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

Regalado, Ellen S.; Mellor‐Crummey, Lauren; Backer, Julie De; Braverman, Alan C.; Adès, Lesley C.; Benedict, Susan; Bradley, Timothy J.; Brickner, M. Elizabeth; Chatfield, Kathryn C.; Child, Anne H.; Feist, Cori; Holmes, Kathryn W.; Iannucci, Glen; Lorenz, Birgit; Mark, Paul R.; Morisaki, Takayuki; Morisaki, Hiroko; Morris, Shaine A.; Mitchell, Anna L.; Østergaard, John R.; Richer, Julie; Sallee, Denver; Shalhub, Sherene; Tekin, Mustafa; Estrera, Anthony L.; Musolino, Patricia L.; Yetman, Anji T.; Pyeritz, Reed E.; Milewicz, Dianna M.

doi:10.1038/gim.2017.245

Cited by 59 publications

(55 citation statements)

References 27 publications

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“…The most common neurologic complication reported in patient's histories was cerebral ischemic stroke. Stroke occurred in 8 females and one male (27% of patients) occurring at a median age of 4 years [16]. The youngest age at stroke was reported in a 2-day-old child with infarction of the bilateral watershed areas and basal ganglia.…”

Section: Clinical Significancementioning

confidence: 96%

“…These individuals exhibited various ACTA2 missense mutations at position 179 including Arg179His (24 patients), Arg179Cys (7 patients), Arg179Ser (1 patient), and Arg179Leu (1 patient). The authors reported proximal internal carotid artery stenosis in 77% of patients [16]. Fifty-three percent of patients demonstrated multi-vessel disease with the second most common site being one of the cerebral arteries (60%).…”

Section: Clinical Significancementioning

confidence: 98%

“…As such, these patients exhibit an elevated risk of developing vaso-occlusive strokes and various other neurologic sequelae, all of which may occur as early as the neonatal period (Table 1). In the largest MSMDS study to date, Regalado et al [16] reported the clinical neurologic history of 33 patients (including 7 patients from Milewicz et al [2] plus addendum) diagnosed with MSMDS. The median age of these patients was 12 years and the median age at diagnosis was 11 years.…”

Section: Clinical Significancementioning

confidence: 99%

“…Twenty-one (64%) were females and 12 (36%) were males. Twenty-six were of European ancestry, 5 were Asian, 1 was African-American, and 1 was Hispanic [16]. These individuals exhibited various ACTA2 missense mutations at position 179 including Arg179His (24 patients), Arg179Cys (7 patients), Arg179Ser (1 patient), and Arg179Leu (1 patient).…”

Section: Clinical Significancementioning

confidence: 99%

“…However, ACTA2 cerebral arteriopathy is now classified as a novel cerebrovascular disease with unique genetic loci, histopathologic findings, and cerebrovascular features. To date, only 58 cases of MSMDS with ACTA2 cerebral arteriopathy have been reported and confirmed via genotyping [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Here, we provide a literature review of ACTA2 cerebral arteriopathy encompassing the history of the disease from first observation to new classification, clinical significance and neurosurgical management strategies.…”

Section: Introductionmentioning

confidence: 99%

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ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke

et al. 2018

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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.

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Section: Clinical Significancementioning

confidence: 96%

Section: Clinical Significancementioning

confidence: 98%

Section: Clinical Significancementioning

confidence: 99%

Section: Clinical Significancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke

et al. 2018

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

Kaw¹,

Kaw²,

Hostetler³

et al. 2022

American J of Med Genetics Pt A

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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.

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

Lupo

Gregorio

Mastrogiorgio

et al. 2023

American J of Med Genetics Pt A

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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.

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

Cited by 59 publications

References 27 publications

<b><i>ACTA2</i></b> Cerebral Arteriopathy: Not Just a Puff of Smoke

<b><i>ACTA2</i></b> Cerebral Arteriopathy: Not Just a Puff of Smoke

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

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

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