Multisystemic Smooth Muscle Dysfunction Syndrome Research Articles

Case of congenital fixed dilated pupils due to ACTA2 gene mutation - Multisystemic Smooth Muscle Dysfunction Syndrome.

Case of congenital fixed dilated pupils due to ACTA2 gene mutation - Multisystemic Smooth Muscle Dysfunction Syndrome.

Abstract WP223: Cerebral Visual Impairment in ACTA2 Patients Assessed by Virtual Reality Testing

Introduction: Heterozygous missense mutations disrupting arginine 179 (Arg179) in the ACTA2 gene which codes for the smooth muscle-specific isoform of α-actin, cause Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS). The clinical manifestations of this genetic condition include congenital mydriasis, patent ductus arteriosus, stroke, and/or aortic aneurysms or dissections among many others. White matter injury, impaired autoregulation, and neurovascular coupling (due to the cerebral vasculopathy affecting cerebral perfusion) are known factors that alter neural network performance and processing speed. The lack of a standardized ophthalmologic examination that detects cerebral visual impairment (CVI), precludes an early diagnosis and creates missed opportunities for intervention. There is a paucity of data regarding CVI in MSMDS patients, and through this novel work, we present data defining their visual processing deficits. Hypothesis: We hypothesize that: 1) individuals with MSMDS will exhibit more pronounced deficits in visual-spatial processing compared to the control group, and 2) their performance will deteriorate as the complexity of visual tasks increases. Methods: Using a virtual reality (VR) based visual search task system, we characterized the impairment of higher-order visual processing in MSMDS patients (n = 4) as compared to healthy controls (n = 13). The VR-based task required searching for targets on a screen among varying levels of visual complexity. Reaction time, gaze error, shifted ellipse area, success rate, and pursuit saccade ratio were statistically analyzed with unpaired group t-tests, with significance being defined as p < 0.05. Results: Compared to controls, MSMDS patients took longer to identify the correct target, were less accurate in finding the target, and exhibited greater impairment in performance with an increasing number of distractors. Both groups showed similar task compliance, measured using an off-screen count metric. Conclusion: This novel work demonstrates that MSMDS patients exhibit impaired higher-order visual processing. This highlights the need for clinical tools that can assess these difficulties with quantitative methods to guide therapies and improve functional outcomes.

Iris and Retinal Findings in Multisystemic Smooth Muscle Dysfunction Syndrome

Iris and Retinal Findings in Multisystemic Smooth Muscle Dysfunction Syndrome

Orphan Heritable Thoracic Aortic Diseases and Pregnancy. Modern Outlooks and Guidance

Pregnancy is a period of high risk for all patients with aortic pathology. Heritable thoracic aortic diseases (HTAD) refer to aortopathies with a high risk of formation and dissection of thoracic aortic aneurysm (TAA). HTAD are caused by a mutation of a certain gene. This paper reviews current perceptions of manifestations of rare hereditary diseases of the thoracic aorta during pregnancy and general recommendations for the medical care of these patients. To date, 16 genes (or loci of unidentified genes) are known to be associated with the development of thoracic aortic aneurysm, and since many families with a history of TAA (about 70%) have no pathogenic changes in any of these 16 genes, additional genes associated with HTAD have not yet been identified.
 In this paper, HTAD are considered which occur (or are identified) quite rare but provide a significant risk for patients, which is significantly increased during pregnancy (multisystemic smooth muscle dysfunction syndrome, Meester Lois syndrome, LOX and PRKG1 genes mutations, vascular Ehlers-Danlos syndrome, mutations in TGFB2, TGFBR1, TGFBR2, SMAD3 loci, Loeys-Dietz syndrome). The article analyzes the frequency of occurrence of the most threatening complication of HTAD – acute aortic dissection – in various syndromes, defines general recommendations for the examination of patients with HTAD, recommendations for conservative treatment of these patients. Recommendations for the patients (especially fertility women) concerning the preventive cardiac surgery are also summarized in the paper. These principles of pregravidary preparation and multidisciplinary medical support during pregnancy are the most effective prophylactic measures for major cardiac events and maternal death. Pregnancy heart team that has been working in Ukraine since 2013 does all its best to organize medical support for every pregnant woman with suspected HTAD. In this context, it is very important to collaborate with general practitioners and genetics to “catch” such patients before they become pregnant or in very early terms. Individualized plan of pregravidary preparation and medical care during pregnancy and delivery should be developed by a multidisciplinary team.

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

BackgroundCongenital 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 presentationThe 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.ConclusionsIn 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.

Case report of multisystemic smooth muscle dysfunction syndrome in child

苏州大学附属儿童医院于2018年6月收治多系统平滑肌功能障碍综合征患儿1例，女，9个月18 d，其临床特点为反复咳嗽、喘息、气促。查体：双侧瞳孔散大、固定，直接及间接对光反射消失，右侧颜面部、颊黏膜、口腔舌部及上颚可见青紫色斑块，呼吸促，双肺可闻及湿啰音及哮鸣音，胸骨左缘可闻及收缩期Ⅱ/6级杂音。腹部B超显示胆囊结石，心脏超声提示卵圆孔未闭，主肺动脉内径增宽。头颅磁共振成像提示双侧脑室体部旁及半卵圆中心区异常信号。基因检测分析发现存在ACTA2基因c.536G>A(p.R179H)杂合突变。予吸氧、抗感染、平喘治疗2周后患儿病情逐步好转，出院后继续予氧疗、小剂量泼尼松口服治疗。多系统平滑肌功能障碍综合征是一种主要由ACTA2基因p.R179H变异引起的罕见遗传病，可引起全身性的平滑肌功能障碍，本例为国内第2例通过基因确诊的患者，提示临床医师对于存在瞳孔固定散大和/或动脉导管未闭的患儿应尽早行基因检测明确诊断。在其诊断及治疗过程中，临床医师应对脑血管、心血管及肺部并发症保持高度警惕。

ACTA2 mutation and postpartum hemorrhage: a case report

BackgroundACTA2 encodes smooth muscle specific α-actin, a critical component or the contractile complex of vascular smooth muscle. Mutations in ACTA2 are the most common genetic cause of thoracic aortic aneurysm, and are also the cause of other disorders, including Moyamoya disease, coronary artery disease and stroke as well as Multisystemic Smooth Muscle Dysfunction Syndrome. We note that ACTA2 is also expressed in uterine smooth muscle, and this raises the possibility that women harboring ACTA2 mutations might exhibit uterine smooth muscle dysfunction.Case presentationWe present a young woman whose ACTA2 mutation was ascertained during pregnancy because of her father’s history of dissecting aneurysms. She was delivered at full term by cesarean section and subsequently had severe uterine hemorrhage due to uterine atony. Although her atony was successfully treated with uterotonic medications, she required blood transfusion.ConclusionsThis case raises the possibility that women with ACTA2 mutations may be at risk of uterine muscle dysfunction and hemorrhage. Obstetricians should be alerted to and prepared for this possibility.

Two patients with the heterozygous R189H mutation in ACTA2 and Complex congenital heart defects expands the cardiac phenotype of multisystemic smooth muscle dysfunction syndrome.

De novo heterozygous mutations changing R179 to histidine, leucine, or cysteine in the ACTA2 gene are associated with Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS). Characteristic hallmarks of this condition, caused only by these specific ACTA2 mutations, are congenital mydriasis (mid-dilated, non-reactive pupils), a large persistent ductus arteriosus (PDA), aortic aneurysms evolving during childhood, and cerebrovascular anomalies. We describe two patients, a 3-day-old newborn and a 26-year-old woman, with this unique mutation in association with a huge PDA and an aorto-pulmonary window. In addition, one showed a coarctation of the aortic arch and the other a complete interruption of the aortic arch type A; thereby expanding the spectrum of cardiac congenital heart defect of this syndrome. Each patient displayed a huge PDA and an extra-cardiovascular phenotype consistent with MSMDS. These observations exemplify that a functional alpha 2 smooth muscle actin is necessary for proper cardiovascular organ development, and demonstrate that a very exceptional congenital heart defect (aortopulmonary window) can be caused by a mutation in a gene encoding a contractile protein of vascular smooth muscle cells. © 2017 Wiley Periodicals, Inc.

Multisystemic Smooth Muscle Dysfunction Syndrome:An Unusual Cause for a Gigantic PDA with Bilateral Mydriasis

Objective: A patent arterial duct (PDA) is a common lesion usually treated by interventional measures. Rarely the PDA requires surgical intervention in babies > 2 kg body weight. Surgical intervention may also be required in premature babies and in those patients where the PDA exceeds the diameter of the aorta.

Congenital Fixed Dilated Pupils Due to ACTA2– Multisystemic Smooth Muscle Dysfunction Syndrome

Congenital fixed dilated pupils (congenital mydriasis) is characterized by hypoplasia or aplasia of the iris muscles, with absence of iris between the collarette and pupillary border, creating a scalloped pupillary margin. This condition has been reported in a multisystemic smooth muscle cell dysfunction syndrome, combined with congenital patent ductus arteriosus, cerebrovascular disease (Moya-moya-like), coronary artery disease, thoracic aorta aneurysm, and dysfunction of smooth muscle cells in organs throughout the body. All affected individuals carry a p.R179H heterozygous mutation in the ACTA2 gene. We add to the ophthalmologic involvement with 3 more patients. Congenital fixed dilated pupils is a rare condition and should alert ophthalmologists to the possibility of the coexistence of systemic life-threatening disorders.

Eye features in three Danish patients with multisystemic smooth muscle dysfunction syndrome

BackgroundA de novo mutation of the ACTA2 gene encoding the smooth muscle cell α-actin has been established in patients with multisystemic smooth muscle dysfunction syndrome associated with patent ductus arteriosus...