. 2018 Oct;20(10):1206-1215.

doi: 10.1038/gim.2017.245. Epub 2018 Jan 4.

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

Ellen S Regalado¹, Lauren Mellor-Crummey¹, Julie De Backer², Alan C Braverman³, Lesley Ades⁴, Susan Benedict⁵, Timothy J Bradley⁶, M Elizabeth Brickner⁷, Kathryn C Chatfield⁸, Anne Child⁹, Cori Feist¹⁰, Kathryn W Holmes¹¹, Glen Iannucci¹², Birgit Lorenz¹³, Paul Mark¹⁴, Takayuki Morisaki¹⁵, Hiroko Morisaki¹⁶, Shaine A Morris¹⁷, Anna L Mitchell¹⁸, John R Ostergaard¹⁹, Julie Richer²⁰, Denver Sallee¹², Sherene Shalhub²¹, Mustafa Tekin²²; Montalcino Aortic Consortium; Anthony Estrera²³, Patricia Musolino²⁴, Anji Yetman²⁵, Reed Pyeritz²⁶, Dianna M Milewicz²⁷

Affiliations

¹ Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA, Texas.
² Center for Medical Genetics, University Hospital Ghent, Ghent, Belgium.
³ Cardiovascular Division, Washington University School of Medicine, St. Louis, USA, Missouri.
⁴ Division of Pediatrics and Child Health, University of Sydney, Sydney, Australia, New South Wales.
⁵ Department of Pediatrics, The University of Utah School of Medicine, Salt Lake City, USA, Utah.
⁶ Division of Cardiology, Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada, Saskatchewan.
⁷ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA, Texas.
⁸ Department of Pediatrics, University of Colorado School of Medicine, Aurora, USA, Colorado.
⁹ Molecular and Clinical Sciences Research Institute, St George's, University of London, London, UK.
¹⁰ Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, USA, Oregon.
¹¹ Department of Pediatrics, Oregon Health and Science University, Portland, USA, Oregon.
¹² Department of Pediatrics, Emory University School of Medicine, Atlanta, USA, Georgia.
¹³ Department of Ophthalmology, Justus-Liebig-University Giessen, Giessen, Germany.
¹⁴ Department of Medical Genetics, Spectrum Health, Grand Rapids, USA, Michigan.
¹⁵ Tokyo University of Technology School of Health Sciences, Tokyo, Japan.
¹⁶ Department of Medical Genetics, Sakakibara Heart Institute, Tokyo, Japan.
¹⁷ Texas Children's Hospital, Baylor College of Medicine, Houston, USA, Texas.
¹⁸ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, USA, Ohio.
¹⁹ Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
²⁰ Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada, Ontario.
²¹ Department of Surgery, University of Washington, Seattle, USA, Washington.
²² John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, USA, Florida.
²³ Department of Cardiothoracic and Vascular Surgery, University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA, Texas.
²⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA, Massachusetts.
²⁵ Department of Pediatrics, Children's Hospital & Medical Center, University of Nebraska, Omaha, USA, Nebraska.
²⁶ Perelman School of Medicine at the, University of Pennsylvania, Philadelphia, USA, Pennsylvania.
²⁷ Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA, Texas. Dianna.M.Milewicz@uth.tmc.edu.

PMID: 29300374
PMCID: PMC6034999
DOI: 10.1038/gim.2017.245

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

Ellen S Regalado et al. Genet Med. 2018 Oct.

. 2018 Oct;20(10):1206-1215.

doi: 10.1038/gim.2017.245. Epub 2018 Jan 4.

Authors

Affiliations

¹ Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA, Texas.
² Center for Medical Genetics, University Hospital Ghent, Ghent, Belgium.
³ Cardiovascular Division, Washington University School of Medicine, St. Louis, USA, Missouri.
⁴ Division of Pediatrics and Child Health, University of Sydney, Sydney, Australia, New South Wales.
⁵ Department of Pediatrics, The University of Utah School of Medicine, Salt Lake City, USA, Utah.
⁶ Division of Cardiology, Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada, Saskatchewan.
⁷ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA, Texas.
⁸ Department of Pediatrics, University of Colorado School of Medicine, Aurora, USA, Colorado.
⁹ Molecular and Clinical Sciences Research Institute, St George's, University of London, London, UK.
¹⁰ Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, USA, Oregon.
¹¹ Department of Pediatrics, Oregon Health and Science University, Portland, USA, Oregon.
¹² Department of Pediatrics, Emory University School of Medicine, Atlanta, USA, Georgia.
¹³ Department of Ophthalmology, Justus-Liebig-University Giessen, Giessen, Germany.
¹⁴ Department of Medical Genetics, Spectrum Health, Grand Rapids, USA, Michigan.
¹⁵ Tokyo University of Technology School of Health Sciences, Tokyo, Japan.
¹⁶ Department of Medical Genetics, Sakakibara Heart Institute, Tokyo, Japan.
¹⁷ Texas Children's Hospital, Baylor College of Medicine, Houston, USA, Texas.
¹⁸ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, USA, Ohio.
¹⁹ Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
²⁰ Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada, Ontario.
²¹ Department of Surgery, University of Washington, Seattle, USA, Washington.
²² John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, USA, Florida.
²³ Department of Cardiothoracic and Vascular Surgery, University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA, Texas.
²⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA, Massachusetts.
²⁵ Department of Pediatrics, Children's Hospital & Medical Center, University of Nebraska, Omaha, USA, Nebraska.
²⁶ Perelman School of Medicine at the, University of Pennsylvania, Philadelphia, USA, Pennsylvania.
²⁷ Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA, Texas. Dianna.M.Milewicz@uth.tmc.edu.

PMID: 29300374
PMCID: PMC6034999
DOI: 10.1038/gim.2017.245

Abstract

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.

Keywords: ACTA2; congenital mydriasis; patent ductus arteriosus; smooth muscle dysfunction syndrome; thoracic aortic aneurysm.

PubMed Disclaimer

Conflict of interest statement

DISCLOSURE

The authors declare no conflict of interest.

Figures

**Figure 1**
Cumulative risk of first aortic event, stroke and death associated with SMDS.

**Figure 2**
Reconstructed MRA images showing dilation of the aortic root and ascending aorta and bilateral subclavian and axillary artery aneurysms (top image) and dilation of the descending and thoracoabdominal aorta (bottom image) in a 13 year old patient with ACTA2 Arg179His alteration.

**Figure 3**
Representative images before (upper panel) and one year after (low panel) indirect revascularization surgery (dural inversion). Angiographic images show multiple abnormalities including straightening of cerebral arteries, dilation of the petrous and cavernous portions followed by severe stenosis of the terminal segment of the right (R) and left (L) internal carotid arteries (ICA), severe stenosis of the middle and anterior cerebral arteries (with distal R M1 occlusion) and areas of parenchymal hypoperfusion (dashed circles). Follow-up angiogram a year after surgery demonstrates new collateral vessels arising from the middle meningeal arteries (arrows) in the watershed regions of hypoperfusion, with concomitant enlargement of the parent middle meningeal vessel indicating compensatory increased flow, and retrograde flow through the R MCA (arrowhead) supporting hemodynamically significant supply from the donor vessels. MRI FLAIR images illustrate white matter injury and ischemic infarcts at both time points.

See this image and copyright information in PMC

References

1. Milewicz DM, Ostergaard JR, la-Kokko LM, Khan N, Grange DK, Mendoza-Londono R, et al. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A. 2010;152A:2437–2443. - PMC - PubMed
1. Moller HU, Fledelius HC, Milewicz DM, Regalado ES, Ostergaard JR. Eye features in three Danish patients with multisystemic smooth muscle dysfunction syndrome. Br J Ophthalmol. 2012 - PMC - PubMed
1. Munot P, Saunders DE, Milewicz DM, Regalado ES, Ostergaard JR, Braun KP, et al. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain. 2012;135:2506–2514. - PMC - PubMed
1. Al-Mohaissen M, Allanson JE, O'Connor MD, Veinot JP, Brandys TM, Maharajh G, et al. Brachial artery occlusion in a young adult with an ACTA2 thoracic aortic aneurysm. Vasc Med. 2012;17:326–329. - PubMed
1. Richer J, Milewicz DM, Gow R, de NJ, Maharajh G, Miller E, et al. R179H mutation in ACTA2 expanding the phenotype to include prune-belly sequence and skin manifestations. Am J Med Genet A. 2012;158A:664–668. - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous