Research

ATS Research

Rare disease, limited understanding

This section is designed to inform healthcare professionals and researchers about what is currently known about ATS. If you are not a healthcare professional, please refer to our About ATS section.

The first annual ATS Conference

View photos from the conference that took place from July 31 to August 1 in Little Rock, Arkansas.

NOTE: The first European ATS Conference is scheduled for July or August 2017. More details to come!


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A Clinical Landscape of ATS

What can I expect from my patient with ATS?

Patients usually present to medical care between the ages of 0 and 5 years and are commonly diagnosed to ATS due to imaging of the arteries for cardiovascular concerns, including fatigue with normal activity. 1,2 Patients with ATS are at a high risk of aneurysm formation, dissections, ischemic events, and some neurologic diseases. 3,4 Though clinical presentation and severity is highly variable from patient to patient, there are common characteristics.

Arterial tortuosity and phenotypic expression vary in severity from patient to patient.

Most common clinical findings of patients with ATS
Cardiovascular abnormalities
  • Arterial tortuosity and lengthening of
    • the aorta, carotid, coronary, pulmonary, vertebral, intracerebral and renal arteries
  • Arterial aneurysm of
    • the aorta, carotid, pulmonary and renal arteries
  • Arterial stenosis
Dysmorphic facial features
  • Elongated face
  • Down-slanting palpebral fissure
  • Cleft palate
  • Beaked nose
  • Prominent ears
  • Micrognathia
Distinct skin features
  • Hyperlaxic/hyperextensible skin
  • Cutis laxa
  • Soft, thin or redundant skin
  • Ecchymosis
Distinct joint features
  • Joint laxity
  • Joint contractures
Hernias
  • Inguinal
  • Umbilical
  • Gastric of diaphragmatic
Other
  • Acrocyanosis
  • Hypotonia
  • Arachnodactyly
  • Mental retardation
  • Myopia
  • Chest deformities: pectus excavactum or pectus carimaatum
  • Scoliosis

You’ve probably heard of Marfan syndrome, but have you heard of ATS?

ATS is closely related to other connective tissue disorders1,3,4:

  • Ehlers-Danlos Syndrome
  • Wrinkly Skin Syndrome
  • Marfan Syndrome
  • Cutis Laxa, Menkes Disease
  • De Barsy Syndrome

All present with common features such as joint laxity, hyperelastic skin, hernias, and cardiovascular anomalies similar to ATS.1

Commonalities with Loeys-Dietz Syndrome

Loeys-Dietz Syndrome seems to be the most closely related to ATS. They are both associated with arterial tortuosity and aneurysm formation. They also share similar phenotypic features including arachnodactyly, joint laxity, microetrognthia, hypertelorism, and cleft palate. Furthermore, both are caused by loss of function mutations in genes encoding for type 1 or type 2 TGFβ receptors leading to a paradoxical increase in TGFβ signaling in the arterial wall.5 The severity of vascular malformation seen in patients with ATS differentiates it from other connective tissue disorders.6 Once ATS is the suspected diagnosis, genetic screening should be performed to confirm.

There are a number of different tests to screen for ATS gene mutations.

Table 2: Available tests to screen for ATS gene mutations

TestTypeMethodLaboratory

ATS Molecular Deletion/Duplication/Copy number (Array, MLPA, Q-PCR, etc) Connective Tissue Gene Tests
Allentown, PA, USA
ATS Molecular Sequencing, Capillary Connective Tissue Gene Tests
Allentown, PA, USA
ATS via the SLC2A10 gene Molecular Sequencing, Capillary PreventionGenetics (Prevention Genetics), Clinical DNA Testing and DNA Banking
Marshfield, WI, USA
ATS Molecular Sequencing, Capillary GENETAQ, Molecular Genetics Centre
Malaga, Spain
ATS Molecular Deletion/Duplication/copy number (Array, MLPA, Q-PCR, etc) University of Washington Medical Center, Collagen Diagnostic Laboratory
Seattle, WA, USA
ATS Molecular Sequencing, Capillary University of Washington Medical Center, Collagen Diagnostic Laboratory
Seattle, WA, USA
ATS Molecular Sequencing, Capillary University Hospital Münster, Institute for Genetics of Heart Diseases (ifGH)
Münster, Germany
ATS Molecular Sequencing, Capillary Centogene AG, Rare Disease Company
Rostock, Germany
Aorta Panel Molecular Panel Sequencing, Next Gen Blueprint Genetics
Helsinki, Finland
Connective Tissue Disorders Sequencing Panel Molecular Panel Emory University School of Medicine, Emory Molecular Genetics Laboratory
Atlanta, GA, USA
Connective Tissue NGS Panel Molecular Panel Sequencing, Next Gen Fulgent Diagnostics
Temple City, CA, USA

What is the pathogenesis of ATS?

The SLC2A10 gene located on chromosome 20q13.5 encodes the facilitative glucose transporter GLUT10. Mutations in this gene have been linked to ATS.

So far twenty mutations have been identified in the SLC2A10 gene.

The pathogenesis of disease is still under investigation; however, there are 2 proposed theories to explain the vascular malformation seen in ATS.

Theory 1

It has been proposed that glucose is normally transported into smooth muscle cells by way of the facilitative glucose transporter, GLUT10. Glucose then activates transcription of decorin, a known inhibitor of the TGFβ signaling pathway. Decorin binds to and inactivates TGFβ, attenuating signaling for connective tissue growth factors to proliferate. In ATS, mutations in the SLC2A10 gene lead to loss of function of GLUT10, reducing nuclear glucose levels and decorin transcription; this results in upregulation of TGFβ signaling and activation of SMAD responsive genes that encode connective tissue growth factors (CTGF). The proliferation of CTGF cells disrupts the elastic fiber network of blood vessels, resulting in aortic weakness and pathogenic remodeling.6 This model emphasizes disregulation of the TGFβ signaling pathway as the main cause of the architectural defects in the arterial wall of ATS patients.7

Theory 1

Table 3: Mutations in the SLC2A10 gene that encode for ATS

Mutation

1 c.685C>T1
2 c.1276G>T1
3 c.730_733delCTAA1
4 c.737G>A1
5 c.394C>T1
6 c.692G>A1
7 c.425G>T1
8 c.318delT2
9 c.510G>A3
10 c.756C>A4
11 c.691C>T4
12 c.1334delG1,3
13 c.1309G>A1
14 c.1334G>A1
15 c.1411+1G>A5
16 c.1330C>T6
17 c.1411+480_
c.1547+299del1
18 c.243C>G3
19 c.961delG3
20 c.313C>T7

Theory 2

Vitamin C circulates in the bloodstream as 2 different forms: reduced ascorbic acid (AA) and oxidized dehydroascorbic acid (DHAA). It has been hypothesized that DHAA enters the endoplasmic reticulum (ER) of smooth muscle cells (SMCs) via GLUT10 where it is reduced to AA by protein disulfide isomerase (PDI), a subunit of prolyl hydroxylases. Prolyl- and lysyl-hydroxylases stabilize collagens and elastin by modifying their residues. This allows for normal synthesis of collagen and elastin, which make up the extracellular matrix (ECM) of connective tissue.

In ATS, mutations in the SLC2A10 gene create loss of function of GLUT10, thereby preventing DHAA from entering the cell. Reduced levels of intracellular vitamin C negatively affect the integrity of deposited collagen and elastin, weakening the ECM of connective tissue and inducing a TGFβ response that stimulates the proliferation of SMCs. Anatomical constraint due to the fixed ends of arteries prevent SMCs from growing longitudinally, and tortuosity of the arteries occurs. This model emphasizes abnormal synthesis of collagen and elastin due to deficiency of intracellular vitamin C metabolism as the main cause of the vascular malfunction seen in ATS.7

Theory 2

How do I manage ATS in my patients?

Currently, there is no standard of care or management guidelines for ATS. Intervention must be decided on a case-by-case basis depending on symptom presentation and the observed vascular complications. Based on the current literature, a hybrid surgical and interventional cardiologic approach may be best for treatment. Case studies of the following interventions used in patients with ATS have been reported in the literature:

  • Median sternotomy
  • Cardiopulmonary bypass
  • Arteriotomy, total pulmonary artery reconstruction
  • Valve sparing aortic root replacement (both remodeling and reimplantation)

All reported cases have been successful with follow-up reported as long as 3-4 years.8-13

Regardless of the procedure, routine imaging and follow-up is recommended for all individuals with ATS.

What is the mortality rate for ATS?

There is no comprehensive data detailing mortality rate in the current population of ATS patients. One paper stated a 40% mortality rate before the age of 5.4 However, this statistic is based on a small cohort of cases and has not been reproduced since the paper was published. Recent research suggests that people with ATS can live longer than previously thought.1

Causes of death are variable but include respiratory insufficiency, ventricular hypertrophy resulting in global heart failure, myocarditis, and ischemic events leading to organs infarction.2

Where are the key research needs in ATS?

A deeper understanding of the molecular pathogenesis of ATS is necessary to increase insight into diagnosis, as well as prevention strategies for related complications. There are multiple avenues for future research that would be beneficial.

Molecular areas of interest include

  • The GLUT10 transporter and the TGFβ signaling pathway
  • TGFβ signaling more broadly, particularly in relation to the development of connective tissue
  • A novel animal model of ATS with a longer life span than zebrafish

More clinical areas of interest include

  • Investigation of disease progression and natural history
  • Diagnosis, including stage of diagnosis for adults
  • Impact on patient quality of life and activities of daily living
  • Health-related costs associated with ATS
  • Patient survival rate
  • Establishment of a standard of care and management guidelines
  • Investigation of surgical success rate and long-term outcomes
  • Exploring the possibility of using novel technologies such as 3D printing in patients with ATS

References

  1. Ekici F, Uçar T, Fitöz S, Atalay S, Tutar E. Cardiovascular findings in a boy with arterial tortuosity syndrome: case report and review of the literature. Turk J Pediatr. 2011;53(1):104-107.
  2. Callewaert BL, Willaert A, Kerstjens-Frederikse WS, et al. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat. 2008;29(1):150-158. doi:10.1002/humu.20623.
  3. Ritelli M, Drera B, Vicchio M, et al. Arterial tortuosity syndrome in two Italian paediatric patients. Orphanet J Rare Dis. 2009;4(20):1-4. doi:10.1186/1750-1172-4-20.
  4. Wessels MW, Catsman-Berrevoets CE, Mancini GMS, et al. Three new families with arterial tortuosity syndrome. Am J Med Genet A. 2004;131(2):134-143. doi:10.1002/ajmg.a.30272.
  5. Coucke PJ, Willaert A, Wessels MW, et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006;38(4):452-457. doi:10.1038/ng1764.
  6. Akhurst RJ. A sweet link between TGFβ and vascular disease? Nat Genet. 2006;38(4):400-401. doi:10.1038/ng0406-400.
  7. Segade F. Glucose transporter 10 and arterial tortuosity syndrome: the vitamin C connection. FEBS Lett. 2010;584(14):2990-2994. doi:10.1016/j.febslet.2010.06.011.
  8. Adès LC, Knight WB, Byard RW, et al. Clinicopathologic findings in congenital aneurysms of the great vessels. Am J Med Genet. 1996;66(3):289-299. doi:10.1002/(sici)1096-8628(19961218)66:33.3.co;2-m.
  9. Al-Khaldi A, Alharbi A, Tamimi O, Mohammed Y. Successful surgical pulmonary artery reconstruction in arterial tortuosity syndrome. Ann Thorac Surg. 2009;88(4):1343-1345. doi:10.1016/j.athoracsur.2009.02.020.
  10. Bottio T, Bisleri G, Piccoli P, Muneretto C. Valve-sparing aortic root replacement in a patient with a rare connective tissue disorder: arterial tortuosity syndrome. J Thorac Cardiovasc Surg. 2007;133(1):252-253. doi:10.1016/j.jtcvs.2006.08.050.
  11. Cine N, Basaran M, Guzelmeric F, Sunar H. Repair of ascending aortic aneurysm in a patient with arterial tortuosity syndrome. Interact Cardiovasc Thorac Surg. 2011;12(6):1051-1053. doi:10.1510/icvts.2010.265082.
  12. Santoro G, Caianiello G, Rossi G, et al. Hybrid transcatheter—surgical approach in complex pulmonary artery stenosis due to arterial tortuosity syndrome. J Cardiovasc Med (Hagerstown). 2009;10(1):104-106. doi:10.2459/JCM.0b013e3283168d37.
  13. Vicchio M, Santoro G, Carrozza M, Caianiello G. Hybrid approach in a case of arterial tortuosity syndrome. Interact Cardiovasc Thorac Surg. 2008;7(4):736-737. doi:10.1510/icvts.2007.165001.

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Meet the healthcare professionals!

The following interviews were conducted with healthcare providers who have had experience working with people with ATS. They have generously provided us with their contact information to answer questions about ATS. Please be mindful of their hectic schedules if you choose to contact them.

Do you have experience with ATS?

We want to hear from you! If you are interested in telling us about your experience with ATS, please contact us at Cambridge BioMarketing.

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