐like cerebrovascular disease, PDA, poorly reactive pupils, and retinal artery tortuosity without evidence of thoracic aortic disease. Other families with variants affecting p.Asn117 had adult onset thoracic aortic disease but were not reported to have cerebrovascular disease (Figure 3, Table S1; Ke et al, 2016; Mc Glacken‐Byrne et al, 2020). Additionally, a patient with a de novo ACTA2 p.Asp181Val mutation was reported to have MMD‐like disease, periventricular white matter hyperintensities, hypoplasia of the corpus callosum, and a prior history of PDA without evidence of aortic disease or ocular dysfunction (Figure 3, Table S1; Pinto, 2020).…”

Persistent anterior tunica vasculosa lentis in multisystemic smooth muscle dysfunction syndrome

“…Congenital mydriasis, which is common in MSMDS, is due to the reduced contractility of iris sphincter and dilator muscles, resulting in fixed dilated pupils. [ 4 ] The absence of iris crypts and furrows, which can be seen in congenital microcoria, may be the result of the dilator muscle hypoplasia. [ 12 ] In summary, we observed congenital mydriasis, persistent anterior TVL and early-onset retinal arteriolar tortuosity in the eyes of a 6-week-old girl with a de novo heterozygous ACTA2 gene missense mutation p.R179H causing MSMDS.…”