👤 Oscar Millet

The relationship between plasma lipoprotein(a) [Lp(a)] levels and metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. The aim of this study was to examine the combined effects of Lp(a) levels on liver and vascular damage. The study was conducted using the Liver-Bible cohort of individuals with metabolic dysfunction (n = 859, 808 with genomic information) and the Milan Biobank (n = 6963). Genome-wide association studies (GWAS) and polygenic risk scores (PRS) were used to evaluate the inherited factors influencing plasma Lp(a) levels. In the Liver-Bible cohort, genetic variation in the LPA gene was the strongest determinant of Lp(a), followed by liver stiffness measurement (LSM). Additionally, circulating Lp(a) levels, but not genetic predisposition, were inversely related to LSM, suggesting that MASLD severity may affect Lp(a) secretion. Among participants with more severe insulin resistance (n = 250), Lp(a) levels (odds ratio 6.7, 95% CI 1.0-53.0, p = 0.046) and LSM (odds ratio 13.7, 95% CI 1.4-172.2, p = 0.023) were associated with greater prevalence of carotid atherosclerotic plaques, regardless of traditional cardiovascular risk factors. In the Milan Biobank, genetically predicted higher Lp(a) levels tended to increase the risk of liver-related outcomes, whereas genetically predicted MASLD was associated with lower circulating Lp(a) levels. The results of this study suggest that liver damage is more likely the cause of reduced plasma Lp(a) levels rather than a consequence. Assessing plasma Lp(a) levels and the extent of liver damage could improve the prediction of vascular damage. 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