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1. Quantum Computation of Reactions on Surfaces Using Local Embedding

Author

Gujarati, Tanvi P., Motta, Mario, Friedhoff, Triet Nguyen, Rice, Julia E., Nguyen, Nam, Barkoutsos, Panagiotis Kl., Thompson, Richard J., Smith, Tyler, Kagele, Marna, Brei, Mark, Jones, Barbara A., and Williams, Kristen

Subjects
Quantum Physics
Abstract

Modeling electronic systems is an important application for quantum computers. In the context of materials science, an important open problem is the computational description of chemical reactions on surfaces. In this work, we outline a workflow to model the adsorption and reaction of molecules on surfaces using quantum computing algorithms. We develop and compare two local embedding methods for the systematic determination of active spaces. These methods are automated and based on the physics of molecule-surface interactions and yield systematically improvable active spaces. Furthermore, to reduce the quantum resources required for the simulation of the selected active spaces using quantum algorithms, we introduce a technique for exact and automated circuit simplification. This technique is applicable to a broad class of quantum circuits and critical to enable demonstration on near-term quantum devices. We apply the proposed combination of active-space selection and circuit simplification to the dissociation of water on a magnesium surface using classical simulators and quantum hardware. Our study identifies reactions of molecules on surfaces, in conjunction with the proposed algorithmic workflow, as a promising research direction in the field of quantum computing applied to materials science., Comment: 24 pages, 6 figures plus supplementary information

Published
2022
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2. Approximate Solutions of Combinatorial Problems via Quantum Relaxations

Author

Fuller, Bryce, Hadfield, Charles, Glick, Jennifer R., Imamichi, Takashi, Itoko, Toshinari, Thompson, Richard J., Jiao, Yang, Kagele, Marna M., Blom-Schieber, Adriana W., Raymond, Rudy, and Mezzacapo, Antonio

Subjects
Quantum Physics, Mathematical Physics
Abstract

Combinatorial problems are formulated to find optimal designs within a fixed set of constraints. They are commonly found across diverse engineering and scientific domains. Understanding how to best use quantum computers for combinatorial optimization is to date an open problem. Here we propose new methods for producing approximate solutions for the maximum cut problem and its weighted version, which are based on relaxations to local quantum Hamiltonians. These relaxations are defined through commutative maps, which in turn are constructed borrowing ideas from quantum random access codes. We establish relations between the spectra of the relaxed Hamiltonians and optimal cuts of the original problems, via two quantum rounding protocols. The first one is based on projections to random magic states. It produces average cuts that approximate the optimal one by a factor of least 0.555 or 0.625, depending on the relaxation chosen, if given access to a quantum state with energy between the optimal classical cut and the maximal relaxed energy. The second rounding protocol is deterministic and it is based on estimation of Pauli observables. The proposed quantum relaxations inherit memory compression from quantum random access codes, which allowed us to test the performances of the methods presented for 3-regular random graphs and a design problem motivated by industry for sizes up to 40 nodes, on superconducting quantum processors., Comment: 19 Pages, 7 Figure; Typos fixed, added ancillary data

Published
2021

3. Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author

Miethke, Alexander G, Moukarzel, Adib, Porta, Gilda, Covarrubias Esquer, Joshue, Czubkowski, Piotr, Ordonez, Felipe, Mosca, Antonella, Aqul, Amal A, Squires, Robert H, Sokal, Etienne, D'Agostino, Daniel, Baumann, Ulrich, D'Antiga, Lorenzo, Kasi, Nagraj, Laborde, Nolwenn, Arikan, Cigdem, Lin, Chuan-Hao, Gilmour, Susan, Mittal, Naveen, Chiou, Fang Kuan, Horslen, Simon P, Huber, Wolf-Dietrich, Jaecklin, Thomas, Nunes, Tiago, Lascau, Anamaria, Longpre, Lara, Mogul, Douglas B, Garner, Will, Vig, Pamela, Hupertz, Vera F, Gonzalez-Peralta, Regino P, Ekong, Udeme, Hartley, Jane, Laverdure, Noemie, Ovchinsky, Nadia, and Thompson, Richard J

Published
2024
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5. Mutation Analysis and Disease Features at Presentation in a Multi‐Center Cohort of Children With Monogenic Cholestasis

Author

Hertel, Paula M, Bull, Laura N, Thompson, Richard J, Goodrich, Nathan P, Ye, Wen, Magee, John C, Squires, Robert H, Bass, Lee M, Heubi, James E, Kim, Grace E, Ranganathan, Sarangarajan, Schwarz, Kathleen B, Bozic, Molly A, Horslen, Simon P, Clifton, Matthew S, Turmelle, Yumirle P, Suchy, Frederick J, Superina, Riccardo A, Wang, Kasper S, Loomes, Kathleen M, Kamath, Binita M, Sokol, Ronald J, Shneider, Benjamin L, and Network, Childhood Liver Disease Research

Subjects
Paediatrics, Biomedical and Clinical Sciences, Clinical Sciences, Nutrition and Dietetics, Liver Disease, Chronic Liver Disease and Cirrhosis, Genetics, Clinical Research, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, ATP-Binding Cassette Transporters, Child, Child, Preschool, Cholestasis, Cholestasis, Intrahepatic, Humans, Longitudinal Studies, Mutation, Childhood Liver Disease Research Network, Medical and Health Sciences, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

ObjectivesTo advance our understanding of monogenic forms of intrahepatic cholestasis.MethodsAnalyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.ResultsNinety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.ConclusionsIn this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

Published
2021

6. Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis

Author

Thompson, Richard J., Artan, Reha, Baumann, Ulrich, Calvo, Pier Luigi, Czubkowski, Piotr, Dalgic, Buket, D’Antiga, Lorenzo, Di Giorgio, Angelo, Durmaz, Özlem, Gonzalès, Emmanuel, Grammatikopoulos, Tassos, Gupte, Girish, Hardikar, Winita, Houwen, Roderick H.J., Kamath, Binita M., Karpen, Saul J., Lacaille, Florence, Lachaux, Alain, Lainka, Elke, Loomes, Kathleen M., Mack, Cara L., Mattsson, Jan P., McKiernan, Patrick, Ni, Quanhong, Özen, Hasan, Rajwal, Sanjay R., Roquelaure, Bertrand, Shteyer, Eyal, Sokal, Etienne, Sokol, Ronald J., Soufi, Nisreen, Sturm, Ekkehard, Tessier, Mary Elizabeth, van der Woerd, Wendy L., Verkade, Henkjan J., Vittorio, Jennifer M., Wallefors, Terese, Warholic, Natalie, Yu, Qifeng, Horn, Patrick, and Kjems, Lise

Published
2023
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8. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Author

Felzen, Antonia, van Wessel, Daan B.E., Gonzales, Emmanuel, Thompson, Richard J., Jankowska, Irena, Shneider, Benjamin L., Sokal, Etienne, Grammatikopoulos, Tassos, Kadaristiana, Agustina, Jacquemin, Emmanuel, Spraul, Anne, Lipiński, Patryk, Czubkowski, Piotr, Rock, Nathalie, Shagrani, Mohammad, Broering, Dieter, Nicastro, Emanuele, Kelly, Deirdre, Nebbia, Gabriella, Arnell, Henrik, Fischler, Björn, Hulscher, Jan B.F., Serranti, Daniele, Arikan, Cigdem, Polat, Esra, Debray, Dominique, Lacaille, Florence, Goncalves, Cristina, Hierro, Loreto, Muñoz Bartolo, Gema, Mozer-Glassberg, Yael, Azaz, Amer, Brecelj, Jernej, Dezsőfi, Antal, Calvo, Pier Luigi, Grabhorn, Enke, Hartleif, Steffen, van der Woerd, Wendy J., Kamath, Binita M., Wang, Jian-She, Li, Liting, Durmaz, Özlem, Kerkar, Nanda, Jørgensen, Marianne Hørby, Fischer, Ryan, Jimenez-Rivera, Carolina, Alam, Seema, Cananzi, Mara, Laverdure, Noemie, Ferreira, Cristina Targa, Guerrero, Felipe Ordoñez, Wang, Heng, Sency, Valerie, Kim, Kyung Mo, Chen, Huey-Ling, de Carvalho, Elisa, Fabre, Alexandre, Bernabeu, Jesus Quintero, Zellos, Aglaia, Alonso, Estella M., Sokol, Ronald J., Suchy, Frederick J., Loomes, Kathleen M., McKiernan, Patrick J., Rosenthal, Philip, Turmelle, Yumirle, Horslen, Simon, Schwarz, Kathleen, Bezerra, Jorge A., Wang, Kasper, Hansen, Bettina E., and Verkade, Henkjan J.

Published
2023
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12. THU-158 Improvements in serum bile acid levels are associated with improvements in key markers of liver health after maralixibat treatment in children with progressive familial intrahepatic cholestasis: data from the MARCH/MARCH-ON trials

Author

D'Antiga, Lorenzo, primary, Miethke, Alexander, additional, Horslen, Simon P., additional, Mogul, Douglas B., additional, Nunes, Tiago, additional, Garner, Will, additional, Vig, Pamela, additional, and Thompson, Richard J., additional

Published
2024
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13. Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

Author

Berauer, John‐Paul, Mezina, Anya I, Okou, David T, Sabo, Aniko, Muzny, Donna M, Gibbs, Richard A, Hegde, Madhuri R, Chopra, Pankaj, Cutler, David J, Perlmutter, David H, Bull, Laura N, Thompson, Richard J, Loomes, Kathleen M, Spinner, Nancy B, Rajagopalan, Ramakrishnan, Guthery, Stephen L, Moore, Barry, Yandell, Mark, Harpavat, Sanjiv, Magee, John C, Kamath, Binita M, Molleston, Jean P, Bezerra, Jorge A, Murray, Karen F, Alonso, Estella M, Rosenthal, Philip, Squires, Robert H, Wang, Kasper S, Finegold, Milton J, Russo, Pierre, Sherker, Averell H, Sokol, Ronald J, Karpen, Saul J, and Network, for the Childhood Liver Disease Research

Subjects
Perinatal Period - Conditions Originating in Perinatal Period, Kidney Disease, Digestive Diseases, Genetics, Chronic Liver Disease and Cirrhosis, Liver Disease, Rare Diseases, Congenital Structural Anomalies, Human Genome, Pediatric, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Congenital, Oral and gastrointestinal, Abnormalities, Multiple, Biliary Atresia, Child, Databases, Factual, Female, Gene Expression Regulation, Developmental, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Polycystic Kidney Diseases, Retrospective Studies, Spleen, Syndrome, Exome Sequencing, Childhood Liver Disease Research Network, Medical Biochemistry and Metabolomics, Clinical Sciences, Immunology, Gastroenterology & Hepatology
Abstract

Biliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations-a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole-exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the National Institute of Diabetes and Digestive and Kidney Diseases-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.

Published
2019

14. Progressive Familial Intrahepatic Cholestasis

Author

Bull, Laura N and Thompson, Richard J

Subjects
Genetics, 2.1 Biological and endogenous factors, Aetiology, ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 11, Adenosine Triphosphatases, Bile Acids and Salts, Cholestasis, Intrahepatic, Homeostasis, Humans, Lipid Metabolism, Myosin Heavy Chains, Myosin Type V, Receptors, Cytoplasmic and Nuclear, Zonula Occludens-2 Protein, Cholestasis, Bile acids, Pediatrics, PFIC, Clinical Sciences, Gastroenterology & Hepatology
Abstract

Genetic cholestasis has been dissected through genetic investigation. The major PFIC genes are now described. ATP8B1 encodes FIC1, ABCB11 encodes BSEP, ABCB4 encodes MDR3, TJP2 encodes TJP2, NR1H4 encodes FXR, and MYO5B encodes MYO5B. The full spectra of phenotypes associated with mutations in each gene are discussed, along with our understanding of the disease mechanisms. Differences in treatment response and targets for future treatment are emerging.

Published
2018

15. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial

Author

Thompson, Richard J, Arnell, Henrik, Artan, Reha, Baumann, Ulrich, Calvo, Pier Luigi, Czubkowski, Piotr, Dalgic, Buket, D'Antiga, Lorenzo, Durmaz, Özlem, Fischler, Björn, Gonzalès, Emmanuel, Grammatikopoulos, Tassos, Gupte, Girish, Hardikar, Winita, Houwen, Roderick H J, Kamath, Binita M, Karpen, Saul J, Kjems, Lise, Lacaille, Florence, Lachaux, Alain, Lainka, Elke, Mack, Cara L, Mattsson, Jan P, McKiernan, Patrick, Özen, Hasan, Rajwal, Sanjay R, Roquelaure, Bertrand, Shagrani, Mohammad, Shteyer, Eyal, Soufi, Nisreen, Sturm, Ekkehard, Tessier, Mary Elizabeth, Verkade, Henkjan J, and Horn, Patrick

Published
2022
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16. Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency

Author

Li, Chao Zheng, Ogawa, Hiromi, Ng, Soon Seng, Chen, Xindi, Kishimoto, Eriko, Sakabe, Kokoro, Fukami, Aiko, Hu, Yueh-Chiang, Mayhew, Christopher N., Hellmann, Jennifer, Miethke, Alexander, Tasnova, Nahrin L., Blackford, Samuel J.I., Tang, Zu Ming, Syanda, Adam M., Ma, Liang, Xiao, Fang, Sambrotta, Melissa, Tavabie, Oliver, Soares, Filipa, Baker, Oliver, Danovi, Davide, Hayashi, Hisamitsu, Thompson, Richard J., Rashid, S. Tamir, and Asai, Akihiro

Published
2022
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17. Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies.

Author

Bull, Laura N, Pawlikowska, Ludmila, Strautnieks, Sandra, Jankowska, Irena, Czubkowski, Piotr, Dodge, Jennifer L, Emerick, Karan, Wanty, Catherine, Wali, Sami, Blanchard, Samra, Lacaille, Florence, Byrne, Jane A, van Eerde, Albertien M, Kolho, Kaija-Leena, Houwen, Roderick, Lobritto, Steven, Hupertz, Vera, McClean, Patricia, Mieli-Vergani, Giorgina, Sokal, Etienne, Rosenthal, Philip, Whitington, Peter F, Pawlowska, Joanna, and Thompson, Richard J

Abstract

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP-common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP-other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP-common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP-other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Conclusion: Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP-other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations. (Hepatology Communications 2018;2:515-528).

Published
2018

19. Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis

Author

Grammatikopoulos, Tassos, Sambrotta, Melissa, Strautnieks, Sandra, Foskett, Pierre, Knisely, AS, Wagner, Bart, Deheragoda, Maesha, Starling, Chris, Mieli-Vergani, Giorgina, Smith, Joshua, Genomics, University of Washington Center for Mendelian, Bull, Laura, and Thompson, Richard J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Liver Disease, Rare Diseases, Biotechnology, Congenital Structural Anomalies, Genetics, Digestive Diseases, Pediatric, Chronic Liver Disease and Cirrhosis, Perinatal Period - Conditions Originating in Perinatal Period, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Cholangitis, Sclerosing, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Newborn, Male, Microtubule-Associated Proteins, Mutation, Neonate, Cholangiopathy, Doublecortin domain containing protein 2, Ciliopathy, Acetylated alpha-tubulin, University of Washington Center for Mendelian Genomics, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences
Abstract

Background & aimsNeonatal sclerosing cholangitis (NSC) is a severe neonatal-onset cholangiopathy commonly leading to liver transplantation (LT) for end-stage liver disease in childhood. Liver biopsy findings histopathologically resemble those in biliary atresia (BA); however, in NSC extrahepatic bile ducts are patent, whilst in BA their lumina are obliterated. NSC is commonly seen in consanguineous kindreds, suggesting autosomal recessive inheritance.MethodsFrom 29 NSC patients (24 families) identified, DNA was available in 24 (21 families). Thirteen (7 male) patients (12 families) of consanguineous parentage were selected for whole exome sequencing. Sequence variants were filtered for homozygosity, pathogenicity, minor allele frequency, quality score, and encoded protein expression pattern.ResultsFour of 13 patients were homozygous and two were compound heterozygous for mutations in the doublecortin domain containing 2 gene (DCDC2), which encodes DCDC2 protein and is expressed in cholangiocyte cilia. Another 11 patients were sequenced: one (with one sibling pair) was compound heterozygous for DCDC2 mutations. All mutations were protein-truncating. In available liver tissue from patients with DCDC2 mutations, immunostaining for human DCDC2 and the ciliary protein acetylated alpha-tubulin (ACALT) showed no expression (n=6) and transmission electron microscopy found that cholangiocytes lacked primary cilia (n=5). DCDC2 and ACALT were expressed in NSC patients without DCDC2 mutations (n=22). Of the patients carrying DCDC2 mutations, one died awaiting LT; five came to LT, of whom one died 2years later. The other 4 are well.ConclusionAmong 24 NSC patients with available DNA, 7 had mutations in DCDC2 (6 of 19 families). NSC patients in substantial proportion harbour mutations in DCDC2. Their disease represents a novel liver-based ciliopathy.Lay summaryNeonatal sclerosing cholangitis (NSC) is a rare genetic form of liver disease presenting in infancy. Through next generation sequencing we identified mutations in the gene encoding for doublecortin domain containing 2 (DCDC2) protein in a group of NSC children. DCDC2 is a signalling and structural protein found in primary cilia of cholangiocytes. Cholangiocytes are the cells forming the biliary system which is the draining system of the liver.

Published
2016

20. Genetic aetiologies of acute liver failure.

Author

Hegarty, Robert and Thompson, Richard J.

Abstract

Acute liver failure (ALF) is a rare, rapidly evolving, clinical syndrome with devastating consequences where definitive treatment is by emergency liver transplantation. Establishing a diagnosis can be challenging and, historically, the cause of ALF was unidentified in up to half of children. However, recent technological and clinical advances in genomic medicine have led to an increasing proportion being diagnosed with monogenic aetiologies of ALF. The conditions encountered include a diverse group of inherited metabolic disorders each with prognostic and treatment implications. Often these disorders are clinically indistinguishable and may even mimic disorders of immune regulation or red cell disorders. Rapid genomic sequencing for children with ALF is, therefore, a key component in the diagnostic work up today. This review focuses on the monogenic aetiologies of ALF. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Genotype correlates with the natural history of severe bile salt export pump deficiency

Author

van Wessel, Daan B.E., Thompson, Richard J., Gonzales, Emmanuel, Jankowska, Irena, Sokal, Etienne, Grammatikopoulos, Tassos, Kadaristiana, Agustina, Jacquemin, Emmanuel, Spraul, Anne, Lipiński, Patryk, Czubkowski, Piotr, Rock, Nathalie, Shagrani, Mohammad, Broering, Dieter, Algoufi, Talal, Mazhar, Nejat, Nicastro, Emanuele, Kelly, Deirdre A., Nebbia, Gabriella, Arnell, Henrik, Björn Fischler, Hulscher, Jan B.F., Serranti, Daniele, Arikan, Cigdem, Polat, Esra, Debray, Dominique, Lacaille, Florence, Goncalves, Cristina, Hierro, Loreto, Muñoz Bartolo, Gema, Mozer-Glassberg, Yael, Azaz, Amer, Brecelj, Jernej, Dezsőfi, Antal, Calvo, Pier Luigi, Grabhorn, Enke, Sturm, Ekkehard, van der Woerd, Wendy J., Kamath, Binita M., Wang, Jian-She, Li, Liting, Durmaz, Özlem, Onal, Zerrin, Bunt, Ton M.G., Hansen, Bettina E., and Verkade, Henkjan J.

Published
2020
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24. Mutations in TJP2 cause progressive cholestatic liver disease

Author

Sambrotta, Melissa, Strautnieks, Sandra, Papouli, Efterpi, Rushton, Peter, Clark, Barnaby E, Parry, David A, Logan, Clare V, Newbury, Lucy J, Kamath, Binita M, Ling, Simon, Grammatikopoulos, Tassos, Wagner, Bart E, Magee, John C, Sokol, Ronald J, Mieli-Vergani, Giorgina, Smith, Joshua D, Johnson, Colin A, McClean, Patricia, Simpson, Michael A, Knisely, AS, Bull, Laura N, and Thompson, Richard J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Liver Disease, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Animals, Base Sequence, Cholestasis, Intrahepatic, High-Throughput Nucleotide Sequencing, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Models, Biological, Molecular Sequence Data, Mutation, Pedigree, Real-Time Polymerase Chain Reaction, Sequence Alignment, Species Specificity, Tight Junctions, Zonula Occludens-2 Protein, University of Washington Center for Mendelian Genomics, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.

Published
2014

27. P1 Analysis of long-term treatment effects of odevixibat on clinical outcomes in children with progressive familial intrahepatic cholestasis in odevixibat clinical studies vs external controls from the NAPPED database

Author

Hansen, Bettina, primary, Valcheva, Velichka, additional, Yu, Qifeng, additional, Wessel, Daan BE van, additional, Thompson, Richard J, additional, Gonzales, Emmanuel, additional, Jankowska, Irena, additional, Sokal, Etienne, additional, Grammatikopoulos, Tassos, additional, Kadaristiana, Agustina, additional, Jacquemin, Emmanuel, additional, Spraul, Anne, additional, Lipiński, Patryk, additional, Czubkowski, Piotr, additional, Rock, Nathalie, additional, Shagrani, Mohammad, additional, Kumar, Kishwer, additional, Alkuraya, Fowzan, additional, Sateesh, Meddirevula, additional, Broering, Dieter, additional, Nicastro, Emanuele, additional, Kelly, Deirdre A, additional, Nebbia, Gabriella, additional, Arnell, Henrik, additional, Fischler, Björn, additional, Serranti, Daniele, additional, Arikan, Cigdem, additional, Polat, Esra, additional, Debray, Dominique, additional, Lacaille, Florence, additional, Goncalves, Cristina, additional, Hierro, Loreto, additional, Bartolo, Gema Muñoz, additional, Mozer-Glassberg, Yael, additional, Azaz, Amer, additional, Brecelj, Jernej, additional, Dezsőfi, Antal, additional, Calvo, Pier Luigi, additional, Grabhorn, Enke, additional, Sturm, Ekkehard, additional, Woerd, Wendy L van der, additional, Kamath, Binita M, additional, Wang, Jian-She, additional, Li, Liting, additional, Durmaz, Özlem, additional, Onal, Zerrin, additional, Felzen, Antonia, additional, Nomden, Mark, additional, Sonajalg, Jaak, additional, Stein, Philip, additional, Ni, Quanhong, additional, Clemson, Christine, additional, Mattsson, Jan P, additional, and Verkade, Henkjan J, additional

Published
2023
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30. Cholestasis Due to USP53 Deficiency

Author

Bull, Laura N., Ellmers, Rebecca, Foskett, Pierre, Strautnieks, Sandra, Sambrotta, Melissa, Czubkowski, Piotr, Jankowska, Irena, Wagner, Bart, Deheragoda, Maesha, and Thompson, Richard J.

Published
2021
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32. Cholestasis Due to USP53 Deficiency

Author

Bull, Laura N., Ellmers, Rebecca, Foskett, Pierre, Strautnieks, Sandra, Sambrotta, Melissa, Czubkowski, Piotr, Jankowska, Irena, Wagner, Bart, Deheragoda, Maesha, and Thompson, Richard J.

Published
2020
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39. Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome: Results from The <scp>GALA</scp> Study

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Vandriel, Shannon M., Li, Li‐Ting, She, Huiyu, Wang, Jian‐She, Gilbert, Melissa A., Jankowska, Irena, Czubkowski, Piotr, Gliwicz‐Miedzińska, Dorota, Gonzales, Emmanuel M., Jacquemin, Emmanuel, Bouligand, Jérôme, Spinner, Nancy B., Loomes, Kathleen M., Piccoli, David A., D'Antiga, Lorenzo, Nicastro, Emanuele, Sokal, Etienne, Demaret,Tanguy, Ebel, Noelle H., Feinstein, Jeffrey A., Fawaz, Rima, Nastasio, Silvia, Lacaille, Florence, Debray, Dominique, Arnell, Henrik, Fischler, Björn, Siew, Susan, Stormon, Michael, Karpen, Saul J., Romero, Rene, Kim, Kyung Mo, Baek, Woo Yim, Hardikar, Winita, Shankar, Sahana, Roberts, Amin J., Evans, Helen M., Jensen, M. Kyle, Kavan, Marianne, Sundaram, Shikha S., Chaidez, Alexander, Karthikeyan, Palaniswamy, Sanchez, Maria Camila, Cavalieri, Maria Lorena, Verkade, Henkjan J., Lee, Way Seah, Squires, James E., Hajinicolaou, Christina, Lertudomphonwanit, Chatmanee, Fischer, Ryan T., Larson‐Nath, Catherine, Mozer‐Glassberg, Yael, Arikan, Cigdem, Lin, Henry C., Quintero Bernabeu, Jesus, Alam, Seema, Kelly, Deirdre, Carvalho, Elisa, Ferreira, Cristina Targa, Indolfi, Giuseppe, Quiros‐Tejeira, Ruben E., Bulut, Pinar, Calvo, Pier Luigi, Önal, Zerrin, Valentino, Pamela L., Desai, Dev M., Eshun, John, Rogalidou, Maria, Dezsőfi, Antal, Wiecek, Sabina, Nebbia, Gabriella, Borges Pinto, Raquel, Wolters, Victorien M., Tamara, María Legarda, Zizzo, Andréanne N., Garcia, Jennifer, Schwarz, Kathleen, Beretta, Marisa, Sandahl, Thomas Damgaard, Jimenez‐Rivera, Carolina, Kerkar, Nanda, Brecelj, Jernej, Mujawar, Quais, Rock, Nathalie, Busoms, Cristina Molera, Karnsakul, Wikrom, Lurz, Eberhard, Santos‐Silva, Ermelinda, Blondet, Niviann, Bujanda, Luis, Shah, Uzma, Thompson, Richard J., Hansen, Bettina E., Kamath, Binita M., UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Vandriel, Shannon M., Li, Li‐Ting, She, Huiyu, Wang, Jian‐She, Gilbert, Melissa A., Jankowska, Irena, Czubkowski, Piotr, Gliwicz‐Miedzińska, Dorota, Gonzales, Emmanuel M., Jacquemin, Emmanuel, Bouligand, Jérôme, Spinner, Nancy B., Loomes, Kathleen M., Piccoli, David A., D'Antiga, Lorenzo, Nicastro, Emanuele, Sokal, Etienne, Demaret,Tanguy, Ebel, Noelle H., Feinstein, Jeffrey A., Fawaz, Rima, Nastasio, Silvia, Lacaille, Florence, Debray, Dominique, Arnell, Henrik, Fischler, Björn, Siew, Susan, Stormon, Michael, Karpen, Saul J., Romero, Rene, Kim, Kyung Mo, Baek, Woo Yim, Hardikar, Winita, Shankar, Sahana, Roberts, Amin J., Evans, Helen M., Jensen, M. Kyle, Kavan, Marianne, Sundaram, Shikha S., Chaidez, Alexander, Karthikeyan, Palaniswamy, Sanchez, Maria Camila, Cavalieri, Maria Lorena, Verkade, Henkjan J., Lee, Way Seah, Squires, James E., Hajinicolaou, Christina, Lertudomphonwanit, Chatmanee, Fischer, Ryan T., Larson‐Nath, Catherine, Mozer‐Glassberg, Yael, Arikan, Cigdem, Lin, Henry C., Quintero Bernabeu, Jesus, Alam, Seema, Kelly, Deirdre, Carvalho, Elisa, Ferreira, Cristina Targa, Indolfi, Giuseppe, Quiros‐Tejeira, Ruben E., Bulut, Pinar, Calvo, Pier Luigi, Önal, Zerrin, Valentino, Pamela L., Desai, Dev M., Eshun, John, Rogalidou, Maria, Dezsőfi, Antal, Wiecek, Sabina, Nebbia, Gabriella, Borges Pinto, Raquel, Wolters, Victorien M., Tamara, María Legarda, Zizzo, Andréanne N., Garcia, Jennifer, Schwarz, Kathleen, Beretta, Marisa, Sandahl, Thomas Damgaard, Jimenez‐Rivera, Carolina, Kerkar, Nanda, Brecelj, Jernej, Mujawar, Quais, Rock, Nathalie, Busoms, Cristina Molera, Karnsakul, Wikrom, Lurz, Eberhard, Santos‐Silva, Ermelinda, Blondet, Niviann, Bujanda, Luis, Shah, Uzma, Thompson, Richard J., Hansen, Bettina E., and Kamath, Binita M.

Abstract

Background: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international, cohort of children with ALGS. Methods: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. Results: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dL had a 4.1-fold (95% CI 1.6 - 10.8) and those ≥10.0 mg/dL had an 8.0-fold (95% CI 3.4 - 18.4) increased risk of developing CEPH compared with those <5.0 mg/dL. Median TB levels between ≥5.0 and <10.0 mg/dL and >10.0 mg/dL were associated with a 4.8 (95% CI 2.4 - 9.7) and 15.6 (95% CI 8.7 - 28.2) increased risk of transplantation relative to <5.0 mg/dL. Median TB <5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p<0.001). Conclusions: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dL between 6-and-12-months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of novel therapies.

Published
2023

40. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Felzen, Antonia, van Wessel, Daan B.E., Gonzales, Emmanuel, Thompson, Richard J., Jankowska, Irena, Shneider, Benjamin L., Sokal, Etienne, Grammatikopoulos, Tassos, Kadaristiana, Agustina, Jacquemin, Emmanuel, Spraul, Anne, Lipiński, Patryk, Czubkowski, Piotr, Rock, Nathalie, Shagrani, Mohammad, Broering, Dieter, Nicastro, Emanuele, Kelly, Deirdre, Nebbia, Gabriella, Arnell, Henrik, Fischler, Björn, Hulscher, Jan B.F., Serranti, Daniele, Arikan, Cigdem, Polat, Esra, Debray, Dominique, Lacaille, Florence, Goncalves, Cristina, Hierro, Loreto, Muñoz Bartolo, Gema, Mozer-Glassberg, Yael, Azaz, Amer, Brecelj, Jernej, Dezsőfi, Antal, Calvo, Pier Luigi, Grabhorn, Enke, Hartleif, Steffen, van der Woerd, Wendy J., Kamath, Binita M., Wang, Jian-She, Li, Liting, Durmaz, Özlem, Kerkar, Nanda, Jørgensen, Marianne Hørby, Fischer, Ryan, Jimenez-Rivera, Carolina, Alam, Seema, Cananzi, Mara, Laverdure, Noemie, Ferreira, Cristina Targa, Guerrero, Felipe Ordoñez, Wang, Heng, Sency, Valerie, Kim, Kyung Mo, Chen, Huey-Ling, de Carvalho, Elisa, Fabre, Alexandre, Bernabeu, Jesus Quintero, Zellos, Aglaia, Alonso, Estella M., Sokol, Ronald J., Suchy, Frederick J., Loomes, Kathleen M., McKiernan, Patrick J., Rosenthal, Philip, Turmelle, Yumirle, Horslen, Simon, Schwarz, Kathleen, Bezerra, Jorge A., Wang, Kasper, Hansen, Bettina E., Verkade, Henkjan J., UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Felzen, Antonia, van Wessel, Daan B.E., Gonzales, Emmanuel, Thompson, Richard J., Jankowska, Irena, Shneider, Benjamin L., Sokal, Etienne, Grammatikopoulos, Tassos, Kadaristiana, Agustina, Jacquemin, Emmanuel, Spraul, Anne, Lipiński, Patryk, Czubkowski, Piotr, Rock, Nathalie, Shagrani, Mohammad, Broering, Dieter, Nicastro, Emanuele, Kelly, Deirdre, Nebbia, Gabriella, Arnell, Henrik, Fischler, Björn, Hulscher, Jan B.F., Serranti, Daniele, Arikan, Cigdem, Polat, Esra, Debray, Dominique, Lacaille, Florence, Goncalves, Cristina, Hierro, Loreto, Muñoz Bartolo, Gema, Mozer-Glassberg, Yael, Azaz, Amer, Brecelj, Jernej, Dezsőfi, Antal, Calvo, Pier Luigi, Grabhorn, Enke, Hartleif, Steffen, van der Woerd, Wendy J., Kamath, Binita M., Wang, Jian-She, Li, Liting, Durmaz, Özlem, Kerkar, Nanda, Jørgensen, Marianne Hørby, Fischer, Ryan, Jimenez-Rivera, Carolina, Alam, Seema, Cananzi, Mara, Laverdure, Noemie, Ferreira, Cristina Targa, Guerrero, Felipe Ordoñez, Wang, Heng, Sency, Valerie, Kim, Kyung Mo, Chen, Huey-Ling, de Carvalho, Elisa, Fabre, Alexandre, Bernabeu, Jesus Quintero, Zellos, Aglaia, Alonso, Estella M., Sokol, Ronald J., Suchy, Frederick J., Loomes, Kathleen M., McKiernan, Patrick J., Rosenthal, Philip, Turmelle, Yumirle, Horslen, Simon, Schwarz, Kathleen, Bezerra, Jorge A., Wang, Kasper, Hansen, Bettina E., and Verkade, Henkjan J.

Abstract

Background & aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until

Published
2023

41. Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor

Author

Sokol, Ronald J., Gonzales, Emmanuel M., Kamath, Binita M., Baker, Alastair, Vig, Pamela, Mogul, Douglas B., Garner, Will, Hansen, Bettina E., Jacquemin, Emmanuel, Thompson, Richard J., Sokol, Ronald J., Gonzales, Emmanuel M., Kamath, Binita M., Baker, Alastair, Vig, Pamela, Mogul, Douglas B., Garner, Will, Hansen, Bettina E., Jacquemin, Emmanuel, and Thompson, Richard J.

Abstract

Background and Aims: Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated predictors of event-free survival and transplant-free survival in patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor. Approach and Results: We assessed patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up. Event-free survival was defined as the absence of LT, surgical biliary diversion, hepatic decompensation, or death; transplant-free survival was the absence of LT or death. Forty-three potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0–4 scale), biochemistries, platelets, and serum bile acids. Harrell’s concordance statistic assessed goodness-of-fit, and then, Cox proportional hazard models confirmed the statistical significance of the predictors identified. A further analysis was performed to identify cutoffs using a grid search. Seventy-six individuals met the criteria of receiving MRX for ≥ 48 weeks with laboratory values available at week 48 (W48). The median duration of MRX was 4.7 years (IQR: 1.6–5.8); 16 had events (10 LT, 3 decompensation, 2 death, and 1 surgical biliary diversion). The 6-year event-free survival improved with a clinically meaningful > 1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival. Conclusions: Improvement in pruritus by 48 weeks, and lower W48 bilirubin and serum bile acid levels were associated with fewer events. These data may help identify potential markers of disease progression for ALGS patients treated with MRX.

Published
2023

42. Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis

Author

MDL patientenzorg, Thompson, Richard J., Artan, Reha, Baumann, Ulrich, Calvo, Pier Luigi, Czubkowski, Piotr, Dalgic, Buket, D'Antiga, Lorenzo, Di Giorgio, Angelo, Durmaz, Özlem, Gonzalès, Emmanuel, Grammatikopoulos, Tassos, Gupte, Girish, Hardikar, Winita, Houwen, Roderick H.J., Kamath, Binita M., Karpen, Saul J., Lacaille, Florence, Lachaux, Alain, Lainka, Elke, Loomes, Kathleen M., Mack, Cara L., Mattsson, Jan P., McKiernan, Patrick, Ni, Quanhong, Özen, Hasan, Rajwal, Sanjay R., Roquelaure, Bertrand, Shteyer, Eyal, Sokal, Etienne, Sokol, Ronald J., Soufi, Nisreen, Sturm, Ekkehard, Tessier, Mary Elizabeth, van der Woerd, Wendy L., Verkade, Henkjan J., Vittorio, Jennifer M., Wallefors, Terese, Warholic, Natalie, Yu, Qifeng, Horn, Patrick, Kjems, Lise, MDL patientenzorg, Thompson, Richard J., Artan, Reha, Baumann, Ulrich, Calvo, Pier Luigi, Czubkowski, Piotr, Dalgic, Buket, D'Antiga, Lorenzo, Di Giorgio, Angelo, Durmaz, Özlem, Gonzalès, Emmanuel, Grammatikopoulos, Tassos, Gupte, Girish, Hardikar, Winita, Houwen, Roderick H.J., Kamath, Binita M., Karpen, Saul J., Lacaille, Florence, Lachaux, Alain, Lainka, Elke, Loomes, Kathleen M., Mack, Cara L., Mattsson, Jan P., McKiernan, Patrick, Ni, Quanhong, Özen, Hasan, Rajwal, Sanjay R., Roquelaure, Bertrand, Shteyer, Eyal, Sokal, Etienne, Sokol, Ronald J., Soufi, Nisreen, Sturm, Ekkehard, Tessier, Mary Elizabeth, van der Woerd, Wendy L., Verkade, Henkjan J., Vittorio, Jennifer M., Wallefors, Terese, Warholic, Natalie, Yu, Qifeng, Horn, Patrick, and Kjems, Lise

Published
2023

43. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Author

Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Felzen, Antonia; van Wessel, Daan B.E.; Gonzales, Emmanuel; Thompson, Richard J.; Jankowska, Irena; Shneider, Benjamin L.; Sokal, Etienne; Grammatikopoulos, Tassos; Kadaristiana, Agustina; Jacquemin, Emmanuel; Spraul, Anne; Lipi?ski, Patryk; Czubkowski, Piotr; Rock, Nathalie; Shagrani, Mohammad; Broering, Dieter; Nicastro, Emanuele; Kelly, Deirdre; Nebbia, Gabriella; Arnell, Henrik; Fischler, Björn; Hulscher, Jan B.F.; Serranti, Daniele; Polat, Esra; Debray, Dominique; Lacaille, Florence; Goncalves, Cristina; Hierro, Loreto; Muñoz Bartolo, Gema; Mozer-Glassberg, Yael; Azaz, Amer; Brecelj, Jernej; Dezs?fi, Antal; Calvo, Pier Luigi; Grabhorn, Enke; Hartleif, Steffen; van der Woerd, Wendy J.; Kamath, Binita M.; Wang, Jian-She; Li, Liting; Durmaz, Özlem; Kerkar, Nanda; Jørgensen, Marianne Hørby; Fischer, Ryan; Jimenez-Rivera, Carolina; Alam, Seema; Cananzi, Mara; Laverdure, Noemie; Ferreira, Cristina Targa; Guerrero, Felipe Ordoñez; Wang, Heng; Sency, Valerie; Kim, Kyung Mo; Chen, Huey-Ling; de Carvalho, Elisa; Fabre, Alexandre; Bernabeu, Jesus Quintero; Zellos, Aglaia; Alonso, Estella M.; Sokol, Ronald J.; Suchy, Frederick J.; Loomes, Kathleen M.; McKiernan, Patrick J.; Rosenthal, Philip; Turmelle, Yumirle; Horslen, Simon; Schwarz, Kathleen; Bezerra, Jorge A.; Wang, Kasper; Hansen, Bettina E.; Verkade, Henkjan J., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Felzen, Antonia; van Wessel, Daan B.E.; Gonzales, Emmanuel; Thompson, Richard J.; Jankowska, Irena; Shneider, Benjamin L.; Sokal, Etienne; Grammatikopoulos, Tassos; Kadaristiana, Agustina; Jacquemin, Emmanuel; Spraul, Anne; Lipi?ski, Patryk; Czubkowski, Piotr; Rock, Nathalie; Shagrani, Mohammad; Broering, Dieter; Nicastro, Emanuele; Kelly, Deirdre; Nebbia, Gabriella; Arnell, Henrik; Fischler, Björn; Hulscher, Jan B.F.; Serranti, Daniele; Polat, Esra; Debray, Dominique; Lacaille, Florence; Goncalves, Cristina; Hierro, Loreto; Muñoz Bartolo, Gema; Mozer-Glassberg, Yael; Azaz, Amer; Brecelj, Jernej; Dezs?fi, Antal; Calvo, Pier Luigi; Grabhorn, Enke; Hartleif, Steffen; van der Woerd, Wendy J.; Kamath, Binita M.; Wang, Jian-She; Li, Liting; Durmaz, Özlem; Kerkar, Nanda; Jørgensen, Marianne Hørby; Fischer, Ryan; Jimenez-Rivera, Carolina; Alam, Seema; Cananzi, Mara; Laverdure, Noemie; Ferreira, Cristina Targa; Guerrero, Felipe Ordoñez; Wang, Heng; Sency, Valerie; Kim, Kyung Mo; Chen, Huey-Ling; de Carvalho, Elisa; Fabre, Alexandre; Bernabeu, Jesus Quintero; Zellos, Aglaia; Alonso, Estella M.; Sokol, Ronald J.; Suchy, Frederick J.; Loomes, Kathleen M.; McKiernan, Patrick J.; Rosenthal, Philip; Turmelle, Yumirle; Horslen, Simon; Schwarz, Kathleen; Bezerra, Jorge A.; Wang, Kasper; Hansen, Bettina E.; Verkade, Henkjan J., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Background & Aims: bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: from the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: the groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: this manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until, 1. MD/PhD scholarship from the University of Groningen, Groningen, The Netherlands 2. ESPGHAN Networking Grant 2019 3. ChiLDReN and CTSA National Institutes of Health grants: Ann & Robert H. Lurie Children's Hospital, Chicago: U01DK062436; University of Colorado, Denver: U01DK62453, UL1 TR002535; Baylor college of Medicine, Houston: U01DK103149; Children's Hospital of Philadelphia, Philadelphia: U01DK062481, UL1TR000003; Children's Hospital of Pittsburgh, Pittsburgh: U01DK062466; University of California, San Francisco U01DK062500; University of California, San Francisco CTSI grant UL1TR001872; Riley Hospital for Children, Indianapolis: U01DK084536; Seattle Children’s Hospital, Seattle: DK084575; Children’s Hospital Los Angeles, California: U01DK084538. 4. Unrestrictive research grant from Albireo 5. Unrestrictive research grant from Mirum Pharmaceuticals. 6. C&W de Boer Stichting research grant.

Published
2023

46. Impact of long-term administration of maralixibat on children with cholestasis secondary to Alagille syndrome

Author

Shneider, Benjamin L., primary, Spino, Catherine A., additional, Kamath, Binita M., additional, Magee, John C., additional, Ignacio, Rosalinda V., additional, Huang, Suiyuan, additional, Horslen, Simon P., additional, Molleston, Jean P., additional, Miethke, Alexander G., additional, Kohli, Rohit, additional, Leung, Daniel H., additional, Jensen, Kyle M., additional, Loomes, Kathleen M., additional, Karpen, Saul J., additional, Mack, Cara, additional, Rosenthal, Philip, additional, Squires, Robert H., additional, Baker, Alastair, additional, Rajwal, Sanjay, additional, Kelly, Deirdre, additional, Sokol, Ronald J., additional, and Thompson, Richard J., additional

Published
2022
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49. Changes in hepatic parameters, growth, sleep, and biochemical markers with odevixibat treatment across patients with various types of progressive familial intrahepatic cholestasis

Author

D’Antiga, Lorenzo, primary, Gupte, Girish, additional, Thompson, Richard J., additional, Sturm, Ekkehard, additional, Calvo, Pier Luigi, additional, Shagrani, Mohammad Ali, additional, Stoll, Janis M., additional, Artan, Reha, additional, Dalgıç, Buket, additional, Ozen, Hasan, additional, Loomes, Kathleen M., additional, Vittorio, Jennifer M., additional, Karpen, Saul J., additional, Di Giorgio, Angelo, additional, Ni, Quanhong, additional, Kjems, Lise, additional, and Horn, Patrick, additional

Published
2022
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50. Analysis of quality of life, hepatic biochemical markers, and sleep in patients with progressive familial intrahepatic cholestasis who had a pruritus response with odevixibat treatment

Author

Gupte, Girish, primary, Thompson, Richard J., additional, D’Antiga, Lorenzo, additional, Grammatikopoulos, Tassos, additional, Gonzalès, Emmanuel, additional, Lacaille, Florence, additional, Lachaux, Alain, additional, Roquelaure, Bertrand, additional, Baumann, Ulrich, additional, Lainka, Elke, additional, Sturm, Ekkehard, additional, Shteyer, Eyal, additional, Czubkowski, Piotr, additional, Artan, Reha, additional, Dalgic, Buket, additional, Ozen, Hasan, additional, Loomes, Kathleen M., additional, Vittorio, Jennifer M., additional, Karpen, Saul J., additional, McKiernan, Patrick, additional, Mack, Cara L., additional, Di Giorgio, Angelo, additional, Yu, Qifeng, additional, Kjems, Lise, additional, and Horn, Patrick, additional

Published
2022
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