Publications by authors named "Ellen S Regalado"

39 Publications

Treatment guidelines for thoracic aortic aneurysms and dissections based on the underlying causative gene.

J Thorac Cardiovasc Surg 2010 Dec;140(6 Suppl):S2-4; discussion S45-51

Department of Internal Medicine, the University of Texas Health Science Center at Houston, Houston, TX, USA.

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http://dx.doi.org/10.1016/j.jtcvs.2010.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584588PMC
December 2010

Rare copy number variants disrupt genes regulating vascular smooth muscle cell adhesion and contractility in sporadic thoracic aortic aneurysms and dissections.

Am J Hum Genet 2010 Dec 18;87(6):743-56. Epub 2010 Nov 18.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Thoracic aortic aneurysms and dissections (TAAD) cause significant morbidity and mortality, but the genetic origins of TAAD remain largely unknown. In a genome-wide analysis of 418 sporadic TAAD cases, we identified 47 copy number variant (CNV) regions that were enriched in or unique to TAAD patients compared to population controls. Gene ontology, expression profiling, and network analysis showed that genes within TAAD CNVs regulate smooth muscle cell adhesion or contractility and interact with the smooth muscle-specific isoforms of α-actin and β-myosin, which are known to cause familial TAAD when altered. Enrichment of these gene functions in rare CNVs was replicated in independent cohorts with sporadic TAAD (STAAD, n = 387) and inherited TAAD (FTAAD, n = 88). The overall prevalence of rare CNVs (23%) was significantly increased in FTAAD compared with STAAD patients (Fisher's exact test, p = 0.03). Our findings suggest that rare CNVs disrupting smooth muscle adhesion or contraction contribute to both sporadic and familial disease.
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http://dx.doi.org/10.1016/j.ajhg.2010.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997376PMC
December 2010

Diffuse and uncontrolled vascular smooth muscle cell proliferation in rapidly progressing pediatric moyamoya disease.

J Neurosurg Pediatr 2010 Sep;6(3):244-9

Department of Internal Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA

Moyamoya disease is a rare stroke syndrome of unknown etiology resulting from stenosis or occlusion of the supraclinoid internal carotid artery (ICA) in association with an abnormal vascular network in the basal ganglia. Although the highest incidence of moyamoya disease is in pediatric patients, pathology reports have been primarily limited to adult samples and describe occlusive fibrocellular lesions in the intimae of affected arteries. We describe the case of a young girl with primary moyamoya disease who presented at 18 months of age with right hemiparesis following an ischemic stroke. Angiography showed stenosis of the distal left ICA, left middle cerebral artery, and right ICA. An emergent left-sided dural inversion was performed. Recurrent strokes and alternating hemiplegia necessitated a right dural inversion 6 months later. Nonetheless, her aggressive disease proved uniquely refractory to surgical revascularization, and she succumbed to recurrent strokes and neurological deterioration at 2.5 years of age. Pathological specimens revealed a striking bilateral occlusion of the anterior carotid circulation resulting from intimal proliferation of smooth muscle cells (SMCs). Most strikingly, the ascending aorta and the superior mesenteric artery demonstrated similar intimal proliferation, along with SMC proliferation in the media. The systemic pathology involving multiple arteries in this extremely young child, the first case of its kind available for autopsy, suggests that globally uncontrolled SMC proliferation, in the absence of environmental risk factors and likely resulting from an underlying genetic alteration, may be a primary etiologic event leading to moyamoya disease.
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http://dx.doi.org/10.3171/2010.5.PEDS09505DOI Listing
September 2010

De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction.

Am J Med Genet A 2010 Oct;152A(10):2437-43

Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

Smooth muscle cells (SMCs) contract to perform many physiological functions, including regulation of blood flow and pressure in arteries, contraction of the pupils, peristalsis of the gut, and voiding of the bladder. SMC lineage in these organs is characterized by cellular expression of the SMC isoform of α-actin, encoded by the ACTA2 gene. We report here on a unique and de novo mutation in ACTA2, R179H, that causes a syndrome characterized by dysfunction of SMCs throughout the body, leading to aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation, and hypoperistalsis of the gut and pulmonary hypertension.
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http://dx.doi.org/10.1002/ajmg.a.33657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573757PMC
October 2010

Genetic testing in aortic aneurysm disease: PRO.

Cardiol Clin 2010 May;28(2):191-7

Department of Internal Medicine, University of Texas Health Science Center at Houston, 6431 Fannin Street MSB 6.100, Houston, TX 77030, USA.

Thoracic aortic aneurysms leading to type A dissections (TAAD) are the major diseases affecting the aorta. A genetic predisposition for TAAD can occur as part of a genetic syndrome. It can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Genetic heterogeneity for familial TAAD has been demonstrated with the identification of four genes leading to TAAD. Genetic testing for TAAD and the phenotype and management of patients harboring mutations in these genes are addressed in this article.
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http://dx.doi.org/10.1016/j.ccl.2010.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615454PMC
May 2010

Genetic variants promoting smooth muscle cell proliferation can result in diffuse and diverse vascular diseases: evidence for a hyperplastic vasculomyopathy.

Genet Med 2010 Apr;12(4):196-203

From the Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Genetic predisposition to early onset of occlusive vascular diseases, including coronary artery disease, ischemic stroke, and Moyamoya disease, may represent varying presentations of a common underlying dysregulation of vascular smooth muscle cell proliferation. We discuss mutations in two genes, NF1 and ACTA2, which predispose affected individuals to diffuse and diverse vascular diseases. These patients show evidence of diffuse occlusive disease in multiple arterial beds or even develop seemingly diverse arterial pathologies, ranging from occlusions to arterial aneurysms. We also present the current evidence that both NF1 and ACTA2 mutations promote increased smooth muscle cell proliferation in vitro and in vivo, which leads us to propose that these diffuse and diverse vascular diseases are the outward signs of a more fundamental disease: a hyperplastic vasculomyopathy. We suggest that the concept of a hyperplastic vasculomyopathy offers a new approach not only to identifying mutated genes that lead to vascular diseases but also to counseling and possibly treating patients harboring such mutations. In other words, this framework may offer the opportunity to therapeutically target the inappropriate smooth muscle cell behavior that predisposes to a variety of vascular diseases throughout the arterial system.
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http://dx.doi.org/10.1097/GIM.0b013e3181cdd687DOI Listing
April 2010

Paucity of skeletal manifestations in Hispanic families with FBN1 mutations.

Eur J Med Genet 2010 Mar-Apr;53(2):80-4. Epub 2009 Nov 23.

Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.

Marfan syndrome (MFS) is an autosomal dominant condition with pleiotropic manifestations involving the skeletal, ocular, and cardiovascular systems. The diagnosis is based primarily on clinical involvement of these and other systems, referred to as the Ghent criteria. We have identified three Hispanic families from Mexico with cardiovascular and ocular manifestations due to novel FBN1 mutations but with paucity of skeletal features. The largest family, hMFS001, had a frameshift mutation in exon 24 (3075delC) identified as the cause of aortic disease in the family. Assessment of eight affected adults revealed no major skeletal manifestation of MFS. Family hMFS002 had a missense mutation (R1530C) in exon 37. Four members fulfilled the criteria for ocular and cardiovascular phenotype but lacked skeletal manifestations. Family hMFS003 had two consecutive missense FBN1 mutations (C515W and R516G) in exon 12. Eight members fulfilled the ocular criteria for MFS and two members had major cardiovascular manifestations, however none of them met criteria for skeletal system. These data suggest that individuals of Hispanic descent with FBN1 mutations may not manifest skeletal features of the MFS to the same extent as Caucasians. We recommend that echocardiogram, ocular examination and FBN1 molecular testing be considered for any patients with possible MFS even in the absence of skeletal features, including Hispanic patients.
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http://dx.doi.org/10.1016/j.ejmg.2009.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354948PMC
July 2010

Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease.

Am J Hum Genet 2009 May 30;84(5):617-27. Epub 2009 Apr 30.

The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.
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http://dx.doi.org/10.1016/j.ajhg.2009.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680995PMC
May 2009

Perinatal transfer of genetic information: developing an algorithm for reporting cystic fibrosis prenatal test results to the newborn screening program.

Genet Med 2008 Nov;10(11):805-10

Sarah Lawrence College, Bronxville, New York, USA.

Purpose: This study explored the feasibility of statewide reporting of cystic fibrosis fetal diagnostic testing results to the newborn screening program through the birth hospital.

Methods: We evaluated trends in offering and documenting cystic fibrosis carrier screening among prenatal care providers through a survey of 100 medical records of patients who gave birth at St. Vincent's Hospital Manhattan. The hospital's protocol for reporting human immunodeficiency virus testing history to the state program was delineated and adapted in developing an algorithm for cystic fibrosis. Feedback from hospital staff with regard to data transcription and the prospect of transferring cystic fibrosis prenatal information was obtained.

Results: Of 98 patients who had prenatal records made available to the birth hospital, 62% had cystic fibrosis carrier screening, 14% declined screening, and 24% had no documentation of their screening history. The hospital staff viewed the transcription of information as relatively simple; however, missing information is a common occurrence that delays the process and results in incomplete data transfer.

Conclusions: Perinatal transfer of cystic fibrosis prenatal information modeled on the system used for reporting human immunodeficiency virus testing history is feasible. However, it will require standardized reporting of cystic fibrosis screening and testing history on the mother's prenatal records among prenatal care providers.
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http://dx.doi.org/10.1097/GIM.0b013e31818a3107DOI Listing
November 2008
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