MFS results from pathogenic variants in FBN1, which encodes fibrillin-1, a component of microfibrils that link the elastic lamellae to cell surface receptors on the SMCs. HTAD was initially identified and characterized in individuals with Marfan syndrome (MfS) and relatively recently in individuals with Loeys-Dietz syndrome (LDS). Additionally, clinical heterogeneity is evident based on additional features co-segregating with TAAD in these families, which can include intracranial aneurysms, aneurysms, dissections/ruptures in other arteries, occlusive vascular diseases leading to early-onset strokes and coronary artery disease, BAV, and patent ductus arteriosus (PDA). 5 families with HTAD demonstrate variable expression of TAAD, including age of disease onset, risk for dissection at a small aortic diameter, risk for type A versus type B dissections, and the formation of aortic aneurysms of the aortic root, the ascending aorta, or both. 3, 4 TAAD in these families is typically inherited in an autosomal dominant manner with decreased penetrance, particularly in women, indicating that heterozygous pathogenic variants, in a particular gene are responsible for the heritable thoracic aortic disease (HTAD). Our studies, along with others, established that up to 20% of all TAAD patients have similarly affected first-degree relatives, indicating a significant genetic predisposition to TAAD. Heritable thoracic aortic disease (HTAD): rare variants in genes that confer a high risk for thoracic aortic disease This review provides an update on our current understanding of the genetic basis of TAAD and how this information impacts clinical care. However, common variants with large effects are rare and rare variants with small effects are difficult to identify. The frequency of a genetic change in the population ( e.g., allele frequency) and effect size ( e.g., risk for thoracic aortic disease) are generally inversely related, with rare variants having large effects e.g., mutations also termed pathogenic variants) and common variants conferring small effects. 1, 3 The genetic risk for TAAD extends from rare and highly penetrant genetic variants that trigger disease in all individuals who inherit the alteration ( e.g., Marfan Syndrome due to FBN1 mutations) to common variants found in the general population that confer only a minimal risk for disease (variants identified in genome wide association studies ). Additional risk factors include bicuspid aortic valve (BAV), male sex, increasing age, inflammatory and infectious conditions, and pregnancy. Therefore, biomarkers are needed to identify individuals at risk for thoracic aortic disease and inform the timing of surgery to prevent dissections.Īlong with genetic variants, the major risk factors for TAAD are increased biomechanical forces on the aorta, primarily due to hypertension and activities or drug use that increase force on the aorta ( e.g., cocaine or methamphetamine abuse, weightlifting). 2 Thus, success of this treatment approach relies on identifying at-risk individuals early in the disease process, prior to dissection to establish appropriate timing for repair of the aorta. surgical repair is typically recommended when the aneurysm’s diameter reaches 5.0–5.5 cm however, studies on patients presenting with acute type A dissections indicate that up to 60% present with aortic diameters smaller than 5.5 cm. Although medical treatments can slow the rate of aneurysm growth, the mainstay of treatment to prevent type A aortic dissection-related deaths is prophylactic surgical repair of the ascending aneurysm. 1 Less-deadly aortic dissections originating in the descending thoracic aorta just distal to the branching of the subclavian artery (type B dissections) are also part of the thoracic aortic disease spectrum. Type A dissections cause sudden death in up to 40% of afflicted individuals, with an increase in mortality of 1% per hour after dissection and 5% to 20% dying during or shortly after emergent surgical repair of the aorta. 1 The natural history of thoracic aortic aneurysms, involving the aortic root and ascending aorta, is to asymptomatically enlarge over time until an acute tear in the intimal layer leads to an ascending aortic dissection (Stanford classification type A dissection). The major diseases affecting the thoracic aorta are aneurysms and acute dissections (TAAD).
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |