Early-onset Disease Research Articles

Coronary Artery Bypass Grafting in Young Adults.

To evaluate the risk factors for early onset of coronary artery disease (CAD) and assess the preoperative presentation, perioperative course, survival, and short-term complications after coronary artery bypass graft (CABG) in patients aged 45 years or younger undergoing CABG. Observational study. Place and Duration of the Study: Department of Cardiothoracic Surgery, The Aga Khan University Hospital, Karachi, Pakistan, from December 2020 to January 2021. All patients aged 45 years or younger who were undergoing CABG were included in the study. Patients with incomplete medical records were excluded. Study variables included preoperative demographic information, intraoperative variables including the number and type of conduits used, and postoperative morbidity and mortality. Descriptive analysis was reported for all variables. The study population cohort included 134 patients, of whom 120 (89.6%) were male, with a mean age of 38.6 ± 5.1 years (range: 30-45 years). The indication for surgery was 3-vessel CAD in 56 (41.7%) patients. A total of 421 grafts were constructed, with a mean of 3.14 grafts per patient. One patient died in the hospital with an overall operative mortality of 1.5%. The most common risk factors were found to be family history, the presence of diabetes mellitus, hypertension, and smoking. The risk factors and outcomes in younger patients (less than 45 years) undergoing CABG are not markedly different from those in older patients and are comparable to the existing literature. Coronary artery disease, Coronary artery bypass graft, Young adults, Risk factors, Three vessel disease.

The impact of initial vascular morphology on outcomes in patients with intracranial vertebral artery dissection presenting with isolated headache.

The prognosis of isolated headache intracranial vertebral artery dissection (iVAD) without subarachnoid hemorrhage (SAH) or stroke is unknown. The authors of this study aimed to evaluate isolated headache iVAD prognosis. This is a single-center retrospective study of consecutive patients who presented with headache as their main complaint and underwent MRI between November 2016 and August 2022; those with acute isolated headache iVAD who were followed up for vascular morphological stability were eligible for study inclusion. The patients were divided into three groups based on the vascular morphology at initial diagnosis: aneurysm dilatation without stenosis (group 1), aneurysm dilatation with stenosis (group 2), and no aneurysm dilatation (group 3). Prognosis, time to radiological stability, and final vascular morphology were compared among the groups. One hundred five patients with isolated headache iVAD were included in the study. During a median follow-up of 478 (IQR 143-1094) days, none of the patients developed SAH or stroke, but 3/41 (7%) patients in group 1 underwent endovascular intervention for aneurysm enlargement. Patients in group 1 required significantly more long-term follow-up for morphological stability (p = 0.013), primarily due to aneurysm enlargement (p < 0.001), and were more likely to require surgical intervention (p = 0.043) than those in the other two groups. Residual aneurysm risk was significantly associated with initial vascular morphology in group 1 (OR 7.28, 95% CI 2.30-23.1, p < 0.001). Most patients with isolated headache iVAD had a favorable prognosis. However, patients with aneurysm dilatation without stenosis required the most careful follow-up, as this group had the highest aneurysm enlargement risk from early disease onset through the chronic phase. In such cases, patients may require surgical intervention to prevent critical conditions.

Overexpression of autophagy enhancer PACER/RUBCNL in neurons accelerates disease in the SOD1G93A ALS mouse model

Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal paralytic disorder associated with motor neuron death. Mutant superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial ALS, with the accumulation of abnormal wild-type SOD1 species being also observed in postmortem tissue of sporadic ALS cases. Both wild-type and mutated SOD1 are reported to contribute to motoneuron cell death. The autophagic pathway has been shown to be dysregulated in ALS. Recent evidence suggests a dual time-dependent role of autophagy in the progression of the disease. PACER, also called RUBCNL (Rubicon-like), is an enhancer of autophagy and has been found diminished in its levels during ALS pathology in mice and humans. Pacer loss of function disturbs the autophagy process and leads to the accumulation of SOD1 aggregates, as well as sensitizes neurons to death. Therefore, here we investigated if constitutive overexpression of PACER in neurons since early development is beneficial in an in vivo model of ALS. We generated a transgenic mouse model overexpressing human PACER in neurons, which then was crossbred with the mutant SOD1G93A ALS mouse model. Unexpectedly, PACER/SOD1G93A double transgenic mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1G93A mice. The overexpression of PACER in neurons in vivo and in vitro increased the accumulation of SOD1 aggregates, possibly due to impaired autophagy. These results suggest that similar to Pacer loss-of function, Pacer gain-of function is detrimental to autophagy, increases SOD1 aggregation and worsens ALS pathogenesis. In a wider context, our results indicate the requirement to maintain a fine balance of PACER protein levels to sustain proteostasis.

Abstract PR016: Early changes to the colon tumor microenvironment during benign-to- malignant transition

Abstract Colorectal cancer (CRC) is now the first and second leading cause of cancer-related deaths in men and women under 50, respectively, upending prior predictions. While many risk factors have been identified, the etiology of early onset disease is poorly understood, and it is unclear why some benign polyps progress to CRC while most do not. The genetic drivers of colon tumor initiation and progression to malignancy are not sufficient to drive disease on their own, as evidenced by the near ubiquitous presence of oncogenic mutations within morphologically “normal” adult tissues like the colon. This raises several fundamental questions: 1) what are the pioneering molecular and cellular events underlying benign-to-malignant transition following oncogenic mutation? 2) Is this sequence of events predetermined by cancer genetics or are additional (micro)environmental stimuli necessary? 3) How does the benign-to-malignant transition reshape tumor clonal architecture and is this immunogenic? We have begun to address these questions using a combination of rare human colon polyps with evidence of early malignant transition and innovative new mouse models that enable control of stepwise colon cancer progression. These autochthonous models combine in vivo CRISPR-Cas9 and an inducible “split-Cre” system to decouple focal tumor initiation in the distal colon (via Apc knockout) from spatiotemporal control of secondary driver events of malignant progression (e.g., Kras G12D, Trp53 knockout) in rare cells of benign adenomas. We have validated the in vivo functionality of these models, generating early “intramucosal carcinoma” and “adenocarcinoma-in-adenoma”—physiologically relevant and elusive stages of human colon cancer development that have never been reliably captured in model systems to date. Comparing these tumors with spatial transcriptomic data from human specimens, we report distinct transcriptional programs of early progression, a unique stromal reaction associated with early progression, and restructuring of glandular architecture and the stem cell niche in early carcinoma. By delineating the earliest events underlying cancer progression, this work promises to inform new strategies for early detection and prevention. We anticipate that the models will also be particularly valuable in functionally interrogating host and environmental factors that impact risk of early onset cancer. Citation Format: Peter M.K. Westcott, Yihan Qin, Daniel Zhang, Nikita Persaud, Zakeria Aminzada, Nischal Bhandari, Colin McLaughlin, William Rideout III, Santiago Naranjo, Song Han, Rodrigo Romero, Claire Regan, Jonathan Preall, Semir Beyaz, Tyler Jacks, Zhen Zhao, Sepideh Gholami. Early changes to the colon tumor microenvironment during benign-to- malignant transition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR016.

Identification of novel ABCB4 variants and genotype-phenotype correlation in progressive familial intrahepatic cholestasis type 3

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe hepatic disorder characterized by cholestasis. Elucidating the genotype-phenotype correlations and expanding the mutational spectrum of the ABCB4 gene are crucial for enhancing diagnostic accuracy and therapeutic strategies.Clinical and genetic data from 2 original PFIC3 patients from our institution, along with 118 additional cases identified through a comprehensive literature review, were integrated for a comprehensive analysis. The study included statistical analysis of clinical information, genetic analysis, multi-species sequence alignment, protein structure modeling, and pathogenicity assessment. Machine learning techniques were applied to identify genotype-phenotype relationships. We identified three novel ABCB4 mutations: two missense mutations (c.904G > T and c.2493G > C) and one splicing mutation (c.1230 + 1G > A). Homozygous mutations were associated with significantly earlier disease onset compared to compound heterozygous mutations (p < 0.0001). Missense mutations were predominant (76.9%), with Exon 7 being the most frequently affected region. A random forest model indicated that Exon 10 had the highest feature importance score (9.9%). Liver transplantation remains the most effective treatment modality for PFIC3. This investigation broadens the known mutation spectrum of the ABCB4 gene and identifies key variant sites associated with clinical manifestations. These insights lay a foundation for early diagnosis, optimal treatment selection, and further research into PFIC3.

Age-specific dynamics of neutralizing antibodies, cytokines, and chemokines in response to La Crosse virus infection in mice.

La Crosse virus (LACV) is a primary cause of pediatric arboviral encephalitis in the United States, particularly affecting children aged 16 years or younger. This age-related susceptibility extends to murine models, where weanling mice (3 weeks old) succumb to LACV infection, while adults (≥6 weeks old) demonstrate resistance. Despite its clinical relevance, the host immune response to LACV is not fully understood. In this study, we investigated the roles of neutralizing antibodies (nAbs), cytokines, and chemokines in weanling and adult mice following infection with 5 × 105 plaque-forming units (PFU) of LACV. Weanling mice demonstrated early disease onset with elevated peripheral viremia, but passive transfer of adult serum, confirmed to have nAbs, to naïve weanlings prior to infection completely rescued them from death. Moreover, adult mice had increased Th1 cytokines, Th9/Th17/Th22/Treg cytokines, and many chemokines. In contrast, weanlings had higher Th2 cytokines, correlating with symptoms onset. Flow cytometry and intracellular cytokine staining further demonstrated that weanling mice produced higher levels of IL-4 by CD4+ and CD8+ T cells compared to adults, regardless of infection status. Conversely, LACV-infected adult mice had increased IFN-γ production by CD8+ T cells compared to uninfected controls. Finally, the adoptive transfer of splenocytes from immune adult mice to naïve weanlings delayed neurological symptoms and improved survival. In conclusion, this study links nAbs and cytokine and chemokine responses to protective immunity in adult mice, contrasting with the pathogenesis seen in weanlings. These findings underscore the importance of further research into innate and adaptive immune mechanisms during LACV infection.IMPORTANCELa Crosse virus (LACV) is a primary cause of pediatric encephalitis in the United States, with an impact on children aged 16 years or younger. This age-related susceptibility is recapitulated in mouse models, where young mice succumb to LACV-induced disease, while adults demonstrate resistance. Our understanding of host responses to LACV remains underexplored. This study sheds light on the dynamics of neutralizing antibodies (nAbs), cytokines, and chemokines following LACV infection in both adult and weanling mice. Our study reveals age-specific variations in viremia, neutralizing antibody titers, survivability, and levels of cytokines and chemokines. Adult mice exhibit significantly elevated levels of Th1 cytokines, contrasting with elevated levels of Th2 cytokines observed in weanling mice, often coinciding with the onset of symptoms. These data reveal age-specific dynamics in cytokines and chemokines associated with protective versus pathogenic immunity, emphasizing the need for further studies on innate and adaptive immunity.

Germline Genetic Susceptibility Testing Among Emirati Nationals at Risk for Hereditary Breast and Ovarian Cancer Syndrome.

Breast cancer among Emirati patients is characterized by early-onset disease and later stages at presentation. Little is known about the germline genetic variants that may contribute to these observations. The goal of this study is to characterize the rate and implications of germline genetic variants among a cohort of Emirati patients at risk for hereditary breast and ovarian cancer syndrome. A retrospective study was performed to analyze the results of clinical germline genetic testing (March 2020-January 2023) among a cohort of consecutive Emirati patients at risk for hereditary breast and ovarian cancer syndrome: group A: patients with personal history of breast or ovarian cancer (n = 135); group B: unaffected patients with family history of breast or ovarian cancer (n = 37); and group C: patients presenting for cascade testing (n = 20). Management of patients identified to have pathogenic/likely pathogenic (P/LP) variants was analyzed. The rate of P/LP germline variants for each group was: group A: 17.3%, group B: 16.6%, group C: 57.9%. BRCA1 gene was the most commonly identified gene harboring P/LP variants, followed by BRCA2, among this cohort. Four unrelated patients had a recurrent BRCA1 pathogenic variant: c.4065_4068del (p.Asn1355Lysfs*10). Only two patients in this series elected risk-reducing mastectomy and four patients elected risk-reducing bilateral salpingo-oophorectomy. A higher rate of P/LP variants is seen among Emirati patients at risk for hereditary breast and ovarian cancer syndrome compared with reports of similar patients from Western populations. Efforts to increase utilization and awareness of germline genetic testing are warranted among Emirati patients.

Impact of acid blocker therapy on growth, gut microbiome, and lung disease in young children with cystic fibrosis.

Acid blocker therapy (ABT) has become common in cystic fibrosis (CF), despite insufficient evidence for benefits and studies showing potentially negative effects. We examined associations between ABT usage and growth, gut microbiome (GM), and early-onset lung disease in young children with CF. One hundred forty-five infants with CF born during 2012-2017, diagnosed through newborn screening by age 3 months and followed to 36 months of age at six CF centers were evaluated. Longitudinal data on growth, pancreatic functional status, pulmonary symptoms, and acid blocker medications were prospectively collected. Early-onset lung disease severity was evaluated by a clinical scoring system. GM composition was assessed by 16S rRNA methodology. ABT use before age 3 years was frequent, with 81 (56%) of patients on H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI), and higher among pancreatic insufficient (60%) versus pancreatic sufficient (26%) children. H2RA was commonly prescribed in infancy before transitioning to PPI. Growth improvements were not significantly greater, while GM α-diversity at 3 years of age was significantly lower and early-onset lung disease more severe, in persistent ABT users compared to nonusers of ABT. In our cohort of young children with CF, early and persistent ABT use was not associated with significant growth benefits and instead showed associations with reduced GM diversity and negative effects on early-onset lung disease. Consequentially, there is a critical need for systematic evaluation and comprehensive risk-benefit analysis of ABT to ensure proper guidelines for children with CF.

Plasma protein profile associated with a family history of early-onset coronary heart disease

Abstract Introduction Although family history of coronary heart disease (CHD) is an established risk factor for subsequent CHD, its relation to the circulating proteome is unknown. Proteins linked to coronary atherosclerosis in subjects with a family history could uncover new pathophysiological mechanisms of heritable CHD. Purpose Firstly, we aimed to study the protein profile associated with a family history of early-onset CHD. Secondly, we aimed to identify proteins among which family history was an effect modifier for the association between each protein and coronary atherosclerosis. Methods Plasma levels of proteins were assessed with Olink panels CVD-II and -III in the population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort. The coronary segment involvement score (SIS) was assessed from computed tomography angiography. Subjects without known CHD were cross-referenced with national registers to identify records of myocardial infarction or coronary revascularization in any parent before 55 or 65 years of age in males and females, respectively. The associations between a family history of CHD and each protein were studied with linear regression adjusted for age, sex and study site, using a False Discovery Rate (FDR) of 5%. Associations were subsequently adjusted for cardiovascular risk factors. Similarly, associations between each protein and SIS were modelled linearly with an FDR of 5%. For significant proteins, the statistical interactions between each protein and family history for the association between proteins and SIS were studied. Results Of 4,251 subjects, 9.5% had a family history CHD. 43 proteins were significantly associated with family history, and when adjusted for risk factors 29 protein associations remained significant (p&amp;lt;0,05) [Figure 1]. The strongest associations were observed for cathepsin D, paraoxonase 3, interleukin-1 receptor antagonist protein and renin. 79 proteins were associated with SIS at FDR&amp;lt;5%, and family history was a significant effect modifier 18 for proteins [Figure 2]. The strongest modifying effects were observed for transferrin receptor protein 1 (β 0.64, 95% CI 0.25–1.04 for those with family history vs β -0.04, 95% CI -0.14–0.06 in those without, p for interaction=0.001), LDL-receptor (β 0.68, 95% CI 0.36–1.00 vs β 0.18, 95% CI 0.08–0.26) and tissue-type plasminogen activator (β 0.45, 95% CI 0.19–0.70 vs β 0.13, 95% CI 0.05–0.21). Conclusion We found that 43 proteins, with biological features of inflammation and vascular function, were associated with a family history of early-onset CHD. Most were also linked to the coronary atherosclerosis burden. Notably, 18 biomarkers, among them transferrin receptor protein 1, LDL-receptor and tissue-type plasminogen activator, exhibited strong statistical interactions with family history in the association with SIS, indicating that they are of particular importance for the genetic susceptibility and the pathophysiology of heritable CHD.

Sex-differences in the clinical features, managements and outcomes of early-onset atherosclerotic coronary artery disease in China

Abstract Background/Introduction There is an alarming rise in the incidence of atherosclerotic coronary artery disease (CAD) among young adults, particularly in young women. Sex disparities of early-onset CAD in the context of contemporary cardiovascular practice are not well understood. Purpose We aimed to delineate the differences in clinical profiles and prognosis between young men and women with established early-onset CAD. Methods This is a nationwide, hospital-based, longitudinal prospective cohort study. Young patients (aged ≥18 years and ≤ 45 years) with angiographically confirmed severe atherosclerotic obstructive coronary arteries (luminal narrowing ≥ 70%) were included from 38 hospitals across China between May 2017 and May 2020. Coronary risk factors, clinical features and treatments were compared between men and women at baseline. Participants were followed for 3 years. The outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction (MI), unplanned revascularization, and ischemic stroke. The Cox regression analyses were used to estimate hazard ratios (HR) with 95% confidence intervals (CIs) for outcome. Results There were 1524 patients (female: 4.4%) included in this study. The female patients were older than the male patients (41.1±4.0 years for females vs. 39.6±4.4 years for males, p=0.006). They showed a lower prevalence of hypertension, lipid disorders, and smoking or drinking (all p&amp;lt;0.01). The female patients were less likely to have at least 1 modifiable risk factors (female: n=45 (67.2%) vs. male: n=1382 [94.6 %], p&amp;lt;0.001); they showed more favorable laboratory results at baseline, including lipids, serum creatinine and uric acid (all p&amp;lt;0.05) as compared to male patients. Besides, young females presented more often with stable angina on admission, whereas young males tended to present with acute MI (p&amp;lt;0.001). There was no significant sex difference in Gensini Score (p=0.15). Female patients were less likely to undergo revascularization procedures than male patients (73.1% vs. 85.3%, p=0.01). During the 3 years of follow-up, female patients were at a significantly higher risk of MACE compared to their male counterparts (13.4% vs. 5.8%, adjusted HR: 3.07, 95% CI:1.36–6.94, p=0.007) after adjusting for age, smoking, drinking, body mass index, hypertension, diabetes, dyslipidemia, diagnosis and revascularization. Conclusions Distinct sex disparities, unfavorable to young females, were documented among patients with early-onset CAD, with the largest gaps noted in the treatment and prognosis. Despite more favorable baseline profiles, young female patients had insufficient care and 3-fold greater risk for MACE compared to young males. These results highlight the need for strengthening the treatment strategies for this vulnerable disease entity.Figure 1

Can variants of genes associated with familial heart block predict conduction disease in the general population? A UK Biobank study.

Abstract Background Progressive familial heart block is a genetic disease that can present with worsening cardiac conduction disease (CCD) and risk of life-threatening bradycardia. The prevalence, penetrance, and expressivity of known rare pathogenic/likely pathogenic variants (P/LP) in the general population is unclear. In addition, the role of common genetic variation in this phenotypic expression is unknown. Understanding this is essential for patient management in clinic. Purpose 1). To investigate the prevalence of variants linked with early-onset CCD and phenotypic expression in a large biobank. 2). To investigate whether a PR interval polygenic risk score (PRS) improves risk prediction. Methods Early-onset conduction disease P/LP or variants of uncertain significance (VUS) were identified from ClinVar, genetic testing reports at a teaching hospital (6 variants), and the literature, mapping to 22 genes. From the full UK Biobank prospective cohort, 469,511 participants passed genetic quality control and were assigned to P/LP, VUS, or genotype negative (G-) groups, using whole exome sequencing analysed with bcftools. A PR-PRS was constructed using weights from a published meta-analysis excluding UKB data. The primary outcome was CCD (atrioventricular (AV) block, bundle branch block, pacemaker or ICD implantation) and secondary outcomes were high-grade AV block or pacemaker insertion, compared with lifetime risk Cox proportional hazards controlled for sex and age as a timescale. Results 55% of participants were female, 95% had European ancestry, and average age at censor was 71 years. There were 25 P/LP carriers, and 8,862 with a VUS, in 6 genes (MYH7, SCN5A, TNNI3K, TRPM4, TTN, and LMNA). Major demographic factors were the same between groups. CCD was significantly more prevalent in P/LP individuals (28% vs 5.8% in VUS vs 5.5% in G-; p&amp;lt;0.001) with a hazard ratio of HR 6.47 [95% CI=3.09-13.6] vs G-. This was driven by AV block and pacemaker implantation (HR 23.2 [95% CI=8.69-61.8] and 13.4 [95% CI=6.01-29.8], respectively). Results were similar in an unrelated subset and controlling for ischaemic heart disease and heart failure. The 7 P/LP individuals with conduction disease were mostly linked to a single LMNA variant (4 out of 6 carriers with penetrant disease). In the full cohort, the PR-PRS was predictive of CCD (HR=1.07 [95% CI=1.06-1.08]), AV block (HR=1.09 [95% CI=1.06-1.13]), and pacemaker implantation (HR=1.04 [95% CI=1.02-1.06]). When combined with P/LP status, both PR-PRS (HR=1.07 [95% CI=1.06-1.08]) and P/LP (HR=6.42 [95% CI=3.06-13.5]) were independent predictors of CCD. Conclusion(s) Rare variant carrier status predicts a 6.5-fold increased lifetime risk of CCD, a 23-fold increased risk of AV block and 13-fold risk for pacemaker requirement. However, phenotypic expression for some variants is highly variable. A PR-PRS captures risk independent of P/LP variants and warrants further investigation with updated PRS construction methods.

Gene-echocardiography: unmasking the covert role of fatty acid metabolism gene mutations in adult cardiomyopathy

Abstract Background Although the role of fatty acid metabolic deficiencies in cardiomyopathy is established, the precise identity of causative genes and their respective phenotypes in adult cardiomyopathy remains unclear. Methods We implemented a combination of echocardiography and whole exome sequencing in clinically diagnosed cardiomyopathy patients to uncover this relationship. This involved recording cardiac phenotypes, identifying genes associated with disrupted fatty acid metabolism, and subsequently followed up with these patients. Results Out of 802 cardiomyopathy patients, 27 exhibited mutations in genes tied to fatty acid metabolism. Specifically, 16 patients demonstrated a hypertrophic cardiomyopathy (HCM) phenotype, and 11 showed a dilated cardiomyopathy (DCM) phenotype. The implicated genes were SLC22A5 (n=7), ACADVL (n=6), ACADS (n=4), ACADM (n=3), SLC25A20 (n=3), ACADL (n=2), HADH (n=1), and AGK (n=1), with a higher prevalence in males. Among these, the SLC22A5 mutation was predominant and correlated with HCM phenotype. Notably, compound mutations were frequently observed (16/27), leading to earlier disease onset and diminished aortic sinus dimension. Further investigation showed that smaller aortic sinus dimensions resulted from abnormal left ventricular myocardial work. HCM phenotype mutation carriers showed more consistent left ventricular hypertrophy and a higher probability of right ventricular hypertrophy, while DCM phenotype mutation carriers exhibited impaired contractile function across all left ventricle segments. After a 24-month follow-up, the DCM phenotype group demonstrated higher cardiovascular risk, including two fatalities. Conclusion Our investigation highlights the significant prevalence of mutations related to abnormal fatty acid metabolism in adult cardiomyopathy patients, underscoring the utility of a gene-echocardiography approach for diagnosis.

Lipid-associated GWAS loci as important markers of the risk, severity, and clinical course of peripheral artery disease

ABSTRACT Background This study investigated the relationship between lipid-associated loci identified through genome-wide association studies (GWAS) and the risk of peripheral artery disease (PAD), its severity, as well as clinical and laboratory features. Research design and methods A study included 1263 unrelated Russian subjects, consisting of 620 patients diagnosed with PAD and 643 healthy controls. Thirteen single nucleotide polymorphisms (SNP) were genotyped using the MassArray-4 system. Results Polymorphisms rs1689800, rs55730499 and rs881844 were found to be associated with an increased risk of PAD, whereas SNPs rs1883025, rs3136441, rs3764261 and rs6065906 showed protective effects against disease (Pperm ≤ 0.05). SNPs rs1689800, rs217406, rs1883025, and rs3136441 exhibited combined effects with cigarette smoking on the PAD risk (Pperm ≤ 0.05). Polymorphisms rs55730499 (beta = 0.124, Pperm = 0.04), rs9987289 (beta = 0.558, Pperm = 0.03), and rs881844 beta = −0.171, Pperm = 0.03) correlated with the ankle-brachial index. Multiple associations have been found between the SNPs and clinically significant characteristics, including disease severity, risk of gangrene, early disease onset, plasma procoagulant and atherogenic lipid changes (Pperm ≤ 0.05). Conclusions We identified novel genetic markers associated with PAD susceptibility and disease-related clinical and laboratory features. The identified biomarkers enhance the potential for predictive genetic testing related to the risk and progression of PAD, facilitating the integration of molecular diagnostics into clinical decision-making processes.

A de novo Missense Mutation in PPP2R5D Alters Dopamine Pathways and Morphology of iPSC-derived Midbrain Neurons.

Induced pluripotent stem cell (iPSC) models of neurodevelopmental disorders (NDDs) have promoted an understanding of commonalities and differences within or across patient populations by revealing the underlying molecular and cellular mechanisms contributing to disease pathology. Here, we focus on developing a human model for PPP2R5D-related NDD, called Jordan syndrome, which has been linked to Early-Onset Parkinson's Disease (EOPD). Here we sought to understand the underlying molecular and cellular phenotypes across multiple cell states and neuronal subtypes in order to gain insight into Jordan syndrome pathology. Our work revealed that iPSC-derived midbrain neurons from Jordan syndrome patients display significant differences in dopamine-associated pathways and neuronal architecture. We then evaluated a CRISPR-based approach for editing heterozygous dominant G-to-A mutations at the transcript level in patient-derived neural stem cells. Our findings show site-directed RNA editing is influenced by sgRNA length and cell type. These studies support the potential for a CRISPR RNA editor system to selectively edit mutant transcripts harboring G-to-A mutations in neural stem cells while providing an alternative editing technology for those suffering from NDDs.

Burden of infant group B Streptococcus disease and impact of maternal screening and antibiotic prophylaxis in Ontario, Canada: a population-based cohort study

Group B Streptococcus (GBS) significantly contributes to neonatal sepsis and meningitis, with varying disease rates reported globally and limited population-based data. We estimated infant GBS disease burden in Ontario, Canada and assessed the association of maternal GBS screening (35-37 weeks' gestation) and intrapartum antibiotic prophylaxis (IAP) provision with infant disease rates. Our population-based cohort study included pregnant individuals and their offspring from April 2012 to March 2018, utilising the provincial birth registry linked to health administrative data. GBS cases were ascertained through culture results and diagnostic codes. We calculated incidence rates for early-onset disease (EOD: 0-6 days), late-onset disease (LOD: 7-89 days), and ultra-LOD (ULOD: 90-365 days). Adjusted incidence rate ratios (aIRR) were derived via log-binomial regression to compare infant GBS rates according to screening and IAP-receipt. Among 776,148 liveborn infants, we identified 803 with GBS, with multiples exhibiting a threefold incidence increase. Incidence rates of EOD, LOD and ULOD were 0.49, 0.46 and 0.07 per 1000 livebirths, respectively. Of eligible pregnancies, 94% were screened; 23% screened positive, and 81% of them received IAP. Nearly 12% of term EOD infants had mothers who missed IAP despite screening positive. Maternal screening was associated with lower rates of any infant GBS disease (aIRR: 0.60; 95% CI: 0.45, 0.80). Among screen-positive births, IAP-receipt was associated with reduced rates of EOD (aIRR: 0.72, 95% CI: 0.48, 1.29) and LOD/ULOD (aIRR: 0.69; 95% CI: 0.46, 1.05), but confidence intervals included 1.0. Our study, the largest Canadian investigation into infant GBS disease, highlights both widespread adoption and ongoing challenges of the current prevention strategy. Canadian Institutes of Health Research.

Very Early-Onset Inflammatory Bowel Disease: Insights into Etiology, Diagnosis, and Treatment Strategies

Very early-onset inflammatory bowel disease: is a subtype of inflammatory bowel disease (IBD) and is defined by its onset in children younger than 6 years of age. The etiology includes the interplay of various factors such as genetic predisposition, environmental factors, gut microbiota and strong family history. The clinical presentation can present with both gastrointestinal symptoms such as bloody and/or mucus-containing diarrhea, recurrent vomiting, peri annal symptoms like fistulas, abscesses and perinatal skin tags and also present as extra-intestinal symptoms like intermittent fevers, arthritis, folliculitis, uveitis etc. In this article we discuss about various treatment methods used in Very early-onset inflammatory bowel disease (VEO IBD) including medical therapy, surgical therapy, hematopoietic stem cell transplantation and nutritional approach. In this systematic review, we have tried to summarized the current knowledge about Very early-onset inflammatory bowel disease

Sex differences in mortality among patients with lupus nephritis

ObjectiveTo evaluate the prognostic importance of sex in lupus nephritis (LN).MethodsA retrospective cohort of 1048 biopsy-confirmed LN patients, diagnosed between January 1, 1996, and December 31, 2018, was analyzed. Demographics, clinical characteristics, laboratory findings, and renal pathology were assessed. The primary outcome was mortality, and the secondary outcomes included doubling of serum creatinine and end-stage renal disease (ESRD). Sex-associated risks were evaluated using Cox regression models.ResultsAmong the1048 patients, 178 (17%) were male and 870 (83%) were female. Male patients exhibited more aggressive features: higher blood pressure, earlier disease onset, and elevated levels of serum creatinine (Scr), uric acid, blood urea nitrogen. Intriguingly, male patients also displayed more severe histopathological alterations, such as more total crescents, cellular crescents formations, higher level of glomerular leukocyte infiltration and Activity Index (AI), even when overall renal pathology was comparable between sexes. During a median follow-up of 112 months, mortality was registered in 141 patients (15.3%). Mortality rates were conspicuously higher in males (24.2% males vs. 13.4% females, p = 0.0029). Secondary outcomes did not show significant sex differences. Cox regression analysis highlighted male, age of renal biopsy, eGFR, and Chronicity Index (CI) as independent risk factors for survival in LN patients. Notably, infections emerged as the leading cause of mortality among LN patients, with a significant higher rate in male patients.ConclusionIn our cohort with LN, there was a higher rate of all-cause mortality and proportion of infection-related death in male. Recognizing and further exploring these sex disparities is crucial for optimized LN patients care.Graphical

An estimation of global genetic prevalence of PLA2G6-associated neurodegeneration

BackgroundPLA2G6-associated neurodegeneration (PLAN) comprises three diseases with overlapping features: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. INAD is an early onset disease characterized by progressive loss of vision, muscular control, and mental skills. The prevalence of PLA2G6-associated diseases has not been previously calculated.MethodsTo provide the most accurate prevalence estimate, we utilized two independent approaches: database-based approach which included collecting variants from ClinVar, Human Gene Mutation Database (HGMD) and high confidence predicted loss-of-function (pLoF) from gnomAD (Rare Genomes Project Genetic Prevalence Estimator; GeniE), and literature-based approach which gathered variants through Mastermind Genomic Search Engine (Genomenon, Inc). Genetic prevalence of PLAN was calculated based on allele frequencies from gnomAD, assuming Hardy–Weinberg equilibrium.ResultsIn the PLA2G6 gene, our analysis found 122 pathogenic, 82 VUS, and 15 variants with conflicting interpretations (pathogenic vs VUS) between two approaches. Allele frequency was available for 58 pathogenic, 42 VUS, and 15 conflicting variants in gnomAD database. If pathogenic and/or conflicting variants are included, the overall genetic prevalence was estimated to be between 1 in 987,267 to 1 in 1,570,079 pregnancies, with the highest genetic prevalence in African/African-American (1 in 421,960 to 1 in 365,197) and East-Asian (1 in 683,978 to 1 in 190,771) populations.ConclusionOur estimates highlight the significant underdiagnosis of PLA2G6-associated neurodegeneration and underscores the need for increased awareness and diagnostic efforts. Furthermore, our study revealed a higher carrier frequency of PLA2G6 variants in African and Asian populations, stressing the importance of expanded genetic sequencing in non-European populations to ensure accurate and comprehensive diagnosis. Future research should focus on confirming our findings and implementing expanded sequencing strategies to facilitate maximal and accurate diagnosis, particularly in non-European populations.

Neuropathology in an α-synuclein preformed fibril mouse model occurs independent of the Parkinson's disease-linked lysosomal ATP13A2 protein

Loss-of-function mutations in the ATP13A2 (PARK9) gene are implicated in early-onset autosomal recessive Parkinson's disease (PD) and other neurodegenerative disorders. ATP13A2 encodes a lysosomal transmembrane P5B-type ATPase that is highly expressed in brain and specifically within the substantia nigra pars compacta (SNc). Recent studies have revealed its normal role as a lysosomal polyamine transporter, although its contribution to PD-related pathology remains unclear. Cellular studies report that ATP13A2 can regulate α-synuclein (α-syn) secretion via exosomes. However, the relationship between ATP13A2 and α-syn in animal models remains inconclusive. ATP13A2 knockout (KO) mice exhibit lysosomal abnormalities and reactive astrogliosis but do not develop PD-related neuropathology. Studies manipulating α-syn levels in mice lacking ATP13A2 indicate minimal effects on pathology. The delivery of α-syn preformed fibrils (PFFs) into the mouse striatum is a well-defined model to study the development and spread of α-syn pathology. In this study we unilaterally injected wild-type (WT) and homozygous ATP13A2 KO mice with mouse α-syn PFFs in the striatum and evaluated mice for neuropathology after 6 months. The distribution, spread and extent of α-syn aggregation in multiple regions of the mouse brain was largely independent of ATP13A2 expression. The loss of nigrostriatal pathway dopaminergic neurons and their nerve terminals induced by PFFs were equivalent in WT and ATP13A2 KO mice. Reactive astrogliosis was induced equivalently by α-syn PFFs in WT and KO mice but was already significantly higher in ATP13A2 KO mice due to pre-existing reactive gliosis. We did not identify asymmetric motor disturbances, microglial activation, or axonal damage induced by α-syn PFFs in WT or KO mice. Although α-syn PFFs induce an increase in lysosomal number in the SNc in general, TH-positive dopaminergic neurons did not exhibit either increased lysosomal area or intensity, regardless of genotype. Our study evaluating the spread of α-syn pathology reveals no exacerbation of α-syn pathology, neuronal loss, astrogliosis or motor deficits in ATP13A2 KO mice, suggesting that selective lysosomal abnormalities resulting from ATP13A2 loss do not play a major role in α-syn clearance or propagation in vivo.

Novel Compound Heterozygous Variants in the FAS Gene Lead to Fetal Onset of Autoimmune Lymphoproliferative Syndrome (ALPS).

FAS gene defects lead to autoimmune lymphoproliferative syndrome (ALPS), which is often inherited in an autosomal dominant and rarely in an autosomal recessive manner. We report a case of a newborn girl with novel compound heterozygous variants in FAS and reveal the underlying mechanism. Whole-exome sequencing (WES) was used to identify pathogenic variants. Multiparametric flow cytometry analysis, phosflow analysis, and FAS-induced apoptosis assays were used to explore the effects of the variants on FAS expression, apoptosis, and immunophenotype. The HEK293T cells were used to assess the impact of the variants on protein expression and FAS-induced apoptosis. The patient was born with hepatosplenomegaly, anemia, and thrombocytopenia. She also experienced COVID-19, rotavirus infection, herpes simplex virus infection, and severe pneumonia. The proportion of double-negative T cells (DNTs) was significantly elevated. Novel FAS compound heterozygous variants c.310T > A (p.C104S) and c.702_704del (p.T235del) were identified. The apoptotic ability of T cells was defective, and FAS expression on the surface of T cells was deficient. The T235del variant decreased FAS expression, and the C104S protein remained in the endoplasmic reticulum (ER) and could not translocate to the cell surface. Both mutations resulted in loss-of-function in terms of FAS-induced apoptosis in HEK293T cells. The DNTs were mainly terminally differentiated T (TEMRA) and CD45RA+HLA-DR+, with high expression of CD85j, PD-1, and CD57. The percentage of Th1, Tfh, and autoreactive B cells were significantly increased in the patient. The abnormal immunophenotyping was partially attenuated by sirolimus treatment. We identified two variants that significantly affect FAS expression or localization, leading to early disease onset of in the fetus. Abnormalities in the mTOR pathway are associated with a favorable response to sirolimus.