Homozygous GLUL deletion is embryonically viable and leads to glutamine synthetase deficiency

Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models

Computed tomography predictors of mortality, stroke and conduction disturbances in women undergoing TAVR: A sub-analysis of the WIN-TAVI registry

Background: Aortic valve calcification patterns were associated with short- and long-term outcomes in previous small observational datasets of patients undergoing transcatheter aortic valve implantation (TAVI). The specific impact of multi detector-row computed tomography (MDCT) findings on outcomes in women has not been reported. We sought to describe the associations between MDCT characteristics and clinical outcomes in a registry of 547 women undergoing TAVI. Methods: WIN-TAVI is the first all-female registry to study the safety and effectiveness of TAVI in women (n = 1019). Thirteen sites participated in the MDCT sub-study and contributed pre-TAVI MDCT studies in 547 consecutive subjects. All MDCT data were analyzed in an independent core lab blinded to clinical outcomes. Key measurements included number of valve leaflets, aortic annulus area and perimeter, left and right coronary artery height, aortic cusp calcium volume, commissural calcification and left ventricular outflow tract (LVOT) calcification. Calcium volume of the aortic valvular complex was quantified using a threshold relative to patient-specific contrast attenuation in the arterial blood pool. We examined univariate and multivariate associations between ECG-gated contrast MDCT characteristics and 1-year mortality or stroke, new pacemaker implantation and new onset atrial fibrillation (AF). Results: The CT sub-study sample had a mean age of 82.8 ± 6.3 years, mean logistic EuroSCORE of 17.8 ± 11.3%, and mean STS score of 8.2 ± 7.4%. Transfemoral access was used in 89.6% of patients. After multivariate adjustment, moderate or severe LVOT calcification was an independent predictor of 1-year mortality or stroke (HR = 1.91; 95% CI: 1.11–3.30; p = 0.02). Calcium volume in the right coronary cusp was an independent predictor of new pacemaker (HR = 1.18 per 100 m3 increment; p = 0.04), whereas calcium volume of the non-coronary cusp had a protective effect (HR = 0.78 per 100 mm3 increment; p = 0.004). Severe calcification of the non-coronary/right-coronary commissure was an independent predictor of new AF (HR = 5.1; p = 0.008). Conclusion: Computed tomography provides important prognostic information in women undergoing TAVI. Moderate or severe LVOT calcification is associated to an almost two-fold increased risk of mortality or stroke at one year. Different calcification patterns of the aortic valve may predict diverse rhythm abnormalities

Acute and 30-Day Outcomes in Women After TAVR: Results From the WIN-TAVI (Women's INternational Transcatheter Aortic Valve Implantation) Real-World Registry

The study sought to examine the safety and performance of transcatheter aortic valve replacement (TAVR) using an all-female registry and to further explore the potential impact of female sex-specific characteristics on clinical outcomes after TAVR

1-Year Clinical Outcomes in Women After Transcatheter Aortic Valve Replacement: Results From the First WIN-TAVI Registry

Objectives This study sought to examine the safety and performance of contemporary transcatheter aortic valve replacement (TAVR) in an exclusive all-women TAVR population, and to further investigate the potential impact of female sexâ\u80\u93specific characteristics on composite 1-year clinical outcomes. Background Women comprise â\u89¥50% patients undergoing TAVR. Several data have shown the noninferiority of TAVR compared with surgical aortic valve replacement for symptomatic significant aortic stenosis, but no study so far has been specifically powered to detect differences by sex. Methods The WIN-TAVI (Women's INternational Transcatheter Aortic Valve Implantation) registry is a multinational, prospective, observational registry of women undergoing TAVR for significant aortic stenosis, across 18 sites in Europe and 1 site in the United States, between January 2013 and December 2015. The primary Valve Academic Research Consortium (VARC)-2 efficacy endpoint was a composite of mortality, stroke, myocardial infarction, hospitalization for valve-related symptoms or heart failure or valve-related dysfunction beyond 30 days. Secondary endpoints included composite 1-year death or stroke. Predictors of 1-year outcomes were determined using Cox regression methods. Results A total of 1,019 intermediate to high-risk women, with mean age 82.5 ± 6.3 years, mean European System for Cardiac Operative Risk Evaluation (EuroSCORE) I 17.8 ± 11.7% and mean Society of Thoracic Surgeons score 8.3 ± 7.4% were enrolled. TAVR was performed via transfemoral access in 90.6% and new-generation devices were used in 42.1%. The primary VARC-2 efficacy composite endpoint occurred in 111 (10.9%) patients beyond 30 days and in 167 (16.5%) patients at 1 year. The incidence of 1-year death or stroke was 13.9% (n = 141). Death occurred in 127 (12.5%) patients and stroke in 22 (2.2%) patients. Prior coronary revascularization (hazard ratio [HR]: 1.72; 95% confidence interval [CI]: 1.17 to 2.52; p = 0.006) and EuroSCORE I (HR: 1.02; 95% CI: 1.00 to 1.04; p = 0.027) were independent predictors of the VARC-2 efficacy endpoint. Similarly, EuroSCORE I (HR: 1.02; 95% CI: 1.00 to 1.04; p = 0.013), baseline atrial fibrillation (HR: 1.58; 95% CI: 1.07 to 2.33; p = 0.022), and prior percutaneous coronary intervention (HR: 1.50; 95% CI: 1.03 to 2.19; p = 0.035) were independent predictors of 1-year death or stroke. After adjustment, no significant association was observed between history of pregnancy or any sex-specific factors and 1-year TAVR outcomes. Conclusions Intermediate to high-risk women enrolled in this first ever all-women contemporary TAVR registry experienced a 1-year VARC-2 composite efficacy endpoint of 16.5%, with a low incidence of 1-year mortality and stroke. Prior revascularization and EuroSCORE I were independent predictors of the VARC-2 efficacy endpoint, whereas EuroSCORE I, baseline atrial fibrillation, and prior percutaneous coronary intervention were independent predictors of the 1-year death or stroke

Impact of Small Valve Size on 1-Year Outcomes After Transcatheter Aortic Valve Implantation in Women (from the WIN-TAVI Registry)

Although most patients with small aortic annulus are women, there is paucity of data on the prognostic impact of small aortic prosthesis in women who underwent transcatheter aortic valve implantation (TAVI). Therefore, we aimed to evaluate the impact of small valve size on 1-year clinical outcomes after TAVI in women. The Women's INternational Transcatheter Aortic Valve Implantation is an all-women registry evaluating patients with severe aortic stenosis who underwent TAVI. Based on the size of the aortic bioprosthesis implanted, women were stratified into small (≤23 mm) and nonsmall (>23 mm) valve. The primary efficacy endpoint was the Valve Academic Research Consortium-2 composite of all-cause death, stroke, myocardial infarction, hospitalization for valve-related symptoms or heart failure or valve-related dysfunction at 1-year follow-up. Of 934 women who underwent TAVI, 388 (41.5%) received a small valve. Women with a small valve size had a lower body mass index, lower surgical risk scores, were less likely to suffer from atrial fibrillation, less often required postdilation and had a lower rate of residual aortic regurgitation grade ≥2. The occurrence of the Valve Academic Research Consortium-2 efficacy endpoint was similar between women treated with small and nonsmall valve (16.0% vs 16.3%, p = 0.881; adjusted hazard ratio 1.34, 95% confidence interval 0.90 to 2.00). Likewise, there were no significant differences in the occurrence of other secondary endpoints after multivariable adjustment. In conclusion, women with severe aortic stenosis who underwent TAVI with the implantation of a small valve bioprosthesis had similar 1-year outcomes as those receiving a nonsmall bioprosthesis