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Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited. Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed. Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK. These data further define the aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.

The purpose of this study is to evaluate the diagnostic and therapeutic yield of a specialized clinic for children with suspicion of a hereditary thoracic aortic disease (HTAD), including Marfan Syndrome (MFS), and to investigate the diagnostic value of presenting symptoms and findings during evaluation. This retrospective observational study included all patients younger than 18 years old at initial referral between 1998 and 2018. Clinical data, medical treatment, surgical interventions, and clinical events during surveillance were collected until December 2023. A case-control comparison between patients with and without an eventual diagnosis of HTAD was performed using logistic regression analysis to investigate the diagnostic value of collected variables. A total of 355 children were referred and evaluated at the clinic, resulting in 89 new diagnoses, with a diagnostic yield of 21% HTAD, including 59 cases of MFS. Younger age at referral, ectopia lentis, aortic dilatation, and facial features were among the strongest predictors of MFS and other HTAD, while pectus excavatum and arm span-height ratio had no predictive value at childhood age. Of patients with MFS, 65% received antihypertensive medication, and 8% of patients with HTAD underwent prophylactic aortic surgery, in some cases even during childhood. Conclusion : Evaluation of children for HTAD in our specialized Marfan clinic resulted in a high diagnostic yield and subsequent therapeutic implications. Indeed, early recognition of symptoms and signs and referral to such a specialized clinic may lead to early diagnosis, surveillance, and timely treatment, thereby possibly limiting acute aortic events and even mortality.

Background There is a lack of data regarding the use of hybrid stent graft prostheses in patients with hereditary thoracic aortic disease (HTAD) involving the aortic arch and proximal descending aorta. This retrospective analysis aimed to evaluate the short- and mid-term outcomes of hybrid stent-graft prostheses in Frozen Elephant Trunk (FET) procedures for patients with HTAD, with a particular focus on its safety and feasibility. Methods A total 280 patients who underwent FET procedures between October 2010 and November 2024 were retrospectively analysed in compliance with the 2024 EACTS/ STS recommendations for shared decision-making within the multidisciplinary aortic team. Among them, 51 patients had genetically confirmed HTAD (Marfan syndrome (FBN1), Loeys-Dietz syndrome (TGFBR1, TGFBR2, SMAD3, TGFB2), vascular Ehlers-Danlos syndrome (COLSA1), and non-syndromic HTAD (ACTA2, MYH11, MYLK)). The Thoraflex™ prosthesis was implanted in 50 of the 51 patients. Short- and mid-term outcomes were assessed descriptively. Survival and subsequent thoracic aortic intervention rates were analysed using the Kaplan-Meier method. Results The overall 30-day mortality was 2.0% ( n  = 1). Perioperatively, permanent neurological deficit was 3.9% ( n  = 2), with minor disability on the modified Rankin Scale (mRS 1 and 2). There were no instances of paraplegia. The median follow-up was 4.0 years. The 1-, 3- and 5-year overall survival rate was 93.9%, 90.6%, and 90.6%, respectively. Freedom from subsequent aortic interventions was at 1, 3, 5 years 55.8%, 45.6%, and 33.1%. Early device-related complications occurred in 7 patients (13.7%), including intraluminal FET thrombosis in 4 patients (12.5%) and distal stent graft-induced new entry in 3 patients (9.4%). Mid-term device-related complications occurred 2 patients (4.3%). Conclusions Hybrid stent graft prostheses can be safely implanted with the FET technique in elective and acute HTAD patients with arch and proximal descending aortic disease. Our single-center short- and mid-term outcomes are encouraging, but long-term durability and efficacy are not yet established. This warrants multi-center studies with extended follow-up.

Purpose Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle–dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. Methods Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. Results All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. Conclusion Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.

Hereditary thoracic aorta diseases (HTADs) are a heterogeneous group of rare disorders whose major manifestation is represented by aneurysm and/or dissection frequently located at the level of the ascending thoracic aorta. The diseases have an insidious evolution and can be encountered as an isolated manifestation or can also be associated with systemic, extra-aortic manifestations (syndromic HTADs). Along with the development of molecular testing technologies, important progress has been made in deciphering the heterogeneous etiology of HTADs. The aim of this study is to identify the genetic variants associated with a group of patients who presented clinical signs suggestive of a syndromic form of HTAD. Genetic testing based on next-generation sequencing (NGS) technology was performed using a gene panel (Illumina TruSight Cardio Sequencing Panel) or whole exome sequencing (WES). In the majority of cases (8/10), de novo mutations in the FBN1 gene were detected and correlated with the Marfan syndrome phenotype. In another case, a known mutation in the TGFBR2 gene associated with Loeys–Dietz syndrome was detected. Two other pathogenic heterozygous variants (one de novo and the other a known mutation) in the SLC2A10 gene (compound heterozygous genotype) were identified in a patient diagnosed with arterial tortuosity syndrome (ATORS). We presented the genotype–phenotype correlations, especially related to the clinical evolution, highlighting the particularities of each patient in a family context. We also emphasized the importance of genetic testing and patient monitoring to avoid acute aortic events.

Thoracic aortic aneurysms (TAAs) are potentially devastating, and due to their asymptomatic behavior, pose a serious health risk characterized by the lack of medical treatment options and high rates of surgical morbidity and mortality. Independent of the inciting stimuli (biochemical/mechanical), TAA development proceeds by a multifactorial process influenced by both cellular and extracellular mechanisms, resulting in alterations of the structure and composition of the vascular extracellular matrix (ECM). While the role of enhanced ECM proteolysis in TAA formation remains undisputed, little attention has been focused on the upstream signaling events that drive the remodeling process. Recent evidence highlighting the dysregulation of transforming growth factor-β (TGF-β) signaling in ascending TAAs from Marfan syndrome patients has stimulated an interest in this intracellular signaling pathway. However, paradoxical discoveries have implicated both enhanced TGF-β signaling and loss of function TGF-β receptor mutations, in aneurysm formation; obfuscating a clear functional role for TGF-β in aneurysm development. In an effort to elucidate this subject, TGF-β signaling and its role in vascular remodeling and pathology will be reviewed, with the aim of identifying potential mechanisms of how TGF-β signaling may contribute to the formation and progression of TAA.

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 ACTA2R179H and TGFBR2G357W 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.

Beals-Hecht (BH) syndrome is a rare autosomal dominant disorder caused by a mutation of the FBN-2 gene that codifies for fibrillin-2 (FBN-2). Its nosology includes congenital contractural arachnodactyly. The aim of this study was to evaluate the possible breakdown of redox homeostasis in the thoracic aortic aneurysm (TAA) from patients with BH. We determined OS markers such as malondialdehyde (MDA), total antioxidant capacity (TAC), carbonyl groups, glutathione (GSH), thiols the nitrate/nitrite ratio (NO 3 − /NO 2 − ) and super oxide radical (O 2 – ) by spectrophotometry in homogenized TAA from BH and the ascending fragment of the thoracic aorta (AFTA) from control subjects (CS). We also measured the activities of some of antioxidant enzymes such as GST, GPx, GR and TrxR. The super oxide dismutase (SOD) isoforms, catalase and peroxidase activities were evaluated by native polyacrylamide gels. The activities of the antioxidant enzymes GPx, TrxR, SOD isoforms, catalase and peroxidases were decreased in the TAA from patients with BH ( p  ≤ 0.04) and the OS markers NO 3 − /NO 2 − , TAC and thiols were decreased( p  ≤ 0.04). In addition, O 2 – was increased in patients with BH ( p  = 0.02). The results suggest a possible loss of redox homeostasis; this loss could be due to the decrease of some of the enzymatic antioxidant system´s enzymes and some antioxidants of the non-enzymatic system. In addition, the decrease in TrxR activity and the concentration of thiol groups could contribute to the alteration and instability of the FBN-2 protein.

Heritable thoracic aortic aneurysms are complex conditions characterised by the dilation or rupture of the thoracic aorta, often occurring as an autosomal-dominant disorder associated with life-threatening complications. In this case report, we present a de novo variant, MFAP5 c.236_237insA (p.N79Kfs9), which is implicated in the development of inherited thoracic aortic aneurysm. The proband, a 15-year-old male, presented with recurrent cough, dull chest pain, chest distress, vomiting, and reduced activity tolerance, leading to the diagnosis of heritable thoracic aortic aneurysms. Whole-exome sequencing identified a novel heterozygous variant in MFAP5 (NM_003480, c.236_237insA, and p.N79Kfs9). MutationTester and PolyPhen-s predicted this variant to be damaging and disease-causing (probability = 1), while the SFIT score indicated protein damage (0.001). Structural analysis using the AlphaFold Protein structure database revealed that this mutation disrupted the N-linked glycosylation site, resulting in a frameshift, amino acid sequence alteration, and truncation of an essential protein site. To our knowledge, this is the first case report describing a young patient with heritable thoracic aortic aneurysm carrying the novel MFAP5 c.236_237insA (p.N79Kfs*9) variant. This variant represents the third identified mutation site associated with heritable thoracic aortic aneurysm. Given the high mortality and morbidity rates associated with thoracic aortic aneurysms, the prevention of severe and fatal complications is crucial in the clinical management of this condition. Our case highlights the importance of whole-exome sequencing and genetic screening in identifying potential pathogenic or likely pathogenic variants, particularly in early-onset patients with aortic dilation, to inform appropriate management strategies.

Central cysts of the iris pigment epithelium, or iris flocculi, are frequently reported in the literature in association with thoracic aortic aneurysm and dissection due to smooth muscle alpha-actin 2 ( ) mutations. Children with mutations may also present with congenital mydriasis. We report our experience regarding the frequency of mutation in children with the above iris anomalies. This is a retrospective, consecutive case series of all children presenting for iris flocculi or congenital mydriasis at a single tertiary centre from October 2012 to December 2016. 13 children with iris flocculi and 3 with congenital mydriasis presented during the study period. 10 children with iris flocculi completed genetic testing, and none were positive for mutation. All children with congenital mydriasis presented with a multisystem smooth muscle dysfunction syndrome; two of these three children tested positive for missense R179 mutations. In this series, mutation or copy number variation was not detected in children presenting for iris flocculi, whereas congenital mydriasis was associated with R179 mutation in both cases that tested positive for mutation. The case of congenital mydriasis without typical cardiac features of the R179 phenotype or intracranial vasculopathy was negative for mutation. While all children presenting with these iris anomalies should be offered a genetic evaluation, incidence data should inform genetic counselling, particularly in the absence of a family history of aneurysm or sudden death, or systemic signs of smooth muscle dysfunction.