Arterial tortuosity syndrome (ATS) is an extremely rare genetic congenital connective tissue disorder characterized by lengthening (elongation) and twisting or distortion (tortuosity) of major arteries with hyperextensible skin and hypermobility of joints, throughout the body clinical observations, have been linked tortuous arteries and veins with aging, atherosclerosis, hypertension, genetic defects, and diabetes mellitus. Arteries are the blood vessels that carry oxygen-rich blood away from the heart. Affected arteries are prone to developing balloon-like bulges (aneurysms) on the wall of the artery, tearing (dissection), or narrowing (stenosis). The main artery that carries blood from the heart and to the rest of the body (aorta) can be affected. The pulmonary arteries are especially prone to narrowing. Additional symptoms affecting connective tissues entering multiple systems of the body can also be present. Affected individuals may have distinctive facial features that are noticeable at birth or during early childhood. Arterial tortuosity syndrome can potentially cause severe life-threatening complications during infancy or early childhood, although individuals with milder symptoms have also been described. Arterial tortuosity syndrome is caused by mutations in the SLC2A10 gene and is inherited in an autosomal recessive manner.
Arterial tortuosity syndrome is a connective tissue disorder. Connective tissues are the major components of the body forming skeleton, joints, skin, vessels, and other organs. Connective tissues are characterized by the presence of cells included in an extracellular matrix network of a large variety of proteins (i.e., collagens), proteins bound to sugars chains of big dimension (proteoglycans), and sugars (hyaluronic acid, etc.). This complex mesh of molecules gives the tissue form and strength and ensures the passage of nutrients and factors controlling cell growth and proliferation. People with arterial tortuosity syndrome often look older than their age and have distinctive facial features including a long, narrow face with droopy cheeks; eye openings that are narrowed (blepharophimosis ) with outside corners that point downward (down slanting palpebral fissures )
Types
Carotid Artery Tortuosity
Clinical studies have shown that internal carotid artery tortuosity may lead to symptoms including dizziness, vertigo, syncopes, blackout or persistent tinnitus (ringing in the ears) [rx]. Severe tortuosity may lead to arterial kinking (acute angulation) which causes artery occlusion and is associated with severe symptoms including transient ischemic attack, stroke [rx], hemiplegia, and other cerebrovascular deficiencies [rx, rx]. Tortuous carotid arteries are often reported in hypertensive patients. They are often associated with atherosclerosis [rx, rx, rx] and there is speculation that they could be a factor leading to atherosclerosis [rx]. Carotid artery tortuosity is often reported in elderly populations with severe tortuosity and angulation being associated with aging. Reduced wall thickness or lumen diameter is associated with a higher prevalence of tortuosity, although there is discrepancy among the clinical reports on the correlation between atherosclerosis and artery tortuosity [rx, rx]. Arterial degenerative disease is often concomitant with internal carotid artery tortuosity, but is not always associated with it [rx, rx, rx, rx].
Cerebral Artery Tortuosity
Tortuous cerebral often occur in basilar, communicating, anterior, and posterior cerebral as well as in arterioles in the white matter. Tortuosity of cerebral arteries has been reported for aged, hypertensive patients [rx, rx, rx, rx] and in patients with ‘Moyamoya’ disease Cerebral arteries may also become tortuous due to malformation or increased flow [rx, rx] associated with elastin degradation. Tortuosity of cerebral arteries was found to be associated with the severity of hypertension [rx].
Coronary Artery Tortuosity
Tortuosity of coronary arteries occurs in patients with hypertension and myocardial infarction. Tortuosity is associated with increased acute occlusion of coronary arteries [rx], diabetes, and coronary artery fistula [rx]. Tortuous coronary arteries hamper ventricular function [31] and have been proposed as an indicator of ventricular dysfunction [rx, rx].
Retinal Artery and Vein Tortuosity
Tortuous retinal arteries and veins are associated with hypertension, diabetes and genetic disorders. Tortuous conjunctival arteries and veins are also reported in patients with diabetic retinopathy and hypertension [rx, rx]. Tortuosity of retinal vessels has been suggested as an indicator of arterial hypertension, retinopathy, cerebral vessel disease, stroke and ischemic heart disease [rx, rx].
Tortuosity of Capillaries
Tortuous capillaries have been observed in both skeletal muscles and in the myocardium as well as in other organs. Capillary tortuosity level increases and decreases with muscle contraction and relaxation allowing the vessel surface area and permeability to remain the same [rx]; a higher level of tortuosity has been associated with hypertension and diabetes [rx, rx, rx, rx].
Artery Tortuosity Syndrome
Artery tortuosity syndrome (ATS) is a rare condition caused by an autosomal recessive disorder (such as mutation of the SLC2A10 gene [rx] and characterized by tortuosity, elongation, and aneurysm formation in major arteries due to the disruption of elastic fiber in the medial layer of the arterial wall. ATS is seen in members of the same family and affects all major arteries [rx, rx, rx]. In addition, tortuous aortas have been observed in mice with an elastin gene knockout [rx rx].
Causes
Arterial tortuosity syndrome is caused by mutations in the SLC2A10 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
To date, a total of 35 mutations in approximately 80 families have been identified in the SLC2A10 gene. The SLC2A10 gene creates (encodes) a protein known as facilitative glucose transporter 10 (GLUT10) that regulates the transport of sugars (i.e., glucose) and dehydroascorbic acid (DAA), the oxidized form of vitamin C, across cellular membranes. Mutation(s) in SLC2A10 lead to low levels of functional GLUT10 protein in ATS patients. Although the pathogenic mechanism underlying all the SLC2A10 mutations is the loss of GLUT10 function, the specific role of the GLUT10 transporter in the pathogenesis of ATS is still debated.
Mutations in the SLC2A10 gene are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
In 2015, a study, performed on skin fibroblasts (a type of cell found in connective tissue that synthesizes the extracellular matrix, collagens, and other proteins) derived from ATS patients, showed that the lack of GLUT10 protein perturbs the canonical transforming growth factor-beta (TGFβ) pathway and causes the disorganization of different structural proteins (i.e., collagens, elastin, fibronectin, decorin), essential for the structural integrity of several connective tissues including blood vessels wall. In addition, molecular findings, obtained by analyzing all mRNAs in skin fibroblasts of different ATS patients, revealed that the lack of GLUT10 alters TGFβ signaling, extracellular matrix integrity, expression of genes that influence the lipid metabolism, and is related to the cellular response against the oxidative stress (maintenance of intracellular redox homeostasis).
Moreover, in 2016 it was demonstrated that the GLUT10 is able to transport DAA across cellular endomembranes system (i.e., endoplasmic reticulum, and nuclear envelope). DAA is the oxidized form of vitamin C (ascorbic acid). Vitamin C is an essential nutrient for humans that acts both as a potent antioxidant, which protects cells from oxidative damage by acting as a scavenger of different free radicals, and as a cofactor essential for the function of enzymes (proteins) that are involved in the synthesis (production) of collagen and elastin proteins. The exact manner in which deficient levels of GLUT10 result in the signs and symptoms of ATS is not fully understood, but it is speculated that the decrease of vitamin C inside the cells lacking GLUT10 leads to the altered production of collagen and elastin, the main structural components of the extracellular matrix of connective tissues and of blood vessels, thus affecting the structural integrity of the wall of the main arteries (i.e., aorta, pulmonary arteries).
Finally, in 2019 it was demonstrated that the decreased nuclear ascorbate accumulation in dermal fibroblasts from ATS patients is accompanied by an altered genomic methylation pattern, strongly suggesting an epigenetic role of ascorbic acid transport in the disease pathomechanism. In view of all these observations, ATS is considered an ascorbate compartmentalization disorder.
Diagnosis
A diagnosis of ATS is based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests and SLC2A10 gene molecular analysis.
Microscopic (histologic) examination of affected arteries can reveal disruption of elastic fibers of affected arterial walls.
A diagnosis of ATS requires a variety of specialized tests to assess the extent of the disease. Such tests include echocardiography, angiography, magnetic resonance angiography (MRA), and computed tomography (CT) scan. During echocardiography, sound waves are bounced off the heart (echoes), enabling physicians to study cardiac function and motion. Angiographies are traditional x-rays designed to evaluate the health and function of blood vessels. An MRA is done with the same equipment use for magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular structures or tissues within the body. An MRA provides detailed information about blood vessels. In some cases, before the scan, an intravenous line is inserted into a vein to release a special dye (contrast). This contrast highlights the blood vessels, thereby enhancing the results of the scan. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.
Molecular genetic testing confirms or excludes a diagnosis of ATS. Molecular genetic testing can detect mutations in the SLC2A10 gene known to cause the disorder but is available only as a diagnostic service at specialized laboratories.
Treatment
The treatment of arterial tortuosity syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dermatologists, neurologists, cardiologists, neurologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Based on a literature review, complications have rarely been observed during cardiovascular surgery in ATS patients, and the risk of fatal events should be similar to the general population.
Other treatment is symptomatic and supportive and can include surgery to repair hernias, skeletal malformations, or intestinal diverticula.
Obstetric aspects of ATS have not been elucidated, to date in literature are reported 4 ATS women with successful pregnancy and uncomplicated deliveries. These data suggest that in ATS, pregnancy can be safely handled with multidisciplinary management including close maternal and fetal surveillance.
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