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EMBO Molecular Medicine Dec 2022Spontaneous bleeds are a leading cause of death in the pediatric JAG1-related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in...
Spontaneous bleeds are a leading cause of death in the pediatric JAG1-related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1 mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non-invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1 mice, using retina as a model. Jag1 mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex-specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non-invasive vascular analysis in patients. Finally, Jag1 mice represent a new model for vascular compromise in ALGS.
Topics: Female; Male; Animals; Mice; Alagille Syndrome; Sex Characteristics; Retina; Risk Factors
PubMed: 36345711
DOI: 10.15252/emmm.202215809 -
Indian Journal of Otolaryngology and... Dec 2022Alagille Syndrome (ALGS) is a rare, autosomal dominant inherited disorder that causes abnormalities of liver, eye, heart, skeleton and distinctive facial appearance....
Alagille Syndrome (ALGS) is a rare, autosomal dominant inherited disorder that causes abnormalities of liver, eye, heart, skeleton and distinctive facial appearance. ALGS is caused by mutation in one of two genes: JAG1 and NOTCH2. There are some reports of Hearing Loss in patients with ALGS raising the possibility of involvement of both structural components of middle ear and sensorineural components of the inner ear. The present case study was to emphasize audiological perspectives of Alagille Syndrome in a nine year old female child. Audiologists must be well aware of the typical features and clinical perspectives of ALGS and should be an expert in selecting appropriate tests and in interpreting findings.
PubMed: 36742831
DOI: 10.1007/s12070-020-02293-y -
World Journal of Gastroenterology Sep 2018Pediatric hepatocellular carcinoma (HCC) is the second common malignant liver tumor in children after hepatoblastoma. It differs from the adult HCC in the etiological... (Review)
Review
Pediatric hepatocellular carcinoma (HCC) is the second common malignant liver tumor in children after hepatoblastoma. It differs from the adult HCC in the etiological predisposition, biological behavior and lower frequency of cirrhosis. Perinatally acquired hepatitis-B virus, hepatorenal tyrosinemia, progressive familial intrahepatic cholestasis, glycogen storage disease, Alagille's syndrome and congenital portosystemic shunts are important predisposing factors. Majority of children (87%) are older than 5 years of age. Following mass immunization against hepatitis-B, there has been a drastic fall in the incidence of new cases of pediatric HCC in the Asia-Pacific region. Management is targeted on complete surgical removal either by resection or liver transplantation. There is a trend towards improving survival of children transplanted for HCC beyond Milan criteria. Chemotherapeutic regimens do not offer good results but may be helpful for down-staging of advanced HCC. Surveillance of children with chronic liver diseases with ultrasound and alpha-fetoprotein may be helpful in timely detection, intervention and overall improvement in outcome of HCC.
Topics: Age Factors; Antineoplastic Agents; Carcinoma, Hepatocellular; Child; Combined Modality Therapy; Early Detection of Cancer; Hepatectomy; Humans; Liver; Liver Neoplasms; Liver Transplantation; Neoplasm Staging; Prevalence; Prognosis; Risk Factors; Survival Rate; Treatment Outcome; Ultrasonography; alpha-Fetoproteins
PubMed: 30254403
DOI: 10.3748/wjg.v24.i35.3980 -
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 -
Current Opinion in Cell Biology Feb 2024Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged... (Review)
Review
Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged canonical Notch ligand 1 (JAG1), and manifests with liver disease and cardiovascular symptoms that are a direct consequence of JAG1 haploinsufficiency. Recent insights into Jag1/Notch-controlled developmental and homeostatic processes explain how pathology develops in the hepatic and cardiovascular systems and, together with recent elucidation of mechanisms modulating liver regeneration, provide a basis for therapeutic efforts. Importantly, disease presentation can be regulated by genetic modifiers, that may also be therapeutically leverageable. Here, we summarize recent insights into how Jag1 controls processes of relevance to Alagille syndrome, focused on Jag1/Notch functions in hepatic and cardiovascular development and homeostasis.
Topics: Humans; Alagille Syndrome; Serrate-Jagged Proteins; Membrane Proteins; Calcium-Binding Proteins; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein
PubMed: 38194749
DOI: 10.1016/j.ceb.2023.102302 -
Euroasian Journal of... 2018Alagille syndrome (ALGS) is an autosomal dominant disorder, with multisystem involvement, which usually occurs due to Notch signaling pathway defects, mostly due to... (Review)
Review
Alagille syndrome (ALGS) is an autosomal dominant disorder, with multisystem involvement, which usually occurs due to Notch signaling pathway defects, mostly due to mutation (ALGS type 1), but rarely due to neurogenic locus notch homolog protein (NOTCH2) mutation (ALGS type 2). It was suspected in cases having at least three out of five major clinical criteria: cholestasis with a paucity of the bile duct, congenital cardiac defects, ocular posterior embryotoxon, typical facial features, and skeletal malformation. Till date, no early predictive marker for hepatic outcome in ALGS has found. No genotypic or, phenotype features or correlation could predict the development of endstage liver disease, which poses a unique management challenge. Cases with progressive liver damage, unremitting cholestasis and intractable pruritus often depend on liver transplantation as last resort. The cardiac, and renal status should be well accessed before liver transplant for the better post-transplantation outcome. Most of the clinical manifestations usually improve the following transplant, except any change in stature. The post liver transplantation outcome was usually comparable with other conditions which require liver transplantation as a last resort, but in this disease the effect of long term immunosuppression on other affected systems not evaluated well till date. Therefore long term post transplant prospective study is required to address these issues. Singh SP, Pati GK. Alagille Syndrome and the Liver: Current Insights. Euroasian J Hepatogastroenterol, 2018;8(2):140-147.
PubMed: 30828556
DOI: 10.5005/jp-journals-10018-1280 -
Diagnostics (Basel, Switzerland) Nov 2020Alagille syndrome (ALGS) is a multisystem disease characterized by cholestasis and bile duct paucity on liver biopsy in addition to variable involvement of the heart,... (Review)
Review
Alagille syndrome (ALGS) is a multisystem disease characterized by cholestasis and bile duct paucity on liver biopsy in addition to variable involvement of the heart, eyes, skeleton, face, kidneys, and vasculature. The identification of and as disease-causing genes has deepened our understanding of the molecular mechanisms underlying ALGS. However, the variable expressivity of the clinical phenotype and the lack of genotype-phenotype relationships creates significant diagnostic and therapeutic challenges. In this review, we provide a comprehensive overview of the clinical characteristics and management of ALGS, and the molecular basis of ALGS pathobiology. We further describe unique diagnostic considerations that pose challenges to clinicians and outline therapeutic concepts and treatment targets that may be available in the near future.
PubMed: 33172025
DOI: 10.3390/diagnostics10110907 -
Translational Gastroenterology and... 2021The observation of bile duct paucity is an important diagnostic finding in children, occurring in roughly 11% of pediatric liver biopsies. Alagille syndrome (ALGS) is a... (Review)
Review
The observation of bile duct paucity is an important diagnostic finding in children, occurring in roughly 11% of pediatric liver biopsies. Alagille syndrome (ALGS) is a well-defined syndromic form of intrahepatic bile duct paucity that is accompanied by a number of other key features, including cardiac, facial, ocular, and vertebral abnormalities. In the absence of these additional clinical characteristics, intrahepatic bile duct paucity results in a broad differential diagnosis that requires supplementary testing and characterization. Nearly 30 years after ALGS was first described, genetic studies identified a causative gene, , which spearheaded over two decades of research aimed to meticulously delineate the molecular underpinnings of ALGS. These advancements have characterized ALGS as a genetic disease and led to testing strategies that offer the ability to detect a pathogenic genetic variant in almost 97% of individuals with ALGS. Having a molecular understanding of ALGS has allowed for the development of numerous and disease models, which have provided hope and promise for the future generation of gene-based and protein-based therapies. Generation of these disease models has offered scientists a mechanism to study the dynamics of bile duct development and regeneration, and in doing so, produced tools that are applicable to the understanding of other congenital and acquired liver diseases.
PubMed: 33824926
DOI: 10.21037/tgh-2020-03 -
Archivos Argentinos de Pediatria Dec 2012Alagille syndrome (AS) is a multisystemic disease autosomal dominant, with variable expression. The major clinical manifestations are: chronic cholestasis, congenital...
Alagille syndrome (AS) is a multisystemic disease autosomal dominant, with variable expression. The major clinical manifestations are: chronic cholestasis, congenital heart disease, posterior embryotoxon in the eye, characteristic facial phenotype, and butterfy vertebrae. AS is caused by mutations in JAGGED1 (more than 90%) and in NOTCH2. Differential diagnosis include: infections, genetic-metabolic diseases, biliary atresia, idiopathic cholestasis. Cholestasis, pruritus and xanthomas have been successfully treated with choleretic agents (ursodeoxycholic acid) and other medications (cholestyramine, rifampin, naltrexone). In certain cases, partial external biliary diversion has also proved successful. Liver transplantation is indicated in children with cirrhosis and liver failure.
Topics: Alagille Syndrome; Child; Humans
PubMed: 23224309
DOI: 10.5546/aap.2012.509 -
World Journal of Gastroenterology Jul 2014Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic... (Review)
Review
Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have "silent" progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.
Topics: Alagille Syndrome; Biliary Atresia; Chemical and Drug Induced Liver Injury; Cholestasis; Cholestasis, Intrahepatic; Female; Genetic Predisposition to Disease; Heredity; Humans; Male; Parenteral Nutrition, Total; Pedigree; Phenotype; Pregnancy; Pregnancy Complications; Prognosis; Recurrence; Risk Factors; Sepsis
PubMed: 25071336
DOI: 10.3748/wjg.v20.i28.9418