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151. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1

Author

Suls, Arvid, Dedeken, Peter, Goffin, Karolien, Van Esch, Hilde, Dupont, Patrick, Cassiman, David, Kempfle, Judith, Wuttke, Thomas V., Weber, Yvonne, Lerche, Holger, Afawi, Zaid, Vandenberghe, Wim, Korczyn, Amos D., Berkovic, Samuel F., Ekstein, Dana, Kivity, Sara, Ryvlin, Philippe, Claes, Lieve R. F., Deprez, Liesbet, Maljevic, Snezana, Vargas, Alberto, Van Dyck, Tine, Goossens, Dirk, Del-Favero, Jurgen, Van Laere, Koen, De Jonghe, Peter, and Van Paesschen, Wim

Published
2008

152. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up

Author

Altassan, Ruqaiah, Péanne, Romain, Jaeken, Jaak, Barone, Rita, Bidet, Muad, Borgel, Delphine, Brasil, Sandra, Cassiman, David, Cechova, Anna, Coman, David, Corral, Javier, Correia, Joana, Morena-Barrio, María Eugenia de la, de Lonlay, Pascale, Reis, Vanessa dos, Ferreira, Carlos R., Fiumara, Agata, Francisco, Rita, Freeze, Hudson, Funke, Simone, Gardeitchik, Thatjana, Gert, Matthijs, Girad, Muriel, Giros, Marisa, Grünewald, Stephanie, Hernández-Caselles, Trinidad, Honzik, Tomas, Hutter, Marlen, Krasnewich, Donna, Lam, Christina, Lee, Joy, Lefeber, Dirk, Marques-da-Silva, Dorinda, Martinez, Antonio F., Moravej, Hossein, Õunap, Katrin, Pascoal, Carlota, Pascreau, Tiffany, Patterson, Marc, Quelhas, Dulce, Raymond, Kimiyo, Sarkhail, Peymaneh, Schiff, Manuel, Seroczyńska, Małgorzata, Serrano, Mercedes, Seta, Nathalie, Sykut-Cegielska, Jolanta, Thiel, Christian, Tort, Federic, Vals, Mari Anne, Videira, Paula, Witters, Peter, Zeevaert, Renate, Morava, Eva, DCV - Departamento de Ciências da Vida, and UCIBIO - Applied Molecular Biosciences Unit

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Genetics, Genetics(clinical)
Abstract

We would like to thank the Metabolic ERN (MetabERN) for their support to our study. Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients. publishersversion published

Published
2019

153. MOESM3 of Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients

Author

Kimber Vliet, Ginkel, Willem, Jahja, Rianne, Daly, Anne, MacDonald, Anita, Laet, Corinne, Vara, Roshni, Yusof Rahman, Cassiman, David, Francois Eyskens, Timmer, Corrie, Mumford, Nicky, Bierau, Jörgen, Hasselt, Peter, Gissen, Paul, Goyens, Philippe, McKiernan, Patrick, Wilcox, Gisela, Morris, Andrew, Jameson, Elisabeth, Huijbregts, Stephan, and Francjan Spronsen

Abstract

Additional file 3. Summarized results of correlation analyses between phenylalanine and tyrosine concentrations and neurocognitive outcome scores. Summarized results of correlation analyses between phenylalanine and tyrosine concentrations and neurocognitive outcome scores. Only scales with significant correlations, with p-values

Published
2019
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154. Case Report of Gastrointestinal Bleeding in an Adult with Chronic Visceral Acid Sphingomyelinase Deficiency

Author

Cassiman, David, Libbrecht, Louis, Meersseman, Wouter, and Wilmer, Alexander

Subjects
Article Subject
Abstract

Introduction. Acid sphingomyelinase deficiency (ASMD, also known as Niemann-Pick Type A and Type B disease) is a rare, inherited metabolic disorder. Liver-related issues, including cirrhosis and variceal haemorrhage, are a leading cause of early mortality in individuals with chronic forms of ASMD. Due to the rarity of this lysosomal storage disorder, there can be a lack of awareness that adults with chronic ASMD disease are at significant risk of cirrhosis, portal hypertension, and variceal bleeding. This case highlights an unusual presentation of recurrent variceal bleeding in an adult with cirrhosis and portal hypertension due to chronic visceral ASMD. Case Presentation. A patient with severe splenomegaly was diagnosed with ASMD at age of 25. At age 64 they had multiple hospital admissions for hematochezia (originally diagnosed as ischemic colitis) accompanied by hypotension (blood pressure 91/45 mmHg), anemia (hemoglobin 8.5g/dL, ref 12-16; INR 1.4, ref ≤1.2), and mild renal insufficiency (creatinine 1.33mg/dL, ref 0.51-0.95). Colonoscopy did not reveal a source of bleeding. Computerized tomography scanning imaging showed diffuse venous collaterals and ascites. Arteriographies during subsequent episodes of bleeding were negative for active arterial intestinal bleeding. Recurrent gastrointestinal bleeding was found to originate from a varicose vein cluster connected to the right iliac vein and the superior mesenteric vein, located in the submucosa of a small intestinal loop. Multiple varices were secondary to portal hypertension in the context of cirrhosis. The patient died from recurrent variceal bleeding that exacerbated liver failure worsened by pneumonia and hypovolemic and septic shock. Conclusions. The variceal bleeding in this patient was atypical in that it originated from venous collaterals bleeding into the small intestine rather than the more typical gastroesophageal varices observed in ASMD. With long standing liver dysfunction and gradual development of portal hypertension, intestinal varices rather than occult intestinal bleeding due to ischemia should be considered in ASMD patients presenting with either hematochezia or hematemesis.

Published
2019
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158. Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity

Author

UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, Vriens, Kim, Christen, Stefan, Parik, Sweta, Broekaert, Dorien, Yoshinaga, Kazuaki, Talebi, Ali, Dehairs, Jonas, Escalona-Noguero, Carmen, Schmieder, Roberta, Cornfield, Thomas, Charlton, Catriona, Romero-Pérez, Laura, Rossi, Matteo, Rinaldi, Gianmarco, Orth, Martin F., Boon, Ruben, Kerstens, Axelle, Kwan, Suet Ying, Faubert, Brandon, Méndez-Lucas, Andrés, Kopitz, Charlotte C., Chen, Ting, Fernandez-Garcia, Juan, Duarte, João A. G., Schmitz, Arndt A., Steigemann, Patrick, Najimi, Mustapha, Hägebarth, Andrea, Van Ginderachter, Jo A., Sokal, Etienne, Gotoh, Naohiro, Wong, Kwok-Kin, Verfaillie, Catherine, Derua, Rita, Munck, Sebastian, Yuneva, Mariia, Beretta, Laura, DeBerardinis, Ralph J., Swinnen, Johannes V., Hodson, Leanne, Cassiman, David, Verslype, Chris, Christian, Sven, Grünewald, Sylvia, Grünewald, Thomas G. P., Fendt, Sarah-Maria, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, Vriens, Kim, Christen, Stefan, Parik, Sweta, Broekaert, Dorien, Yoshinaga, Kazuaki, Talebi, Ali, Dehairs, Jonas, Escalona-Noguero, Carmen, Schmieder, Roberta, Cornfield, Thomas, Charlton, Catriona, Romero-Pérez, Laura, Rossi, Matteo, Rinaldi, Gianmarco, Orth, Martin F., Boon, Ruben, Kerstens, Axelle, Kwan, Suet Ying, Faubert, Brandon, Méndez-Lucas, Andrés, Kopitz, Charlotte C., Chen, Ting, Fernandez-Garcia, Juan, Duarte, João A. G., Schmitz, Arndt A., Steigemann, Patrick, Najimi, Mustapha, Hägebarth, Andrea, Van Ginderachter, Jo A., Sokal, Etienne, Gotoh, Naohiro, Wong, Kwok-Kin, Verfaillie, Catherine, Derua, Rita, Munck, Sebastian, Yuneva, Mariia, Beretta, Laura, DeBerardinis, Ralph J., Swinnen, Johannes V., Hodson, Leanne, Cassiman, David, Verslype, Chris, Christian, Sven, Grünewald, Sylvia, Grünewald, Thomas G. P., and Fendt, Sarah-Maria

Abstract

Most tumours have an aberrantly activated lipid metabolism1,2 that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation3. This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

Published
2019

159. Case Report of Gastrointestinal Bleeding in an Adult with Chronic Visceral Acid Sphingomyelinase Deficiency

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Cassiman, David, Libbrecht, Louis, Meersseman, Wouter, Wilmer, Alexander, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Cassiman, David, Libbrecht, Louis, Meersseman, Wouter, and Wilmer, Alexander

Abstract

INTRODUCTION: Acid sphingomyelinase deficiency (ASMD, also known as Niemann-Pick Type A and Type B disease) is a rare, inherited metabolic disorder. Liver-related issues, including cirrhosis and variceal haemorrhage, are a leading cause of early mortality in individuals with chronic forms of ASMD. Due to the rarity of this lysosomal storage disorder, there can be a lack of awareness that adults with chronic ASMD disease are at significant risk of cirrhosis, portal hypertension, and variceal bleeding. This case highlights an unusual presentation of recurrent variceal bleeding in an adult with cirrhosis and portal hypertension due to chronic visceral ASMD. CASE PRESENTATION: A patient with severe splenomegaly was diagnosed with ASMD at age of 25. At age 64 they had multiple hospital admissions for hematochezia (originally diagnosed as ischemic colitis) accompanied by hypotension (blood pressure 91/45 mmHg), anemia (hemoglobin 8.5g/dL, ref 12-16; INR 1.4, ref ≤1.2), and mild renal insufficiency (creatinine 1.33mg/dL, ref 0.51-0.95). Colonoscopy did not reveal a source of bleeding. Computerized tomography scanning imaging showed diffuse venous collaterals and ascites. Arteriographies during subsequent episodes of bleeding were negative for active arterial intestinal bleeding. Recurrent gastrointestinal bleeding was found to originate from a varicose vein cluster connected to the right iliac vein and the superior mesenteric vein, located in the submucosa of a small intestinal loop. Multiple varices were secondary to portal hypertension in the context of cirrhosis. The patient died from recurrent variceal bleeding that exacerbated liver failure worsened by pneumonia and hypovolemic and septic shock. CONCLUSIONS: The variceal bleeding in this patient was atypical in that it originated from venous collaterals bleeding into the small intestine rather than the more typical gastroesophageal varices observed in ASMD. With long standing liver dysfunction and gradual development

Published
2019

160. Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content

Author

Simons, Nynke, Simons, Nynke, Debray, Francois-Guillaume, Schaper, Nicolaas C., Kooi, M. Eline, Feskens, Edith J. M., Hollak, Carla E. M., Lindeboom, Lucas, Koek, Ger H., Bons, Judith A. P., Lefeber, Dirk J., Hodson, Leanne, Schalkwijk, Casper G., Stehouwer, Coen D. A., Cassiman, David, Brouwers, Martijn C. G. J., Simons, Nynke, Simons, Nynke, Debray, Francois-Guillaume, Schaper, Nicolaas C., Kooi, M. Eline, Feskens, Edith J. M., Hollak, Carla E. M., Lindeboom, Lucas, Koek, Ger H., Bons, Judith A. P., Lefeber, Dirk J., Hodson, Leanne, Schalkwijk, Casper G., Stehouwer, Coen D. A., Cassiman, David, and Brouwers, Martijn C. G. J.

Abstract

Context: There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates.Objective: To translate these experimental findings to the human situation.Design: Case-control study.Setting: Outpatient clinic for inborn errors of metabolism.Patients or Other Participants: Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15).Main Outcome Measure: IHTG content, assessed by proton magnetic resonance spectroscopy.Results: IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m(2), respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P <0.001). Finally, plasma beta-hydroxybutyrate, a biomarker of hepatic beta-oxidation, was lower in aldo B-/- patients than controls (P = 0.009).Conclusions: This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of beta-oxidation are involved in the pathogenesis.

Published
2019

161. Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients

Author

Cluster C, Metabole ziekten patientenzorg, Child Health, van Vliet, Kimber, van Ginkel, Willem G., Jahja, Rianne, Daly, Anne, MacDonald, Anita, De Laet, Corinne, Vara, Roshni, Rahman, Yusof, Cassiman, David, Eyskens, Francois, Timmer, Corrie, Mumford, Nicky, Bierau, Jörgen, van Hasselt, Peter M., Gissen, Paul, Goyens, Philippe J., McKiernan, Patrick J., Wilcox, Gisela, Morris, Andrew A.M., Jameson, Elisabeth A., Huijbregts, Stephan C.J., van Spronsen, Francjan J., Cluster C, Metabole ziekten patientenzorg, Child Health, van Vliet, Kimber, van Ginkel, Willem G., Jahja, Rianne, Daly, Anne, MacDonald, Anita, De Laet, Corinne, Vara, Roshni, Rahman, Yusof, Cassiman, David, Eyskens, Francois, Timmer, Corrie, Mumford, Nicky, Bierau, Jörgen, van Hasselt, Peter M., Gissen, Paul, Goyens, Philippe J., McKiernan, Patrick J., Wilcox, Gisela, Morris, Andrew A.M., Jameson, Elisabeth A., Huijbregts, Stephan C.J., and van Spronsen, Francjan J.

Published
2019

162. Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity

Author

Korf, Hannelie, Du Plessis, Johannie, Van Pelt, Jos, De Groote, Sofie, Cassiman, David, Verbeke, Len, Ghesquière, Bart, Fendt, Sarah-Maria, Bird, Matthew MJ, Talebi, Ali, Van Haele, Matthias, Feio-Azevedo, Rita, Meelberghs, Lore, Roskams, Tania, Mookerjee, Rajeshwar, Mehta, Gautam, Jalan, Rajiv, Gustot, Thierry, Laleman, Wim, Nevens, Frederik, Van Der Merwe, Schalk Willem, Korf, Hannelie, Du Plessis, Johannie, Van Pelt, Jos, De Groote, Sofie, Cassiman, David, Verbeke, Len, Ghesquière, Bart, Fendt, Sarah-Maria, Bird, Matthew MJ, Talebi, Ali, Van Haele, Matthias, Feio-Azevedo, Rita, Meelberghs, Lore, Roskams, Tania, Mookerjee, Rajeshwar, Mehta, Gautam, Jalan, Rajiv, Gustot, Thierry, Laleman, Wim, Nevens, Frederik, and Van Der Merwe, Schalk Willem

Abstract

Objective Acute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity. Design Following phenotypic characterisation, we performed RNA sequencing on CD14 + CD16-monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function. Results Monocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14 + CD16-monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated-as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores. Conclusion In ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes parti, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

165. The SLC40A1 R178Q mutation is a recurrent cause of hemochromatosis and is associated with a novel pathogenic mechanism

Author

Ka, Chandran, Guellec, Julie, Pepermans, Xavier, Kannengiesser, Caroline, Ged, Cecile, Wuyts, Wim, Cassiman, David, De Ledinghen, Victor, Varet, Bruno, De Kerguenec, Caroline, Oudin, Claire, Gourlaouen, Isabelle, Lefebvre, Thibaud, Férec, Claude, Callebaut, Isabelle, Le Gac, Gerald, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire et Histocompatibilité, CHRU de Brest, Hôpital Morvan, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Association Gaétan Saleun Brest, Center for Human Genetics, University Hospital of St-Luc, Bruxelles, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inserm U1035, Biotherapies des Maladies Genetiques et Cancers, Universite' de Bordeaux,CHU de Bordeaux,Pole de Biologie et Pathologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical genetics, University of Antwerp (UA), Department of Gastroenterology-Hepatology and Metabolic Center, University Hospital of Leuven, Belgium, Hôpital Haut-Lévêque, CHU Bordeaux [Bordeaux]-Université Sciences et Technologies - Bordeaux 1, Université Paris Descartes - Paris 5 (UPD5), Hôpital Beaujon, Laboratoire de Génétique Moléculaire et Histocompatibilité, CHRU de Brest, Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Hôpital Beaujon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Cytogenetics and Molecular Genetics, [SDV]Life Sciences [q-bio], Hemochromatosis, Human medicine, Clinical and Molecular Epidemiology, Ferroportin disease, Iron Metabolism, ComputingMilieux_MISCELLANEOUS
Abstract

Hemochromatosis type 4 is one of the most common causes of primary iron overload, after HFE-related hemochromatosis. It is an autosomal dominant disorder, primarily due to missense mutations in SLC40A1 This gene encodes ferroportin 1 (FPN1), which is the sole iron export protein reported in mammals. Not all heterozygous missense mutations in SLC40A1 are disease-causing. Due to phenocopies and an increased demand for genetic testing, rare SLC40A1 variations are fortuitously observed in patients with a secondary cause of hyperferritinemia. Structure/function analysis is the most effective way of establishing causality when clinical and segregation data are lacking. It can also provide important insights into the mechanism of iron egress and FPN1 regulation by hepcidin. The present study aimed to determine the pathogenicity of the previously reported p.Arg178Gln variant. We present the biological, clinical, histological and radiological findings of 22 patients from six independent families of French, Belgian or Iraqi decent. Despite phenotypic variability, all patients with p.Arg178Gln had elevated serum ferritin concentrations and normal to low transferrin saturation levels. In vitro experiments demonstrated that the p.Arg178Gln mutant reduces the ability of FPN1 to export iron without causing protein mislocalization. Based on a comparative model of the 3D structure of human FPN1 in an outward facing conformation, we argue that p.Arg178 is part of an interaction network modulating the conformational changes required for iron transport. We conclude that p.Arg178Gln represents a new category of loss-of-function mutations and that the study of "gating residues" is necessary in order to fully understand the action mechanism of FPN1. ispartof: HAEMATOLOGICA vol:103 issue:11 pages:1796-1805 ispartof: location:Italy status: published

Published
2018

168. The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG

Author

Radenkovic, Silvia, primary, Bird, Matthew J., additional, Emmerzaal, Tim L., additional, Wong, Sunnie Y., additional, Felgueira, Catarina, additional, Stiers, Kyle M., additional, Sabbagh, Leila, additional, Himmelreich, Nastassja, additional, Poschet, Gernot, additional, Windmolders, Petra, additional, Verheijen, Jan, additional, Witters, Peter, additional, Altassan, Ruqaiah, additional, Honzik, Tomas, additional, Eminoglu, Tuba F., additional, James, Phillip M., additional, Edmondson, Andrew C., additional, Hertecant, Jozef, additional, Kozicz, Tamas, additional, Thiel, Christian, additional, Vermeersch, Pieter, additional, Cassiman, David, additional, Beamer, Lesa, additional, Morava, Eva, additional, and Ghesquière, Bart, additional

Published
2019
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169. LBP-36-Inhibition of glutamine synthetase in monocytes from patients with Acute-on-Chronic Liver Failure resuscitates their antibacterial and inflammatory capacity

Author

Korf, Hannelie, primary, Plessis, Johannie Du, additional, Pelt, Jos van, additional, Groote, Sofie De, additional, Cassiman, David, additional, Verbeke, Len, additional, Ghesquière, Bart, additional, Fendt, Sarah-Maria, additional, Bird, Matthew, additional, Talebi, Ali, additional, Haele, Matthias Van, additional, Feio-Azevedo, Rita, additional, Meelberghs, Lore, additional, Roskams, Tania, additional, Mookerjee, Rajeshwar, additional, Mehta, Gautam, additional, Jalan, Rajiv, additional, Gustot, Thierry, additional, Laleman, Wim, additional, Nevens, Frederik, additional, and Merwe, Schalk van der, additional

Published
2019
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170. Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content

Author

Simons, Nynke, primary, Debray, François-Guillaume, additional, Schaper, Nicolaas C, additional, Kooi, M Eline, additional, Feskens, Edith J M, additional, Hollak, Carla E M, additional, Lindeboom, Lucas, additional, Koek, Ger H, additional, Bons, Judith A P, additional, Lefeber, Dirk J, additional, Hodson, Leanne, additional, Schalkwijk, Casper G, additional, Stehouwer, Coen D A, additional, Cassiman, David, additional, and Brouwers, Martijn C G J, additional

Published
2019
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171. Pneumococcal Immunization Reduces Neurological and Hepatic Symptoms in a Mouse Model for Niemann-Pick Type C1 Disease

Author

Houben, Tom, primary, Magro dos Reis, Inês, additional, Oligschlaeger, Yvonne, additional, Steinbusch, Hellen, additional, Gijbels, Marion J. J., additional, Hendrikx, Tim, additional, Binder, Christoph J., additional, Cassiman, David, additional, Westerterp, Marit, additional, Prickaerts, Jos, additional, and Shiri-Sverdlov, Ronit, additional

Published
2019
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172. International clinical guidelines for the management of phosphomannomutase 2‐congenital disorders of glycosylation: Diagnosis, treatment and follow up

Author

Altassan, Ruqaiah, primary, Péanne, Romain, additional, Jaeken, Jaak, additional, Barone, Rita, additional, Bidet, Muad, additional, Borgel, Delphine, additional, Brasil, Sandra, additional, Cassiman, David, additional, Cechova, Anna, additional, Coman, David, additional, Corral, Javier, additional, Correia, Joana, additional, de la Morena‐Barrio, María Eugenia, additional, de Lonlay, Pascale, additional, Dos Reis, Vanessa, additional, Ferreira, Carlos R, additional, Fiumara, Agata, additional, Francisco, Rita, additional, Freeze, Hudson, additional, Funke, Simone, additional, Gardeitchik, Thatjana, additional, Gert, Matthijs, additional, Girad, Muriel, additional, Giros, Marisa, additional, Grünewald, Stephanie, additional, Hernández‐Caselles, Trinidad, additional, Honzik, Tomas, additional, Hutter, Marlen, additional, Krasnewich, Donna, additional, Lam, Christina, additional, Lee, Joy, additional, Lefeber, Dirk, additional, Marques‐da‐Silva, Dorinda, additional, Martinez, Antonio F, additional, Moravej, Hossein, additional, Õunap, Katrin, additional, Pascoal, Carlota, additional, Pascreau, Tiffany, additional, Patterson, Marc, additional, Quelhas, Dulce, additional, Raymond, Kimiyo, additional, Sarkhail, Peymaneh, additional, Schiff, Manuel, additional, Seroczyńska, Małgorzata, additional, Serrano, Mercedes, additional, Seta, Nathalie, additional, Sykut‐Cegielska, Jolanta, additional, Thiel, Christian, additional, Tort, Federic, additional, Vals, Mari‐Anne, additional, Videira, Paula, additional, Witters, Peter, additional, Zeevaert, Renate, additional, and Morava, Eva, additional

Published
2019
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173. Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity

Author

Korf, Hannelie, primary, du Plessis, Johannie, additional, van Pelt, Jos, additional, De Groote, Sofie, additional, Cassiman, David, additional, Verbeke, Len, additional, Ghesquière, Bart, additional, Fendt, Sarah-Maria, additional, Bird, Matthew J, additional, Talebi, Ali, additional, Van Haele, Matthias, additional, Feio-Azevedo, Rita, additional, Meelberghs, Lore, additional, Roskams, Tania, additional, Mookerjee, Rajeshwar P, additional, Mehta, Gautam, additional, Jalan, Rajiv, additional, Gustot, Thierry, additional, Laleman, Wim, additional, Nevens, Frederik, additional, and van der Merwe, Schalk Willem, additional

Published
2018
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174. Corrigendum to “Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases” [Mol. Genet. Metab. 118 (2016) 206–213]

Author

Cassiman, David, primary, Packman, Seymour, additional, Bembi, Bruno, additional, Turkia, Hadhami Ben, additional, Al-Sayed, Moeenaldeen, additional, Schiff, Manuel, additional, Imrie, Jackie, additional, Mabe, Paulina, additional, Takahashi, Tsutomu, additional, Mengel, Karl Eugen, additional, Giugliani, Roberto, additional, and Cox, Gerald F., additional

Published
2018
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176. A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report

Author

Kvittingen Eli-Anne, Holme Elisabeth, Zeevaert Renate, Cassiman David, and Jaeken Jaak

Subjects
Medicine
Abstract

Abstract A male patient, born to unrelated Belgian parents, presented at 4 months with epistaxis, haematemesis and haematochezia. On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. Serum transaminases were elevated to 5-10 times upper limit of normal, alkaline phosphatases were 1685 U/L (180 s ( Fumarylacetoacetase (FAH) protein and activity in cultured fibroblasts and liver tissue were decreased but not absent. 4-hydroxyphenylpyruvate dioxygenase activity in liver was normal, which is atypical for tyrosinemia type I. A novel mutation was found in the FAH gene: c.103G>A (Ala35Thr). In vitro expression studies showed this mutation results in a strongly decreased FAH protein expression. Dietary treatment with phenylalanine and tyrosine restriction was initiated at 4 months, leading to complete clinical and biochemical normalisation. The patient, currently aged 12 years, shows a normal physical and psychomotor development. This is the first report of mild tyrosinemia type I disease caused by an Ala35Thr mutation in the FAH gene, presenting atypically without increase of the diagnostically important toxic metabolites succinylacetone and succinylacetoacetate.

Published
2009
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179. The SLC40A1 R178Q mutation is a recurrent cause of hemochromatosis and is associated with a novel pathogenic mechanism

Author

UCL - (SLuc) Centre de génétique médicale UCL, Ka, Chandran, Guellec, Julie, Pepermans, Xavier, Kannengiesser, Caroline, Ged, Cécile, Wuyts, Wim, Cassiman, David, de Ledinghen, Victor, Varet, Bruno, de Kerguenec, Caroline, Oudin, Claire, Gourlaouen, Isabelle, Lefebvre, Thibaud, Férec, Claude, Callebaut, Isabelle, Le Gac, Gérald, UCL - (SLuc) Centre de génétique médicale UCL, Ka, Chandran, Guellec, Julie, Pepermans, Xavier, Kannengiesser, Caroline, Ged, Cécile, Wuyts, Wim, Cassiman, David, de Ledinghen, Victor, Varet, Bruno, de Kerguenec, Caroline, Oudin, Claire, Gourlaouen, Isabelle, Lefebvre, Thibaud, Férec, Claude, Callebaut, Isabelle, and Le Gac, Gérald

Abstract

Hemochromatosis type 4 is one of the most common causes of primary iron overload, after HFE-related hemochromatosis. It is an autosomal dominant disorder, primarily due to missense mutations in SLC40A1. This gene encodes ferroportin 1 (FPN1), which is the sole iron export protein reported in mammals. Not all heterozygous missense mutations in SLC40A1 are disease-causing. Due to phenocopies and an increased demand for genetic testing, rare SLC40A1 variations are fortuitously observed in patients with a secondary cause of hyperferritinemia. Structure/function analysis is the most effective way of establishing causality when clinical and segregation data are lacking. It can also provide important insights into the mechanism of iron egress and FPN1 regulation by hepcidin. The present study aimed to determine the pathogenicity of the previously reported p.Arg178Gln variant. We present the biological, clinical, histological and radiological findings of 22 patients from six independent families of French, Belgian or Iraqi decent. Despite phenotypic variability, all patients with p.Arg178Gln had elevated serum ferritin concentrations and normal to low transferrin saturation levels. In vitro experiments demonstrated that the p.Arg178Gln mutant reduces the ability of FPN1 to export iron without causing protein mislocalization. Based on a comparative model of the 3D structure of human FPN1 in an outward facing conformation, we argue that p.Arg178 is part of an interaction network modulating the conformational changes required for iron transport. We conclude that p.Arg178Gln represents a new category of loss-of-function mutations and that the study of “gating residues” is necessary in order to fully understand the action mechanism of FPN1.

Published
2018

180. The Belgian association for study of the liver guidance document on the management of adult and paediatric non-alcoholic fatty liver disease

Author

Francque, Sven, Cassiman, David, Smets, F., Komuta, Mina, Driessen, Ann, Dirinck, Eveline, Danse, Etienne, Op de Beeck, Beeck, van Craenenbroeck, Emeline, Van Nieuwenhove, Yves, Hubens, Guy, Lanthier, Nicolas, Geerts, Anja, Moreno, Christophe, Verbeke, Len, Reynaert, Hendrik, van Steenkiste, Christophe, Vonghia, Luisa, Kwanten, Wilhelmus W.J., Weyler, Joost, Trepo, Eric, Francque, Sven, Cassiman, David, Smets, F., Komuta, Mina, Driessen, Ann, Dirinck, Eveline, Danse, Etienne, Op de Beeck, Beeck, van Craenenbroeck, Emeline, Van Nieuwenhove, Yves, Hubens, Guy, Lanthier, Nicolas, Geerts, Anja, Moreno, Christophe, Verbeke, Len, Reynaert, Hendrik, van Steenkiste, Christophe, Vonghia, Luisa, Kwanten, Wilhelmus W.J., Weyler, Joost, and Trepo, Eric

Abstract

Non-Alcoholic Fatty Liver Disease (NAFLD) is highly prevalent and associated with considerable liver-related and non-liverrelated morbidity and mortality. There is, however, a lot of uncertainty on how to handle NAFLD in clinical practice. The current guidance document, compiled under the aegis of the Belgian Association for the Study of the Liver by a panel of experts in NAFLD, from a broad range of different specialties, covers many questions encountered in daily clinical practice regarding diagnosis, screening, therapy and follow-up in adult and paediatric patients. Guidance statements in this document are based on the available evidence whenever possible. In case of absence of evidence or inconsistency of the data, guidance statements were formulated based on consensus of the expert panel. This guidance document is intended as a help for clinicians (general practitioners and all involved specialties) to implement the most recent evidence and insights in the field of NAFLD within a Belgian perspective., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

182. Biallelic mutations in TMEM126B cause severe complex i deficiency with a variable clinical phenotype

Author

Alston, Charlotte, Compton, Alison G., Formosa, Luke E., Strecker, Valentina, Oláhová, Monika, Haack, Tobias, Smet, Joél, Stouffs, Katrien, Diakumis, Peter, Ciara, Elżbieta, Cassiman, David, Romain, Nadine, Yarham, John W., He, Langping, De Paepe, Boel, Vanlander, Arnaud V., Seneca, Sara, Feichtinger, René G., Płoski, Rafał, Rokicki, Dariusz, Pronicka, Ewa, Haller, Ronald G., Hove, Johan L. K. van, Bahlo, Melanie, Mayr, Johannes A., Coster, Rudy van, Prokisch, Holger, Wittig, Ilka, Ryan, Michael T., Thorburn, David R., and Taylor, Robert W.

Subjects
ddc:610
Abstract

Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs∗2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.

Published
2017

183. Dietary practices in methylmalonic acidaemia: a European survey.

Author

Pinto, Alex, Evans, Sharon, Daly, Anne, Almeida, Manuela Ferreira, Assoun, Murielle, Belanger-Quintana, Amaya, Bernabei, Silvia Maria, Bollhalder, Sandra, Cassiman, David, Champion, Helena, Chan, Heidi, Corthouts, Karen, Dalmau, Jaime, Boer, Foekje de, Laet, Corinne De, Meyer, An de, Desloovere, An, Dianin, Alice, Dixon, Marjorie, and Dokoupil, Katharina

Abstract

Background: The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability. Aim: To describe the dietary management of patients with MMA across Europe. Methods: A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0–6 months; 7–12 months; 1–10 years; 11–16 years; >16 years). Results: Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy. Conclusions: A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice. [ABSTRACT FROM AUTHOR]

Published
2020
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184. Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy

Author

Lemoine, Mathilde, primary, François, Arnaud, additional, Grangé, Steven, additional, Rabant, Marion, additional, Châtelet, Valérie, additional, Cassiman, David, additional, Cornec-Le Gall, Emilie, additional, Ambrosetti, Damien, additional, Deschênes, Georges, additional, Benoist, Jean-François, additional, and Guerrot, Dominique, additional

Published
2018
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185. The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL

Author

Kampen, Kim R., primary, Sulima, Sergey O., additional, Verbelen, Benno, additional, Girardi, Tiziana, additional, Vereecke, Stijn, additional, Rinaldi, Gianmarco, additional, Verbeeck, Jelle, additional, Op de Beeck, Joyce, additional, Uyttebroeck, Anne, additional, Meijerink, Jules P. P., additional, Moorman, Anthony V., additional, Harrison, Christine J., additional, Spincemaille, Pieter, additional, Cools, Jan, additional, Cassiman, David, additional, Fendt, Sarah-Maria, additional, Vermeersch, Pieter, additional, and De Keersmaecker, Kim, additional

Published
2018
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186. Renal involvement in PMM2-CDG, a mini-review

Author

Altassan, Ruqaiah, primary, Witters, Peter, additional, Saifudeen, Zubaida, additional, Quelhas, Dulce, additional, Jaeken, Jaak, additional, Levtchenko, Elena, additional, Cassiman, David, additional, and Morava, Eva, additional

Published
2018
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190. De novo loss-of-function variants in X-linked MED12are associated with Hardikar syndrome in females

Author

Li, Dong, Strong, Alanna, Shen, Kaitlyn M., Cassiman, David, Van Dyck, Maria, Linhares, Natalia Duarte, Valadares, Eugenia Ribeiro, Wang, Tiancheng, Pena, Sergio D.J., Jaeken, Jaak, Vergano, Samantha, Zackai, Elaine, Hing, Anne, Chow, Penny, Ganguly, Arupa, Scholz, Tasja, Bierhals, Tatjana, Philipp, Deindl, Hakonarson, Hakon, and Bhoj, Elizabeth

Abstract

Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder.

Published
2021
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191. An autosomal dominant neurological disorder caused by de novo variants in FAR1resulting in uncontrolled synthesis of ether lipids

Author

Ferdinandusse, Sacha, McWalter, Kirsty, te Brinke, Heleen, IJlst, Lodewijk, Mooijer, Petra M., Ruiter, Jos P.N., van Lint, Alida E.M., Pras-Raves, Mia, Wever, Eric, Millan, Francisca, Guillen Sacoto, Maria J., Begtrup, Amber, Tarnopolsky, Mark, Brady, Lauren, Ladda, Roger L., Sell, Susan L., Nowak, Catherine B., Douglas, Jessica, Tian, Cuixia, Ulm, Elizabeth, Perlman, Seth, Drack, Arlene V., Chong, Karen, Martin, Nicole, Brault, Jennifer, Brokamp, Elly, Toro, Camilo, Gahl, William A., Macnamara, Ellen F., Wolfe, Lynne, Alejandro, Mercedes E., Azamian, Mahshid S., Bacino, Carlos A., Balasubramanyam, Ashok, Burrage, Lindsay C., Chao, Hsiao-Tuan, Clark, Gary D., Craigen, William J., Dai, Hongzheng, Dhar, Shweta U., Emrick, Lisa T., Goldman, Alica M., Hanchard, Neil A., Jamal, Fariha, Karaviti, Lefkothea, Lalani, Seema R., Lee, Brendan H., Lewis, Richard A., Marom, Ronit, Moretti, Paolo M., Murdock, David R., Nicholas, Sarah K., Orengo, James P., Posey, Jennifer E., Potocki, Lorraine, Rosenfeld, Jill A., Samson, Susan L., Scott, Daryl A., Tran, Alyssa A., Vogel, Tiphanie P., Wangler, Michael F., Yamamoto, Shinya, Eng, Christine M., Liu, Pengfei, Ward, Patricia A., Behrens, Edward, Deardorff, Matthew, Falk, Marni, Hassey, Kelly, Sullivan, Kathleen, Vanderver, Adeline, Goldstein, David B., Cope, Heidi, McConkie-Rosell, Allyn, Schoch, Kelly, Shashi, Vandana, Smith, Edward C., Spillmann, Rebecca C., Sullivan, Jennifer A., Tan, Queenie K.-G., Walley, Nicole M., Agrawal, Pankaj B., Beggs, Alan H., Berry, Gerard T., Briere, Lauren C., Cobban, Laurel A., Coggins, Matthew, Cooper, Cynthia M., Fieg, Elizabeth L., High, Frances, Holm, Ingrid A., Korrick, Susan, Krier, Joel B., Lincoln, Sharyn A., Loscalzo, Joseph, Maas, Richard L., MacRae, Calum A., Pallais, J. Carl, Rao, Deepak A., Rodan, Lance H., Silverman, Edwin K., Stoler, Joan M., Sweetser, David A., Walker, Melissa, Walsh, Chris A., Esteves, Cecilia, Kelley, Emily G., Kohane, Isaac S., LeBlanc, Kimberly, McCray, Alexa T., Nagy, Anna, Dasari, Surendra, Lanpher, Brendan C., Lanza, Ian R., Morava, Eva, Oglesbee, Devin, Bademci, Guney, Barbouth, Deborah, Bivona, Stephanie, Carrasquillo, Olveen, Chang, Ta Chen Peter, Forghani, Irman, Grajewski, Alana, Isasi, Rosario, Lam, Byron, Levitt, Roy, Liu, Xue Zhong, McCauley, Jacob, Sacco, Ralph, Saporta, Mario, Schaechter, Judy, Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Zuchner, Stephan, Colley, Heather A., Dayal, Jyoti G., Eckstein, David J., Findley, Laurie C., Krasnewich, Donna M., Mamounas, Laura A., Manolio, Teri A., Mulvihill, John J., LaMoure, Grace L., Goldrich, Madison P., Urv, Tiina K., Doss, Argenia L., Acosta, Maria T., Bonnenmann, Carsten, D’Souza, Precilla, Draper, David D., Ferreira, Carlos, Godfrey, Rena A., Groden, Catherine A., Macnamara, Ellen F., Maduro, Valerie V., Markello, Thomas C., Nath, Avi, Novacic, Donna, Pusey, Barbara N., Toro, Camilo, Wahl, Colleen E., Baker, Eva, Burke, Elizabeth A., Adams, David R., Gahl, William A., Malicdan, May Christine V., Tifft, Cynthia J., Wolfe, Lynne A., Yang, John, Power, Bradley, Gochuico, Bernadette, Huryn, Laryssa, Latham, Lea, Davis, Joie, Mosbrook-Davis, Deborah, Rossignol, Francis, Solomon, Ben, MacDowall, John, Thurm, Audrey, Zein, Wadih, Yousef, Muhammad, Adam, Margaret, Amendola, Laura, Bamshad, Michael, Beck, Anita, Bennett, Jimmy, Berg-Rood, Beverly, Blue, Elizabeth, Boyd, Brenna, Byers, Peter, Chanprasert, Sirisak, Cunningham, Michael, Dipple, Katrina, Doherty, Daniel, Earl, Dawn, Glass, Ian, Golden-Grant, Katie, Hahn, Sihoun, Hing, Anne, Hisama, Fuki M., Horike-Pyne, Martha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Lam, Christina, Maravilla, Kenneth, Mefford, Heather, Merritt, J. Lawrence, Mirzaa, Ghayda, Nickerson, Deborah, Raskind, Wendy, Rosenwasser, Natalie, Scott, C. Ron, Sun, Angela, Sybert, Virginia, Wallace, Stephanie, Wener, Mark, Wenger, Tara, Ashley, Euan A., Bejerano, Gill, Bernstein, Jonathan A., Bonner, Devon, Coakley, Terra R., Fernandez, Liliana, Fisher, Paul G., Fresard, Laure, Hom, Jason, Huang, Yong, Kohler, Jennefer N., Kravets, Elijah, Majcherska, Marta M., Martin, Beth A., Marwaha, Shruti, McCormack, Colleen E., Raja, Archana N., Reuter, Chloe M., Ruzhnikov, Maura, Sampson, Jacinda B., Smith, Kevin S., Sutton, Shirley, Tabor, Holly K., Tucker, Brianna M., Wheeler, Matthew T., Zastrow, Diane B., Zhao, Chunli, Byrd, William E., Crouse, Andrew B., Might, Matthew, Nakano-Okuno, Mariko, Whitlock, Jordan, Brown, Gabrielle, Butte, Manish J., Dell’Angelica, Esteban C., Dorrani, Naghmeh, Douine, Emilie D., Fogel, Brent L., Gutierrez, Irma, Huang, Alden, Krakow, Deborah, Lee, Hane, Loo, Sandra K., Mak, Bryan C., Martin, Martin G., Martínez-Agosto, Julian A., McGee, Elisabeth, Nelson, Stanley F., Nieves-Rodriguez, Shirley, Palmer, Christina G.S., Papp, Jeanette C., Parker, Neil H., Renteria, Genecee, Signer, Rebecca H., Sinsheimer, Janet S., Wan, Jijun, Wang, Lee-kai, Perry, Katherine Wesseling, Woods, Jeremy D., Alvey, Justin, Andrews, Ashley, Bale, Jim, Bohnsack, John, Botto, Lorenzo, Carey, John, Pace, Laura, Longo, Nicola, Marth, Gabor, Moretti, Paolo, Quinlan, Aaron, Velinder, Matt, Viskochil, Dave, Bayrak-Toydemir, Pinar, Mao, Rong, Westerfield, Monte, Bican, Anna, Brokamp, Elly, Duncan, Laura, Hamid, Rizwan, Kennedy, Jennifer, Kozuira, Mary, Newman, John H., Phillips, John A., Rives, Lynette, Robertson, Amy K., Solem, Emily, Cogan, Joy D., Cole, F. Sessions, Hayes, Nichole, Kiley, Dana, Sisco, Kathy, Wambach, Jennifer, Wegner, Daniel, Baldridge, Dustin, Pak, Stephen, Schedl, Timothy, Shin, Jimann, Solnica-Krezel, Lilianna, Waisfisz, Quinten, Zwijnenburg, Petra J.G., Ziegler, Alban, Barth, Magalie, Smith, Rosemarie, Ellingwood, Sara, Gaebler-Spira, Deborah, Bakhtiari, Somayeh, Kruer, Michael C., van Kampen, Antoine H.C., Wanders, Ronald J.A., Waterham, Hans R., Cassiman, David, and Vaz, Frédéric M.

Abstract

In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).

Published
2021
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192. On the Pathogenesis of Central Liver Nodules in Alagille Syndrome

Author

UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service d'anatomie pathologique, Libbrecht, Louis, Cassiman, David, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service d'anatomie pathologique, Libbrecht, Louis, and Cassiman, David

Published
2017

193. Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Witters, Peter, Libbrecht, Louis, Roskams, Tania, De Boeck, Kris, Dupont, Lieven, Proesmans, Marijke, Vermeulen, François, Maleux, Geert, Monbaliu, Diethard, Pirenne, Jacques, Cassiman, David, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Witters, Peter, Libbrecht, Louis, Roskams, Tania, De Boeck, Kris, Dupont, Lieven, Proesmans, Marijke, Vermeulen, François, Maleux, Geert, Monbaliu, Diethard, Pirenne, Jacques, and Cassiman, David

Published
2017

194. Identification of survival-promoting OSIP108 peptide variants and their internalization in human cells

Author

Verbandt, Sara, Troeira Henriques, Sonia, Spincemaille, Pieter, Harvey, Peta, Chandhok, Gursimran, Sauer, Vanessa, De Coninck, Barbara, Cassiman, David, Craik, David, Cammue, Bruno, De Cremer, Kaat, Thevissen, Karin, Verbandt, Sara, Troeira Henriques, Sonia, Spincemaille, Pieter, Harvey, Peta, Chandhok, Gursimran, Sauer, Vanessa, De Coninck, Barbara, Cassiman, David, Craik, David, Cammue, Bruno, De Cremer, Kaat, and Thevissen, Karin

Abstract

he plant-derived decapeptide OSIP108 increases tolerance of yeast and human cells to apoptosis-inducing agents, such as copper and cisplatin. We performed a whole amino acid scan of OSIP108 and conducted structure-activity relationship studies on the induction of cisplatin tolerance (CT) in yeast. The use of cisplatin as apoptosis-inducing trigger in this study should be considered as a tool to better understand the survival-promoting nature of OSIP108 and not for purposes related to anti-cancer treatment. We found that charged residues (Arg, His, Lys, Glu or Asp) or a Pro on positions 4-7 improved OSIP108 activity by 10% or more. The variant OSIP108[G7P] induced the most pronounced tolerance to toxic concentrations of copper and cisplatin in yeast and/or HepG2 cells. Both OSIP108 and OSIP108[G7P] were shown to internalize equally into HeLa cells, but at a higher rate than the inactive OSIP108[E10A], suggesting that the peptides can internalize into cells and that OSIP108 activity is dependent on subsequent intracellular interactions. In conclusion, our studies demonstrated that tolerance/survival-promoting properties of OSIP108 can be significantly improved by single amino acid substitutions, and that these properties are dependent on (an) intracellular target(s), yet to be determined.

Published
2017

195. Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype

Author

Alston, Charlotte L., Compton, Alison G., Formosa, Luke E., Strecker, Valentina, Oláhová, Monika, Haack, Tobias B., Smet, Joél, Stouffs, Katrien, Diakumis, Peter, Ciara, Elżbieta, Cassiman, David, Romain, Nadine, Yarham, John W., He, Langping, De Paepe, Boel, Vanlander, Arnaud V., Seneca, Sara, Feichtinger, René G., Płoski, Rafal, Rokicki, Dariusz, Pronicka, Ewa, Haller, Ronald G., Van Hove, Johan L.K., Bahlo, Melanie, Mayr, Johannes A., Van Coster, Rudy, Prokisch, Holger, Wittig, Ilka, Ryan, Michael T., Thorburn, David R., Taylor, Robert W., Reproduction and Genetics, and Clinical sciences

Subjects
Adult, Male, Mitochondrial Diseases, Adolescent, PREDICTION, MITOCHONDRIAL COMPLEX, PROTEIN, ASSEMBLY FACTOR, DISEASE, Young Adult, Report, Genetics, Humans, Genetics(clinical), Amino Acid Sequence, Age of Onset, Child, Alleles, Electron Transport Complex I, Biology and Life Sciences, Infant, Membrane Proteins, ASSOCIATION, DEFECTS, QUANTIFICATION, Middle Aged, COMPONENT, Pedigree, Phenotype, Mutation, Female, RESPIRATORY-CHAIN
Abstract

Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs(∗)2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined. publisher: Elsevier articletitle: Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype journaltitle: The American Journal of Human Genetics articlelink: http://dx.doi.org/10.1016/j.ajhg.2016.05.021 associatedlink: http://dx.doi.org/10.1016/j.ajhg.2016.05.022 content_type: article copyright: © 2016 The Author(s). ispartof: American Journal of Human Genetics vol:99 issue:1 pages:217-227 ispartof: location:United States status: published

Published
2016

196. Experience with Direct Acting Agents for the Treatment of Hepatitis C in Flanders

Author

Bielen, Rob, Robaeys, Geert, Cool, M., Decaestecker, J., Janssens, F., George, C., Laleman, W., Verslype, C., Cassiman, David, Van der Merwe, S., and Nevens, F.

Subjects
virus diseases, digestive system diseases
Abstract

Introduction: Hepatitis C (HCV) remains one of the main causes of chronic liver disease worldwide. The impact of chronic HCV on the long-term ranges widely, from minimal histologic changes to decompensated cirrhosis or hepatocellular carcinoma. These last years, the development of direct acting antivirals have revolutionized HCV care. We present the experience in the KU Leuven affiliated hospitals with the latest generation of direct acting antivirals. These are therapies without concomitant use of interferon, such as simeprevir, sofosbuvir, daclatasvir, and ombitasvir/paritaprevir ritonavir – dasabuvir. Aim Goal of this abstract is to demonstrate the safety and efficacy of the newest generation of direct acting antivirals in the general population in Belgium (the KU Leuven affiliated hospitals). Methods A national retrospective, interventional cohort study conducted between December 2013 and November 2015 in 6 Belgian centers during which patients infected with HCV were treated with the new regimes of DAA. All centers were experienced in treating HCV. In case antiviral treatment was started data were collected in a central database, with main focus on treatment outcome and side effects. Results and discussion In total, 134 patients (age 58 ± 12 years) were treated with one of the newest generation DAAs. All patients had multiple comorbidities, with an average rate of 1.55 ± 1.6. These were highest in the simeprevir/sofosbuvir group. HCV genotype 1b was most prevalent. 45.9% of the patients were treatment naïve, and 38.7% % was once treated before. 59 patients were treated with daclatasvir/sofosbuvir ± ribavirin, 48 with simeprevir/sofosbuvir ± ribavirin, and 27 with ombitasvir/ paritaprevir, ritonavir – dasabuvir ± ribavirin. Treatment is completed in only 60.4% of all patients. Moreover, only 42.5% were treated long enough so they could achieve SVR. From this group, almost everyone obtained SVR (96.5%). Subanalysis showed an SVR-rate of 100% (10/10) in the daclatasvir/sofosbuvir ± ribavirin group, 92.6% (25/27) in the simeprevir/sofosbuvir ± ribavirin group, and 100% (20/20) in the ombitasvir/ paritaprevir, ritonavir – dasabuvir ± ribavirin group. Side effects were present in 49.3 % of the total population, most frequent were an increase in fatigue and skin eruptions. Only in 9.7 %, this required a change in therapy. Ribavirin was lowered in dose or stopped in these cases. These are preliminary results, we will present larger data at the time of the congress. Conclusion Real-life experience with DAAs in Belgium shows comparable excellent results in achieving SVR for the treatment of HCV. Side effects were frequent, but rarely cause a need for therapy change. This study is part of the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by the foundation Limburg SterkMerk, Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital.

Published
2016

200. Investigating rare haematological disorders : a celebration of 10 years of the Sherlock Holmes Symposia

Author

Cappellini, Maria-Domenica, Cassiman, David, Marikanis, Theodoros, Rosenbaum, Hanna, Bauduer, Frédéric, Bjerrum, Ole Weis, Fraga, Cristina, Hughes, Derralynn, Jager, Ulrich, Machaczka, Maciej, Massenkeil, Gero, Mehta, Atul, Vallejo, Carlos, Università degli Studi di Milano [Milano] (UNIMI), University Hospitals Leuven [Leuven], Southern Illinois University [Carbondale] (SIU), The Bruce Rappaport Faculty of Medicine, Centre Hospitalier de la Côte Basque, De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie (PACEA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Hospital do Divino Espirito Santo, Royal Free London NHS Foundation Trust, University College of London [London] (UCL), Medizinische Universität Wien = Medical University of Vienna, Karolinska University Hospital Huddinge, Karolinska Institutet, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University College London Medical School, University College London (UCL), and Donostia Hospital Universitario San Sebastian

Subjects
préhistoire, [SHS.ARCHEO]Humanities and Social Sciences/Archaeology and Prehistory, ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2016

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