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1. Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program

Author

Roberto Giugliani, Antonio Gonzalez-Meneses, Maurizio Scarpa, Barbara Burton, Raymond Wang, Esmeralda Martins, Esmeralda Oussoren, Julia B. Hennermann, Brigitte Chabrol, Christina L. Grant, Angela Sun, Consuelo Durand, Joel Hetzer, Betsy Malkus, Deborah Marsden, and J. Lawrence Merritt II

Subjects
Lysosomal storage disease, Non-immune hydrops fetalis, β-glucuronidase deficiency, Mucopolysaccharidosis VII, MPS VII, Medicine
Abstract

Abstract Background Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII. Methods This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022. Results As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and − 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died. Conclusions To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.

Published
2024
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2. P261: Vestronidase alfa for the treatment of mucopolysaccharidosis VII (MPS VII): Updated results from a longitudinal, multicenter disease monitoring program (DMP)

Author

Roberto Giugliani, Antonio Gonzalez-Meneses, Christina Grant, Maurizio Scarpa, Angela Sun, Raymond Wang, Barbara Burton, Ans van der Ploeg, Esmeralda Martins, Consuelo Durand, Brigitte Chabrol, Joel Hetzer, Deborah Marsden, and J. Lawrence Merritt, II

Subjects
Genetics, QH426-470, Medicine
Published
2024
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5. Contributors

Author

Steven H. Abman, Noorjahan Ali, Karel Allegaert, Jamie E. Anderson, Deidra A. Ansah, Bhawna Arya, David Askenazi, Susan W. Aucott, Stephen A. Back, Gerri R. Baer, H. Scott Baldwin, Jerasimos Ballas, Maneesh Batra, Cheryl Bayart, Gary A. Bellus, John T. Benjamin, Gerard T. Berry, Zeenia C. Billimoria, Gil Binenbaum, Matthew S. Blessing, Markus D. Boos, Brad Bosse, Maryse L. Bouchard, Heather A. Brandling-Bennett, Colleen Brown, Erin G. Brown, Katherine H. Campbell, Katie Carlberg, Brian S. Carter, Shilpi Chabra, Irene J. Chang, Edith Y. Cheng, Kai-wen Chiang, Robert D. Christensen, Terrence Chun, Ronald I. Clyman, Donna, Maria E. Cortezzo, C.M. Cotten, Sherry E. Courtney, Jonathan M. Davis, Alejandra G. de Alba Campomanes, Benjamin Dean, Ellen Dees, Sara B. De, Mauro, Scott C. Denne, Emöke Deschmann, Carolina Cecilia Di Blasi, Sara A. Di, Vall, Dan Doherty, David J. Durand, Nicolle Fernández Dyess, Eric C. Eichenwald, Kelsey B. Eitel, Rachel M. Engen, Kelly N. Evans, Diana L. Farmer, Emily Fay, Patricia Y. Fechner, Rachel Fleishman, Bobbi Fleiss, Joseph Flynn, Katherine T. Flynn-O’Brien, G. Kyle Fulton, Renata C. Gallagher, Estelle B. Gauda, W. Christopher Golden, Michelle M. Gontasz, Natasha González Estévez, Sidney M. Gospe, Pierre Gressens, Deepti Gupta, Sangeeta Hingorani, Ashley P. Hinson, Susan R. Hintz, W. Alan Hodson, Kara K. Hoppe, Alyssa Huang, Benjamin Huang, Kathy Huen, Katie A. Huff, Cristian Ionita, J. Craig Jackson, Jordan E. Jackson, Tom Jaksic, Patrick J. Javid, Julia Johnson, Cassandra D. Josephson, Emily S. Jungheim, Sandra E. Juul, Mohammad Nasser Kabbany, Heidi Karpen, Gregory Keefe, Jennifer C. Keene, Amaris M. Keiser, Roberta L. Keller, Thomas F. Kelly, Kate Khorsand, Grace Kim, John P. Kinsella, Allison S. Komorowski, Ildiko H. Koves, Joanne M. Lagatta, Satyan Lakshminrusimha, Christina Lam, John D. Lantos, Janessa B. Law, Su Yeon Lee, Ofer Levy, David B. Lewis, Philana Ling Lin, Scott A. Lorch, Tiffany L. Lucas, Akhil Maheshwari, Emin Maltepe, Erica Mandell, Winston M. Manimtim, Richard J. Martin, Dennis E. Mayock, Irene Mc, Aleer, Patrick McQuillen, Ann J. Melvin, Paul A. Merguerian, Lina Merjaneh, J. Lawrence Merritt, Valerie Mezger, Marian G. Michaels, Ulrike Mietzsch, Steven P. Miller, Thomas R. Moore, Karen F. Murray, Debika Nandi-Munshi, Niranjana Natarajan, Kathryn D. Ness, Josef Neu, Shahab Noori, Thomas Michael O’Shea, Julius T. Oatts, Nigel Paneth, Thomas A. Parker, Ravi Mangal Patel, Simran Patel, Anna A. Penn, Christian M. Pettker, Shabnam Peyvandi, Catherine Pihoker, Erin Plosa, Brenda Poindexter, Michael A. Posencheg, Mihai Puia-Dumitrescu, Vilmaris Quiñones Cardona, Samuel E. Rice-Townsend, Art Riddle, Elizabeth Robbins, Mark D. Rollins, Mark A. Rosen, Courtney K. Rowe, Inderneel Sahai, Sulagna C. Saitta, Parisa Salehi, Pablo J. Sanchez, Taylor Sawyer, Matthew A. Saxonhouse, Katherine M. Schroeder, David T. Selewski, T. Niroshi Senaratne, Istvan Seri, Emily E. Sharpe, Sarah E. Sheppard, Margarett Shnorhavorian, Robert Sidbury, La, Vone Simmons, Rebecca A. Simmons, Rachana Singh, Martha C. Sola-Visner, Lakshmi Srinivasan, Heidi J. Steflik, Robin H. Steinhorn, Caleb Stokes, Helen Stolp, Jennifer Sucre, Angela Sun, Dalal K. Taha, Jessica Tenney, Janet A. Thomas, George E. Tiller, Benjamin A. Torres, William E. Truog, Kirtikumar Upadhyay, Gregory C. Valentine, John N. van den Anker, Betty Vohr, Linda D. Wallen, Peter (Zhan Tao) Wang, Bradley A. Warady, Robert M. Ward, Jon F. Watchko, Elias Wehbi, Joern-Hendrik Weitkamp, David Werny, Klane K. White, K. Taylor Wild, Susan Wiley, Laurel Willig, George A. Woodward, Clyde J. Wright, Karyn Yonekawa, Elizabeth Yu, and Elaine H. Zackai

Published
2024

6. Long-term Burosumab Administration Is Safe and Effective in Adults With X-linked Hypophosphatemia

Author

Thomas J Weber, Erik A Imel, Thomas O Carpenter, Munro Peacock, Anthony A Portale, Joel Hetzer, J Lawrence Merritt, and Karl Insogna

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, Biochemistry
Abstract

Context Burosumab was developed as a treatment option for patients with the rare, lifelong, chronically debilitating, genetic bone disease X-linked hypophosphatemia (XLH). Objective Collect additional information on the safety, immunogenicity, and clinical response to long-term administration of burosumab. Methods UX023-CL203 (NCT02312687) was a Phase 2b, open-label, single-arm, long-term extension study of adult subjects with XLH who participated in KRN23-INT-001 or KRN23-INT-002 studies. The long-term UX023-CL203 study (January 5, 2015 through November 30, 2018) provided data up to 184 weeks. Participants in UX023-CL203 received burosumab based on the last dose in the prior KRN23-INT-001 or KRN23-INT-002 studies (0.3, 0.6, or 1.0 mg/kg given by subcutaneous injection every 4 weeks). At Week 12, burosumab could be titrated upward/downward to achieve fasting serum phosphate levels within the normal range. Primary objectives included long-term safety, the proportion of subjects achieving fasting serum phosphate in the normal range, changes in bone turnover markers, patient-reported outcomes for pain and stiffness, and measures of mobility. Results Fasting serum phosphate levels at the midpoint of the dosing interval (2 weeks postdose, the time of peak effect) were within the normal range in 85% to 100% of subjects. Measures of phosphate metabolism and bone biomarkers generally improved with burosumab therapy, approaching or reaching their respective normal ranges by study end. Improvements in patient-reported outcomes and mobility were sustained throughout the observation period. No new safety findings emerged with longer-term burosumab treatment. Conclusion These data support the conclusion that burosumab therapy may be a safe and effective long-term treatment option for adult patients with XLH.

Published
2022

7. Elevated oxysterol and N-palmitoyl-O-phosphocholineserine levels in congenital disorders of glycosylation

Author

An N. Dang Do, Irene J. Chang, Xutian Jiang, Lynne A. Wolfe, Bobby G. Ng, Christina Lam, Rhonda E. Schnur, Katrina Allis, Hana Hansikova, Nina Ondruskova, Shawn D. O'Connor, Amarilis Sanchez‐Valle, Arve Vollo, Raymond Y. Wang, Zoe Wolfenson, John Perreault, Daniel S. Ory, Hudson H. Freeze, J. Lawrence Merritt, and Forbes D. Porter

Subjects
bile acids, Pediatric, Genetics & Heredity, Vacuolar Proton-Translocating ATPases, Glycosylation, Hydrolases, Liver Disease, Clinical Sciences, Infant, Oxysterols, Niemann-pick type C, Type C, Article, Bile Acids and Salts, Congenital Disorders of Glycosylation, N-palmitoyl-O-phosphocholineserine, Clinical Research, Niemann-Pick Disease, Genetics, Humans, Child, Digestive Diseases, Genetics (clinical), ATP6AP1
Abstract

Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multi-systemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.

Published
2023

9. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Author

Zou Pan, Marielle E. van Gijn, Marjolein H. Willemsen, Mariet W. Elting, Susanne Koning, Daniel C. Koboldt, Rebecca Baud, Renzo Guerrini, Ghayda M. Mirzaa, Laurence E. Walsh, Kim L. McBride, Jenny Thies, Andrew E. Timms, Shaoping Huang, Gretchen E. Rosso, Joshua Scheck, Haley McConkey, Matthew A. Deardorff, Peter D. Turnpenny, Suzanne M. Leal, Sanjay M. Sisodiya, Lin Yang, Melissa Lees, Cacha M.P.C.D. Peeters-Scholte, Henry Houlden, Marielle Alders, J. Austin Hamm, Karla A. Peña-Guerra, Richard E. Person, Leena Lauronen, Hannah K. Robinson, Theresa Mihalic Mosher, Alexandra Garza-Flores, Victoria Harrison, Tuomo Määttä, Daniela Q.C.M. Barge-Schaapveld, James R. Lupski, Houda Zghal Elloumi, Francisco J. Guzmán-Vega, Tamison Jewett, Siddharth Banka, Barbara W. van Paassen, J. Lawrence Merritt, Angela Sun, Yana Lara-Taranchenko, Irma Järvelä, Ivan K. Chinn, Claudia A. L. Ruivenkamp, Nicholas M. Allen, Xiaodong Wang, Amy Crunk, Selina H. Banu, Maura R.Z. Ruzhnikov, Jeffery McGlothlin, Mashaya Zaman, Adam Jackson, Stefan T. Arold, Bert B.A. de Vries, Jing Peng, Lauren Schenck, Isabelle Schrauwen, Marjon van Slegtenhorst, Luis Alberto Pedroza, Bekim Sadikovic, Annalisa Vetro, Reshmi Ramakrishnan, Kristin G. Monaghan, Kelly J. Cardona-Londoño, Catherine Quindipan, Kristina Lanko, Rolph Pfundt, Caroline M. Kehoe, Martino Montomoli, Christian Gilissen, Hamid Galehdari, Yolande van Bever, Jennifer Keller-Ramey, Sadegheh Haghshenas, Neda Mazaheri, Stephanie Efthymiou, Reza Maroofian, Lewis Pang, Fleur Vansenne, Abeltje M. Polstra, Kara C. Klemp, Marjolein J.A. Weerts, Xi Lin, Julia Baptista, Tahsin Stefan Barakat, Anneke Kievit, Adi Reich, Stephen R. Braddock, Shehla Mohammed, Abbey M. Putnam, Jennifer Kerkhof, Matthew Pastore, Sally Ann Lynch, Graduate School, ANS - Neuroinfection & -inflammation, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, MUMC+: DA KG Polikliniek (9), RS: FHML non-thematic output, Human genetics, VU University medical center, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Irma Järvelä / Principal Investigator, Medicum, Department of Medical and Clinical Genetics, HUS Medical Imaging Center, Clinicum, BioMag Laboratory, HUS Children and Adolescents, and Kliinisen neurofysiologian yksikkö

Subjects
Male, INTELLECTUAL DISABILITY, GENES, Language delay, VARIANTS, Biology, Bioinformatics, 3124 Neurology and psychiatry, Article, 12Q24.31, SETD1B, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Neurodevelopmental disorder, Seizures, Intellectual disability, medicine, Humans, MICRODELETION, Global developmental delay, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 3112 Neurosciences, RECOGNITION, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Histone-Lysine N-Methyltransferase, medicine.disease, Penetrance, Human genetics, Phenotype, Neurodevelopmental Disorders, MOTIF, Autism, METHYLTRANSFERASE, 3111 Biomedicine, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 243955.pdf (Publisher’s version ) (Open Access) PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Published
2021

10. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11

Author

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

Subjects
0301 basic medicine, Craniofacial abnormality, Mutation, Missense, 030105 genetics & heredity, Biology, Article, Frameshift mutation, Craniofacial Abnormalities, 03 medical and health sciences, medicine, Animals, Humans, Missense mutation, Craniofacial, Allele, Zebrafish, Genetics (clinical), Loss function, Genetics, medicine.disease, biology.organism_classification, Phenotype, Spine, Growth Differentiation Factors, 030104 developmental biology, Bone Morphogenetic Proteins
Abstract

Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6) , vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6) and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) alleles whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.

Published
2021

11. Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined Nonketotic Hyperglycinemia and Lipoate Deficiency

Author

Laura Arribas-Carreira, Cristina Dallabona, Michael A Swanson, Joseph Farris, Elsebet Østergaard, Konstantinos Tsiakas, Maja Hempel, Cecile Aquaviva-Bourdain, Stefanos Koutsoukos, Nicholas V Stence, Martina Magistrati, Elaine B Spector, Kathryn Kronquist, Mette Christensen, Helena G Karstensen, René G Feichtinger, Melanie T Achleitner, J Lawrence Merritt II, Belén Pérez, Magdalena Ugarte, Stephanie Grünewald, Anthony R Riela, Natalia Julve, Jean-Baptiste Arnoux, Kasturi Haldar, Claudia Donnini, René Santer, Allan M Lund, Johannes A Mayr, Pilar Rodriguez-Pombo, and Johan L K Van Hove

Subjects
Genetics, General Medicine, Molecular Biology, Genetics (clinical)
Abstract

Maintaining protein lipoylation is vital for cell metabolism. The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system, intersecting two vital roles for cell survival. Here, we report six patients with biallelic pathogenic variants in GCSH and a broad clinical spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated phenotype of developmental delay, behavioral problems, limited epilepsy and variable movement problems. The mutational spectrum includes one insertion c.293-2_293–1insT, one deletion c.122_(228 + 1_229–1) del, one duplication of exons 4 and 5, one nonsense variant p.Gln76*and four missense p.His57Arg, p.Pro115Leu and p.Thr148Pro and the previously described p.Met1?. Via functional studies in patient’s fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies, we demonstrate for the first time that most variants identified in our cohort produced a hypomorphic effect on both mitochondrial activities, protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affect primarily one function only. The clinical features of the patients reflect the impact of the GCSH changes on any of the two functions analyzed. Our analysis illustrates the complex interplay of functional and clinical impact when pathogenic variants affect a multifunctional protein involved in two metabolic pathways and emphasizes the value of the functional assays to select the treatment and investigate new personalized options.

Published
2022

12. A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder

Author

Suma P. Shankar, Kristin Grimsrud, Louise Lanoue, Alena Egense, Brandon Willis, Johanna Hörberg, Lama AlAbdi, Klaus Mayer, Koray Ütkür, Kristin G. Monaghan, Joel Krier, Joan Stoler, Maha Alnemer, Prabhu R. Shankar, Raffael Schaffrath, Fowzan S. Alkuraya, Ulrich Brinkmann, Leif A. Eriksson, Kent Lloyd, Katherine A. Rauen, Maria T. Acosta, Margaret Adam, David R. Adams, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Thomas Cassini, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell'Angelica, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Madison P. Goldrich, Alana Grajewski, Irma Gutierrez, Don Hadley, Sihoun Hahn, Rizwan Hamid, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Wendy Introne, Rosario Isasi, Kosuke Izumi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Lefkothea Karaviti, Jennifer Kennedy, Shamika Ketkar, Dana Kiley, Gonench Kilich, Shilpa N. Kobren, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Kimberly LeBlanc, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Mariko Nakano-Okuno, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Anna Raper, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, K.-G. Queenie, Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Monika Weisz-Hubshman, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Kim Worley, Changrui Xiao, Shinya Yamamoto, John Yang, Diane B. Zastrow, Zhe Zhang, Chunli Zhao, Stephan Zuchner, Hugo Bellen, and Rachel Mahoney

Subjects
Adenosine Diphosphate, Mice, Inbred C57BL, Mice, Saccharomyces cerevisiae Proteins, Neurodevelopmental Disorders, Animals, Humans, Histidine, Methyltransferases, Saccharomyces cerevisiae, Syndrome, Genetics (clinical), Article
Abstract

Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

Published
2022

13. OR13-2 Characterizing the Impact of Burosumab on Bone Health in Children with X-Linked Hypophosphatemia: Results from Year 1 of the Disease Monitoring Program

Author

Thomas Carpenter, Hamilton Cassinelli, Francis Glorieux, Joel Hetzer, J Lawrence Merritt II, Carolina A Moreira, Anthony Portale, Leanne Ward, Claudine Woo, and Erik Imel

Subjects
Endocrinology, Diabetes and Metabolism
Abstract

X-linked hypophosphatemia (XLH) is a rare, heritable disorder wherein excess FGF23 leads to renal phosphate wasting and impaired activation of vitamin D. XLH is characterized by rickets and osteomalacia leading to bone pain, skeletal deformities, and short stature. The XLH Disease Monitoring Program (DMP; NCT03651505) is a prospective, multinational outcomes study of the longitudinal progression of clinical, radiographic, and biochemical features of XLH in children and adults. We assessed the impact of the recombinant human IgG1 monoclonal antibody to FGF23, burosumab, on measures of bone health in children with XLH at Year 1 of the DMP. As of March 2021, 287 children ( Before receiving burosumab, serum phosphorus levels were below normal; after burosumab initiation, serum phosphorus in Groups 1 and 2 rapidly normalized, with sustained improvements up to 3 years of treatment. Serum phosphorus remained low in Group 3. Before burosumab, serum alkaline phosphatase levels were above normal; with continued burosumab therapy, mean levels gradually declined towards normal and were maintained for up to 4 years. The Radiographic Global Impression of Change (RGI-C) assessed rickets and lower limb deformity from DMP baseline to Year 1, with positive values denoting improvement. Mean (SD) RGI-C rickets global scores were +1.0 (0.9) for Group 1 (n=44), +1.5 (0.7) for Group 2 (n=39), and +0.3 (1.2) for Group 3 (n=3). Lower limb deformity RGI-C scores were +0.3 (0.6) for Group 1 (n=42), +0.4 (0.8) for Group 2 (n=39), and +0.8 (1.1) for Group 3 (n=3). Height Z-score change from DMP baseline at Year 1 was 0.1 (0.3) for Group 1 (n=58), 0.1 (0.4) for Group 2 (n=90), and -0.8 (3.1) for Group 3 (n=18). There were no new safety concerns or reports of hyperphosphatemia. These real-world data affirm that normalization of serum phosphorus is rapid and sustained following burosumab initiation, resulting in improved serum alkaline phosphatase levels which positively impact bone mineralization. Improvements in rickets, growth, and lower limb deformity occur in the first year of burosumab treatment and continue in those who started burosumab prior to entering the DMP. The absence of new safety concerns or reports of hyperphosphatemia up to 4 years after burosumab initiation is also notable. The 10-year DMP study design will provide understanding of long-term effects in these patients with continued burosumab therapy. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.

Published
2022

14. A concurrent dual analysis of genomic data augments diagnoses: Experiences of 2 clinical sites in the Undiagnosed Diseases Network

Author

Rebecca C. Spillmann, Queenie K.-G. Tan, Chloe Reuter, Kelly Schoch, Jennefer Kohler, Devon Bonner, Diane Zastrow, Anna Alkelai, Evan Baugh, Heidi Cope, Shruti Marwaha, Matthew T. Wheeler, Jonathan A. Bernstein, Vandana Shashi, Maria T. Acosta, Margaret Adam, David R. Adams, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Hugo J. Bellen, Jimmy Bennet, Beverly Berg-Rood, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Thomas Cassini, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Madison P. Goldrich, Alana Grajewski, Irma Gutierrez, Don Hadley, Sihoun Hahn, Rizwan Hamid, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Wendy Introne, Rosario Isasi, Kosuke Izumi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Lefkothea Karaviti, Jennifer Kennedy, Shamika Ketkar, Dana Kiley, Gonench Kilich, Shilpa N. Kobren, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Kimberly LeBlanc, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Rachel Mahoney, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Jacob McCauley, Allyn McConkie-Rosell, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Mariko Nakano-Okuno, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Anna Raper, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Mario Saporta, Judy Schaechter, Timothy Schedl, C. Ron Scott, Daryl A. Scott, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Monika Weisz-Hubshman, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Jordan Whitlock, Lynne A. Wolfe, Kim Worley, Changrui Xiao, Shinya Yamamoto, John Yang, Diane B. Zastrow, Zhe Zhang, Chunli Zhao, and Stephan Zuchner

Subjects
Genetics (clinical)
Published
2023

16. MaP NATURAL HISTORY STUDY: CLINICAL AND BIOMARKER FINDINGS IN PROPIONIC ACIDEMIA

Author

Bernd C. Schwahn, Gerard T. Berry, Saikat Santra, Hilary Vernon, Hong Li, J. Lawrence Merritt, Manuel Schiff, Brigitte Chabrol, Javier De las Heras, Jerry Vockley, Chung Lee, Dwight Koeberl, Barbara Burton, Stephanie Grunewald, Thomas Morgan, George Diaz, Can Ficicioglu, Junxiang Luo, Husain Attarwala, Vanja Sikirica, Min Liang, Lin T. Guey, Christine Lukacs, Paolo G.V. Martini, Ruchira Glaser, and Nuria Carrillo

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, Genetics, Molecular Biology, Biochemistry
Published
2023

18. MaP NATURAL HISTORY STUDY: CLINICAL AND BIOMARKER FINDINGS IN METHYLMALONIC ACIDEMIA DUE TO MUT DEFICIENCY

Author

Manuel Schiff, Bernd C. Schwahn, Brigitte Chabrol, J. Lawrence Merritt, Jerry Vockley, Hilary Vernon, Gerard T. Berry, Saikat Santra, Chung Lee, Dwight Koeberl, Hong Li, Barbara Burton, Javier De las Heras, George Diaz, Mariana Faria-Urbina, Junxiang Luo, Husain Attarwala, Vanja Sikirica, Min Liang, Lin T. Guey, Christine Lukacs, Paolo G.V. Martini, Ruchira Glaser, and Nuria Carrillo

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, Genetics, Molecular Biology, Biochemistry
Published
2023

20. Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.

Author

Arribas-Carreira, Laura, Dallabona, Cristina, Swanson, Michael A, Farris, Joseph, Østergaard, Elsebet, Tsiakas, Konstantinos, Hempel, Maja, Aquaviva-Bourdain, Cecile, Koutsoukos, Stefanos, Stence, Nicholas V, Magistrati, Martina, Spector, Elaine B, Kronquist, Kathryn, Christensen, Mette, Karstensen, Helena G, Feichtinger, René G, Achleitner, Melanie T, II, J Lawrence Merritt, Pérez, Belén, and Ugarte, Magdalena

Published
2023
Full Text
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21. OR13-1 Long-Term Burosumab Therapy Provides Sustained Benefit in Patients with Tumor-Induced Osteomalacia: End of Study Findings From the Pivotal Phase 2 Study

Author

Thomas Carpenter, Tricia Cimms, Joel Hetzer, Karl Insogna, Rajiv Kumar, J Lawrence Merritt II, Paul Miller, Munro Peacock, Frank Rauch, Irinel Stanciu, Thomas Weber, and Suzanne Jan De Beur

Subjects
Endocrinology, Diabetes and Metabolism
Abstract

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome wherein small tumors secrete excess fibroblast growth factor 23 (FGF23) leading to hypophosphatemia, osteomalacia, bone pain, fractures, and muscle weakness. Burosumab is an anti-FGF23 monoclonal antibody approved for treatment of TIO. We report end of study (EOS) data from the open-label phase 2 UX023T-CL201 trial (NCT02304367) of burosumab in adults with TIO. In UX023T-CL201, participants received burosumab (0.3–2.0 mg/kg) by subcutaneous injection every 4 weeks for 48 weeks with an extension up to 300 weeks (∼6 years). Co-primary endpoints were change in serum phosphorus at Week 24 and change in excess osteoid by trans-iliac crest bone biopsy at Week 48. Additional endpoints included changes in bone biomarkers, activity on radionucleotide bone scan representing fractures/pseudofractures, patient-reported outcomes, and safety measures. This analysis included 14/17 UX023T-CL201 participants; excluding those with other diagnoses (n=3). Mean (SD) serum phosphorus improved from 1.6 (0.5) mg/dL at baseline to 2.3 (0.5) mg/dL when averaged across the mid-point of the dose interval through Week 24 (co-primary endpoint). Levels further improved (2.6 [0.4] mg/dL; n=7) to within the normal range (2.5–3.6 mg/dL) at Week 240. Most measures of osteomalacia improved at Week 48 (co-primary endpoint), including osteoid/bone volume, osteoid thickness, and mineralization lag time. However, osteoid surface/bone surface showed no change. Bone biomarkers (P1NP, CTx, BALP) followed similar trends. Upon initiation of burosumab, markers briefly increased by Week 24 as bone healing began, then gradually decreased with further treatment, reaching normal (P1NP, CTx) or near-normal (BALP) ranges by Week 240. At baseline, 249 areas of increased radionucleotide uptake indicating fracture activity were detected across 14 participants. By Week 144, 36% (72/201) and 13% (26/201) regions of abnormal uptake were fully or partially restored, respectively. By EOS, further reduction of active fractures and fewer new areas of uptake were observed. New fractures at Week 144 were observed in a single participant (considered a burosumab partial responder) and between Week 144 and EOS in another participant unrelated to burosumab (car accident). Participants reported sustained mean reduction from baseline pain at Week 240 per Brief Pain Inventory and significantly per SF-36 Bodily Pain score. Significant reductions in baseline fatigue at Week 240 were reported per Brief Fatigue Inventory and SF-36 Vitality scores. SF-36 physical health (Role Physical, Bodily Pain, Component Score) and mental health (Social Function, Vitality) significantly improved from baseline at Week 240. The observed safety profile of long-term burosumab in participants with TIO was consistent with the known safety profile of burosumab and similar to patients with XLH. Long-term burosumab therapy was associated with improved serum phosphorus, osteomalacia, bone turnover, fracture incidence and healing, health-related quality of life, and reductions in pain and fatigue in adults with TIO. Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

Published
2022

25. Correction to: An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Author

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

Subjects
Phenotype, Spastic Paraplegia, Hereditary, Correction, Humans, Aldehyde Oxidoreductases, Lipids, Genetics (clinical), Ethers
Abstract

In 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).Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.All 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.Heterozygous 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

26. Correction: Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author

Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, and Ping Yee Billie Au

Subjects
Genetics (clinical)
Published
2021

27. Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period.

Author

Ward LM, Högler W, Glorieux FH, Portale AA, Whyte MP, Munns CF, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Sochett E, Muroya K, Tanaka H, Pitukcheewanont P, Gottesman GS, Biggin A, Perwad F, Chen A, Lawrence Merritt Ii J, and Imel EA

Abstract

In a randomized, open-label phase 3 study of 61 children aged 1-12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64-88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n  = 6; crossover, n  = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z -score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks., Competing Interests: L.M.W. has been a consultant to Ultragenyx and Kyowa Kirin and participated in clinical trials with Ultragenyx Pharmaceutical Inc., with funds to Dr Ward’s institution. W.H. served as an investigator in clinical trials with, and as a consultant for, Ultragenyx Pharmaceutical Inc. and serves as a clinical investigator in clinical trials with, and has received research funding from, Kyowa Kirin. F.H.G. has been a consultant to, and participated in clinical trials with, Ultragenyx Pharmaceutical Inc. and Kyowa Kirin. A.A.P. has been a consultant to, and served as an investigator in clinical trials with, Ultragenyx Pharmaceutical Inc. M.P.W. has lectured for Ultragenyx Pharmaceutical Inc. C.F.M. is a consultant for Kyowa Kirin and has received research funding from Kyowa Kirin. O.N. has received speakers’ honoraria from Kyowa Kirin, Abbott, and BioMarin, consulting fees from Kyowa Kirin and BioMarin, and research support from Kyowa Kirin. J.H.S. has received institutional research funding from and personal honoraria for participation in an advisory board from Ultragenyx Pharmaceutical Inc. R.P. has no conflicts to disclose. N.N. has been a consultant to, and participated in clinical trials with, Kyowa Kirin. H.I.C. has been a consultant to, and participated in clinical trials with, Ultragenyx Pharmaceutical Inc. H.T. has received research funding from Kyowa Kirin co. Ltd. P.P. has been an employee of Lumos Pharma Inc. and owns stock in Lumos Pharma Inc. and Ascendis Pharma. G.S.G. has been a consultant for Ultragenyx Pharmaceutical Inc. A.C. and J.L.M. are employees of and own stock in Ultragenyx Pharmaceutical Inc. E.A.I. has been a consultant to, and participated in clinical trials with, Ultragenyx Pharmaceutical Inc. E.S., K.M., A.B., and F.P. report no conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Published
2024
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