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Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA ), a gene located at Xq13 that functions as a thyroid receptor–associated protein in the Mediator complex.

Ageing may be due to mutation accumulation across the lifespan, leading to tissue dysfunction, disease, and death. We tested whether germline autosomal mutation rates in young adults predict their remaining survival, and, for women, their reproductive lifespans. Age-adjusted mutation rates (AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d’Etude du Polymorphisme Humain) families were determined. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Utah Cancer Registry, and Utah Genetic Reference Project. Higher AAMRs were significantly associated with higher all-cause mortality in both sexes combined. Subjects in the top quartile of AAMRs experienced more than twice the mortality of bottom quartile subjects (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.21–3.56; p  =  0.008; median survival difference  =  4.7 years). Fertility analyses were restricted to women whose age at last birth (ALB) was  ≥  30 years, the age when fertility begins to decline. Women with higher AAMRs had significantly fewer live births and a younger ALB. Adult germline mutation accumulation rates are established in adolescence, and later menarche in women is associated with delayed mutation accumulation. We conclude that germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic ageing. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair systems begin their lifelong decline.

Background Amatoxin-related acute liver failure (AT-ALF) carries high mortality without liver transplantation (LTX). While therapeutic plasma exchange (PEX) might improve LTX-free survival in other ALF cases, its role in AT-ALF is unclear. Clinical practice varies, and, given the rarity of this ALF entity, the feasibility of conducting a randomized controlled trial to investigate PEX in AT-ALF is more or less impossible. Methods The Amanita-PEX study is a multi-center, international, retrospective study analyzing patients with AT-ALF from 2013 to 2024. The primary outcome was 28-day LTX-free survival (composite endpoint: death or LTX) after ALF diagnosis. Results The study included 111 patients from 25 centers: 82 received standard-of-care (SOC), and 29 received at least one PEX-session. PEX and SOC-groups were comparable at baseline, but 76% of PEX- vs. 58% of SOC-patients developed hepatic-encephalopathy (HE) grade ≥ 2 ( p  = 0.021). While the primary outcome of 28-day LTX-free survival in all patients was not different between the SOC and PEX-groups, in the subgroup of patients with maximal HE grade ≥ 2, LTX-free survival was 19.1% ( n  = 8/42) in the SOC group, while it was 36.4% ( n  = 8/22) in patients receiving adjunctive PEX (Gehan-Breslow-Wilcoxon- p  = 0.041, Log-Rank- p  = 0.060). PEX was independently associated with reduced risk of the combined endpoint death or liver transplantation within 28 days from inclusion in patients with HE grade ≥ 2 (HR 0.37, 95%-CI 0.19–0.73, p  = 0.004). After propensity-score-matching, LTX-free survival was 28% in the SOC- and 52% in the PEX group (Gehan-Breslow- p  = 0.036; Log-Rank- p  = 0.035). Conclusions In this real-world study, adjunctive use of PEX was associated with increased LTX-free-survival in patients with AT-ALF and HE grade ≥ 2. Highlights Acute liver failure due to ingestion of mushrooms containing amatoxins has a poor prognosis when higher grade hepatic encephalopathy develops. Adjunctive use of therapeutic plasma exchange was independently associated with increased liver transplant-free-survival in patients with amatoxin associated acute liver failure and maximum hepatic encephalopathy grade ≥ 2. Therapeutic plasma exchange was not associated with increased liver transplant-free-survival in patients with hepatic encephalopathy grade 1 and did not improve overall-survival or other secondary endpoints such as shorter length of hospital stay or lower incidence of acute kidney injury, need for renal-replacement therapy, invasive ventilation or vasopressor support. Impact and Implications Therapeutic plasma exchange is frequently used in the management of patients with acute liver failure but its effect on improving liver transplant-free-survival has recently been questioned. Amatoxin-associated acute liver failure is a rare entity of acute liver failure and solid data concerning clinical outcomes are scarce. This multi-national, multi-center, real-world, retrospective study suggests that therapeutic plasma exchange is significantly associated with improved liver transplant-free survival only in patients with amatoxin-associated acute liver failure and higher-grade hepatic encephalopathy. These results might help to guide the future use of therapeutic plasma exchange in this specific patient population. Graphical abstract