The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Nancy B. Spinner - One of the best experts on this subject based on the ideXlab platform.
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Alagille Syndrome genetics and functional models
Current Pathobiology Reports, 2017Co-Authors: Melissa A Gilbert, Nancy B. SpinnerAbstract:We review the genetics of the autosomal dominant, multi-system disorder Alagille Syndrome, and provide a summary on how current functional models and emerging biotechnologies are equipped to guide scientists towards novel therapies. The importance of haploinsufficiency as a disease mechanism will be underscored throughout this discussion. Alagille Syndrome, a human disorder affecting the liver, heart, vasculature, kidney, and other systems, is caused by mutations in the Notch signaling pathway ligand, Jagged1 (JAG1) or the receptor, NOTCH2. Current advances in animal modeling, in vitro cell culture, and human-induced pluripotent stem cells provide new opportunities in which to study disease mechanisms and manifestations. We anticipate that the availability of innovative functional models will allow scientists to test new gene therapies or small molecule treatments in physiologically-relevant systems. With these advances, we look forward to the development of new methods to help Alagille Syndrome patients.
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spectrum of jag1 gene mutations in polish patients with Alagille Syndrome
Journal of Applied Genetics, 2014Co-Authors: Dorota Jurkiewicz, Nancy B. Spinner, Jennifer Gerfen, Dorota Gliwicz, Elzbieta Ciara, Magdalena Pelc, Dorota Piekutowskaabramczuk, Monika Kugaudo, Krystyna H Chrzanowska, Malgorzata KrajewskawalasekAbstract:Alagille Syndrome (ALGS) is an autosomal dominant disorder characterized by developmental abnormalities in several organs including the liver, heart, eyes, vertebrae, kidneys, and face. The majority (90-94%) of ALGS cases are caused by mutations in the JAG1 (JAGGED1) gene, and in a small percent of patients (∼1%) mutations in the NOTCH2 gene have been described. Both genes are involved in the Notch signaling pathway. To date, over 440 different JAG1 gene mutations and ten NOTCH2 mutations have been identified in ALGS patients. The present study was conducted on a group of 35 Polish ALGS patients and revealed JAG1 gene mutations in 26 of them. Twenty-three different mutations were detected including 13 novel point mutations and six large deletions affecting the JAG1 gene. Review of all mutations identified to date in individuals from Poland allowed us to propose an effective diagnostic strategy based on the mutations identified in the reported patients of Polish descent. However, the distribution of mutations seen in this cohort was not substantively different than the mutation distribution in other reported populations.
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spectrum of jag1 gene mutations in polish patients with Alagille Syndrome
Journal of Applied Genetics, 2014Co-Authors: Dorota Jurkiewicz, Nancy B. Spinner, Jennifer Gerfen, Dorota Gliwicz, Elzbieta Ciara, Magdalena Pelc, Dorota Piekutowskaabramczuk, Monika Kugaudo, Krystyna H Chrzanowska, Malgorzata KrajewskawalasekAbstract:Alagille Syndrome (ALGS) is an autosomal dominant disorder characterized by developmental abnormalities in several organs including the liver, heart, eyes, vertebrae, kidneys, and face. The majority (90-94 %) of ALGS cases are caused by mutations in the JAG1 (JAGGED1) gene, and in a small percent of patients (∼1 %) mutations in the NOTCH2 gene have been described. Both genes are involved in the Notch signaling pathway. To date, over 440 different JAG1 gene mutations and ten NOTCH2 mutations have been identified in ALGS patients. The present study was conducted on a group of 35 Polish ALGS patients and revealed JAG1 gene mutations in 26 of them. Twenty-three different mutations were detected including 13 novel point mutations and six large deletions affecting the JAG1 gene. Review of all mutations identified to date in individuals from Poland allowed us to propose an effective diagnostic strategy based on the mutations identified in the reported patients of Polish descent. However, the distribution of mutations seen in this cohort was not substantively different than the mutation distribution in other reported populations.
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clinical utility gene card for Alagille Syndrome algs
European Journal of Human Genetics, 2014Co-Authors: Laura D Leonard, Grace Chao, Kathleen M Loomes, Alastair Baker, Nancy B. SpinnerAbstract:Name of the disease (synonyms) Alagille Syndrome (ALGS); Alagille Syndrome 1 (ALGS1); Alagille Syndrome 2 (ALGS2). Other synonyms include Alagille–Watson Syndrome (AWS); cholestasis with peripheral pulmonary stenosis; arteriohepatic dysplasia (AHD); hepatic ductular hypoplasia, Syndrome; Miller–Watson Syndrome.1, 2, 3, 4 OMIM# of the disease ALGS1: 118450; ALGS2: 610205 Analysed genes or DNA/chromosome segments JAG1 (Jagged1 gene; locus 20p12.2; disease ALGS1); NOTCH2 (Notch2 gene; locus 1p12-p11; disease ALGS2). OMIM# of the gene(s) JAG1 (601920); NOTCH2 (600275). Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the JAG1 and NOTCH2 genes in diagnostic, predictive and prenatal settings and for risk assessment in relatives.
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renal involvement and the role of notch signalling in Alagille Syndrome
Nature Reviews Nephrology, 2013Co-Authors: Binita M Kamath, Nancy B. Spinner, Norman D RosenblumAbstract:Alagille Syndrome is an autosomal dominant disorder with variable multisystem organ involvement that is caused by mutations in one of two genes in the Notch signalling pathway, JAG1 or NOTCH2. Alagille Syndrome is characterized by bile duct paucity, along with at least three of the following features: cholestasis, cardiac defects, skeletal abnormalities, ocular abnormalities and characteristic facies. However, the clinical features of Alagille Syndrome are highly variable, and children or adults may also present with predominantly renal findings and little or no hepatic involvement. Renal involvement occurs in 40% of JAG1-mutation-positive individuals. Renal insufficiency is common and has been specifically reported in children with Alagille Syndrome who have end-stage liver disease. The role of NOTCH2 and JAG1 in formation of proximal nephron structures and podocytes might explain the observed phenotypes of renal dysplasia and proteinuria in patients with Alagille Syndrome, and renal tubular acidosis may be the result of JAG1 expression in the collecting ducts. Renal vascular hypertension in patients with Alagille Syndrome is explained by the widespread vasculopathy and the role of Notch signalling in vascular development. Increased awareness of Alagille Syndrome amongst nephrologists may lead to more diagnoses of Alagille Syndrome in patients with apparently isolated renal disease.
David A. Piccoli - One of the best experts on this subject based on the ideXlab platform.
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bone geometry and microarchitecture deficits in children with Alagille Syndrome
Bone, 2020Co-Authors: Joseph M Kindler, David A. Piccoli, Kathleen M Loomes, Mary B Leonard, Adda Grimberg, Babette S Zemel, Ellen MitchellAbstract:ABSTRACT Alagille Syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility fracture of unknown etiology. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS. This was a cross-sectional study of 10 children (9 females), ages 8-18 years, with a clinical diagnosis of ALGS. Bone density was assessed via DXA (Hologic Discovery A) at several skeletal regions. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II) at an ultradistal site located at 4% of tibia length and a cortical site at 30% of tibia length. Z-scores were calculated for DXA and pQCT measures. In the absence of XtremeCT II HR-pQCT reference data, these outcome measures were descriptively compared to a sample of healthy children ages 5-20 years (n=247). Anthropometrics and labs were also collected. Based on one-sample t-tests, mean Z-scores for height and weight (both p
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thbs2 is a candidate modifier of liver disease severity in Alagille Syndrome
Cellular and molecular gastroenterology and hepatology, 2016Co-Authors: Ellen A Tsai, Christopher M Grochowski, Melissa A Gilbert, Kurt D Hankenson, Lara A Underkoffler, He Meng, Xiaojie Zhang, Michael M Wang, Hailu Shitaye, David A. PiccoliAbstract:Background & Aims Alagille Syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille Syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder. Methods We performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus. Results We identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased microvessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1–NOTCH2 interactions. Conclusions Based on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1–NOTCH2 signaling in patients harboring a JAG1 mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille Syndrome.
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early life predictive markers of liver disease outcome in an international multicentre cohort of children with Alagille Syndrome
Liver International, 2016Co-Authors: Marialena Mouzaki, David A. Piccoli, Kathleen M Loomes, James E Heubi, Lee M Bass, Ronald J Sokol, Claudia Quammie, Paula M Hertel, Rene Scheenstra, Katryn N FuruyaAbstract:Background & Aims Liver disease in Alagille Syndrome is highly variable. Many of the patients presenting with severe cholestasis early in life improve spontaneously; 10–20%, however, have progressive disease. It is currently not possible to predict long-term hepatic outcomes in Alagille Syndrome. This international, multicentre study was aimed at identifying early life predictors of liver disease outcome. Methods Retrospective clinical, laboratory and radiographic data from a cohort of 144 Alagille Syndrome patients, whose long-term hepatic outcomes had been determined a priori based on previously published criteria, were collected. Results Sixty-seven patients had mild and 77 had severe hepatic outcome. Univariate analysis demonstrated that cholestasis and fibrosis on biopsy, as well as the presence of xanthomata were significantly different between the groups (P < 0.05 for all). Mixed model analysis revealed that total serum bilirubin and serum cholesterol were also associated with outcome (P = 0.001 and P = 0.002, respectively). Graphical representation of the data revealed a change in total bilirubin levels between 12 and 24 months of age in the mild group. Recursive partitioning identified a threshold for total bilirubin of 3.8 mg/dl (65 mmol/L) in that age-frame that differentiated between outcomes. A multivariable logistic regression model was developed using fibrosis, xanthomata and the total bilirubin cut-off of 3.8 mg/dl (65 mmol/L), which generated an area under the ROC curve of 0.792. Conclusions The long-term hepatic outcomes of patients with Alagille Syndrome can be predicted based on serum total bilirubin between the ages of 12–24 months combined with fibrosis on liver biopsy and the presence of xanthomata on physical examination.
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moyamoya Syndrome associated with Alagille Syndrome outcome after surgical revascularization
The Journal of Pediatrics, 2015Co-Authors: David A. Piccoli, Lissa C Baird, Edward R Smith, Rebecca Ichord, Timothy J BernardAbstract:Vasculopathy is well-described in Alagille Syndrome (ALGS); however, few data exist regarding neurosurgical interventions. We report 5 children with ALGS with moyamoya who underwent revascularization surgery. Postsurgical complications included 1 stroke and 1 death from thalamic hemorrhage. Global function improved in survivors. Revascularization is reasonably safe in patients with ALGS and may improve neurologic outcomes.
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pathologic lower extremity fractures in children with Alagille Syndrome
Journal of Pediatric Gastroenterology and Nutrition, 2010Co-Authors: Christina Bales, Binita M Kamath, David A. Piccoli, Nancy B. Spinner, Pedro S Munoz, Alexander Nguyen, David Horn, Justine Shults, Mary B Leonard, Adda GrimbergAbstract:ABSTRACTObjectives:In this retrospective study, we aimed to determine the incidence and distribution of fractures in patients with Alagille Syndrome, 1 of the leading inherited causes of pediatric cholestatic liver disease.Materials and Methods:Surveys regarding growth, nutrition, and organ involvem
Ian D. Krantz - One of the best experts on this subject based on the ideXlab platform.
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Alagille Syndrome in a vietnamese cohort mutation analysis and assessment of facial features
American Journal of Medical Genetics Part A, 2012Co-Authors: Henry C Lin, Grace Chao, Binita M Kamath, Ian D. Krantz, Kathleen M Loomes, Jennifer Gerfen, Anne L Hutchinson, Phuc Le Hoang, Nancy B. SpinnerAbstract:Alagille Syndrome (ALGS, OMIM #118450) is an autosomal dominant disorder that affects multiple organ systems including the liver, heart, eyes, vertebrae, and face. ALGS is caused by mutations in one of two genes in the Notch Signaling Pathway, Jagged1 (JAG1) or NOTCH2. In this study, analysis of 21 Vietnamese ALGS individuals led to the identification of 19 different mutations (18 JAG1 and 1 NOTCH2), 17 of which are novel, including the third reported NOTCH2 mutation in Alagille Syndrome. The spectrum of JAG1 mutations in the Vietnamese patients is similar to that previously reported, including nine frameshift, three missense, two splice site, one nonsense, two whole gene, and one partial gene deletion. The missense mutations are all likely to be disease causing, as two are loss of cysteines (C22R and C78G) and the third creates a cryptic splice site in exon 9 (G386R). No correlation between genotype and phenotype was observed. Assessment of clinical phenotype revealed that skeletal manifestations occur with a higher frequency than in previously reported Alagille cohorts. Facial features were difficult to assess and a Vietnamese pediatric gastroenterologist was only able to identify the facial phenotype in 61% of the cohort. To assess the agreement among North American dysmorphologists at detecting the presence of ALGS facial features in the Vietnamese patients, 37 clinical dysmorphologists evaluated a photographic panel of 20 Vietnamese children with and without ALGS. The dysmorphologists were unable to identify the individuals with ALGS in the majority of cases, suggesting that evaluation of facial features should not be used in the diagnosis of ALGS in this population. This is the first report of mutations and phenotypic spectrum of ALGS in a Vietnamese population.
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notch2 mutations in Alagille Syndrome
Journal of Medical Genetics, 2012Co-Authors: Binita M Kamath, Robert C Bauer, Grace Chao, Kathleen M Loomes, Jennifer Gerfen, Anne L Hutchinson, Winita Hardikar, Gideon M Hirschfield, P Jara, Ian D. KrantzAbstract:Background Alagille Syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation. Methods The study screened a cohort of JAG1 -negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations. Results Eight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1 ). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort. Conclusions This work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype.
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NOTCH2 Mutations Cause Alagille Syndrome, a Heterogeneous Disorder of the Notch Signaling Pathway
American journal of human genetics, 2006Co-Authors: Ryan Mcdaniell, Ian D. Krantz, Daniel M. Warthen, Pedro A. Sanchez-lara, Athma A. Pai, David A. Piccoli, Nancy B. SpinnerAbstract:Alagille Syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients. To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2). We found NOTCH2 mutations segregating in two families and identified five affected individuals. Renal manifestations, a minor feature in AGS, were present in all the affected individuals. This demonstrates that AGS is a heterogeneous disorder and implicates NOTCH2 mutations in human disease.
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jagged1 jag1 mutations in Alagille Syndrome increasing the mutation detection rate
Human Mutation, 2006Co-Authors: Daniel M. Warthen, Binita M Kamath, Ian D. Krantz, David A. Piccoli, E C Moore, Jennifer J D Morrissette, Pedro A Sanchezlara, Nancy B. SpinnerAbstract:Alagille Syndrome (AGS) is caused by heterozygous mutations in JAG1, and mutations have been previously reported in about 70% of patients who meet clinical diagnostic criteria. We studied a cohort of 247 clinically well-defined patients, and using an aggressive and sequential screening approach we identified JAG1 mutations in 94% of individuals. Mutations were found in 232 out of 247 patients studied and 83 of the mutations were novel. This increase in the mutation rate was accomplished by combining rigorous clinical phenotyping, with a combination of mutation detection techniques, including fluorescence in situ hybridization (FISH), genomic and cDNA sequencing, and quantitative PCR. This higher rate of mutation identification has implications for clinical practice, facilitating genetic counseling, prenatal diagnosis, and evaluation of living-related liver transplant donors. Our results suggest that more aggressive screening may similarly increase the rate of mutation detection in other dominant and recessive disorders. Hum Mutat 27(5):436–443, 2006. Published 2006 Wiley-Liss, Inc.
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jagged1 jag1 mutations in Alagille Syndrome increasing the mutation detection rate
Human Mutation, 2006Co-Authors: Daniel M. Warthen, Binita M Kamath, Ian D. Krantz, David A. Piccoli, E C Moore, Jennifer J D Morrissette, Pedro A Sanchezlara, Nancy B. SpinnerAbstract:Alagille Syndrome (AGS) is caused by heterozygous mutations in JAG1, and mutations have been previously reported in about 70% of patients who meet clinical diagnostic criteria. We studied a cohort of 247 clinically well-defined patients, and using an aggressive and sequential screening approach we identified JAG1 mutations in 94% of individuals. Mutations were found in 232 out of 247 patients studied and 83 of the mutations were novel. This increase in the mutation rate was accomplished by combining rigorous clinical phenotyping, with a combination of mutation detection techniques, including fluorescence in situ hybridization (FISH), genomic and cDNA sequencing, and quantitative PCR. This higher rate of mutation identification has implications for clinical practice, facilitating genetic counseling, prenatal diagnosis, and evaluation of living-related liver transplant donors. Our results suggest that more aggressive screening may similarly increase the rate of mutation detection in other dominant and recessive disorders.
Binita M Kamath - One of the best experts on this subject based on the ideXlab platform.
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Alagille Syndrome diagnostic challenges and advances in management
Diagnostics (Basel Switzerland), 2020Co-Authors: Mohammed D Ayoub, Binita M KamathAbstract: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 JAG1 and NOTCH2 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.
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Alagille Syndrome mutation update comprehensive overview of jag1 and notch2 mutation frequencies and insight into missense variant classification
Human Mutation, 2019Co-Authors: Melissa A Gilbert, Bryan L. Krock, Christopher M Grochowski, Robert C Bauer, Grace Chao, Deborah Mceldrew, James A Nassur, Ramakrishnan Rajagopalan, Elizabeth B. Rand, Binita M KamathAbstract: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.
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placebo controlled randomized trial of an intestinal bile salt transport inhibitor for pruritus in Alagille Syndrome
Hepatology Communications, 2018Co-Authors: Benjamin L Shneider, Binita M Kamath, Cathie Spino, John C Magee, Lee M Bass, Kenneth D R Setchell, Alexander Miethke, Jean P Molleston, Cara L Mack, Robert H SquiresAbstract:Medically refractory, severe, cholestasis-induced pruritus in Alagille Syndrome may be improved by surgical interruption of the enterohepatic circulation. This multicenter trial (NCT02057692) tested the hypothesis that the intestinal bile acid transport inhibitor maralixibat would similarly reduce pruritus in Alagille Syndrome. Thirty-seven children with Alagille Syndrome were randomly assigned to double-blinded administration of placebo, 70, 140, or 280 µg/kg/day of maralixibat for 13 weeks. Pruritus was assessed by caregiver (itch-reported outcome instrument [ItchRO]) and clinician report (range, 0-4 [severe]). Liver chemistries and serum bile acids were measured. The primary outcome was the change from baseline to week 13 in ItchRO relative to placebo. In the a priori first analysis of the primary efficacy endpoint, the mean adjusted difference between participants receiving 140 or 280 µg/kg/day and placebo was -0.47 (95% confidence interval [CI], -1.14, 0.20; P = 0.16). Statistically significant decreases were observed with doses of 70 and 140 µg/kg/day (mean adjusted difference, -0.89; 95% CI, -1.70, -0.08; P = 0.032; and mean adjusted difference, -0.91; 95% CI, -1.62, -0.19; P = 0.014) but not 280 µg/kg/day (mean adjusted difference, -0.04; 95% CI, -0.94, 0.86; P = 0.44) or all doses combined (mean adjusted difference, -0.61; 95% CI, -1.24, 0.20; P = 0.055). A 1-point reduction in pruritus was more common in maralixibat-treated versus placebo-treated participants (caregiver ItchRO, 65% versus 25%; P = 0.06; clinician score, 76% versus 25%; P = 0.01). There were no significant changes in liver chemistries or bile acids relative to placebo. Adverse and serious adverse events were similar between maralixibat and placebo. Conclusion: Although the prespecified primary analyses of ItchRO were not all statistically significant, the data suggest that maralixibat is safe and may reduce pruritus in Alagille Syndrome.
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Alagille Syndrome clinical perspectives
The application of clinical genetics, 2016Co-Authors: Maha Saleh, Binita M Kamath, David ChitayatAbstract:Alagille Syndrome is an autosomal dominant, complex multisystem disorder characterized by the presence of three out of five major clinical criteria: cholestasis with bile duct paucity on liver biopsy, congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae. Renal and vascular abnormalities can also occur. Inter- and intrafamilial variabilities in the clinical manifestations are common. We reviewed the clinical features and management as well as the molecular basis of Alagille Syndrome.
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williams Syndrome presenting with findings consistent with Alagille Syndrome
Clinical Case Reports, 2015Co-Authors: Pankaj Sakhuja, Binita M Kamath, Hilary Whyte, Nicole Martin, David ChitayatAbstract:Conjugated hyperbilirubinemia, posterior embryotoxon, and vertebral anomalies are not features of William Syndrome (WS). We herein report a preterm infant who presented with features suggestive of Alagille Syndrome, but microarray showed findings consistent with WS. This further extends the phenotype of WS and emphasizes the need for microarray analysis.
Kathleen M Loomes - One of the best experts on this subject based on the ideXlab platform.
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Alagille Syndrome a focused review on clinical features genetics and treatment
Seminars in Liver Disease, 2021Co-Authors: Taisa Kohut, Melissa A Gilbert, Kathleen M LoomesAbstract:Alagille Syndrome (ALGS) is an autosomal dominant disorder caused by pathogenic variants in JAG1 or NOTCH2, 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 JAG1 and NOTCH2 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.
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bone geometry and microarchitecture deficits in children with Alagille Syndrome
Bone, 2020Co-Authors: Joseph M Kindler, David A. Piccoli, Kathleen M Loomes, Mary B Leonard, Adda Grimberg, Babette S Zemel, Ellen MitchellAbstract:ABSTRACT Alagille Syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility fracture of unknown etiology. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS. This was a cross-sectional study of 10 children (9 females), ages 8-18 years, with a clinical diagnosis of ALGS. Bone density was assessed via DXA (Hologic Discovery A) at several skeletal regions. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II) at an ultradistal site located at 4% of tibia length and a cortical site at 30% of tibia length. Z-scores were calculated for DXA and pQCT measures. In the absence of XtremeCT II HR-pQCT reference data, these outcome measures were descriptively compared to a sample of healthy children ages 5-20 years (n=247). Anthropometrics and labs were also collected. Based on one-sample t-tests, mean Z-scores for height and weight (both p
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skeletal involvement in Alagille Syndrome
2018Co-Authors: Yadav Wagley, Kathleen M Loomes, Troy Mitchell, Jason W Ashley, Kurt D HankensonAbstract:Alagille Syndrome results in a spectrum of skeletal abnormalities in patients. Distinct facies are pathognomonic for the disease, and butterfly vertebrae are common. Patients have reduced bone mass and a propensity to fracture. While some of these abnormalities are developmental, others may be associated with alterations in nutrition (malabsorption) and systemic metabolism during growth. Emerging data demonstrate that Notch signaling and Jagged1 in particular have direct effects on adult bone cells. Activating Notch signaling with Jagged1 in human cells promotes osteoblast differentiation. However, data in genetically modified mice suggests that the regulation of Jagged1-Notch on the skeleton is complex, and Notch signaling may have variable effects depending on the site of the bone and the differentiation status of the target cell. Excitingly, the most recent work in the field demonstrates that delivery of Jagged1 bound to biomaterials promotes bone formation. This has broad implications for treating Alagille Syndrome patients with acute fractures as well as treating patients with osteopenia.
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early life predictive markers of liver disease outcome in an international multicentre cohort of children with Alagille Syndrome
Liver International, 2016Co-Authors: Marialena Mouzaki, David A. Piccoli, Kathleen M Loomes, James E Heubi, Lee M Bass, Ronald J Sokol, Claudia Quammie, Paula M Hertel, Rene Scheenstra, Katryn N FuruyaAbstract:Background & Aims Liver disease in Alagille Syndrome is highly variable. Many of the patients presenting with severe cholestasis early in life improve spontaneously; 10–20%, however, have progressive disease. It is currently not possible to predict long-term hepatic outcomes in Alagille Syndrome. This international, multicentre study was aimed at identifying early life predictors of liver disease outcome. Methods Retrospective clinical, laboratory and radiographic data from a cohort of 144 Alagille Syndrome patients, whose long-term hepatic outcomes had been determined a priori based on previously published criteria, were collected. Results Sixty-seven patients had mild and 77 had severe hepatic outcome. Univariate analysis demonstrated that cholestasis and fibrosis on biopsy, as well as the presence of xanthomata were significantly different between the groups (P < 0.05 for all). Mixed model analysis revealed that total serum bilirubin and serum cholesterol were also associated with outcome (P = 0.001 and P = 0.002, respectively). Graphical representation of the data revealed a change in total bilirubin levels between 12 and 24 months of age in the mild group. Recursive partitioning identified a threshold for total bilirubin of 3.8 mg/dl (65 mmol/L) in that age-frame that differentiated between outcomes. A multivariable logistic regression model was developed using fibrosis, xanthomata and the total bilirubin cut-off of 3.8 mg/dl (65 mmol/L), which generated an area under the ROC curve of 0.792. Conclusions The long-term hepatic outcomes of patients with Alagille Syndrome can be predicted based on serum total bilirubin between the ages of 12–24 months combined with fibrosis on liver biopsy and the presence of xanthomata on physical examination.
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clinical utility gene card for Alagille Syndrome algs
European Journal of Human Genetics, 2014Co-Authors: Laura D Leonard, Grace Chao, Kathleen M Loomes, Alastair Baker, Nancy B. SpinnerAbstract:Name of the disease (synonyms) Alagille Syndrome (ALGS); Alagille Syndrome 1 (ALGS1); Alagille Syndrome 2 (ALGS2). Other synonyms include Alagille–Watson Syndrome (AWS); cholestasis with peripheral pulmonary stenosis; arteriohepatic dysplasia (AHD); hepatic ductular hypoplasia, Syndrome; Miller–Watson Syndrome.1, 2, 3, 4 OMIM# of the disease ALGS1: 118450; ALGS2: 610205 Analysed genes or DNA/chromosome segments JAG1 (Jagged1 gene; locus 20p12.2; disease ALGS1); NOTCH2 (Notch2 gene; locus 1p12-p11; disease ALGS2). OMIM# of the gene(s) JAG1 (601920); NOTCH2 (600275). Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the JAG1 and NOTCH2 genes in diagnostic, predictive and prenatal settings and for risk assessment in relatives.