Search Results (135)

Autosomal recessive types of both syndromic and non-syndromic inherited myopia are common in Saudi Arabia (SA) because many people marry their relatives. The prevalence of syndromic myopathies in SA, like Stickler syndrome (SS), Knobloch syndrome (KS), and Marfan syndrome (MFS), further complicates the disease spectrum. The causative genes linked to the Knobloch, Marfan, and Pierson syndromes are COL18A1, FBN1, and LAMB2, respectively. Additionally, we found recessive types of non-syndromic high myopia that have a high chance of causing retinal detachment, like those linked to LRPAP1 and LEPREL1. In these cases, regular evaluation and early intervention, including prophylactic laser photocoagulation and pars plana vitrectomy, may improve the outcome. Advancements in genetic testing for diagnosis and prevention accelerate detection, facilitate early interventions, and provide genetic counseling. The utilization of artificial intelligence (AI), machine learning (ML), and the advancement of gene therapy offer promising avenues for personalized care. We place a high value on using genetic knowledge to create a national screening program and patient registry aimed at understanding the national burden of myopia, knowing that we have a high rate of consanguinity, which reflects pathogenic homozygous alleles and founder mutations. This initiative will incorporate genetic counseling and leverage innovative technologies, which are crucial for disease management, early identification, and prevention in Saudi Arabia’s healthcare system. Full article

Background: The PATHFINDER-CHD Registry is a prospective, multicenter, non-interventional registry across tertiary care centers in Germany. The aim is to analyze real-world data on adults with congenital heart defects (ACHD) or hereditary connective tissue disorders who have manifest heart failure (HF), a history of HF, or are at significant risk of developing HF. This analysis investigates the prevalence and clinical impact of overweight and obesity in this unique population. Methods: As of 1st February, 2025, a total of 1490 ACHD had been enrolled. The mean age was 39.4 ± 12.4 years, and 47.9% were female. Patients were categorized according to Perloff’s functional class and the Munich Heart Failure Classification for Congenital Heart Disease (MUC-HF-Class). Results: The most common congenital heart disease (CHD) in this cohort was Tetralogy of Fallot, transposition of the great arteries, and congenital aortic valve disease. Marfan syndrome was the most common hereditary connective tissue disease. Of the patients, 46.1% were classified as overweight (32.8%) or obese (13.3%), while 4.8% were underweight. The highest prevalence of overweight (47.1%) was observed among patients who had undergone palliative surgery, whereas untreated patients showed the highest proportion of normal weight (57.2%). Cyanotic patients were predominantly of normal weight. Patients with univentricular circulation exhibited significantly lower rates of overweight and obesity (35%; p = 0.001). Overweight and obesity were statistically significantly associated with arterial hypertension, diabetes mellitus, and sleep apnea (all p < 0.001). High BMI was linked to increased use of HF-specific medications, including SGLT2 inhibitors (p = 0.040), diuretics (p = 0.014), and angiotensin receptor blockers (p = 0.005). Conclusions: The data highlight the clinical relevance of overweight and obesity in ACHD with HF, emphasizing the need for individualized prevention and treatment strategies. The registry serves as a critical foundation for the optimization of long-term care in this population. Full article

Mitral annular calcification (MAC) is usually considered an incidental, benign, age-related finding without serious complications in patients evaluated for cardiovascular or pulmonary disease with imaging studies that may result in mitral regurgitation or stenosis when severe. Therefore, it is usually not considered a significant alteration. However, there is accumulating evidence that it is associated with a higher risk of cardiovascular events, such as atherosclerotic coronary artery disease, aortic artery disease, carotid artery disease, peripheral artery disease, stroke, atrial fibrillation, atrioventricular and/or intraventricular conduction disturbance, systemic embolization, infective endocarditis, heart failure and mortality. The presence of MAC also significantly influences the outcome of mitral valve transcatheter and surgical interventions. Several conditions may predispose to MAC. MAC is strongly related to cardiovascular risk factors, such as hypertension, diabetes, smoking and cardiovascular atherosclerosis, and inflammation may also play a role in the pathogenesis of MAC. Also, conditions that increase mitral valve stress, such as hypertension, aortic stenosis and hypertrophic cardiomyopathy, predispose to accelerated degenerative calcification of the mitral annulus area. Congenital disorders, e.g., Marfan syndrome and Hurler syndrome, are also associated with MAC, due to an intrinsic abnormality of the connective tissue composing the annulus. Full article

Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging evidence suggests the key role of mitochondrial dysfunction. Here, we show that the overexpression of ACTA2^R179H and TGFBR2^G357W in murine aortic VSMCs reduces Mitochondrial Transcription Factor A (Tfam) expression, decreases mitochondrial DNA (mtDNA) content, and impairs oxidative phosphorylation, shifting metabolism toward glycolysis. Notably, nicotinamide riboside, a NAD⁺ precursor, restores mitochondrial respiration, increases Tfam and mtDNA levels, and promotes a contractile phenotype by enhancing actin polymerization and reducing matrix metalloproteinase activity. These findings identify mitochondrial dysfunction as a shared feature in hereditary thoracic aortic aneurysm, not only in Marfan syndrome, but also in other genetic forms, and highlight mitochondrial boosters as a potential therapeutic strategy. Full article

Marfan syndrome is caused by a mutation in the FBN1 gene encoding fibrillin-1. This extracellular matrix glycoprotein, which assembles into microfibrils, is best known for its scaffolding role in the production of elastic fibers responsible for connective tissue elasticity and tensile strength. Research into Marfan syndrome mainly focuses on the pathophysiology involved in the degeneration of elastin-rich elastic fibers, which are essential components of the aortic wall. However, fibrillin-1 also exists in elastin-poor (elaunin) or elastin-free (oxytalan) microfibril bundles that were first described in the periodontal ligament (PDL). This dynamic, densely cellular, and highly vascularized tissue anchors teeth in their bone sockets and acts as a protective shock absorber during chewing. Current knowledge suggests that fibrillin microfibrils mechanically support blood vessels in the PDL and ensure their proper functioning. However, many more insights on the roles of fibrillin, especially independently of elastin, can be extracted from this tissue. Here, we review the phenotypic and functional characteristics of the PDL in connection with fibrillin-1, focusing on those related to microvessels. This review aims to shed light on this often-overlooked fibrillin-rich resource as a model for future studies investigating fibrillin functions in health and Marfan disease. Full article

Thoracic aortic aneurysms (TAAs) pose a significant health burden due to their asymptomatic progression, often culminating in life-threatening aortic rupture, and due to the lack of effective pharmacological treatments. Risk factors include elevated hemodynamic stress on the ascending aorta, frequently associated with hypertension and hereditary genetic mutations. Among the hereditary causes, Marfan syndrome is the most prevalent, characterized as a connective tissue disorder driven by FBN1 mutations that lead to life-threatening thoracic aortic ruptures. Similarly, mutations affecting the TGF-β pathway underlie Loeys–Dietz syndrome, while mutations in genes encoding extracellular or contractile apparatus proteins, such as ACTA2, are linked to non-syndromic familial TAA. Despite differences in genetic origin, these hereditary conditions share central pathophysiological features, including aortic medial degeneration, smooth muscle cell dysfunction, and extracellular remodeling, which collectively weaken the aortic wall. Recent evidence highlights mitochondrial dysfunction as a crucial contributor to aneurysm formation in Marfan syndrome. Disruption of the extracellular matrix–mitochondrial homeostasis axis exacerbates aortic wall remodeling, further promoting aneurysm development. Beyond its structural role in maintaining vascular integrity, the ECM plays a pivotal role in supporting mitochondrial function. This intricate relationship between extracellular matrix integrity and mitochondrial homeostasis reveals a novel dimension of TAA pathophysiology, extending beyond established paradigms of extracellular matrix remodeling and smooth muscle cell dysfunction. This review summarizes mitochondrial dysfunction as a potential unifying mechanism in hereditary TAA and explores how understanding mitochondrial dysfunction, in conjunction with established mechanisms of TAA pathogenesis, opens new avenues for developing targeted treatments to address these life-threatening conditions. Mitochondrial boosters could represent a new clinical opportunity for patients with hereditary TAA. Full article

Marfan syndrome (MFS) is an inherited connective tissue disorder, with aortic root aneurysm and/or dissection being the most severe and life-threatening complication. These conditions have been linked to pathogenic variants in the FBN1 gene and dysregulated TGFβ signaling. Our objective was to evaluate the mRNA expression of FBN1, TGFBR1, TGFBR2, and TGFB2 in aortic tissue from MFS patients undergoing surgery for aortic dilation. This prospective study (2014–2023) included 20 MFS patients diagnosed according to the 2010 Ghent criteria, who underwent surgery for aneurysm or dissection based on Heart Team recommendations, along with 20 non-MFS controls. RNA was extracted, and mRNA levels were quantified using RT-qPCR. Patients with dissection showed significantly higher FBN1 mRNA levels [79 (48.1–110.1)] compared to controls [37.2 (25.1–79)] (p = 0.03). Conversely, TGFB2 expression was significantly lower in MFS patients [12.17 (6.54–24.70)] than in controls [44.29 (25.85–85.36)] (p = 0.029). A positive correlation was observed between higher FBN1 expression and a larger sinotubular junction diameter (r = 0.42, p = 0.07), while increased FBN1 expression was particularly evident in MFS patients with dissection. Additionally, TGFB2 expression showed an inverse correlation with ascending aortic diameter (r = 0.53, p = 0.01). In aortic tissue, we found decreased TGFB2 and receptor levels alongside increased FBN1 mRNA levels. These molecular alterations may reflect compensatory mechanisms in response to tissue damage caused by mechanical stress, leading to dysregulation of physiological signaling pathways and ultimately contributing to aortic dilation in MFS. Full article

Background: Pathogenic variants within the gene encoding transforming growth factor β (TGF-β) are responsible for Loeys-Dietz syndrome (LDS), a heritable thoracic aortic disease sharing clinical features with Marfan syndrome, including craniofacial and skeletal abnormalities as well as aortic root aneurysms and dissections. In contrast to Marfan syndrome patients, who rarely develop aneurysms or dissections beyond the aortic root, LDS patients frequently exhibit vessel aneurysms in locations other than the aortic root. Here, we report the case of a 61-year-old patient who initially presented with marfanoid characteristics and an aortic root aneurysm and was presumed to have Marfan syndrome two decades ago. Later, the patient developed an abdominal aorta aneurysm, necessitating endovascular repair and stent placement. That fact raised doubts regarding the initial diagnosis of Marfan syndrome, and we decided to investigate the genetic cause of the disorder. Methods: Genetic testing was performed using WES analysis and Sanger sequencing. Results: The genetic analysis detected a de novo heterozygous pathogenic variant c.896G>A in exon 5 of the TGFB2 gene, resulting in the amino acid substitution p. Arg299Gln that has devastating destabilizing structural effects on 3D folding of the protein, as demonstrated by the molecular modeling study we performed. This variant is pathogenic for LDS type 4, partially consistent with the patient’s clinical presentation. Conclusions: Our case emphasizes the significance of precise clinical assessment and genetic verification in patients exhibiting marfanoid characteristics. Furthermore, our findings contribute to the understanding of the diverse clinical spectrum associated with this specific pathogenic variant of TGFB2, underscoring the importance of detailed clinical assessment in expanding knowledge of genotype-phenotype correlations. Accurate diagnosis is crucial for tailored and appropriate management of individuals with heritable thoracic aortic diseases. Full article

Background: Cerebral protection during aortic surgery is crucial for improving surgical outcomes and reducing neurological complications. Selective antegrade cerebral perfusion (SACP) is increasingly used, and innominate artery (IA) side graft cannulation presents an innovative alternative to conventional axillary artery cannulation, with the potential to reduce complications associated with the latter. Methods: In this retrospective study, 196 patients who underwent proximal aortic surgery with IA graft cannulation for SACP between January 2021 and June 2024 were analyzed. Demographic data, intraoperative parameters, and postoperative outcomes were evaluated. Complications such as new stroke, postoperative delirium, mortality, and acute renal failure (ARF) were assessed. Results: The median age of the patients was 63 years, and 18.37% underwent emergency surgery for Type A acute aortic dissection (TAAAD). The most frequently performed surgical procedure was ascending aorta and hemiarch replacement (36.74%). The median cardiopulmonary bypass, cross-clamp, and SACP durations were 120.5, 93, and 23 min, respectively. The postoperative mortality rate was 3.06%, stroke rate was 2.04%, delirium rate was 9.18%, and ARF rate was 3.06%. All cases of delirium resolved spontaneously within 2–3 days. The mortality rate among Marfan syndrome (MFS) patients was 4.35%, with no reported stroke cases in this group. Conclusions: IA graft cannulation is a safe and effective method for providing SACP in aortic surgery, particularly in high-risk patient groups such as those with TAAAD and MFS. This technique ensures optimal cerebral perfusion, minimizes neurological and systemic complications, and enhances surgical efficiency by reducing operative duration. However, large-scale, multicenter, and prospective studies are needed to evaluate its long-term efficacy and safety. Full article

Background: Marfan syndrome (MFS) is a rare autosomal dominant disorder affecting connective tissues due to mutations in the fibrillin-1 gene. These genetic changes often result in severe cardiovascular conditions, including asymptomatic thoracic aortic dilation potentially leading to dissection or rupture. Perivascular adipose tissue attenuation (PVAT) observed on computed tomography may serve as a marker of localized inflammation and indicate early histopathological changes in the vascular walls of MFS patients compared to healthy individuals. Objective: This study aimed to compare PVAT values between patients with MFS and healthy controls in order to explore whether MFS patients show higher PVAT secondary to these histopathological abnormalities. Methods: This case–control study assessed PVAT on ascending aorta through computed tomography angiography (CTA) in 54 genetically confirmed MFS patients and 43 controls with low ischemic risk, excluding those with known aortic aneurysms. Results: PVAT analysis revealed significant differences between the MFS patients and healthy controls (−70.6 HU [−72.6 HU to −68.5 HU] versus −75.1 HU [−77.1 HU to −73.1 HU], p = 0.002), suggesting potential early vascular changes in the MFS group. Conclusions: The findings underscore the potential diagnostic role of PVAT in patients with genetically confirmed MFS but normal ascending aorta diameter. Full article

Marfan syndrome (MFS) is a genetic disorder that affects the connective tissue in several systems, with ocular, cardiovascular, and skeletal system manifestations. Its ocular manifestations include ectopia lentis (EL), myopia, astigmatism, and corneal abnormalities. This review examines refractive alterations related to MFS such as EL, microspherophakia, lens coloboma, altered corneal biomechanics (flattening, thinning, and astigmatism), and myopia and their impact on visual acuity. The pathogenesis of these manifestations stems from mutations in the FBN1 gene (encoding fibrillin-1). Moreover, the current medical and surgical management strategies for MFS-related refractive errors, including optical correction (eyeglasses, contact lenses, etc.), and surgical interventions like lensectomy, intraocular lens (IOL) implantation (anterior chamber, posterior chamber, scleral-fixated, iris-fixated), and the use of capsular tension rings/segments are further discussed. Considering the likelihood of underdiagnosing and underestimating ocular involvement in MFS, this updated review highlights the critical need to identify and address these refractive issues to enhance the visual outcomes for those affected. Full article

Introduction: Marfan syndrome (MFS) is an autosomal dominant genetic disorder, caused by a mutation in the FBN-1 gene, affecting the cardiovascular, musculoskeletal, ocular, and central nervous systems. Cardiovascular abnormalities associated with MFS lead to different pathological conditions, such as cardiac arrhythmias, coronary artery disease, and aortic dilatation. The latter are the primary causes of mortality in MFS patients. To date, the role of altered oral microbiota (OM) in MFS is unknown, and so the aim of our study was to determine whether there are differences in the oral microbiota of MFS patients with aortic dilatation and non-dilatation. Methods: We enrolled 36 MFS patients, who were divided into groups with aortic non-dilatation (n = 12) and with aortic dilatation (n = 24). Dental plaque samples were used for OM analysis, and serum was used for cytokine evaluation. Results: The main genera were compared between patients with aortic dilatation and non-dilatation, revealing three genera with significant differences: Actinomyces (p = 0.007) and Rothia (p = 0.002) were more abundant in those with aortic dilatation, while Fusobacterium (p = 0.044) was more abundant in non-dilatation patients. However, no significant differences in cytokine levels were observed between the presence and absence of aortic dilatation, except that the IL-1β levels were higher in non-dilatation patients (165.09 pg/mL) than in those with dilatation (117.15 pg/mL), with a significance of p = 0.057. Conclusions: This study represents the initial, tentative pilot study to understand the relationship between oral health and systemic conditions in patients with Marfan syndrome. Full article

Normal development of joints starts in utero with the establishment of a cellular and extracellular matrix template. Following birth, individual joint tissues grow and mature in response to biochemical and mechanical signals, leading to a coordinated pattern of further maturation resulting in a joint that functions as an organ system. Each joint develops and matures as an organ system defined by the biomechanical environment in which it will function. For those with joint hypermobility syndromes, either defined by specific genetic mutations or not (i.e., Ehlers–Danlos syndrome, Marfan syndrome, Loey–Dietz syndrome, hypermobility-type Ehlers–Danlos syndrome), this process is partially compromised, but many aspects of joint tissue maturation and resulting joint function is retained such that the organs form and retain partial function, but it is compromised. Comparing the characteristics of what is known regarding development, growth, maturation, and response to stressors such as puberty, pregnancy, and aging in joints of those without and with joint hypermobility leads to the conclusion that in those that have hypermobility syndromes, the joint systems may be compromised via a failure to undergo mechanical maturation, possibly via defective mechanotransduction. Given the breadth of the mutations involved in such hypermobility syndromes, further characterization of this concept may reveal commonalities in their impact on tissue maturation, which will further inform regulatory aspects of normal tissue and functional integrity. This review/perspective piece will attempt to detail such comparisons and summarize how further study will aid in further understanding. Full article

Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, often leading to cardiovascular complications such as aortic aneurysms and mitral valve prolapse. Cardiovascular multimodality imaging plays a crucial role in the diagnosis, monitoring, and management of MFS patients. This review explores the advancements in echocardiography, cardiovascular magnetic resonance (CMR), cardiac computed tomography (CCT), and nuclear medicine techniques in MFS. Echocardiography remains the first-line tool, essential for assessing aortic root, mitral valve abnormalities, and cardiac function. CMR provides detailed anatomical and functional assessments without radiation exposure, making it ideal for long-term follow-up. CT offers high-resolution imaging of the aorta, crucial for surgical planning, despite its ionizing radiation. Emerging nuclear medicine techniques, though less common, show promise in evaluating myocardial involvement and inflammatory conditions. This review underscores the importance of a comprehensive imaging approach to improve outcomes and guide interventions in MFS patients. It also introduces novel aspects of multimodality approaches, emphasizing their impact on early detection and management of cardiovascular complications in MFS. Full article

Thoracoabdominal aortic aneurysms (TAAAs) are rare but serious conditions characterized by dilation of the aorta characterized by remodeling of the vessel wall, with changes in the elastin and collagen content. Individuals with Marfan syndrome have a genetic predisposition for elastic fiber fragmentation and elastin degradation and are prone to early aneurysm formation and progression. Our objective was to analyze the medial collagen characteristics through histological, polarized light microscopy, and electron microscopy methods across the thoracic and abdominal aorta in twenty-five patients undergoing open surgical repair, including nine with Marfan syndrome. While age at surgery differed significantly between the groups, maximum aortic diameter and aneurysm extent did not. Collagen content increased from thoracic to infrarenal segments in both cohorts, with non-Marfan patients exhibiting higher collagen percentages, notably in the infrarenal aorta (729.3 nm vs. 1068.3 nm, p = 0.02). Both groups predominantly displayed mature collagen fibers, with the suprarenal segment containing the highest proportion of less mature fibers. Electron microscopy revealed comparable collagen fibril diameters across segments irrespective of Marfan status. Our findings underscore non-uniform histological patterns in TAAAs and suggest that ECM remodeling involves mature collagen deposition, albeit with lower collagen content observed in the infrarenal aorta of Marfan patients. Full article