👤 Juliette Svahn

Brain death induces systemic inflammation and hemodynamic changes that can lead to lung injury, impacting the quality of donor organs for transplantation. Extracellular vesicles (EVs) are cell-derived nanoparticles that carry functional biomolecules and reflect the physiological state of their cells of origin. We hypothesized that EVs from brain-dead donors may indicate lung injury and may be used to predict primary graft dysfunction (PGD) in lung transplant recipients. We performed transcriptomic profiling of plasma EVs from 44 brain-dead lung donors and 9 healthy controls using next-generation sequencing. Differential gene expression was assessed, followed by pathway enrichment analyses. The results were validated by quantitative polymerase chain reaction using the study cohort and an independent cohort. Variable importance of projection score analysis and regression models were used to identify EV transcripts associated with PGD in recipients. Transcriptomic analysis revealed that 13% of protein-coding genes were differentially expressed in lung donor EVs compared with controls, with 92% of these genes upregulated. Upregulated genes were enriched in pathways related to inflammation, coagulation, tissue remodeling, and metabolism. Seven key EV transcripts, RAD51D, ABL2, FGFR1, WDR82, PTBP3, OPRL1, and XG were identified as potential PGD indicator. These transcripts were associated with processes such as DNA damage repair, signal transduction, and inflammation, which may contribute to posttransplant lung injury. Donor plasma EVs carry distinct transcriptomic signatures associated with injury and inflammation. Specific EV transcripts, such as RAD51D and XG, hold promise as independent predictive biomarkers for PGD, possibly providing new tools for evaluating donor organ quality and improving lung transplant outcomes. Show less

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking, and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years [standard deviation (SD) = 15.1]. Pathogenic variants were found in 19 disease-related genes. CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE-LE, CHRND, FCCMS), distal group (SCCMS), limb-girdle group (RAPSN, COLQ, DOK7, GMPPB, GFPT1), and a variable-phenotype group (MUSK, AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7, SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE-LE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved. Show less