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1. Tracer metabolomics reveals the role of aldose reductase in glycosylation

Author

Radenkovic, Silvia, Ligezka, Anna N, Mokashi, Sneha S, Driesen, Karen, Dukes-Rimsky, Lynn, Preston, Graeme, Owuocha, Luckio F, Sabbagh, Leila, Mousa, Jehan, Lam, Christina, Edmondson, Andrew, Larson, Austin, Schultz, Matthew, Vermeersch, Pieter, Cassiman, David, Witters, Peter, Beamer, Lesa J, Kozicz, Tamas, Flanagan-Steet, Heather, Ghesquière, Bart, and Morava, Eva

Subjects
aldose reductase inhibition, congenital disorder of glycosylation, phoshomannomutase-2 deficiency, glycosylation, polyol metabolism, aldose reductase
Abstract

Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement. ispartof: Cell Rep Med vol:4 issue:6 pages:101056- ispartof: location:United States status: published

Published
2023

2. Plasma virome dynamics in chronic hepatitis B virus infected patients

Author

Thijssen, Marijn, Tacke, Frank, Van Espen, Lore, Cassiman, David, Aldine, Mahmoud Naser, Nevens, Frederik, Van Ranst, Marc, Matthijnssens, Jelle, and Pourkarim, Mahmoud Reza

Subjects
Microbiology (medical), virome, blood, pegivirus, anellovirus, metagenomic, hepatitis B virus, Microbiology, plasma
Abstract

The virome remains an understudied domain of the human microbiome. The role of commensal viruses on the outcome of infections with known pathogens is not well characterized. In this study we aimed to characterize the longitudinal plasma virome dynamics in chronic hepatitis B virus (HBV) infected patients. Eighty-five longitudinal plasma samples were collected from 12 chronic HBV infected individuals that were classified in the four stages of HBV infection. The virome was characterized with an optimized viral extraction protocol and deep-sequenced on a NextSeq 2500 platform. The plasma virome was primarily composed of members of the Anello- Flavi-, and Hepadnaviridae (HBV) families. The virome structure and dynamics did not correlate with the different stages of chronic HBV infection nor with the administration of antiviral therapy. We observed a higher intrapersonal similarity of viral contigs. Genomic analysis of viruses observed in multiple timepoint demonstrated the presence of a dynamic community. This study comprehensively assessed the blood virome structure in chronic HBV infected individuals and provided insights in the longitudinal development of this viral community.

Published
2023

3. An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Author

Ferdinandusse, Sacha, McWalter, Kirsty, Te Brinke, Heleen, IJlst, Lodewijk, Mooijer, Petra M, Ruiter, Jos PN, van Lint, Alida EM, 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, Undiagnosed Diseases Network, Waisfisz, Quinten, Zwijnenburg, Petra JG, Ziegler, Alban, Barth, Magalie, Smith, Rosemarie, Ellingwood, Sara, Gaebler-Spira, Deborah, Bakhtiari, Somayeh, Kruer, Michael C, van Kampen, Antoine HC, Wanders, Ronald JA, Waterham, Hans R, Cassiman, David, and Vaz, Frédéric M

Subjects
Pediatric, Genetics & Heredity, Clinical Sciences, Neurosciences, Undiagnosed Diseases Network, Aldehyde Oxidoreductases, Lipids, Hereditary, Phenotype, Clinical Research, Neurological, Genetics, Humans, Spastic Paraplegia, 2.1 Biological and endogenous factors, Aetiology, Ethers
Abstract

PurposeIn this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).MethodsFollowing next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.ResultsAll patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.ConclusionHeterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

Published
2021

4. Correction to:An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids (Genetics in Medicine, (2021), 23, 4, (740-750), 10.1038/s41436-020-01027-3)

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 A., 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, 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., Maduro, Valerie V., Markello, Thomas C., Nath, Avi, Novacic, Donna, Pusey, Barbara N., Wahl, Colleen E., Baker, Eva, Burke, Elizabeth A., Adams, David R., Malicdan, May Christine V., Tifft, Cynthia J., 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, Quinlan, Aaron, Velinder, Matt, Viskochil, Dave, Bayrak-Toydemir, Pinar, Mao, Rong, Westerfield, Monte, Bican, Anna, 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, Vaz, Frédéric M., Clinical chemistry, Human genetics, ACS - Atherosclerosis & ischemic syndromes, and Amsterdam Reproduction & Development (AR&D)

Abstract

In the original author list, Seth Perlman’s degrees were listed as MD, PhD. Dr Perlman’s degree is MD. The original version has been corrected.

Published
2021

6. 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

7. 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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8. 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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9. MOESM1 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

Subjects
humanities
Abstract

Additional file 1. Correlations between ASEBA questionnaires and QoL questionnaires for children. Correlations between ASEBA questionnaires and QoL questionnaires for children (N = 19). Bold and underlined results are significant correlations. The QoL domain peers only consists of children aged 12–15 years (N = 5).

Published
2019
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10. 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

11. 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

12. 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

13. 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

17. 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

21. Do ultra-orphan medicinal products warrant ultra-high prices? A review

Author

Picavet, Eline, Cassiman,David, and Simoens,Steven

Subjects
Research and Reviews [Orphan Drugs]
Abstract

Eline Picavet,1 David Cassiman,2 Steven Simoens1 1Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; 2Department of Hepatology, University Hospital Leuven, Leuven, Belgium Abstract: Ultra-orphan medicinal products (ultra-OMPs) are intended for the treatment, prevention, or diagnosis of ultra-rare diseases, ie, life-threatening or chronically debilitating diseases that affect less than one per 50,000 individuals. Recently, high prices for ultra-OMPs have given rise to debate on the sustainability and justification of these prices. The aim of this article is to review the international scientific literature on the pricing of ultra-OMPs and to provide an overview of the current knowledge on the drivers of ultra-OMP pricing. The pricing process of ultra-OMPs is a complex and nontransparent issue. Evidence in the literature seems to indicate that ultra-OMPs are priced according to rarity and what the manufacturer believes the market will bear. Additionally, there appears to be a trend between the price of an ultra-OMP and the number of available alternatives. Patients, third-party payers, and pharmaceutical companies could benefit from more transparent pricing strategies. With a view to containing health care costs, it is likely that cost-sharing strategies, such as performance-based risk sharing arrangements, will become increasingly more important. However, it is vital that any measures for price control are consistent with the intended goals of the incentives to promote the development of new OMPs. Ideally, a balance must be struck between attaining affordable prices for ultra-OMPs and securing a realistic return on investment for the pharmaceutical industry. Keywords: ultra-orphan medicinal product, ultra-rare disease, pricing

Published
2013

28. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (vol 48, pg 1185, 2016)

Author

Jenkinson, Emma M., Rodero, Mathieu P., Kasher, Paul R., Uggenti, Carolina, Oojageer, Anthony, Goosey, Laurence C., Rose, Yoann, Kershaw, Christopher J., Urquhart, Jill E., Williams, Simon G., Bhaskar, Sanjeev S., O Sullivan, James, Baerlocher, Gabriela M., Haubitz, Monika, Aubert, Geraldine, Baranano, Kristin W., Barnicoat, Angela J., Battini, Roberta, Berger, Andrea, Blair, Edward M., Brunstrom-Hernandez, Janice E., Buckard, Johannes A., Cassiman, David M., Caumes, Rosaline, Cordelli, Duccio M., Waele, Liesbeth M., Fay, Alexander J., Ferreira, Patrick, Fletcher, Nicholas A., Fryer, Alan E., Goel, Himanshu, Hemingway, Cheryl A., Henneke, Marco, Hughes, Imelda, Jefferson, Rosalind J., Kumar, Ram, Lagae, Lieven, Landrieu, Pierre G., Lourenco, Charles M., Malpas, Timothy J., Mehta, Sarju G., Metz, Imke, Naidu, Sakkubai, Ounap, Katrin, Panzer, Axel, Prabhakar, Prab, Quaghebeur, Gerardine, Schiffmann, Raphael, Sherr, Elliott H., Sinnathuray, Kanaga R., Soh, Calvin, Stewart, Helen S., Stone, John, Esch, Hilde, Mol, Christine E. G., Vanderver, Adeline, Wakeling, Emma L., Whitney, Andrea, Graham Pavitt, Griffiths-Jones, Sam, Rice, Gillian I., Revy, Patrick, Knaap, Marjo S., Livingston, John H., O Keefe, Raymond T., Crow, Yanick J., Other departments, and Paediatric Neurology

35. Budd-Chiari syndrome : reassessment of a step-wise treatment strategy

Author

Martens, Pieter, Maleux, Geert Albert, Devos, Timothy, Diethard Monbaliu, Heye, Sam, Verslype, C., Laleman, Wim, Cassiman, David, Merwe, Schalk Willem, Steenbergen, Werner, Jochmans, Ina, Aerts, Raymond, Pirenne, Jacques, and Nevens, Frederik

Abstract

The Budd-Chiari syndrome is a rare disorder characterized by hepatic venous outflow obstruction. A step-wise management was recently proposed. The aim of this study is to reassess our treatment approach and long-term outcome.The data of 37 Budd-Chiari patients, seen in our unit, were critically analyzed and compared with the ENVIE (European Network For Vascular Disorders of the Liver) data.Most patients had multiple prothrombotic conditions (41%), of which an underlying myeloproliferative neoplasm was the most frequent (59%). The JAK2V617F mutation was associated with more complete occlusion of all hepatic veins (JAK2 mutation +: 70% vs JAK2 mutation -: 23% and a higher severity score. The step-wise treatment algorithm used in our unit, in function of the severity of the liver impairment and the number and the extension of hepatic veins occluded, resulted in the following treatments: only anticoagulation (n = 7.21%), recanalization procedure (n = 4.21%), portosystemic shunts (n = 9.26%) and liver transplantation (n = 14.44%). This resulted in a 10 year survival rate of 90%. Treatment of the underlying hemostatic disorder offered a low recurrence rate. None of the 21 patients with a myeloproliferative neoplasm died in relation to the hematologic disorder.An individualized treatment regimen consisting of anticoagulation and interventional radiology and/or transplantation when necessary and strict follow-up of the underlying hematologic disorder, provided an excellent long-term survival, which confirm the data of the ENVIE study.

36. Combined Liver and Kidney Transplantation

Author

Darius, Tom, Monbaliu, Diethard, Aerts, Raymond, Roskams, Tania, Lerut, Evelyne, Cassiman, David, Verslype, Chris, Laleman, Wim, Vanrenterghem, Yves, Nevens, Frederik, and Jacques PIRENNE

37. Mapping and treating metabolic rewiring in mitochondrial disease : In kaart brengen en behandelen van metabole herschikking in mitochondriale ziekte

Author

Adant, Isabelle, Vermeersch, Pieter, Witters, Peter, Ghesquière, Bart, and Cassiman, David

Abstract

The mitochondrial oxidative phosphorylation system (OXPHOS) generates most of the cellular energy in the form of ATP. Pathogenic variants in genes crucial for mitochondrial function cause primary mitochondrial diseases (PMD). PMD form a large, heterogeneous group of disorders that affect at least 1 in 5000 individuals. Patients may present at any age, with symptoms in any organ, at any severity. Due to the diversity in clinical presentation and the lack of a single clear biochemical profile, diagnosis of PMD remains a challenge. Most PMD have a poor prognosis and lack effective therapies. There is thus a need for the development of specific, sensitive and rapid diagnostic markers, and for the discovery of effective therapeutic interventions. We hypothesised that PMD causes important metabolic changes due to the key role of mitochondria in numerous biochemical pathways. This project aimed to understand the cellular metabolic re-wiring occurring in PMD by characterising the metabolic consequences of OXPHOS dysfunction in skin fibroblasts derived from patients with PMD and healthy controls. The objectives were 3-fold: first to develop a new diagnostic technique, second to unravel the cellular profile in OXPHOS dysfunction, and third, to identify and test novel treatment strategies. First, the potential of oxygraphy as a diagnostic tool for PMD was investigated and compared to the gold standard of enzymology. The results showed that oxygraphy is a powerful new tool for the biochemical detection of PMD. However, oxygraphy and enzymology are complementary techniques, and should ideally be combined. The biochemical results must also be interpreted in regard to the clinical presentation, the other investigations already performed, and genetic testing results. Second, the metabolic profile of OXPHOS dysfunction was described in skin-derived fibroblasts obtained from patients with diverse PMD and validated in pharmacological models of OXPHOS dysfunction. Growth rate was determined using the Incucyte technology and steady-state glucose and glutamine tracing studies were performed with LC-MS quantification of cellular metabolites. Our results revealed that OXPHOS deficiency causes a proliferation defect and is associated with a distinct metabolic profile. The main features of this signature are a depletion of aspartic acid, of TCA intermediates and increased levels of glycerol-3-phosphate. This profile seems to be related to an NAD+/NADH imbalance. Finally, the therapeutic potential of numerous nutritional supplements was tested by assessing their effect on proliferation and on the metabolomics profile. In fibroblasts, therapy with pyruvate and uridine rescued the metabolic signature of OXPHOS dysfunction and the subsequent proliferation defect. Additionally, in zebrafish, pyruvate and uridine treatment increased the survival after rotenone exposure. This project highlights the importance of the NAD+/NADH imbalance following OXPHOS dysfunction and opens the door to novel diagnostic techniques and therapeutic interventions for PMD. status: published

Published
2023

38. Worldwide experience of homozygous familial hypercholesterolaemia:retrospective cohort study

Author

Tycho R Tromp, Merel L Hartgers, G Kees Hovingh, Antonio J Vallejo-Vaz, Kausik K Ray, Handrean Soran, Tomas Freiberger, Stefano Bertolini, Mariko Harada-Shiba, Dirk J Blom, Frederick J Raal, Marina Cuchel, Tycho R. Tromp, Merel L. Hartgers, G. Kees Hovingh, Antonio J. Vallejo-Vaz, Kausik K. Ray, Stefano A. Bertolini, Jing Pang, Gerald F. Watts, Susanne Greber-Platzer, Martin Mäser, Thomas M. Stulnig, Christoph F. Ebenbichler, Khalid Bin Thani, David Cassiman, Olivier S. Descamps, Daisy Rymen, Peter Witters, Raul D. Santos, Liam R. Brunham, Gordon A. Francis, Jacques Genest, Robert A. Hegele, Brooke A. Kennedy, Isabelle Ruel, Mark H. Sherman, Long Jiang, Luya Wang, Željko Reiner, Vladimir Blaha, Richard Ceska, Jana Dvorakova, Lubomir Dlouhy, Pavel Horak, Vladimir Soska, Lukas Tichy, Robin Urbanek, Helena Vaverkova, Michal Vrablik, Stanislav Zemek, Lukas Zlatohlavek, Sameh Emil, Tarek Naguib, Ashraf Reda, Sophie Béliard, Eric Bruckert, Antonio Gallo, Moses S. Elisaf, Genovefa Kolovou, Hofit Cohen, Ronen Durst, Eldad J. Dann, Avishay Elis, Osama Hussein, Eran Leitersdorf, Daniel Schurr, Nitika Setia, Ishwar C. Verma, Mohammed D. Alareedh, Mutaz Al-Khnifsawi, Ali F. Abdalsahib Al-Zamili, Sabah H. Rhadi, Foaad K. Shaghee, Marcello Arca, Maurizio Averna, Andrea Bartuli, Marco Bucci, Paola S. Buonuomo, Paolo Calabrò, Sebastiano Calandra, Manuela Casula, Alberico L. Catapano, Angelo B. Cefalù, Arrigo F.G. Cicero, Sergio D'Addato, Laura D'Erasmo, Alessia Di Costanzo, Tommaso Fasano, Marta Gazzotti, Antonina Giammanco, Gabriella Iannuzzo, Anastasia Ibba, Emanuele A. Negri, Andrea Pasta, Chiara Pavanello, Livia Pisciotta, Claudio Rabacchi, Carlo Ripoli, Tiziana Sampietro, Francesco Sbrana, Fulvio Sileo, Patrizia Suppressa, Patrizia Tarugi, Chiara Trenti, Maria G. Zenti, Mika Hori, Mahmoud H. Ayesh, Sami T. Azar, Fadi F. Bitar, Akl C. Fahed, Elie M. Moubarak, Georges Nemer, Hapizah M. Nawawi, Ramón Madriz, Roopa Mehta, Arjen J. Cupido, Joep C. Defesche, M. Doortje Reijman, Jeanine E. Roeters-van Lennep, Erik S.G. Stroes, Albert Wiegman, Linda Zuurbier, Khalid Al-Waili, Fouzia Sadiq, Krzysztof Chlebus, Mafalda Bourbon, Isabel M. Gaspar, Katarina S. Lalic, Marat V. Ezhov, Andrey V. Susekov, Urh Groselj, Min-Ji Charng, Weerapan Khovidhunkit, Melih Aktan, Bulent B. Altunkeser, Sinan Demircioglu, Melis Kose, Cumali Gokce, Osman Ilhan, Meral Kayikcioglu, Leyla G. Kaynar, Irfan Kuku, Erdal Kurtoglu, Harika Okutan, Osman I. Ozcebe, Zafer Pekkolay, Saim Sag, Osman Z. Salcioglu, Ahmet Temizhan, Mustafa Yenercag, Mehmet Yilmaz, Hamiyet Yilmaz Yasar, Olena Mitchenko, Alexander R.M. Lyons, Christophe A.T. Stevens, Julie A. Brothers, Lisa C. Hudgins, Christina Nguyen, Rano Alieva, Aleksandr Shek, Doan-Loi Do, Ngoc-Thanh Kim, Hong-An Le, Thanh-Tung Le, Mai-Ngoc T. Nguyen, Thanh-Huong Truong, Dirk J. Blom, Frederick J. Raal, VU University medical center, Tromp T.R., Hartgers M.L., Hovingh G.K., Vallejo-Vaz A.J., Ray K.K., Soran H., Freiberger T., Bertolini S., Harada-Shiba M., Blom D.J., Raal F.J., Cuchel M., Bertolini S.A., Pang J., Watts G.F., Greber-Platzer S., Maser M., Stulnig T.M., Ebenbichler C.F., Bin Thani K., Cassiman D., Descamps O.S., Rymen D., Witters P., Santos R.D., Brunham L.R., Francis G.A., Genest J., Hegele R.A., Kennedy B.A., Ruel I., Sherman M.H., Jiang L., Wang L., Reiner Z., Blaha V., Ceska R., Dvorakova J., Dlouhy L., Horak P., Soska V., Tichy L., Urbanek R., Vaverkova H., Vrablik M., Zemek S., Zlatohlavek L., Emil S., Naguib T., Reda A., Beliard S., Bruckert E., Gallo A., Elisaf M.S., Kolovou G., Cohen H., Durst R., Dann E.J., Elis A., Hussein O., Leitersdorf E., Schurr D., Setia N., Verma I.C., Alareedh M.D., Al-Khnifsawi M., Abdalsahib Al-Zamili A.F., Rhadi S.H., Shaghee F.K., Arca M., Averna M., Bartuli A., Bucci M., Buonuomo P.S., Calabro P., Calandra S., Casula M., Catapano A.L., Cefalu A.B., Cicero A.F.G., D'Addato S., D'Erasmo L., Di Costanzo A., Fasano T., Gazzotti M., Giammanco A., Iannuzzo G., Ibba A., Negri E.A., Pasta A., Pavanello C., Pisciotta L., Rabacchi C., Ripoli C., Sampietro T., Sbrana F., Sileo F., Suppressa P., Tarugi P., Trenti C., Zenti M.G., Hori M., Ayesh M.H., Azar S.T., Bitar F.F., Fahed A.C., Moubarak E.M., Nemer G., Nawawi H.M., Madriz R., Mehta R., Cupido A.J., Defesche J.C., Reijman M.D., Roeters-van Lennep J.E., Stroes E.S.G., Wiegman A., Zuurbier L., Al-Waili K., Sadiq F., Chlebus K., Bourbon M., Gaspar I.M., Lalic K.S., Ezhov M.V., Susekov A.V., Groselj U., Charng M.-J., Khovidhunkit W., Aktan M., Altunkeser B.B., Demircioglu S., Kose M., Gokce C., Ilhan O., Kayikcioglu M., Kaynar L.G., Kuku I., Kurtoglu E., Okutan H., Ozcebe O.I., Pekkolay Z., Sag S., Salcioglu O.Z., Temizhan A., Yenercag M., Yilmaz M., Yilmaz Yasar H., Mitchenko O., Lyons A.R.M., Stevens C.A.T., Brothers J.A., Hudgins L.C., Nguyen C., Alieva R., Shek A., Do D.-L., Kim N.-T., Le H.-A., Le T.-T., Nguyen M.-N.T., Truong T.-H., University of Amsterdam, University of Pennsylvania, European Atherosclerosis Society, Experimental Vascular Medicine, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Human Genetics, Paediatric Metabolic Diseases, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Heart failure & arrhythmias, R Tromp, Tycho, L Hartgers, Merel, Kees Hovingh, G, J Vallejo-Vaz, Antonio, K Ray, Kausik, Soran, Handrean, Freiberger, Toma, A Bertolini, Stefano, Harada-Shiba, Mariko, Pang, Jing, F Watts, Gerald, Greber-Platzer, Susanne, Mäser, Martin, M Stulnig, Thoma, F Ebenbichler, Christoph, Bin Thani, Khalid, Cassiman, David, S Descamps, Olivier, Rymen, Daisy, Witters, Peter, D Santos, Raul, R Brunham, Liam, A Francis, Gordon, Genest, Jacque, A Hegele, Robert, A Kennedy, Brooke, Ruel, Isabelle, H Sherman, Mark, Jiang, Long, Wang, Luya, Reiner, Željko, Blaha, Vladimir, Ceska, Richard, Dvorakova, Jana, Dlouhy, Lubomir, Horak, Pavel, Soska, Vladimir, Tichy, Luka, Urbanek, Robin, Vaverkova, Helena, Vrablik, Michal, Zemek, Stanislav, Zlatohlavek, Luka, Emil, Sameh, Naguib, Tarek, Reda, Ashraf, Béliard, Sophie, Bruckert, Eric, Gallo, Antonio, S Elisaf, Mose, Kolovou, Genovefa, Cohen, Hofit, Durst, Ronen, J Dann, Eldad, Elis, Avishay, Hussein, Osama, Leitersdorf, Eran, Schurr, Daniel, Setia, Nitika, C Verma, Ishwar, D Alareedh, Mohammed, Al-Khnifsawi, Mutaz, F Abdalsahib Al-Zamili, Ali, H Rhadi, Sabah, K Shaghee, Foaad, Arca, Marcello, Averna, Maurizio, Bartuli, Andrea, Bucci, Marco, S Buonuomo, Paola, Calabrò, Paolo, Calandra, Sebastiano, Casula, Manuela, L Catapano, Alberico, B Cefalù, Angelo, G Cicero, Arrigo F, D'Addato, Sergio, D'Erasmo, Laura, Di Costanzo, Alessia, Fasano, Tommaso, Gazzotti, Marta, Giammanco, Antonina, Iannuzzo, Gabriella, Ibba, Anastasia, A Negri, Emanuele, Pasta, Andrea, Pavanello, Chiara, Pisciotta, Livia, Rabacchi, Claudio, Ripoli, Carlo, Sampietro, Tiziana, Sbrana, Francesco, Sileo, Fulvio, Suppressa, Patrizia, Tarugi, Patrizia, Trenti, Chiara, G Zenti, Maria, Hori, Mika, H Ayesh, Mahmoud, T Azar, Sami, F Bitar, Fadi, C Fahed, Akl, M Moubarak, Elie, Nemer, George, M Nawawi, Hapizah, Madriz, Ramón, Mehta, Roopa, J Cupido, Arjen, C Defesche, Joep, Doortje Reijman, M, E Roeters-van Lennep, Jeanine, G Stroes, Erik S, Wiegman, Albert, Zuurbier, Linda, Al-Waili, Khalid, Sadiq, Fouzia, Chlebus, Krzysztof, Bourbon, Mafalda, M Gaspar, Isabel, S Lalic, Katarina, V Ezhov, Marat, V Susekov, Andrey, Groselj, Urh, Charng, Min-Ji, Khovidhunkit, Weerapan, Aktan, Melih, B Altunkeser, Bulent, Demircioglu, Sinan, Kose, Meli, Gokce, Cumali, Ilhan, Osman, Kayikcioglu, Meral, G Kaynar, Leyla, Kuku, Irfan, Kurtoglu, Erdal, Okutan, Harika, I Ozcebe, Osman, Pekkolay, Zafer, Sag, Saim, Z Salcioglu, Osman, Temizhan, Ahmet, Yenercag, Mustafa, Yilmaz, Mehmet, Yilmaz Yasar, Hamiyet, Mitchenko, Olena, M Lyons, Alexander R, T Stevens, Christophe A, A Brothers, Julie, C Hudgins, Lisa, Nguyen, Christina, Alieva, Rano, Shek, Aleksandr, Do, Doan-Loi, Kim, Ngoc-Thanh, Le, Hong-An, Le, Thanh-Tung, T Nguyen, Mai-Ngoc, Truong, Thanh-Huong, J Blom, Dirk, J Raal, Frederick, and Cuchel, Marina

Subjects
Adult, Male, Homozygous Familial Hypercholesterolemia, Adolescent, retrospective study, CHILDREN, Doenças Cardio e Cérebro-vasculares, Cohort Studies, Young Adult, Medicine, General & Internal, General & Internal Medicine, Cardiovascular Disease, Humans, Registries, LIPOPROTEIN-APHERESIS, Child, 11 Medical and Health Sciences, Retrospective Studies, Homozygous Familial Hypercholesterolaemia International Clinical Collaborators, Science & Technology, GUIDANCE, clinical characteristic, EVOLOCUMAB, Homozygous familial hypercholesterolemia, Worldwide, Therapies, Cardiovascular disease, General Medicine, CARE, OPEN-LABEL, EFFICACY, INSIGHTS, Child, Preschool, outcome, Female, genetic, Familial Hypercholesterolaemia, Life Sciences & Biomedicine
Abstract

[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

Published
2022

39. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts

Author

Elliott H. Sherr, Edward Blair, Charles Marques Lourenço, James O'Sullivan, Imke Metz, Paul R. Kasher, Gabriela M. Baerlocher, Adeline Vanderver, David Cassiman, Himanshu Goel, Nicholas A. Fletcher, Patrick Ferreira, Patrick Revy, Emma Wakeling, Ram L. Kumar, Lieven Lagae, Christopher J. Kershaw, Pierre Landrieu, Andrea Whitney, Calvin Soh, Christine E. G. van Mol, Sakkubai Naidu, John H. Livingston, Geraldine Aubert, H. Stewart, Laurence C. Goosey, Liesbeth De Waele, Kristin W. Barañano, Rosalind J. Jefferson, Axel Panzer, Gerardine Quaghebeur, Raphael Schiffmann, Yanick J. Crow, Hilde Van Esch, Raymond T. O'Keefe, Jill E. Urquhart, Alan Fryer, Mathieu P Rodero, Alex J. Fay, Monika Haubitz, Andrea Berger, Johannes A. Buckard, Cheryl Hemingway, Angela Barnicoat, Sam Griffiths-Jones, Duccio Maria Cordelli, Imelda Hughes, Katrin Õunap, Graham D. Pavitt, Roberta Battini, Yoann Rose, Marjo S. van der Knaap, Sanjeev S. Bhaskar, John Stone, Gillian I. Rice, Marco Henneke, Kanaga R. Sinnathuray, Emma M. Jenkinson, Timothy J. Malpas, Simon G. Williams, Anthony Oojageer, Carolina Uggenti, Rosaline Caumes, Prab Prabhakar, Sarju G. Mehta, Janice E. Brunstrom-Hernandez, Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Manchester [Manchester], Department of Medical Genetics, HMNC Brain Health, Other departments, Jenkinson, Emma M., Rodero, Mathieu P., Kasher, Paul R., Uggenti, Carolina, Oojageer, Anthony, Goosey, Laurence C., Rose, Yoann, Kershaw, Christopher J., Urquhart, Jill E., Williams, Simon G., Bhaskar, Sanjeev S., O'Sullivan, Jame, Baerlocher, Gabriela M., Haubitz, Monika, Aubert, Geraldine, Barañano, Kristin W., Barnicoat, Angela J., Battini, Roberta, Berger, Andrea, Blair, Edward M., Brunstrom-Hernandez, Janice E., Buckard, Johannes A., Cassiman, David M., Caumes, Rosaline, Cordelli, Duccio M., De Waele, Liesbeth M., Fay, Alexander J., Ferreira, Patrick, Fletcher, Nicholas A., Fryer, Alan E., Goel, Himanshu, Hemingway, Cheryl A., Henneke, Marco, Hughes, Imelda, Jefferson, Rosalind J., Kumar, Ram, Lagae, Lieven, Landrieu, Pierre G., Lourenço, Charles M., Malpas, Timothy J., Mehta, Sarju G., Metz, Imke, Naidu, Sakkubai, Õunap, Katrin, Panzer, Axel, Prabhakar, Prab, Quaghebeur, Gerardine, Schiffmann, Raphael, Sherr, Elliott H., Sinnathuray, Kanaga R., Soh, Calvin, Stewart, Helen S., Stone, John, Van Esch, Hilde, Van Mol, Christine E. G., Vanderver, Adeline, Wakeling, Emma L., Whitney, Andrea, Pavitt, Graham D., Griffiths-Jones, Sam, Rice, Gillian I., Revy, Patrick, Van Der Knaap, Marjo S., Livingston, John H., O'Keefe, Raymond T., Crow, Yanick J., Pediatric surgery, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms

Subjects
0301 basic medicine, Male, Genetic Linkage, [SDV]Life Sciences [q-bio], Ribosome biogenesis, medicine.disease_cause, Leukoencephalopathy, Leukoencephalopathie, Cohort Studies, 0302 clinical medicine, Leukoencephalopathies, Exome, Small nucleolar RNA, 610 Medicine & health, Child, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, Genome, Cysts, Calcinosis, Middle Aged, Phenotype, Child, Preschool, Calcinosi, Female, Sequence Analysis, Human, Adult, Adolescent, Biology, Chromosomes, Cell Line, 03 medical and health sciences, Young Adult, medicine, RNA, Small Nucleolar, Humans, Preschool, Gene, Small Nucleolar, Genome, Human, Pair 17, RNA, Infant, Sequence Analysis, DNA, DNA, Cerebral Small Vessel Diseases, Chromosomes, Human, Pair 17, medicine.disease, Cerebral Small Vessel Disease, 030104 developmental biology, Cyst, Cohort Studie, 030217 neurology & neurosurgery
Abstract

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Published
2016

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