背景:由于基因突变,先天性散瞳和视网膜小动脉弯曲与危及生命的多系统平滑肌功能障碍综合征(MSMDS)有关,ACTA2,其编码α-平滑肌肌动蛋白(α-SMA)。以前的报道将MSMDS相关的先天性散瞳归因于虹膜括约肌的缺失。同样,据推测,在MSMDS中,血管平滑肌细胞的异常增殖会导致视网膜小动脉的明显弯曲。在这份报告中,高分辨率眼部成像揭示了意想不到的发现,这些发现拒绝了先前的假设。
方法:先证者是一名37岁女性,有新生儿动脉导管未闭(PDA)结扎术史,11岁时出现左侧舞蹈样运动,30岁时出现短暂性失语症伴右侧无力。她的姐姐也患有PDA结扎术和先天性散瞳症,但直到41岁时都没有神经功能缺损。磁共振血管造影显示脑血管病变与烟雾病相似但不同,以颈内动脉扩张为特征,末端节段狭窄和基底络脉缺失。他们的母亲的瞳孔反应不佳,无症状的脑动脉病与女儿相似。所有三个都有明显的视网膜小动脉弯曲。女儿是杂合的,母亲是新颖的c.351C>G的体细胞马赛克(p。Asn117Lys)在ACTA2中的转化。虹膜光学相干断层扫描(OCT)显示色素上皮前方的低反射带,表明存在功能失调的括约肌。自适应光学视网膜成像显示小动脉血管壁没有增厚,而OCT血管造影显示小动脉的极端开瓶器运动表明血管伸长。
结论:除了已知Met46、Arg179和Arg258置换与ACTA2相关动脉病之间的关联外,这种情况说明Asn117在脑血管平滑肌细胞内的α-SMA功能中也起重要作用的可能性。MSMDS相关的先天性散瞳是由于虹膜括约肌收缩性降低而不是缺乏。视网膜小动脉弯曲可能是由于小动脉平滑肌细胞的纵向增殖。所描述的脑血管和眼部体征与ACTA2中新型Asn117Lys置换的预测效果一致。
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.
METHODS: 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 ACTA2-related 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.