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Clinics in Liver Disease Nov 2018Alagille syndrome is a complex multisystem autosomal dominant disorder with a wide variability in penetrance of clinical features. A majority of patients have pathogenic... (Review)
Review
Alagille syndrome is a complex multisystem autosomal dominant disorder with a wide variability in penetrance of clinical features. A majority of patients have pathogenic mutations in either the JAG1 gene, encoding a Notch pathway ligand, or the receptor NOTCH2. No genotype-phenotype correlations have been found in any organ system. Liver disease is a major cause of morbidity in this population, whereas cardiac and vascular involvement accounts for most of the mortality. Current therapies are supportive, but the future is promising for the development of targeted interventions to augment Notch pathway signaling in involved tissues.
Topics: Alagille Syndrome; Genetic Testing; Humans; Jagged-1 Protein; Liver Transplantation; Receptor, Notch2; Signal Transduction
PubMed: 30266153
DOI: 10.1016/j.cld.2018.06.001 -
European Journal of Human Genetics :... Mar 2012Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a multisystem disorder due to defects in components of the Notch signalling pathway, most commonly... (Review)
Review
Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a multisystem disorder due to defects in components of the Notch signalling pathway, most commonly due to mutation in JAG1 (ALGS type 1), but in a small proportion of cases mutation in NOTCH2 (ALGS type 2). The main clinical and pathological features are chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, minor vertebral segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys. It follows autosomal dominant inheritance, but reduced penetrance and variable expression are common in this disorder, and somatic/germline mosaicism may also be relatively frequent. This review discusses the clinical features of ALGS, including long-term complications, the clinical and molecular diagnosis, and management.
Topics: Alagille Syndrome; Calcium-Binding Proteins; Facies; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Mutation; Receptor, Notch2; Serrate-Jagged Proteins
PubMed: 21934706
DOI: 10.1038/ejhg.2011.181 -
Seminars in Liver Disease Nov 2021Alagille syndrome (ALGS) is an autosomal dominant disorder caused by pathogenic variants in or , which encode fundamental components of the Notch signaling pathway.... (Review)
Review
Alagille syndrome (ALGS) is an autosomal dominant disorder caused by pathogenic variants in or , which encode fundamental components of the Notch signaling pathway. Clinical features span multiple organ systems including hepatic, cardiac, vascular, renal, skeletal, craniofacial, and ocular, and occur with variable phenotypic penetrance. Genotype-phenotype correlation studies have not yet shown associations between mutation type and clinical manifestations or severity, and it has been hypothesized that modifier genes may modulate the effects of and pathogenic variants. Medical management is supportive, focusing on clinical manifestations of disease, with liver transplant indicated for severe pruritus, liver synthetic dysfunction, portal hypertension, bone fractures, and/or growth failure. New therapeutic approaches are under investigation, including ileal bile acid transporter (IBAT) inhibitors and other approaches that may involve targeted interventions to augment the Notch signaling pathway in involved tissues.
Topics: Alagille Syndrome; Humans; Jagged-1 Protein; Mutation; Receptor, Notch2; Signal Transduction
PubMed: 34215014
DOI: 10.1055/s-0041-1730951 -
Clinics in Liver Disease Aug 2022Alagille syndrome (ALGS) is a complex heterogenous disease with a wide array of clinical manifestations in association with cholestatic liver disease. Major clinical and... (Review)
Review
Alagille syndrome (ALGS) is a complex heterogenous disease with a wide array of clinical manifestations in association with cholestatic liver disease. Major clinical and genetic advancements have taken place since its first description in 1969. However, clinicians continue to face considerable challenges in the management of ALGS, particularly in the absence of targeted molecular therapies. In this article, we provide an overview of the broad ALGS phenotype, current approaches to diagnosis and with particular focus on key clinical challenges encountered in the management of these patients.
Topics: Alagille Syndrome; Humans; Jagged-1 Protein; Phenotype; Receptor, Notch2
PubMed: 35868679
DOI: 10.1016/j.cld.2022.03.002 -
Hepatology International Oct 2023Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is... (Review)
Review
Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is inherited in an autosomal dominant manner in 40% of patients, it carries many implications for genetic counselling of patients and screening of family members. In addition, the considerable variable expression and absence of a clear genotype-phenotype correlation, results in a diverse range of clinical manifestations, even in affected individuals within the same family. With recent therapeutic advancements in cholestasis treatment and the improved survival rates with liver transplantation (LT), many patients with ALGS survive into adulthood. Although LT is curative for liver disease secondary to ALGS, complications secondary to extrahepatic involvement remain problematic lifelong. This review is aimed at providing a comprehensive review of ALGS to adult clinicians who will take over the medical care of these patients following transition, with particular focus on certain aspects of the condition that require lifelong surveillance. We also provide a diagnostic framework for adult patients with suspected ALGS and highlight key aspects to consider when determining eligibility for LT in patients with this syndrome.
Topics: Adult; Humans; Alagille Syndrome; Liver Transplantation
PubMed: 37584849
DOI: 10.1007/s12072-023-10578-x -
Neonatal Network : NN Nov 2017Alagille syndrome (AGS) is a highly complex, multisystem, autosomal dominant disorder that is caused by a defect in the Notch signaling pathway. This syndrome mainly... (Review)
Review
Alagille syndrome (AGS) is a highly complex, multisystem, autosomal dominant disorder that is caused by a defect in the Notch signaling pathway. This syndrome mainly affects the liver, causing significant cholestasis, which is caused by a paucity of intrahepatic bile ducts. There can be cardiac involvement, including, but not limited to, pulmonary stenosis and tetralogy of Fallot. Patients can also present with butterfly vertebra, ocular issues, and vascular events. Because this syndrome follows an autosomal dominant inheritance, it can have variable expression even in the same family line. For infants in the NICU who have a cardiac defect and persistent hyperbilirubinemia after two weeks of age, genetic testing for AGS should be considered. Early detection and diagnosis can lead to improved outcomes. In this discussion of AGS, the clinical features as well as management are discussed.
Topics: Alagille Syndrome; Disease Management; Humans; Infant; Jagged-1 Protein; Neonatal Nursing; Receptors, Notch; Signal Transduction
PubMed: 29185945
DOI: 10.1891/0730-0832.36.6.343 -
Journal of Medical Genetics Feb 1997Alagille syndrome (OMIM 118450) is an autosomal dominant disorder associated with abnormalities of the liver, heart, eye, skeleton, and a characteristic facial... (Review)
Review
Alagille syndrome (OMIM 118450) is an autosomal dominant disorder associated with abnormalities of the liver, heart, eye, skeleton, and a characteristic facial appearance. Also referred to as the Alagille-Watson syndrome, syndromic bile duct paucity, and arteriohepatic dysplasia, it is a significant cause of neonatal jaundice and cholestasis in older children. In the fully expressed syndrome, affected subjects have intrahepatic bile duct paucity and cholestasis, in conjunction with cardiac malformations (most frequently peripheral pulmonary stenosis), ophthalmological abnormalities (typically of the anterior chamber with posterior embryotoxon being the most common), skeletal anomalies (most commonly butterfly vertebrae), and characteristic facial appearance. Inheritance is autosomal dominant, but expressivity is highly variable. Sibs and parents of probands are often found to have mild expression of the presumptive disease gene, with abnormalities of only one or two systems. The frequency of new mutations appears relatively high, estimated at between 15 and 50%. The disease gene has been mapped to chromosome 20 band p12 based on multiple patients described with cytogenetic or molecular rearrangements of this region. However, the frequency of detectable deletions of 20p12 is low (less than 7%). Progress has been made in the molecular definition of an Alagille syndrome critical region within the short arm of chromosome 20. We will review the clinical, genetic, cytogenetic, and molecular findings in this syndrome.
Topics: Alagille Syndrome; Female; Humans; Male; Molecular Sequence Data
PubMed: 9039994
DOI: 10.1136/jmg.34.2.152 -
Expert Review of Gastroenterology &... 2023Alagille syndrome (ALGS) is an autosomal dominant, multisystem genetic disorder with wide phenotypic variability caused by mutations in the Notch signaling pathway,... (Review)
Review
INTRODUCTION
Alagille syndrome (ALGS) is an autosomal dominant, multisystem genetic disorder with wide phenotypic variability caused by mutations in the Notch signaling pathway, specifically from mutations in either the Jagged1 (JAG1) or NOTCH2 gene. The range of clinical features in ALGS can involve various organ systems including the liver, heart, eyes, skeleton, kidney, and vasculature. Despite the genetic mutations being well-defined, there is variable expressivity and individuals with the same mutation may have different clinical phenotypes.
AREAS COVERED
While no clear genotype-phenotype correlation has been identified in ALGS, this review will summarize what is currently known about the genotype-phenotype relationship and how this relationship influences the treatment of the multisystemic disorder. This review includes discussion of numerous studies which have focused on describing the genotype-phenotype relationship of different organ systems in ALGS as well as relevant basic science and population studies of ALGS. A thorough literature search was completed via the PubMed and National Library of Medicine GeneReviews databases including dates from 1969, when ALGS was first identified, to February 2023.
EXPERT OPINION
The genetics of ALGS are well defined; however, ongoing investigation to identify genotype-phenotype relationships as well as genetic modifiers as potential therapeutic targets is needed. Clinicians and patients alike would benefit from identification of a correlation to aid in diagnostic evaluation and management.
Topics: Humans; Alagille Syndrome; Mutation; Phenotype; Genotype
PubMed: 37668532
DOI: 10.1080/17474124.2023.2255518 -
Revue Medicale Suisse Aug 2019Alagille syndrome is a rare disorder with low physician awareness. It affects multiple organs and thus patient management involves several medical specialties. It is an... (Review)
Review
Alagille syndrome is a rare disorder with low physician awareness. It affects multiple organs and thus patient management involves several medical specialties. It is an autosomal dominant disorder with significant intrafamilial variability. The most frequent clinical manifestations are neonatal jaundice, chronic cholestasis as well as cardiac, ocular and skeletal malformations associated with characteristic facial features. Inherited mutations affect the Notch pathway. Although the molecular basis of Alagille syndrome is well defined, no specific targeted therapy exists.
Topics: Alagille Syndrome; Humans
PubMed: 31496175
DOI: No ID Found -
Human Mutation Dec 2019Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1...
Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1 (JAG1), but also by variants in NOTCH2. The majority of JAG1 variants result in loss of function, however disease has also been attributed to lesser understood missense variants. Conversely, the majority of NOTCH2 variants are missense, though fewer of these variants have been described. In addition, there is a small group of patients with a clear clinical phenotype in the absence of a pathogenic variant. Here, we catalog our single-center study, which includes 401 probands and 111 affected family members amassed over a 27-year period, to provide updated mutation frequencies in JAG1 and NOTCH2 as well as functional validation of nine missense variants. Combining our cohort of 86 novel JAG1 and three novel NOTCH2 variants with previously published data (totaling 713 variants), we present the most comprehensive pathogenic variant overview for Alagille syndrome. Using this data set, we developed new guidance to help with the classification of JAG1 missense variants. Finally, we report clinically consistent cases for which a molecular etiology has not been identified and discuss the potential for next generation sequencing methodologies in novel variant discovery.
Topics: Alagille Syndrome; Female; Genetic Predisposition to Disease; Humans; Jagged-1 Protein; Loss of Function Mutation; Male; Mutation Rate; Mutation, Missense; Pedigree; Receptor, Notch2
PubMed: 31343788
DOI: 10.1002/humu.23879