Neonatal diagnosis of ACTA2-related disease: A case report and review of literature.

Multisystemic smooth muscle dysfunction syndrome (MSMDS, OMIM # 613834) is a rare autosomal dominant condition caused by pathogenetic variants of ACTA2 gene that result in impaired muscle contraction. MSMDS is characterized by an increased susceptibility to aneurismal dilatations and dissections, patent ductus arteriosus, early onset coronary artery disease, congenital mydriasis, chronic interstitial lung disease, hypoperistalsis, hydrops of gall bladder, and hypotonic bladder. Here, we report an early diagnosis of a MSMDS related to ACTA2 p.Arg179His (R179H) mutation in a newborn and performed a review of the literature. An early diagnosis of MSMDS is extremely important, because of the severe involvement of cardiovascular system in the MSMDS. Multidisciplinary care and surveillance and timely management of symptoms are important to reduce the risk of complications.

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

Pathogenic variants in ACTA2, encoding smooth muscle α-actin, predispose to thoracic aortic aneurysms and dissections. ACTA2 variants altering arginine 179 predispose to a more severe, multisystemic disease termed smooth muscle dysfunction syndrome (SMDS; OMIM 613834). Vascular complications of SMDS include patent ductus arteriosus (PDA) or aortopulmonary window, early-onset thoracic aortic disease (TAD), moyamoya-like cerebrovascular disease, and primary pulmonary hypertension. Patients also have dysfunction of other smooth muscle-dependent systems, including congenital mydriasis, hypotonic bladder, and gut hypoperistalsis. Here, we describe five patients with novel heterozygous ACTA2 missense variants, p.Arg179Gly, p.Met46Arg, p.Thr204Ile, p.Arg39Cys, and p.Ile66Asn, who have clinical complications that align or overlap with SMDS. Patients with the ACTA2 p.Arg179Gly and p.Thr204Ile variants display classic features of SMDS. The patient with the ACTA2 p.Met46Arg variant exhibits exclusively vascular complications of SMDS, including early-onset TAD, PDA, and moyamoya-like cerebrovascular disease. The patient with the ACTA2 p.Ile66Asn variant has an unusual vascular complication, a large fusiform internal carotid artery aneurysm. The patient with the ACTA2 p.Arg39Cys variant has pulmonary, gastrointestinal, and genitourinary complications of SMDS but no vascular manifestations. Identifying pathogenic ACTA2 variants associated with features of SMDS is critical for aggressive surveillance and management of vascular and nonvascular complications and delineating the molecular pathogenesis of SMDS.

Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations.

PURPOSE: Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. METHODS: Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. RESULTS: All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. CONCLUSION: Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.

ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke.

BACKGROUND: Missense mutations in the gene that codes for smooth muscle actin, ACTA2, cause diffuse smooth muscle dysfunction and a distinct cerebral arteriopathy collectively known as multisystemic smooth muscle dysfunction syndrome (MSMDS). Until recently, ACTA2 cerebral arteriopathy was considered to be a variant of moyamoya disease. However, recent basic science and clinical data have demonstrated that the cerebral arteriopathy caused by mutant ACTA2 exhibits genetic loci, histopathology, neurological sequelae, and radiographic findings unique from moyamoya disease. We conducted a literature review to provide insight into the history, clinical significance, and neurosurgical management of this recently described novel cerebral arteriopathy. SUMMARY: We performed a literature search using PubMed with the key words "ACTA2 mutation," "ACTA2 cerebral arteriopathy," and "multisystemic smooth muscle dysfunction syndrome." Case reports with confirmed ACTA2 mutations and cerebral arteriopathy were included in our review. Our literature search revealed 15 articles (58 cases) of confirmed ACTA2 cerebral arteriopathy. Distinctive features of this arteriopathy included an aberrant internal carotid circulation with dilatation of the proximal segments, occlusive disease at the distal segments, and dolichoectasia. As such, mutant ACTA2 predisposed patients to ischemic strokes as children. Direct and indirect cerebral revascularization procedures are the mainstay treatment options with varying degrees of success. Key Messages: ACTA2 cerebral arteriopathy is a recently described novel cerebrovascular disease seen in patients with MSMDS. Patients currently diagnosed with moyamoya disease who also have dysfunction of smooth muscle organs may benefit from reevaluation by a medical geneticist and ACTA2 genotyping.

ACTA2 mutation is responsible for multisystemic smooth muscle dysfunction syndrome with seizures: A case report and review of literature.

BACKGROUND: ACTA2 gene is a specific gene that encodes actin α2. Multisystem smooth muscle dysfunction syndrome (MSMDS) is a multisystem disease characterized by aortic and cerebrovascular lesions caused by ACTA2 gene mutations. There have been many reports of cardiac, pulmonary and cerebrovascular lesions caused by MSMDS; however, few studies have focused on seizures caused by MSMDS. CASE SUMMARY: Our patient was a girl aged 7 years and 8 mo with recurrent cough, asthma and seizures for 7 years. She was diagnosed with severe pneumonia, congenital heart disease, cardiac insufficiency, and malnutrition in the local hospital. Cardiac ultrasonography revealed congenital heart disease, patent ductus arteriosus (with a diameter of 0.68 cm), left coronary arteriectasis, patent oval foramen (0.12 cm), tricuspid and pulmonary regurgitation, and pulmonary hypertension. Cerebral magnetic resonance imaging and magnetic resonance angiography indicated stiffness in the brain vessels, together with multiple aberrant signaling shadows in bilateral paraventricular regions. A heterozygous mutation (c.536G>A) was identified in the ACTA2 gene, resulting in generation of p.R179H. Finally, the girl was diagnosed with MSMDS combined with epilepsy. The patient had 4 episodes of seizures before treatment, and no onset of seizure was reported after oral administration of sodium valproate for 1 year. CONCLUSION: MSMDS has a variety of clinical manifestations and unique cranial imaging features. Cerebrovascular injury and white matter injury may lead to seizures. Gene detection can confirm the diagnosis and prevent missed diagnosis or misdiagnosis.

Multisystem smooth muscle dysfunction syndrome in a Chinese girl: A case report and review of the literature.

BACKGROUND: Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a rare genetic disease worldwide. The main mutation is the actin alpha 2 (ACTA2) gene p.R179H. In this paper, we report a Chinese MSMDS patient and systematically review the previous literature. CASE SUMMARY: Here, we report a 9.6-month-old Chinese girl who was diagnosed with MSMDS based on her history and symptoms, such as recurrent cough, wheezing, and complications with congenital fixed dilated pupils. Chest high-resolution computed tomography revealed inhomogeneous lung transparency, obvious exudative lesions, and some lung fissures that were markedly thickened. Cranial magnetic resonance imaging excluded bleeding and infarction but showed abnormal signals in the centrum ovale majus and bilateral periventricular regions. Echocardiography only showed patent foramen ovale, and no patent ductus arteriosus, pulmonary artery dilatation, or pulmonary hypertension was found. Bronchoscopy indicated moderate bronchial malacia. These examinations in conjunction with the typical eye abnormality suggested a diagnosis of MSMDS, and sequencing of exon 6 of the ACTA2 gene demonstrated the heterozygous mutation c.536G>A, p.R179H. However, her parents' gene analyses were normal. CONCLUSION: MSMDS is a rare genetic disease mainly caused by the mutation of the ACTA2 gene p.R179H. Early genetic diagnosis should be performed for children presenting with congenital fixed dilated pupils and patent ductus arteriosus. During the process of diagnosis and treatment, clinicians should be on high alert for cerebrovascular, cardiovascular, and pulmonary complications.

Iris anomalies and the incidence of ACTA2 mutation.

BACKGROUND: Central cysts of the iris pigment epithelium, or iris flocculi, are frequently reported in the literature in association with thoracic aortic aneurysm and dissection due to smooth muscle alpha-actin 2 (ACTA2) mutations. Children with ACTA2 mutations may also present with congenital mydriasis. We report our experience regarding the frequency of ACTA2 mutation in children with the above iris anomalies. METHODS: This is a retrospective, consecutive case series of all children presenting for iris flocculi or congenital mydriasis at a single tertiary centre from October 2012 to December 2016. RESULTS: 13 children with iris flocculi and 3 with congenital mydriasis presented during the study period. 10 children with iris flocculi completed genetic testing, and none were positive for ACTA2 mutation. All children with congenital mydriasis presented with a multisystem smooth muscle dysfunction syndrome; two of these three children tested positive for missense R179 ACTA2 mutations. CONCLUSIONS: In this series, ACTA2 mutation or copy number variation was not detected in children presenting for iris flocculi, whereas congenital mydriasis was associated with R179 mutation in both cases that tested positive for ACTA2 mutation. The case of congenital mydriasis without typical cardiac features of the R179 ACTA2 phenotype or intracranial vasculopathy was negative for ACTA2 mutation. While all children presenting with these iris anomalies should be offered a genetic evaluation, incidence data should inform genetic counselling, particularly in the absence of a family history of aneurysm or sudden death, or systemic signs of smooth muscle dysfunction.