Familial Aneurysms Research Articles

Whole aorta imaging shows increased risk for thoracic aortic aneurysms and dilatations in relatives of abdominal aortic aneurysm patients

ObjectiveFor relatives of abdominal aortic aneurysm (AAA) patients, guidelines recommend abdominal imaging aimed at early detection and management of AAA, and do not include screening for thoracic aortic aneurysms (TAA). We aimed to investigate if TAA occur in undiagnosed relatives of AAA patients without a known genetic susceptibility for aneurysms, similar to families with identified genetic susceptibilities for aneurysms like in Marfan and Loeys-Dietz syndrome, where both AAA and TAA occur. MethodsRelatives of AAA patients were invited for non-contrast whole aorta CT screening. Systematic measurements of the CT scans were used to detect aneurysms and dilatations. Classification into familial and non-familial was based on reported family histories. In addition, aneurysm gene panel testing of AAA index cases was used for the classification of high vs unknown genetic risk (high genetic risk: familial aneurysm or a (likely) pathogenic variant (P/LP) in an aneurysm gene; unknown genetic risk: no family history or P/LP). ResultsWhole aorta imaging of 301 relatives of 115 abdominal aortic aneurysm index-patients with non-contrast CT scans showed a 28-fold increase in thoracic aortic aneurysms in relatives (1.7%, p<0.001 versus the age adjusted population) and a high frequency of thoracic dilatations in 18% of the relatives. Thoracic aneurysms and dilatations in relatives occurred even when index patients were unaware of familial aneurysms. AAA was increased in the relatives compared to the age adjusted population (8%, p<0.001). ConclusionsAn increased risk for thoracic aneurysms and dilatations was detected by whole aorta imaging of relatives of AAA index patients, even when index patients were unaware of familial aneurysms.These results indicate -still unknown- shared genetic susceptibilities for thoracic and abdominal aneurysms. Therefore, imaging of the whole aorta of relatives of all abdominal aneurysm patients, will improve early detection of aortic aneurysms in relatives of all AAA patients.

Association Between Intracranial Aneurysms and Genes

Ruptured intracranial aneurysm(IA) leads to aneurysmal subarachnoid hemorrhage(aSAH), which is the most severe type of stroke. Besides age, sex, and alcohol consumption, family history is considered an important risk factor. Approximately 5% of the Japanese population is affected by unruptured cerebral aneurysms. However, their developmental processes and pathologies remain unclear. Familial cerebral aneurysms account for 10% of all cerebral aneurysm cases, and somatic gene mutations are believed to be involved in their development. This review summarizes the recent findings from family-based, genome-wide association, sequencing, and somatic gene mutation studies on IA.

Surgical Management of Familial Aortic Disease

Pregnancy may increase the risk of aortic dissection in young women genetically predisposed in the third trimester and the peri-partum period. This disease must be managed with emergency. Later, aortic familial diseases must be screened in the children by genetic tests, because of the high risk of rapid developing dissection or aneurysm in the childhood, whose management is challenging. We report the cases of a pregnant woman operated for aortic dissection, and her son operated four years later for aneurysm of the ascending aorta, and aortic insufficiency. Children with familial aortic root aneurysm may have intervention of valve sparing and aortic replacement if the aortic regurgitation is minimal. But, long-term clinical and echocardiographic follow-up is mandatory.

Family History of Aortic Disease Has No Effect on Outcomes of Fenestrated-branched Endovascular Aortic Repair in Patients with Complex Aortic Aneurysms

Prior reports have indicated an increased risk of aneurysm-related complications after endovascular repair in patients with familial aortic aneurysms. The aim of this study was to evaluate outcomes of fenestrated-branched endovascular aortic repair (F-BEVAR) for the treatment of complex abdominal (CAAAs) and thoracoabdominal aortic aneurysms (TAAAs) in patients with familial history of aortic aneurysms or dissections (FAA). The clinical data of 506 consecutive patients (69% male; 74 ± 8 years old) enrolled in a prospective non-randomized study to investigate outcomes of F-BEVAR for the treatment of CAAAs and TAAAs between 2013 and 2022 was reviewed. Outcomes were analyzed in patients with FAA affecting a first or second-degree relative and compared with patients with sporadic aortic aneurysms (SAAs). Endpoints included differences in the distribution of aortic disease, procedural metrics, 30-day mortality, and major adverse events (MAEs), patient survival, and mid-term stent-graft-related outcomes. There were 68 patients (13%) with FAAs and 438 (87%) with SAAs. Both groups had similar cardiovascular risk factors, history of aortic dissection, and aneurysm extent. FAA patients had significantly (P < .05) longer fluoroscopy time (82 vs 71 minutes) and higher radiation dose (1782 vs 1210 mGy). Technical success was achieved in 94.1% of the FAA group and in 96.6% of SAA group (P = .51). Median follow-up was 19 months. There was no difference in 30-day mortality and MAEs, and long-term patient survival, freedom from aortic-related mortality, and freedom from secondary interventions. Patients with FAA had higher sac shrinkage >5mm as compared with patients with SAAs (P = .006). FB-EVAR was performed with high technical success, low mortality, and low incidence of MAEs regardless of the presence of FAAs. There was no difference in the distribution of aortic disease nor in stent graft-related outcomes.TableVariablesFAA (n = 68)SAA (n = 438)P valueAneurysm type (Crawford class)0.862 Extent I4 (8.0)23 (7.4) Extent II22 (44.0)103 (33.1) Extent III8 (16.0)47 (15.1) Infrarenal short neck0 (0.0)1 (0.2) Pararenal18 (26.5)125 (28.6)30-day mortality1 (1.5)4 (0.9)1.00030-day MAESpinal cord injury0.588 No62 (91.2)411 (94.3) Motor (able to ambulate)2 (2.9)7 (1.6) Non-ambulatory4 (5.9)18 (4.1)Myocardial infarction2 (2.9)10 (2.3)1.000Major stroke0 (0.0)3 (0.7)1.000Respiratory failure5 (7.4)12 (2.8)0.111Acute kidney injury0.016 No61 (89.7)396 (90.8) Creatinine >2 but no dialysis3 (4.4)34 (7.8) Temporary dialysis3 (4.4)2 (0.5) Permanent dialysis1 (1.5)4 (0.9)Long-term secondary intervention17 (25.4)96 (22.5)0.721Aneurysm sac behavior Stable17 (25.4)199 (47.2)0.001 Enlarged >5 mm3 (4.5)33 (7.8)0.471 Shrunk >5 mm47 (70.1)189 (44.8)<0.001Final sac diameter53.8 (14.9)59.3 (15.1)0.006FAA, Familial history of aortic aneurysms or dissections; MAE, major adverse event; SAA, sporadic aortic aneurysms.Data are presented as number (%) or mean (standard deviation).Boldface P values indicate statistical significance. Open table in a new tab

A Case of Intracranial Aneurysm Masquerading as Space-Occupying Lesion

Cerebral or intracranial aneurysms result from abnormal focal dilation of an artery in the brain due to weakening of the blood vessel wall. They occur at the bifurcations of large to medium sized intracranial arteries. Approximately 80% aneurysms occur in the anterior circulation and about 20% have multiple aneurysm sites. Familial aneurysms rupture at a smaller size and younger age than sporadic cases. We present a case of cerebral artery aneurysm in a 49-year-old female patient. The patient was admitted as a case of the intracranial space-occupying lesion with complaints of headache subsequently found to have an internal carotid artery aneurysm.

Case report: giant ascending aorta at a young age

Erina Aukščiūnienė1, Rūta Dirsienė2, Vaida Mizarienė2 1 Lithuanian University of Health Sciences, Kaunas, Lithuania 2 Department of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania Abstract Introduction: The aneurysms of the thoracic aorta are most common in the VI–VII life decade. In this case report we present a young female with an aneurysm of ascending aorta and severe aortic valve regurgitation. Case report: A 33-year-old woman with shortness of breath and other typical symptoms of the aneurysm of the aorta and a severe regurgitation of the aortic valve had underwent several tests to find the main cause of this mentioned disease. The patient was treated surgically – the David Procedure was performed, and the aortic valve was repaired. Conclusion: This case report shows that the aneurysm of ascending aorta could be present at a young age without any specific obvious predisposing factors such as congenital bicuspid aortic valve, phenotypic signs of Marfan syndrome or known familiar history. KEYWORDS: thoracic aorta aneurysm; aortic valve regurgitation; familial aneurysms syndrome.

Surgery for multiple cerebral aneurysms: Literature review and case report

We report a case of simultaneous microsurgical clipping of 5 cerebral aneurysms in a patient with multiple aneurysms of the anterior brain.We analyzed the existing treatment approaches to multiple cerebral aneurysms, including endovascular isolation, microsurgical clipping, as well as surgical tactics in case of subarachnoid hemorrhage. We covered the recommendations for screening, surgical risks, and approaches to aneurysm isolation (single-stage and multiple-stage).Using our own experience (since no strict guidelines are currently available), we concluded that it is important to screen cerebral vessels of all close relatives of patients with multiple and familial cerebral aneurysms.

Endovascular therapy for patients with heritable thoracic aortic disease.

Patients with genetic or heritable aortic conditions and thoracic aortic aneurysm syndrome often develop cardiovascular abnormalities originating at the aortic root and affecting the entire thoracoabdominal aorta. Although thoracic endovascular aortic repair (TEVAR) is usually avoided in these patients, TEVAR may be worthwhile for those at high risk for surgical complications and in certain emergency circumstances. We explored indications for TEVAR in patients with suspected or confirmed genetic or heritable aortic conditions and investigated early and mid-term outcomes. Our institutional aortic surgery database was queried for patients with suspected or confirmed Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome, Turner syndrome, neurofibromatosis, or familial aortic aneurysm and dissection who underwent TEVAR between February 1, 2002 and October 31, 2020. We extracted operative details and in-hospital, follow-up, and survival data. Thirty-seven patients who underwent 40 endovascular interventions met the inclusion criteria; 25 previously underwent ascending aorta or aortic root surgery, and 21 previously underwent open thoracoabdominal surgery. Postoperative complications included respiratory failure (24.3%), cardiac complications (16.2%), renal failure (13.5%), tracheostomy (8.1%), and spinal cord ischemia (paraplegia/paraparesis) (8.1%). Follow-up ranged from 1.3 to 8.5 years (median: 3.6 years), with 15 deaths overall (three early/in-hospital). Thirteen patients (35.1%) had 22 repeat interventions (open and endovascular) post-TEVAR; five had the endograft removed. Despite consensus that thoracic aneurysms in patients with genetic or heritable aortic conditions should be treated with conventional open surgery, the outcomes from our study suggest that TEVAR might be suitable in emergency settings or for patients in this population who are not candidates for open surgery, who are at high risk for reintervention, or who have a previously implanted Dacron graft. Nonetheless, lifelong surveillance is important for these patients after TEVAR to monitor for new dissection at distal or proximal landing zones, as repeat interventions are frequent.

ANGPTL6 Genetic Variants Are an Underlying Cause of Familial Intracranial Aneurysms.

PurposeTo understand the role of the angiopoietin-like 6 gene (ANGPTL6) in intracranial aneurysms (IAs), we investigated its role in a large cohort of familial IAs.MethodsIndividuals with family history of IA were recruited to the Genetic and Observational Subarachnoid Haemorrhage (GOSH) study. The ANGPTL6 gene was sequenced using Sanger sequencing. Identified genetic variants were compared to a control population.ResultsWe found 6 rare ANGPTL6 genetic variants in 9/275 individuals with a family history of IA (3.3%) (5 missense mutations and 1 nonsense mutation leading to a premature stop codon), none present in controls. One of these had been previously reported: c.392A>T (p.Glu131Val) on exon 2; another was very close: c.332G>A (p.Arg111His). Two further genetic variants lie within the fibrinogen-like domain of the ANGPTL6 gene, which may influence function or level of the ANGPTL6 protein. The last 2 missense mutations lie within the coiled-coil domain of the ANGPTL6 protein. All genetic variants were well conserved across species.ConclusionANGPTL6 genetic variants are an important cause of IA. Defective or lack of ANGPTL6 protein is therefore an important factor in blood vessel proliferation leading to IA; dysfunction of this protein is likely to cause abnormal proliferation or weakness of vessel walls. With these data, not only do we emphasize the importance of screening familial IA cases for ANGPTL6 and other genes involved in IA, but also highlight the ANGPTL6 pathway as a potential therapeutic target.Classification of EvidenceThis is a Class III study showing some specificity of presence of the ANGPTL6 gene variant as a marker of familial intracranial aneurysms in a small subset of individuals with familial aneurysms.

Heritability of territory of ruptured and unruptured intracranial aneurysms in families.

BackgroundA previous study suggested that intracranial aneurysms are more likely to occur in the same arterial territory within families. We aimed to replicate this analysis in independent families and in a sample limited to intracranial aneurysms that ruptured.MethodsAmong families with ≥2 first-degree relatives with intracranial aneurysms, we randomly matched index families to comparison families, and compared concordance in intracranial aneurysm territory between index and comparison families using a conditional logistic events/trials model. We analyzed three European cohorts separately, and pooled the results with those of the Familial Intracranial Aneurysm study by performing an inverse variance fixed effects meta-analysis. The main analysis included both unruptured and ruptured intracranial aneurysms, and a secondary analysis only ruptured intracranial aneurysms.ResultsAmong 70 Dutch, 142 Finnish, and 34 French families, concordance regarding intracranial aneurysm territory was higher within families than between families, although not statistically significant. Meta-analysis revealed higher concordance in territory within families overall (odds ratio [OR] 1.7, 95%CI 1.3–2.2) and for each separate territory except the anterior cerebral artery. In the analysis of ruptured intracranial aneurysms, overall territory concordance was higher within families than between families (OR 1.8; 95%CI 1.1–2.7) but the territory-specific analysis showed statistical significance only for the internal carotid artery territory.ConclusionsWe confirmed that familial intracranial aneurysms are more likely to occur in the same arterial territory within families. Moreover, we found that ruptured aneurysms were also more likely to occur in the same arterial territory within families.

Understanding how defects in familial thoracic aneurysm and dissection (FTAAD)‐associated mutations in MAGP2 (MFAP5) affect its extracellular matrix localization and regulation of TGF‐β/SMAD signaling

In familial thoracic aneurysm and dissection (FTAAD), the aorta becomes weakened, stretching the vessel, a process known as aortic dilation, which in extreme cases can lead to tearing of the vessel wall layers, commonly referred to as aortic dissection. The direct consequences of FTAAD are stroke or heart attack that can potentially result in death of the patient. Research on Marfan Syndrome (MFS) and Loeys‐Dietz Syndrome (LDS) have shown that genes associated with similar aortic abnormalities have alterations in the TGF‐β/SMAD signaling pathway as well as extracellular matrix proteins (Faivre et al., 2007, Mizuguchi et al., 2004, and Loeys et al., 2006). Mutations in MFAP5, a gene that encodes for microfibril‐associated glycoprotein 2 (MAGP2), have been found in two FTAAD families, a nonsense mutation R158* and a missense mutation W21L (Barbier et al., 2014). The current working hypothesis is that MAGP2 normally plays an inhibitory role in TGF‐β/SMAD signaling, and that the FTAAD‐associated mutations are loss of function, since aortic tissue from a patient with the W21L mutation showed high phospho‐SMAD (p‐SMAD) levels. Moreover, MAGP2 has been shown to directly bind to active TGF‐β1 in vitro (Combs et al., 2013), and we have confirmed the results of Barbier et al. that the R158* mutant is poorly secreted. In contrast, the defect in the W21L mutant protein remains unidentified. It was secreted and bound to extracellular fibrillin microfibrils similar to wild‐type MAGP2 in our cell culture studies. What remains untested is whether FTAAD‐associated MAGP2 mutant proteins directly or indirectly affect TGF‐β/SMAD signaling. Therefore, the objective of this study is to determine whether R158* MAGP2 and W21L MAGP2 mutant proteins lose the ability to regulate TGF‐β signaling, leading to an increase in p‐SMAD2/3 levels in the cell. A TGF‐β signaling assay will be used to test soluble MAGP2 proteins, and fluorescent western blotting will then quantify the level of p‐SMAD 2/3 in whole cell lysate of MG63 cells, which expresses the TGF‐β receptor. Verification of both p‐SMAD2/3 and total SMAD antibodies have been completed via standard chemiluminescent protocols, and are currently being optimized for fluorescent detection. In parallel, stable cell lines are being produced to express wild‐type, R158*, or W21L MAGP2. A cell line expressing wild‐type MAGP2 has been generated, and the other two cell lines are being checked via immunofluorescence and western blotting to confirm that the cell lines express MAGP2. An understanding of how MAGP2 regulates the TGF‐β signaling could lead to the engineering of drugs to target mutant MAGP2 in hopes of improving the outcomes of FTAAD.Support or Funding InformationThis work was supported by the Department of Biological Science research funds (A. Miyamoto), CIRM Bridges to Stem Cell Research (A. Burcham, A. Keith), and HHMI (R. Daniels).

Familial Abdominal Aortic Aneurysms Don't Occur Earlier in Life, Neither do they Progress More Rapidly – Observations from Two Population Based Screening Trials

Introduction: Familial Abdominal Aortic Aneurysm (fAAA) is believed to develop earlier in life and progress faster than non-fAAAs. Consequently, current European guidelines recommend screening of first degree relatives to AAA patients from the age of 50. But this recommendation is based on only a few small sized studies. The objective of this study was to compare patient age and size of AAA at diagnosis, and progression of fAAA versus non-fAAAs in two large population-based screening trials. Methods: Study design: Combined population-based cross-sectional and cohort study. Materials: 1099 male participants screened positive for AAA in the VIVA- and DANCAVAS trials. Of these, follow-up data regarding growth rate, the need for aneurysmal repair and death were available in the 617 cases found through the VIVA-study. Using two nationwide registers, the national patient register registering diagnosis and performed procedures, the cause of death register registering causes of death. Ultrasound- and CT-scans were used to determine the maximum abdominal aortic diameter. Data regarding family history, traditional risk factors, prior CVD and medication were obtained by questionnaire at baseline. Difference between the two groups were tested using Wilcoxons ranksum test. Multiple linear regression and multiple cox-regression were used to adjust for potential confounding from age, comorbidities and medication. Finally, using the National Patient Register and Cause of Death register, we investigated the number of patients nationwide diagnosed with a ruptured AAA in different age groups between 1996 and 2016. Results: Of the 1099 AAAs, 77 (7.0%) were fAAAs. We observed no significant difference in age between the two groups, mean age being 70.2 and 69.9 years in the fAAA group and the non-fAAA group, respectively (p=0.99). We did not find any significant difference in median size of the aneurysms (fAAA=38.6 mm versus non-fAAA=36.4 mm. p=0.48). No significant difference was found in the growth rate of the aneurysms (adj. coef. -0.26 cm/y. 95% CI: -1.2 to 0.69), nor in the need for aneurysmal repair (adj. HR=1.10 95% CI: 0.67-1.78) or mortality (Adj. HR=0.43. 95 % CI: 0.16-1.19). Using data from the national patient register and cause of death register we found that 3.9 % percent of aneurysms ruptured before the age of 60 years old and 10.5 % before the age of 65 years. Conclusion: In two large population-based screening trials we found no evidence corroborating the hypothesis that fAAAs develop earlier in life or shows a more aggressive disease progression than non-fAAAs. This questions the current guidelines of screening relatives to AAA patients from a much earlier age than the rest of the population. Disclosure: Nothing to disclose

P6500Genetics links abdominal and thoracic aorta aneurysm

Abstract Introduction Familial disease, with a genetic cause, occurs in at least 20–30% of the families of patients with an aortic aneurysm. In these families there is an increased risk for relatives. Therefor family screening is recommended around the age of 50–60 years for first degree relatives of patients with an abdominal aneurysm (AAA) and relatives of patients with thoracic aorta aneurysms (TAA). However current guidelines do not specify the extend of aorta screening for relatives of patients with AAA and patients with TAA. Current practice is that first degree relatives of AAA patients are offered abdominal echo screening for AAA and relatives of TAA patients cardiologic echo for TAAA. Although co- occurrence of AAA with TAAA in rare genetic disease is well known, for other familial aneurysm disease, the frequency of the co-occurrence of AAA and TAAA has not been established. Purpose To improve family screening for familial aneurysm, and identify the role of underlying genetic defects. Methods To determine the genetics of AAA, whole exome sequencing and CT family screening of the complete aorta was performed in 391 families with familial aneurysm. These families are nested in a patient cohort ascertained form unselected consecutively diagnosed AAA patients visiting the Vascular Surgery Clinic at the our MC. Results In 391 families, 360 relatives had a dilated aorta. The spectrum of aortic features in the relatives included 210 (58%) relatives with AAA, 102 (28%) relatives with TAA. Co-occurrence of AAA and TAA was noted in 41 (11%) relatives. In addition 66 (18%) and 79 (22%) had a dilation in the arteria iliaca communis sinistra resp. dextra. In 18 families pathogenic mutations in 11 aneurysm genes were detected. Conclusion To reduce underdiagnoses of relatives of AAA patients, CT screening of the total aorta and the iliac arteries is the method of choice, and should replace echo screening of specific parts of the aorta in relatives. Updating the guidelines for family screening for aortic aneurysms is needed to improve early detection and treatment of family members with aorta dilatations. Acknowledgement/Funding Stichting Lijf en Leven

Exome sequencing reveals a novel variant in NFX1 causing intracranial aneurysm in a Chinese family

BackgroundGenetic risk factors play an important role in the pathogenesis of familial intracranial aneurysms (FIAs); however, the molecular mechanisms remain largely unknown.ObjectiveTo investigate potential FIA-causing genetic variants by rare variant...

Coronary ostial aneurysms following aortic root replacement in patients with familial aortic aneurysm are common and support the need for long-term surveillance

BackgroundFollowing the successful aortic root replacement (ARR) in patients with familial forms of aortic aneurysms (FFAA), few studies have defined the long-term outcomes of the re-implanted coronary arteries. The goal of the study was to describe late coronary complications following ARR in patients with FFAA. Methods40 patients with a genetically confirmed form of FFAA S/P ARR whom had undergone at least 1 CT scan or cardiac MRI study following ARR were identified. All studies were reviewed retrospectively and the coronary ostium were measured offline by two independent observers. ResultsThe majority of patients had Marfan Syndrome (80%), 15% had Loeys-Dietz Syndrome (TGFBR1 or TGFBR2), and 2 patients a MYLK or ACTA2 mutation. Mean age at time of ARR was 30.7 years, range 10–65. Mean length of follow-up from ARR 6.2 years, range 0.5–19. At last follow-up, 55% had developed at least 1 coronary complication. Nineteen (48%) had developed a coronary ostium aneurysm and 3 patients coronary ostium stenosis. All patients were alive at last follow-up. No patient had developed a coronary button rupture or dissection. Patients with aneurysms were more likely to have a mutation other than Marfan Syndrome (p < .05) and were more likely to have undergone emergent ARR following dissection (p = .008). Progressive coronary ostium dilation was rare. Two patients however did develop severe dilation and required button revision, both with TGFBR2 mutation. ConclusionCoronary ostium dilation is common following ARR in patients with FFAA. Progressive dilation and risk for coronary button rupture appears to be low. Patients with non-fibrillin 1 mutations, are at higher risk for severe dilation and some may require intervention. Long term surveillance in particular in patients with non-fibrillin1 forms of familial aortic aneurysm and dissection syndrome should be considered.

Felix Mendelssohn's family's brain condition

Like Mozart, the German musician Felix Mendelssohn was recognised early as a child prodigy, became popular as a young man, grew old quickly, and died young. He revealed the genius of Johann Sebastian Bach after almost a century of oblivion and was Goethe's favourite musician. Of a fragile constitution, Mendelssohn was a very friendly but rather introverted and sensitive person. 1 Breitenfeld T Breitenfeld D Vargek-Solter V Delija A Sostar Z Demarin V Felix Mendelssohn Bartholdy (1809–1847). Goethe's favorite. Acta Clin Croat. 2009; 48: 315-318 PubMed Google Scholar After the sudden death of his sister Fanny in May 1847, he began to show signs of clear depression, together with physical weakness and decrease in creativity. 1 Breitenfeld T Breitenfeld D Vargek-Solter V Delija A Sostar Z Demarin V Felix Mendelssohn Bartholdy (1809–1847). Goethe's favorite. Acta Clin Croat. 2009; 48: 315-318 PubMed Google Scholar In October 1847, he started to complain about sudden severe headache and probably had epileptic seizures. His condition deteriorated abruptly on Nov 3, 1847, when he suddenly screamed because he felt a terrible headache, dropped in his bed, and fainted. His alertness fluctuated, he showed slowed psychomotor responses, and finally became comatose hours before he died on Nov 4, 1847, at the age of 38 years. 1 Breitenfeld T Breitenfeld D Vargek-Solter V Delija A Sostar Z Demarin V Felix Mendelssohn Bartholdy (1809–1847). Goethe's favorite. Acta Clin Croat. 2009; 48: 315-318 PubMed Google Scholar The most plausible cause of his death is aneurysmal subarachnoid haemorrhage. 1 Breitenfeld T Breitenfeld D Vargek-Solter V Delija A Sostar Z Demarin V Felix Mendelssohn Bartholdy (1809–1847). Goethe's favorite. Acta Clin Croat. 2009; 48: 315-318 PubMed Google Scholar , 2 Schmideler S Somburg O Steinberg H Splett T Felix Mendelssohn Bartholdy (1809–1847): the mystery of his early death. Fortschr Neurol Psychiatr. 2006; 74: 522-527 Crossref PubMed Scopus (4) Google Scholar , 3 Gasenzer ER Neugebauer EA Felix Mendelssohn-Bartholdy and Fanny Hensel: two cases of intracerebral hemorrage and great composers of the nineteenth century. Acta Neurochir (Wien). 2014; 156: 1047-1051 Crossref PubMed Scopus (3) Google Scholar His sister had shown similar symptoms before her death at age 42 years. His grandfather Moses and both his parents had died from similar strokes. Although the primary evidence from the time is scarce, it points towards a possibility of familial cerebral aneurysms and subarachnoid haemorrhage, making the Mendelssohn family a rare and interesting, although speculative, medical and historical example. Even more speculative, but similarly intriguing, is the possible familial diagnosis of Ehlers-Danlos-Syndrome Type IV, which is inherited as an autosomal dominant trait. This syndrome occurs with arterial aneurysms, dissection or rupture of arterial vessels of large and medium diameter, together with characteristic facial features (acrogeria). 4 Steinmann B Royce PM Superti-Furga A The Ehlers-Danlos syndromes. in: Royce PM Steinmann B Connective tissue and its heritable disorders: molecular, genetic, and medical aspects. Wiley-Liss, New York2002 Crossref Google Scholar The latter may be found in contemporary depictions of Felix and Fanny Mendelssohn.

Autosomal dominant Marfan syndrome caused by a previously reported recessive FBN1 variant.

BackgroundPathogenic variants in FBN1 cause autosomal dominant Marfan syndrome but can also be found in patients presenting with apparently isolated features of Marfan syndrome. Moreover, several families with autosomal recessive Marfan syndrome caused by pathogenic variants in FBN1 have been described. The aim of this report was to underline the clinical variability that can be associated with the pathogenic variant c.1453C>T, p.(Arg485Cys) in FBN1.MethodsWe provide the clinical details of two autosomal dominant families with this specific FBN1 variant, which was previously associated with autosomal recessive Marfan syndrome.ResultsClinical data of 14 individuals carrying this variant from these two families were collected retrospectively. In both families, the diagnosis of autosomal dominant Marfan syndrome was established based on the characteristics of the variant and the phenotype which includes aortic aneurysms and dissections. Of interest, in one of the families, multiple relatives were diagnosed with early onset abdominal aortic aneurysms.ConclusionIn conclusion, FBN1 variant c.1453C>T, p.(Arg485Cys) is a pathogenic variant that can cause autosomal dominant Marfan syndrome characterized by a high degree of clinical variability and apparently isolated early onset familial abdominal aortic aneurysms.

Outcomes of familial abdominal aortic aneurysm repair in the Vascular Quality Initiative

ObjectiveRecent investigations have reported increased rates of aneurysm-related complications after endovascular aneurysm repair (EVAR) in familial abdominal aortic aneurysm (fAAA) patients. The purpose of this study was to evaluate the outcomes of open aortic repair (OAR) and EVAR in sporadic AAA (spAAA) and fAAA patients in the Society for Vascular Surgery Vascular Quality Initiative. MethodsThis was a retrospective review of all AAA repairs in the Vascular Quality Initiative from 2003 to 2017. Patients' data were summarized, and standard statistical analysis was performed. Patients with known genetic syndromes and centers with long-term follow-up of <50% of patients were excluded. ResultsFrom 2003 to 2017, there were 1997 fAAA patients compared with 18,185 spAAA patients undergoing OAR and EVAR during the same study period. Compared with their spAAA counterparts, fAAA patients were younger (P < .001), were more likely to be living at home before surgery (P = .008), and demonstrated a lower incidence of coronary artery disease (P = .001) and hypertension (P = .039). Rates of smoking and end-stage renal disease did not differ between groups. However, fAAA patients were more likely to have aneurysmal degeneration of their iliac arteries (P < .001) and to undergo OAR (P < .001). When analyzing patients undergoing OAR, we found that fAAA patients were more likely to require concomitant renal bypass surgery (P = .012) but were extubated sooner (P = .005), received fewer blood transfusions (P < .001), and had a shorter length of stay (P = .018). Although individual complication rates did not differ between fAAA and spAAA groups after OAR, a composite end point of all early postoperative complications was decreased in fAAA patients (P = .020). When comparing fAAA and spAAA patients who underwent EVAR, we found a greater incidence of early lumbar branch endoleaks (type II) in fAAA patients; however, the rate of proximal type IA endoleaks (P = .279) and the rate of late reintervention for sac growth (P = .786), any endoleak (P = .439), or rupture (P = .649) did not differ between the groups. Whereas spAAA patients undergoing EVAR required longer postoperative intensive care unit stays (P < .001) and had a greater incidence of blood transfusions (P < .001), fAAA and spAAA patients had similar rates of postoperative complications (P = .510), 30-day mortality (P = .177), and long-term mortality (P = .259). ConclusionsThis study shows that patients with a familial form of AAA do not have increased morbidity or mortality after AAA repair. Our findings suggest that EVAR and OAR are both safe and effective for fAAA patients. Further studies with longer follow-up are needed to best care for this unique cohort of patients.

Unruptured intracranial aneurysms in patients over 80years: natural history and management implications.

Patients over the age of 80years when diagnosed with an unruptured intracranial aneurysm (UIA) pose unique decision-making challenges due to shortened life-expectancy and increased risk of treatment. Thus, we investigated the risk of rupture and survival of a consecutive series of patients who were diagnosed with an UIA after the age of 80years. Data of consecutive patients with an UIA were reviewed, and patients were included in our study if they were first evaluated for a UIA by the senior author during their ninth decade of life. Outcomes were aneurysm rupture and overall survival after diagnosis. Survival was estimated from a Kaplan-Meier survival curve. Incidence of risk factors was compared to a population of patients less than 65years who were seen by the senior author over the same time period. Eighty-three patients who were over 80years when diagnosed with a UIA were included in this study. In our population, there is a risk of rupture of 3.2% per patient-year. One-, three-, and five-year survival rates for our population were estimated to be 92, 64, and 35%, respectively. When compared to patients under 65years diagnosed with a UIA, "over 80" patients had a significantly higher incidence of hypertension, and a significantly lower incidence of smoking history and familial aneurysm history. In our study population, UIAs greater than 7mm carry a non-negligible risk of rupture of 3.2% per patient-year, and further studies investigating the risk-to-benefit ratio of treatment in this population are warranted.

Fatal thoracic aortic aneurysm and dissection in a large family with a novel MYLK gene mutation: delineation of the clinical phenotype

BackgroundThoracic and abdominal aortic aneurysms and dissection often develop in hypertensive elderly patients. At higher risk are smokers and those who have a family history of aortic aneurysms. In most affected families, the aortic aneurysms and dissection is inherited in an autosomal dominant manner with decreased penetrance and variable expressivity. Mutations at two chromosomal loci, TAA1 at 11q23 and the TAA2 at 5q13–14, and eight genes, MYLK, MYH11, TGFBR2, TGFBR1, ACTA2, SMAD3, TGFB2, and MAT2A, have been identified as being responsible for the disease in 23% of affected families.ResultsHerein, we inform on the clinical, genetic and pathological characteristics of nine living and deceased members of a large consanguineous Arab family with thoracic aortic aneurysm and dissection who carry a missense mutation c.4471G > T (Ala1491Ser), in exon 27 of MYLK gene. We show a reduced kinase activity of the Ala1491Ser protein compared to wildtype protein. This mutation is expressed as aortic aneurysm and dissection in one of two distinct phenotypes. A severe fatal and early onset symptom in homozygous or mild late onset in heterozygous genotypes.ConclusionsWe found that MYLK gene Ala1491Ser mutation affect the kinase activity and clinically, it presents with vascular aneurysms and dissection. We describe a distinct genotype phenotype correlation where; heterozygous patients have mild late onset and incomplete penetrance disease compared with the early onset severe and generally fatal outcome in homozygous patients.