2026-08-12 | Long-Term Outcomes of Living Donor Liver Transplantation in Children With Alagille Syndrome: Results From Vanguard Multicenter Study of International Living Donor Liver Transplantation Group.
The morbidity and mortality after living donor liver transplantation (LDLT) in children with Alagille syndrome (AGS) are complex because of the multisystem involvement of the disease. Evidence on long-term outcomes and donor selection remains limited. This multicenter retrospective study included 49 pediatric patients with AGS who underwent LDLT between 2001 and 2020 at eight institutions in Japan, Korea, and Turkey. Clinical characteristics, transplant indications, donor selection, posttransplant growth, renal function, and complications were analyzed. The median age at LDLT was 1.1 years. Major indications for transplantation were severe growth failure (91.8%) and advanced liver disease with hepatic dysfunction. Based on donor evaluations, 11% of candidates were excluded due to genetic or anatomical concerns. The 5-year patient and graft survival rates were 93.7% and 91.5%, respectively. LDLT before 2 years of age was associated with significantly greater catch-up in height and weight. Long-term renal deterioration was observed, particularly beyond 15 years after transplantation, and older age at LDLT was an independent predictor of lower long-term estimated glomerular filtration rate. Cardiac anomalies were manageable with appropriate preoperative evaluation, whereas vasculopathies were observed after adolescence. A history of Kasai portoenterostomy did not significantly affect posttransplant outcomes. LDLT provides excellent short- and long-term outcomes in pediatric AGS. Timely LT may improve growth and preserve renal function before progressive multisystem complications become established. Long-term surveillance and comprehensive donor evaluation remain essential.
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2026-07-25 | Three high throughput compatible cell-based assays for identifying small molecule JAG1 upregulators for Alagille syndrome.
Haploinsufficiency disorders arise when loss of function mutations in one allele of a gene reduce gene dosage below the level required for normal physiology. Pharmacologic upregulation of the remaining functional allele represents a promising therapeutic strategy but requires screening assays capable of detecting modest changes in endogenous gene expression. Here we developed and compared three high throughput cell-based assays for identifying small molecule upregulators of JAG1, the gene most frequently mutated in Alagille syndrome (ALGS). The assays measure JAG1 expression at different molecular levels: RNA fluorescence in situ hybridization (RNA FISH) for JAG1 mRNA, immunofluorescence (IF) for endogenous JAG1 protein, and a HiBiT luminescence assay using CRISPR engineered LX-2 hepatic stellate cells expressing HiBiT tagged JAG1. Each assay was optimized in 384-well format and benchmarked using a panel of 32 histone deacetylase inhibitors (HDACi), compounds known to broadly increase gene expression. All three assays detected JAG1 upregulation and identified overlapping sets of active compounds. The homogeneous HiBiT assay showed the most favorable high throughput screening statistics (S/B = 2.7 and Z' > 0.5) and the lowest well to well variability, whereas the RNA FISH and IF assays provided higher signal to basal ratios and single cell resolution. Entinostat, Mocetinostat, and Chidamide were consistently identified as the most potent JAG1 upregulators across all assays. These complementary assays provide a flexible platform for identifying small molecule modulators of gene dosage and may be broadly applicable to drug discovery efforts targeting haploinsufficiency diseases.
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2026-06-18 | Heterozygous variants in NOTCH2 in a cohort of juvenile and adult patients with cholestatic liver disease: Disease modifiers or innocent bystanders?
Background and objective: Genetic cholestatic liver diseases are increasingly stratified using NGS. The resulting information can guide treatment with novel drugs such as IBAT inhibitors, which have demonstrated efficacy in congenital liver disorders including Alagille syndrome and PFIC. We hypothesised [for full text, please go to the a.m. URL]
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2026-06-18 | Use of genetic analysis in adult cholestatic liver disease: lessons from progressive paediatric syndromes and cohort studies.
The increasing availability and decreasing costs of DNA sequencing have resulted in the re-grouping of rare, severe paediatric cases of progressive familial intrahepatic cholestasis (PFIC) with more frequent, later-onset cases of cholestasis (eg, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis, low phospholipid-associated cholelithiasis) under the umbrella of genetic cholestasis. The common denominator is the presence of functional variants in the PFIC-associated genes, predominantly in ABCB4, ABCB11 and ATP8B1, which cause PFIC types 1-3. Several other congenital diseases such as Alagille syndrome and alpha1-antitrypsin deficiency comprise cholestatic pruritus as frequent symptoms.With the availability of intestinal bile acid transporter inhibitors (IBATi) as new and efficacious therapeutics for pruritus, the most debilitating symptom of PFIC, it is essential to envision their usefulness for patients with later-onset cholestatic liver disease suffering from pruritus.In this review, we summarise published studies on the genetic makeup of patients with paediatric, juvenile and adult-onset cholestasis, and discuss their findings with respect to genotype-specific treatment with IBATi, ursodeoxycholic acid, or alternative drugs. The aim is to provide an overview of the genetic variants likely to be encountered in future sequencing investigations of patients with cholestatic liver diseases, and how to translate this genetic information into personalised treatment recommendations.
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2026-05-04 | From supportive to targeted treatment strategies: the changing landscape of therapeutics in Alagille syndrome
1. Alagille syndrome (ALGS) is an autosomal dominant developmental disorder characterized by highly variable, multisystem involvement and caused by pathogenic variants in the genes Jagged1 (JAG1) a...
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