221 results on '"Joel Charrow"'
Search Results
2. P139: Persistent growth-promoting effects of vosoritide in children with achondroplasia for up to 4 years: Update from phase 3 extension study
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Ravi Savarirayan, Louise Tofts, Melita Irving, William Wilcox, Carlos Bacino, Julie Hoover-Fong, Rosendo Ullot Font, Paul Harmatz, Frank Rutsch, Ricki Carroll, Lynda Polgreen, Ignacio Ginebreda, Klaus Mohnike, Joel Charrow, Carlos Prada, Daniel Hoernschemeyer, Keiichi Ozono, Takuo Kubota, Yasemin Alanay, Paul Arundel, Yumiko Kotani, Natsuo Yasui, Klane White, Shelley Brandstetter, Howard Saal, Antonio Leiva-Gea, Felipe Luna-González, Hiroshi Mochizuki, Asako Tajima, Donald Basel, Elena Fisheleva, Andrea Low, Sue Lawrinson, and Jonathan Day
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Genetics ,QH426-470 ,Medicine - Published
- 2024
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3. P141: Persistent growth-promoting effects of vosoritide in children with achondroplasia is accompanied by improvement in physical aspects of quality of life
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Ravi Savarirayan, Louise Tofts, Melita Irving, William Wilcox, Carlos Bacino, Julie Hoover-Fong, Rosendo Ullot Font, Paul Harmatz, Frank Rutsch, Ricki Carroll, Lynda Polgreen, Ignacio Ginebreda, Klaus Mohnike, Joel Charrow, Carlos Prada, Daniel Hoernschemeyer, Keiichi Ozono, Takuo Kubota, Yasemin Alanay, Paul Arundel, Yumiko Kotani, Natsuo Yasui, Klane White, Shelley Brandstetter, Howard Saal, Antonio Leiva-Gea, Felipe Luna-González, Hiroshi Mochizuki, Asako Tajima, Donald Basel, Elena Fisheleva, Richard Rowell, Alice Huntsman Labed, and Jonathan Day
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Genetics ,QH426-470 ,Medicine - Published
- 2024
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4. P144: Persistence of growth-promoting effects in children with achondroplasia up to 7 years: Update from phase 2 extension study with vosoritide
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Julie Hoover-Fong, Melita Irving, Carlos Bacino, Joel Charrow, Carlos Prada, Valerie Cormier-Daire, Lynda Polgreen, Paul Harmatz, Sajda Ghani, Elena Fisheleva, Andrea Low, Jonathan Day, John Phillips, III, and Ravi Savarirayan
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Genetics ,QH426-470 ,Medicine - Published
- 2024
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5. P1588: LONG-TERM REAL-WORLD EFFECTIVENESS OF ELIGLUSTAT IN TREATMENT-NAÏVE AND SWITCH PATIENTS ENROLLED IN THE INTERNATIONAL COLLABORATIVE GAUCHER GROUP (ICGG) GAUCHER REGISTRY
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Pramod Mistry, Manisha Balwani, Joel Charrow, Jeremy Lorber, Claus Niederau, Jenny Carwile, Sefika Uslu, and Priya S. Kishnani
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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6. A rapid LC-MS/MS assay for detection and monitoring of underivatized branched-chain amino acids in maple syrup urine disease
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Hamed Piri-Moghadam, Alan Miller, Debra Pronger, Faye Vicente, Joel Charrow, Shannon Haymond, and David C. Lin
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Mass spectrometry ,Branched-chain amino acid ,Quantitation ,Maple syrup urine disease ,Clinical assay ,Medical technology ,R855-855.5 - Abstract
Introduction: Quantitation of the isomeric branched-chain amino acids (BCAA; valine, alloisoleucine, isoleucine, leucine) is a challenging task that typically requires derivatization steps or long runtimes if a traditional chromatographic method involving a ninhydrin ion pairing reagent is used. Objectives: To develop and perform clinical validation of a rapid, LC-MS/MS-based targeted metabolomics assay for detection and monitoring of underivatized BCAA in human plasma. Methods:: Various columns and modes of chromatography were tested. The final optimized method utilized mixed mode chromatography with an Intrada column under isocratic condition. Sample preparation utilized the 96-well format. Briefly, extraction solvent containing the internal standard is added to 20 uL of sample, followed by shaking and positive pressure filtering, and the resulting extracted sample is analyzed. The assay was validated based on accepted quality standards (e.g., CLIA and CLSI) for clinical assays. Results: The method is linear over a wide range of concentrations, 2.0–1500 µM, with LOD of 0.60 µM and LOQ of 2.0 µM. The precision of the assay was 4–10% across analytes. The method was also validated against reference laboratories via blinded split-sample analysis and demonstrated good agreement with accuracy: 89–95% relative to the external group mean. Conclusion: We have developed a method that is accurate, rapid, and reliable for routine clinical testing of patient sample BCAA, which is used in the diagnosis and management of maple syrup urine disease (MSUD). The assay also has desirable characteristics, such as short run time, small sample volume requirement, simple sample preparation without the need for derivatization, and high throughput.
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- 2022
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7. O22: A randomized controlled trial of vosoritide in infants and toddlers with achondroplasia
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Carlos Bacino, Ravi Savarirayan, William Wilcox, Paul Harmatz, John Phillips, Lynda Polgreen, Louise Tofts, Keiichi Ozono, Paul Arundel, Melita Irving, Donald Basel, Michael Bober, Joel Charrow, Hiroshi Mochizuki, Yumiko Kotani, Howard Saal, George Jeha, Lynn Han, Elena Fisheleva, Alice Huntsman-Labed, and Jonathan Day
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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8. P194: Persistence of growth promoting effects in children with achondroplasia over seven years: Update from phase II extension study with vosoritide
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Julie Hoover-Fong, Melita Irving, Carlos Bacino, Joel Charrow, Valérie Cormier-Daire, Lynda Polgreen, Paul Harmatz, Alice Huntsman-Labed, Elena Fisheleva, Ian Sabir, Jonathan Day, John Phillips, and Ravi Savarirayan
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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9. P193: Persistent growth-promoting effects of vosoritide in children with achondroplasia for up to 3.5 years: Update from phase 3 extension study
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Julie Hoover-Fong, Ravi Savarirayan, Louise Tofts, Melita Irving, William Wilcox, Carlos Bacino, Rosendo Ullot Font, Paul Harmatz, Frank Rutsch, Michael Bober, Lynda Polgreen, Ignacio Ginebreda, Klaus Mohnike, Joel Charrow, Daniel Hoernschemeyer, Keiichi Ozono, Yasemin Alanay, Paul Arundel, Shoji Kagami, Natsuo Yasui, Klane White, Howard Saal, Antonio Leiva-Gea, Felipe Luna-González, Hiroshi Mochizuki, Donald Basel, Dania Porco, Kala Jayaram, Elena Fisheleva, Sue Lawrinson, and Jonathan Day
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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10. P400: Implementation of genetic inpatient consultation services in pediatrics: DNA (Discover New Answers) Consult Team
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Merlene Peter, Rachel Hickey, Miguel Moran, Anne McRae, Joel Charrow, Joshua Baker, and Carlos Prada
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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11. P591: Assessing the performance of automated HPO term extraction for deep phenotyping of patients receiving WES/WGS in a clinical diagnostic laboratory
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Kai Lee Yap, Anthony Wong, Sachleen Tuteja, Andrew Skol, Andy Drackley, Alexander Ing, Eleanor Hilton, Michael Carroll, Christopher McCabe, Sabah Kadri, Pamela Rathbun, Katrin Leuer, and Joel Charrow
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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12. Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?
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Marie Morimoto, Clara Myung, Kimberly Beirnes, Kunho Choi, Yumi Asakura, Arend Bokenkamp, Dominique Bonneau, Milena Brugnara, Joel Charrow, Estelle Colin, Amira Davis, Georges Deschenes, Mattia Gentile, Mario Giordano, Andrew K. Gormley, Rajeshree Govender, Mark Joseph, Kory Keller, Evelyne Lerut, Elena Levtchenko, Laura Massella, Christy Mayfield, Behzad Najafian, David Parham, Jurgen Spranger, Peter Stenzel, Uluc Yis, Zhongxin Yu, Jonathan Zonana, Glenda Hendson, and Cornelius F. Boerkoel
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Schimke immuno-osseous dysplasia ,SMARCAL1 protein ,Focal segmental glomerulosclerosis ,Wnt signaling pathway ,Notch signaling pathway ,Medicine - Abstract
Abstract Background Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. Results We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. Conclusions We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.
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- 2016
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13. Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants
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Barbara K. Burton, Joel Charrow, George E. Hoganson, Julie Fleischer, Dorothy K. Grange, Stephen R. Braddock, Lauren Hitchins, Rachel Hickey, Katherine M. Christensen, Daniel Groeppner, Heather Shryock, Pamela Smith, Rong Shao, and Khaja Basheeruddin
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pompe disease ,newborn screening ,Pediatrics ,RJ1-570 - Abstract
Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing.
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- 2020
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14. Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT.
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Suhrad G Banugaria, Sean N Prater, Trusha T Patel, Stephanie M Dearmey, Christie Milleson, Kathryn B Sheets, Deeksha S Bali, Catherine W Rehder, Julian A J Raiman, Raymond A Wang, Francois Labarthe, Joel Charrow, Paul Harmatz, Pranesh Chakraborty, Amy S Rosenberg, and Priya S Kishnani
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Medicine ,Science - Abstract
Although enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy.We evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy.Seven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1-1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients.The ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.
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- 2013
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15. Utility and Outcomes of the 2019 American College of Medical Genetics and Genomics–Clinical Genome Resource Guidelines for Interpretation of Copy Number Variants with Borderline Classifications at an Academic Clinical Diagnostic Laboratory
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Andy Drackley, Casey Brew, Alissa Wlodaver, Sara Spencer, Katrin Leuer, Pamela Rathbun, Joel Charrow, Xuwen Wieneke, Kai Lee Yap, and Alexander Ing
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DNA Copy Number Variations ,Genetics, Medical ,Genetic Variation ,Humans ,Molecular Medicine ,Genetic Testing ,Genomics ,United States ,Pathology and Forensic Medicine - Abstract
In 2019, the American College of Medical Genetics and Genomics and the Clinical Genome Resource published updated technical standards for the interpretation and reporting of copy number variants (CNVs), introducing a semiquantitative classification system to improve standardization and consistency between laboratories. Evaluation of these guidelines' performance will inform laboratories about the impact of their implementation into clinical practice. A total of 145 difficult-to-classify CNVs, originally assessed by an academic molecular diagnostic laboratory, were re-interpreted/classified according to the American College of Medical Genetics and Genomics-Clinical Genome Resource guidelines. Classifications between interpretation systems were then compared. The concordance rate was 60.7%, and significantly more variants of uncertain significance were obtained when using the guidelines (n = 98) versus the laboratory's classification system (n = 49; P 0.001). The concordance rate was presumably impacted by the intentionally unclear nature of the selected variants. The difference in variant of uncertain significance rate was largely due to laboratory-specific practices for variant interpretation and reporting and differences in utilization of general population data. Laboratory-specific policies and practices may need to be addressed for true standardization. Challenges to consistent guideline utilization are centered around the general lack of high-quality curated data available for CNV interpretations and the inherent subjectivity in the selection of evidence criteria and application of evidence points. Multiple aspects of the guidelines were highlighted to further improve classification standardization.
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- 2022
16. Neurocognitive Manifestations of Individuals with NF1 Microdeletions (P14-9.007)
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Jenny Garzon, Andrea Patete, Carolyn Serbinski, Madison Hankins, Michael Sawin, Allison Weisman, Katherine Kim, Joel Charrow, Robert Listernick, and Carlos Prada
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- 2023
17. Effects of oral eliglustat on skeletal manifestations in patients with type 1 Gaucher disease: Results from four completed clinical trials after long-term treatment
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Sebastiaan J.M. Gaemers, Pramod K. Mistry, Joel Charrow, Theodore Marinakis, Meredith C. Foster, Timothy M. Cox, M. Judith Peterschmitt, and Elena Lukina
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Pediatrics ,medicine.medical_specialty ,Long term treatment ,business.industry ,Endocrinology, Diabetes and Metabolism ,Type 1 Gaucher Disease ,32 Biomedical and Clinical Sciences ,Biochemistry ,Clinical trial ,Endocrinology ,3203 Dentistry ,Genetics ,Medicine ,In patient ,business ,Molecular Biology ,Eliglustat - Abstract
Debilitating bone complications are common among patients with Gaucher disease type 1 (GD1). We analyzed changes in bone parameters among 393 GD1 patients treated with oral eliglustat for 4–8 years in 4 Sanofi Genzyme-sponsored clinical trials (Phase 2/NCT00358150 [N=26]; Phase 3: ENGAGE/NCT00891202 [N=40]; ENCORE/NCT00943111 [N=157]; EDGE/NCT01074944 [N=170]. In treatment-naïve patients (Phase 2/ ENGAGE), mean spine T-scores moved from the osteopenic range at baseline to the healthy range after 2–3 years. Mean±SEM spine T score increased from 1.55±0.28 to 0.59±0.34 (n=14) after 8 years in Phase 2, and increased to 0.53±0.27 in ENGAGE after 4.5 years (n=9). In both trials, spine Z-scores improved and femur T- and Z-scores remained normal. In ENCORE (patients stabilized after a mean of 10 years of enzyme replacement therapy [ERT]), T- and Z-scores remained in reference ranges for up to 4 years; least-square mean spine Z-scores improved by 0.29 (P
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- 2022
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18. Quantification of Branched-Chain Amino Acids in Plasma by High-Performance Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)
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Hamed, Piri-Moghadam, Alan, Miller, Debra, Pronger, Faye, Vicente, Joel, Charrow, Shannon, Haymond, and David C, Lin
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Nitrogen Isotopes ,Methanol ,Infant, Newborn ,Valine ,Maple Syrup Urine Disease ,Leucine ,Tandem Mass Spectrometry ,Humans ,Amino Acids ,Isoleucine ,Oxidoreductases ,Amino Acids, Branched-Chain ,Chromatography, High Pressure Liquid ,Chromatography, Liquid - Abstract
Branched-chain amino acids (BCAA), including valine, alloisoleucine, isoleucine, and leucine, play significant roles in a number of metabolic pathways in the body. Deficiency in branched-chain ketoacid dehydrogenase complex, an enzyme required for metabolism of those amino acids, will lead to elevation and accumulation of BCAA and ketoacids in bodily fluids. This results in maple syrup urine disease (MSUD), a condition estimated to affect 1 in 100,000-300,000 births. If MSUD is not diagnosed in the first few days of life, progression of this disease can lead to intellectual disability, coma, irreversible brain damage, seizures, or even death. If diagnosed early, MSUD can be managed by monitoring the blood concentrations of BCAA and adjusting the patient's dietary intake accordingly. Therefore, it is critical to have a rapid, accurate, and reliable BCAA assay for confirmation of MSUD in newborns as well as routine monitoring of MSUD patients. Here, we describe a high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method for BCAA measurement which requires only 20 μL of plasma. The sample preparation does not require derivatization and only involves protein precipitation with LC/MS-grade methanol, which contains leucine(13C6;15N), isoleucine(13C6;15N), and valine(13C5;15N) as the internal standards. The final sample extracts do not require dry-down and reconstitution and are readily compatible with the liquid chromatography (LC) method. BCAA are separated using the isocratic gradient method on a mixed-mode Intrada column. Multiple-reaction monitoring (MRM) mode is used for MS/MS detection to monitor the parent-to-daughter transitions m/z 132.2 to 86.4 for leucine, isoleucine, and alloisoleucine; m/z 118.2 to 72.4 for valine; m/z 139.2 to 92.4 for leucine(13C6;15N) and isoleucine(13C6;15N); and m/z 124.2 to 77.4 for valine(13C5;15N).
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- 2022
19. Growth parameters in children with achondroplasia: A 7-year, prospective, multinational, observational study
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Ravi Savarirayan, Melita Irving, Paul Harmatz, Borja Delgado, William R. Wilcox, John Philips, Natalie Owen, Carlos A. Bacino, Louise Tofts, Joel Charrow, Lynda E. Polgreen, Julie Hoover-Fong, Paul Arundel, Ignacio Ginebreda, Howard M. Saal, Donald Basel, Rosendo Ullot Font, Keiichi Ozono, Michael B. Bober, Valerie Cormier-Daire, Kim-Hanh Le Quan Sang, Genevieve Baujat, Yasemin Alanay, Frank Rutsch, Daniel Hoernschemeyer, Klaus Mohnike, Hiroshi Mochizuki, Asako Tajima, Yumiko Kotani, David D. Weaver, Klane K. White, Clare Army, Kevin Larrimore, Keith Gregg, George Jeha, Claire Milligan, Elena Fisheleva, Alice Huntsman-Labed, and Jonathan Day
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Male ,Anthropometrics ,Pediatrics ,Body Height ,Achondroplasia ,Annualized growth velocity ,Child, Preschool ,Humans ,Female ,Prospective Studies ,Child ,Observational ,Genetics (clinical) - Abstract
This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control.In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing.A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward.This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.
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- 2022
20. Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study
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Howard M. Saal, Carlos A. Bacino, Klaus Mohnike, Daniel Hoernschemeyer, Paul Harmatz, Yumiko Kotani, Julie Hoover-Fong, Jonathan Day, Frank Rutsch, Keiichi Ozono, Alice Huntsman-Labed, Joel Charrow, Rosendo Ullot Font, Elena Fisheleva, Antonio Leiva-Gea, Felipe Luna-González, Donald Basel, Natsuo Yasui, Lynda E. Polgreen, Kala Jayaram, Hiroshi Mochizuki, Ravi Savarirayan, Ignacio Ginebreda, Louise Tofts, Paul Arundel, Michael B. Bober, William R. Wilcox, Yasemin Alanay, Klane K. White, Melita Irving, Dania M Porco, and Acibadem University Dspace
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Pediatrics ,medicine.medical_specialty ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Brief Communication ,Placebo ,Achondroplasia ,Growth velocity ,Double-Blind Method ,Clinical Research ,Genetics ,medicine ,Humans ,Child ,Genetics (clinical) ,Vosoritide ,Pediatric ,Genetics & Heredity ,Growth promoting ,business.industry ,Extension study ,Natriuretic Peptide, C-Type ,medicine.disease ,Endochondral bone growth ,Treatment Outcome ,6.1 Pharmaceuticals ,Open label ,business ,General Economics, Econometrics and Finance - Abstract
Author(s): Savarirayan, Ravi; Tofts, Louise; Irving, Melita; Wilcox, William R; Bacino, Carlos A; Hoover-Fong, Julie; Font, Rosendo Ullot; Harmatz, Paul; Rutsch, Frank; Bober, Michael B; Polgreen, Lynda E; Ginebreda, Ignacio; Mohnike, Klaus; Charrow, Joel; Hoernschemeyer, Daniel; Ozono, Keiichi; Alanay, Yasemin; Arundel, Paul; Kotani, Yumiko; Yasui, Natsuo; White, Klane K; Saal, Howard M; Leiva-Gea, Antonio; Luna-Gonzalez, Felipe; Mochizuki, Hiroshi; Basel, Donald; Porco, Dania M; Jayaram, Kala; Fisheleva, Elena; Huntsman-Labed, Alice; Day, Jonathan RS | Abstract: PurposeAchondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported.MethodsAfter completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day.ResultsIn children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected.ConclusionVosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.
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- 2022
21. LBMON196 A Randomized Controlled Trial Of Vosoritide In Infants And Toddlers With Achondroplasia
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Ravi Savarirayan, William W Wilcox, Paul Harmatz, John Phillips III, Lynda E Polgreen, Louise Tofts, Keiichi Ozono, Paul Arundel, Melita Irving, Carlos A Bacino, Donald Basel, Michael B Bober, Joel Charrow, Hiroshi Mochizuki, Yumiko Kotani, Howard M Saal, George Jeha, Lynn Han, Elena Fisheleva, Alice Huntsman-Labed, and Jonathan Day
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Endocrinology, Diabetes and Metabolism - Abstract
Background Vosoritide increases annualized growth velocity (AGV) in children with achondroplasia aged 5 to 18 years. This global, phase 2, randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of vosoritide on growth in children with achondroplasia aged 3 months to Methods This study compared once-daily subcutaneous administration of vosoritide, at doses of 15 or 30 μg/kg of body weight, with placebo. Eligible patients had participated, for up to 6 months, in an observational growth study to calculate their baseline AGV. The primary objective was to evaluate the safety and tolerability of vosoritide in children with achondroplasia. The primary efficacy evaluation was the change from baseline in height Z-score versus placebo at week 52 using an ANCOVA model. Secondary efficacy analyses included change from baseline in AGV and upper-to-lower body segment ratio versus placebo at Week 52 using an ANCOVA model. Results A total of 75 patients were enrolled, with 11 sentinel subjects who received vosoritide to establish PK and safety. A further 32 were randomized to receive vosoritide and 32 to receive placebo. A total of 73 patients completed the 52-week trial. All patients reported at least one adverse event. Four serious adverse events occurred with vosoritide and 8 with placebo, none were treatment-related. Two participants discontinued, one on vosoritide with pre-existing respiratory morbidity who had a fatal respiratory arrest and one on placebo who withdrew consent. In the full analysis population, vosoritide (n=43) compared to placebo (n=32), increased height Z-score by 0.30 SD (95% CI 0. 07, 0.54); increased AGV by 0.92cm/year (95% CI 0.24, 1.59); and did not worsen upper-to-lower body segment ratio which changed by -0. 06 (95% CI -0.15, 0. 03). Conclusions Daily, subcutaneous administration of vosoritide to young children with achondroplasia was safe and resulted in increases in height Z-score and AGV. (Funded by BioMarin; ClinicalTrials.gov NCT03583697) Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
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- 2022
22. Long-term effects of eliglustat on skeletal manifestations in clinical trials of patients with Gaucher disease type 1
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Timothy M. Cox, Joel Charrow, Elena Lukina, Pramod K. Mistry, Meredith C. Foster, and M. Judith Peterschmitt
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Genetics (clinical) - Abstract
Most patients with Gaucher disease have progressive and often disabling skeletal manifestations. We examined the long-term effect of eliglustat treatment on bone outcomes in clinical trials in adults with Gaucher disease type 1.Data from 4 completed phase 2 and 3 trials were evaluated in treatment-naïve patients or patients switching to eliglustat from enzyme replacement therapy (ERT).Overall, 319 of 393 (81%) eliglustat-treated patients remained in their trials until completion or commercial eliglustat became available. Mean eliglustat treatment duration ranged from 3.3 to 6.5 years. In treatment-naïve patients and ERT-switch patients, frequency and severity of bone pain decreased during eliglustat treatment. Mean lumbar spine T-scores shifted from abnormal to normal in treatment-naïve patients and remained in the healthy reference range or improved modestly in ERT-switch patients. Mean total bone marrow burden score shifted from marked-to-severe to moderate in treatment-naïve patients and remained moderate in ERT-switch patients. MIP-1β (marker of active bone disease) was elevated at baseline and decreased to the healthy reference range in treatment-naïve patients and remained in the healthy reference range among ERT-switch patients.These findings confirm the long-term efficacy of eliglustat on skeletal complications of Gaucher disease in treatment-naïve and ERT-switch patients.
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- 2023
23. Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7
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Robert A. Hegele, Maria Iascone, Kevin A. Shapiro, Nicolas Chatron, Marwan Shinawi, Joel Charrow, Jeffrey W. Innis, Luitgard Graul-Neumann, Joanna Goes Castro Meira, Anna Lehman, Dawn L. Earl, Victoria R. Sanders, Shannon Rego, David A. Sweetser, Clémantine Dimartino, Wilhelmina S. Kerstjens-Frederikse, Antonio Vitobello, Davor Lessel, Daniel Grinberg, Laurence Faivre, Ryan Peretz, Katherine M. Christensen, Emma Reesor, Erin Beaver, Elizabeth Wohler, Margot R.F. Reijnders, Deborah Barbouth, Anna Cereda, Kaja Kristine Selmer, Melissa A. Walker, Barbro Stadheim, Alessandro Serretti, Helen Kingston, Jill Clayton-Smith, Raymond Lewandowski, Bernarda Lozić, Robert Stratton, Amelia Kirby, Anne H. O’Donnell-Luria, Sara Gabbiadini, Susanna Balcells, Myriam Oufadem, Christel Thauvin, Maha Aly, Wendy K. Chung, Susan M. White, Lauren C. Briere, Thomas Smol, Stanislas Lyonnet, Roberto Colombo, Catherine E. Keegan, Marie T. McDonald, Melanie Parisot, Tiong Yang Tan, Brian Wong, Christopher T. Gordon, Magnus Dehli Vigeland, Frances A. High, Emily Bryant, Audrey Labalme, Nara Sobreira, Arnold Munnich, Jeanne Amiel, Dayna Morel Swols, Raquel Rabionet, Laura Castilla-Vallmanya, Jennifer Heeley, Gunnar Houge, Michael J. Gambello, Bernardo Blanco-Sánchez, Lynn Pais, Olena M. Vaske, Roser Urreizti, Alison Wray, Veronique Pingault, Damien Sanlaville, John Christodoulou, John Millichap, Valérie Cormier-Daire, Parul Jayakar, Helen Cox, Frédéric Tran Mau-Them, Belinda Chong, Victoria Mok Siu, Anne Slavotinek, Antonie J. van Essen, Ingvild Aukrust, Lorne A. Clarke, Rachel Gannaway, Anne Dieux-Coeslier, Patrick Nitschké, Tony Yao, Simon Sadedin, Danielle Karlowicz, Christelle Rougeot, Christine Bole-Feysot, Sandra Yang, Megan T. Cho, Gaetan Lesca, Christiane Zweier, Castilla-Vallmanya L., Selmer K.K., Dimartino C., Rabionet R., Blanco-Sanchez B., Yang S., Reijnders M.R.F., van Essen A.J., Oufadem M., Vigeland M.D., Stadheim B., Houge G., Cox H., Kingston H., Clayton-Smith J., Innis J.W., Iascone M., Cereda A., Gabbiadini S., Chung W.K., Sanders V., Charrow J., Bryant E., Millichap J., Vitobello A., Thauvin C., Mau-Them F.T., Faivre L., Lesca G., Labalme A., Rougeot C., Chatron N., Sanlaville D., Christensen K.M., Kirby A., Lewandowski R., Gannaway R., Aly M., Lehman A., Clarke L., Graul-Neumann L., Zweier C., Lessel D., Lozic B., Aukrust I., Peretz R., Stratton R., Smol T., Dieux-Coeslier A., Meira J., Wohler E., Sobreira N., Beaver E.M., Heeley J., Briere L.C., High F.A., Sweetser D.A., Walker M.A., Keegan C.E., Jayakar P., Shinawi M., Kerstjens-Frederikse W.S., Earl D.L., Siu V.M., Reesor E., Yao T., Hegele R.A., Vaske O.M., Rego S., Shapiro K.A., Wong B., Gambello M.J., McDonald M., Karlowicz D., Colombo R., Serretti A., Pais L., O'Donnell-Luria A., Wray A., Sadedin S., Chong B., Tan T.Y., Christodoulou J., White S.M., Slavotinek A., Barbouth D., Morel Swols D., Parisot M., Bole-Feysot C., Nitschke P., Pingault V., Munnich A., Cho M.T., Cormier-Daire V., Balcells S., Lyonnet S., Grinberg D., Amiel J., Urreizti R., Gordon C.T., MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
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0301 basic medicine ,NF-KAPPA-B ,PROTEIN ,030105 genetics & heredity ,medicine.disease_cause ,Germline ,Transcriptome ,ACTIVATION ,POLYUBIQUITINATION ,Missense mutation ,Exome ,Genetics (clinical) ,Genetics ,Sanger sequencing ,Mutation ,leads ,Necrosi ,craniofacial development ,Phenotype ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,intellectual disability ,patent ductus arteriosu ,symbols ,Mutation, Missense ,Biology ,traf7 ,Article ,akt1 ,target ,03 medical and health sciences ,symbols.namesake ,Necrosis ,patent ductus arteriosus ,medicine ,Humans ,blepharophimosi ,Tumors ,MUTATIONS ,Fibroblasts ,medicine.disease ,Blepharophimosis ,TRAF7 ,blepharophimosis ,GENOMIC ANALYSIS ,Germ Cells ,030104 developmental biology ,MENINGIOMAS - Abstract
PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.
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- 2020
24. Real‐world effectiveness of eliglustat in treatment‐naïve and switch patients enrolled in the International Collaborative Gaucher Group Gaucher Registry
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Lisa H. Underhill, Monica R. McClain, Claus Niederau, Joel Charrow, Manisha Balwani, Priya S. Kishnani, and Pramod K. Mistry
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Adult ,Male ,medicine.medical_specialty ,Pyrrolidines ,Adolescent ,Hemoglobin increased ,Liver volume ,Gastroenterology ,Therapy naive ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Longitudinal Studies ,Registries ,Oral therapy ,Research Articles ,Gaucher Disease ,Platelet Count ,business.industry ,Organ Size ,Hematology ,Middle Aged ,Hexosaminidases ,Liver ,030220 oncology & carcinogenesis ,Splenectomy ,Female ,Lumbar spine ,Hemoglobin ,business ,Spleen ,Eliglustat ,Research Article ,030215 immunology - Abstract
Eliglustat is a first‐line oral therapy for adults with Gaucher disease type 1 (GD1) with extensive, intermediate, or poor CYP2D6‐metabolizer phenotypes (90% of patients). We report real‐world outcomes after 2 years of eliglustat therapy in the International Collaborative Gaucher Group Gaucher Registry (NCT00358943). As of January 2019, baseline and 2‐year data (±1 year) were available for 231 eliglustat‐treated GD1 patients: 19 treatment‐naïve (zero splenectomized) and 212 ERT patients who switched to eliglustat (36 splenectomized). Most patients (89%) were from the United States, where eliglustat was first approved. In treatment‐naïve patients, mean hemoglobin increased from 12.4 to 13.4 g/dL (P = .004, n = 18), mean platelet count increased from 113 to 156 × 109/L (P
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- 2020
25. Oligosaccharyltransferase complex‐congenital disorders of glycosylation: A novel congenital disorder of glycosylation
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Gemma L. Carvill, Jacqueline J Wolak, Joel Charrow, Christopher Miller, Emily Bryant, Victoria R. Sanders, Jeffrey D. Calhoun, Jessica Giannelli, John Millichap, and Egidio Spinelli
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Microcephaly ,Glycosylation ,Protein subunit ,030105 genetics & heredity ,03 medical and health sciences ,chemistry.chemical_compound ,Internal medicine ,Genetics ,medicine ,Genetics (clinical) ,chemistry.chemical_classification ,business.industry ,medicine.disease ,Phenotype ,carbohydrates (lipids) ,030104 developmental biology ,Endocrinology ,chemistry ,Oligosaccharyltransferase complex ,Transferrin ,Dysplasia ,lipids (amino acids, peptides, and proteins) ,business ,Congenital disorder of glycosylation - Abstract
Congenital disorders of glycosylation (CDG) are metabolic disorders that affect the glycosylation of proteins and lipids. Since glycosylation affects all organs, CDG show a wide spectrum of phenotypes. We present a patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type 1 serum transferrin isoelectrofocusing due to a novel CDG caused by a homozygous variant in the oligosaccharyltransferase complex noncatalytic subunit (OSTC) gene involved in glycosylation and confirmed by serum transferrin electrophoresis.
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- 2020
26. Quantification of Branched-Chain Amino Acids in Plasma by High-Performance Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)
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Hamed Piri-Moghadam, Alan Miller, Debra Pronger, Faye Vicente, Joel Charrow, Shannon Haymond, and David C. Lin
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- 2022
27. OP021: Vosoritide for children with achondroplasia: Growth velocity and pubertal milestones
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Melita Irving, Julie Hoover-Fong, Carlos Bacino, Joel Charrow, Valérie Cormier-Daire, Lynda Polgreen, Paul Harmatz, Patricia Dickson, Michael Bober, Klaus Mohnike, William Wilcox, Alice Huntsman Labed, Sue Lawrinson, Elena Fisheleva, George Jeha, Jonathan Day, John Phillips, and Ravi Savarirayan
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Genetics (clinical) - Published
- 2022
28. Newborn screening for Krabbe disease in Illinois: A single center's experience
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Chelsey N. Walsh, Rachel E. Hickey, Barbara K. Burton, Joel Charrow, Katherine H. Kim, Allegra Quadri, Jennifer P. Rubin, Lauren E. Hitchens, and Joshua Baker
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Endocrinology ,Endocrinology, Diabetes and Metabolism ,Genetics ,Molecular Biology ,Biochemistry - Published
- 2022
29. Cervical spinal cord compression in infants with achondroplasia: should neuroimaging be routine?
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Joel Charrow, Victoria R. Sanders, and Stephen H. Sheldon
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musculoskeletal diseases ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Cord ,medicine.diagnostic_test ,business.industry ,Medical record ,Magnetic resonance imaging ,Cervical cord compression ,030105 genetics & heredity ,medicine.disease ,Sudden death ,Hypotonia ,03 medical and health sciences ,030104 developmental biology ,Neuroimaging ,medicine ,Radiology ,medicine.symptom ,Achondroplasia ,business ,Genetics (clinical) - Abstract
To examine results of magnetic resonance imaging (MRI), polysomnograms (PSG), and patient outcomes in patients with achondroplasia in light of recent screening recommendations for infants with achondroplasia. We reviewed medical records of 49 patients with achondroplasia followed at our institution between September 1997 and January 2017, including physical exams, MRIs, PSGs (when available), and surgical histories. Appropriate PSG data were available for 39 of these patients. Twenty-seven of 49 patients had cervical cord compression on MRI, and 20 of those patients required surgery. Central apnea was detected in 2/23 patients with cervical cord compression in whom PSG data was available. Physical exam revealed depressed deep-tendon reflexes in two patients with cord compression and one patient without cord compression. Besides hypotonia in some, the neurological exams of these patients were unremarkable. Cervical cord compression is a common occurrence in infants with achondroplasia and necessitates surgical intervention in some patients. Physical exam and PSG are poor predictors of the presence of cord compression or the need for surgery. All infants with achondroplasia should have MRIs of the craniocervical junction in the first 6 months of life.
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- 2019
30. Persistent and Stable Growth Promoting Effects of Vosoritide in Children With Achondroplasia for up to 2 Years: Results From the Ongoing Phase 3 Extension Study
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Paul Arundel, Lynda E. Polgreen, Michael B. Bober, Ignacio Ginebreda, Ravi Savarirayan, Antonio Leiva-Gea, Louise Tofts, Hiroshi Mochizuki, Elena Fisheleva, Julie Hoover-Fong, Shoji Kagami, Kala Jayaram, Lynn Han, Dania M Porco, William R. Wilcox, Yasemin Alanay, Frank Rutsch, Howard M. Saal, Natsuo Yasui, Carlos A. Bacino, Klaus Mohnike, Donald Basel, Joel Charrow, Jonathan Day, Keiichi Ozono, Felipe Luna-González, Melita Irving, Rosendo Ullot Font, Daniel Hoernschemeyer, Paul Harmatz, and Klane K. White
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Pediatrics ,medicine.medical_specialty ,Growth promoting ,business.industry ,Emerging Endocrine Therapies Across the Lifespan ,Endocrinology, Diabetes and Metabolism ,Extension study ,medicine.disease ,Phase (combat) ,Pediatric Endocrinology ,medicine ,Achondroplasia ,business ,AcademicSubjects/MED00250 ,Vosoritide - Abstract
Objectives: Vosoritide is a potent stimulator of endochondral bone growth and is in development for the treatment of achondroplasia, the most common form of disproportionate short stature. We previously reported on a 52-week, phase 3, pivotal study that demonstrated a highly statistically significant improvement in annualized growth velocity (AGV) when vosoritide was compared to placebo in children with achondroplasia aged 5-18 years (Savarirayan et al, Lancet, 2020). This is an analysis of data after an additional 52 weeks of treatment in the ongoing phase 3 extension study. Methods: After completion of the phase 3 placebo-controlled study, 119 children were enrolled into the extension study, where they all receive open label 15 μg/kg/day vosoritide. AGV, height Z-score and body proportion ratio were analyzed to assess efficacy of vosoritide in children who were treated with vosoritide for up to 2 years. Fifty-eight continued treatment with vosoritide and 61 switched from placebo to vosoritide. Two participants on continuous vosoritide treatment discontinued before the Week 52 timepoint. Four participants on continuous vosoritide treatment and 7 participants who switched from placebo to vosoritide missed the Week 52 assessment due to Covid-19. Results: In children randomized to receive daily vosoritide, baseline mean (SD) AGV was 4.26 (1.53) cm/year. After the first 52 weeks of treatment, mean (SD) AGV was 5.67 (0.98) cm/year. Mean (SD) AGV over the second year was 5.57 (1.10) cm/year. Mean (SD) change from baseline in height Z-score improved by +0.24 (0.31) at Week 52 in the pivotal study and +0.45 (0.56) at Week 52 in the extension study. Mean (SD) upper-to-lower body segment ratio improved with a change from baseline of -0.03 (0.11) at Week 52 in the pivotal study and -0.09 (0.11) at Week 52 in the extension study. In children who switched from placebo to vosoritide after 52 weeks, baseline AGV was 4.06 (1.20) cm/year and 3.94 (1.07) cm/year after 52 weeks on placebo. In the second year, after receiving 52 weeks of vosoritide, mean AGV was 5.65 (1.47) cm/year, the mean (SD) change in height Z-score was +0.24 (0.34), and the change in upper-to-lower body segment ratio was -0.03 (0.08). No new adverse events associated with vosoritide treatment were detected with up to 2 years of continuous daily, subcutaneous treatment. Most adverse events were mild and no serious adverse events were attributed to vosoritide. The most common adverse event remains mild and transient injection site reactions. Conclusions: The effect of vosoritide administration on growth as measured through AGV and height Z-score was maintained for up to 2-years in children with achondroplasia aged 5 to 18 years, with an improvement of body proportions.
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- 2021
31. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy
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Rhonda E. Schnur, Fabio Sirchia, Olga Levchenko, Caroline Nava, Jane Juusola, Sarah Verheyen, Marketa Vlckova, Lindsay Rhodes, Gregory M. Cooper, Darina Prchalova, Thomas Courtin, Øystein L. Holla, David Kronn, Akemi J. Tanaka, E. Martina Bebin, Tara Funari, Miroslava Hancarova, Ennio Del Giudice, Nicolas Guex, Astrid Eisenkölbl, Dawn L. Earl, Toshiki Takenouchi, Ursula Gruber-Sedlmayr, Sedlácek Z, Sofia Douzgou, Heidelis A. Seebacher, Gerarda Cappuccio, Jasmin Blatterer, Anna Mikhaleva, Dian Donnai, Wendy K. Chung, Else Merckoll, Natasha J Brown, Elizabeth A. Sellars, Stefan Mundlos, Susan M. Hiatt, Giuliana Giannuzzi, Sinje Geuer, Giuseppina Vitiello, Séverine Lorrain, Alexandre Reymond, David J. Amor, Nicolas Chatron, Julien Delafontaine, Martine Doco, Kristian Tveten, Cecilie F. Rustad, Sylvain Pradervand, Delphine Héron, Alfredo Brusco, Elena L. Dadali, Nicola Brunetti-Pierri, Boris Keren, Yuri A. Zarate, Crystle Lee, Joel Charrow, Binnaz Yalcin, Heidi Taska-Tench, Elin Tønne, Tomoko Uehara, Alexander Lavrov, Jennifer Norman, Norine Voisin, Anna C.E. Hurst, Victoria R. Sanders, Ganka Douglas, Diana Johnson, Kenjiro Kosaki, Université de Lausanne = University of Lausanne (UNIL), Cooper Medical School of Rowan University [Camden] (CMSRU), Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], HudsonAlpha Institute for Biotechnology [Huntsville, AL], Oslo University Hospital [Oslo], Victorian Clinical Genetics Services [Melbourne, VIC, Australia] (VCGS), Murdoch Children's Research Institute (MCRI), University of Melbourne, Seattle Children’s Hospital, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme [ CHU Pitié-Salpêtrière AP-HP] (GRC : DIA), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Research Centre for Medical Genetics [Moscow, Russia] (RCMG), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Medical University of Graz, Sheffield Children's NHS Foundation Trust, University of Arkansas at Little Rock, Charles University [Prague] (CU), University Hospital Motol [Prague], University of Alabama at Birmingham [ Birmingham] (UAB), Università degli studi di Torino = University of Turin (UNITO), Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, University of Naples Federico II = Università degli studi di Napoli Federico II, Ann & Robert H. Lurie Children's Hospital of Chicago, Swiss Institute of Bioinformatics [Lausanne] (SIB), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), GeneDx [Gaithersburg, MD, USA], Johannes Kepler University Linz [Linz] (JKU), Telemark Hospital Trust [Skien, Norway], New York Medical College (NYMC), Integris Pediatric Neurology [Oklahoma City, OK, USA] (IPN), Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo' [Trieste], Keio University School of Medicine [Tokyo, Japan], Columbia University [New York], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dupuis, Christine, Voisin, N., Schnur, R. E., Douzgou, S., Hiatt, S. M., Rustad, C. F., Brown, N. J., Earl, D. L., Keren, B., Levchenko, O., Geuer, S., Verheyen, S., Johnson, D., Zarate, Y. A., Hancarova, M., Amor, D. J., Bebin, E. M., Blatterer, J., Brusco, A., Cappuccio, G., Charrow, J., Chatron, N., Cooper, G. M., Courtin, T., Dadali, E., Delafontaine, J., Del Giudice, E., Doco, M., Douglas, G., Eisenkolbl, A., Funari, T., Giannuzzi, G., Gruber-Sedlmayr, U., Guex, N., Heron, D., Holla, O. L., Hurst, A. C. E., Juusola, J., Kronn, D., Lavrov, A., Lee, C., Lorrain, S., Merckoll, E., Mikhaleva, A., Norman, J., Pradervand, S., Prchalova, D., Rhodes, L., Sanders, V. R., Sedlacek, Z., Seebacher, H. A., Sellars, E. A., Sirchia, F., Takenouchi, T., Tanaka, A. J., Taska-Tench, H., Tonne, E., Tveten, K., Vitiello, G., Vlckova, M., Uehara, T., Nava, C., Yalcin, B., Kosaki, K., Donnai, D., Mundlos, S., Brunetti Pierri, N., Chung, W. K., and Reymond, A.
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Male ,Models, Molecular ,Hypertrichosis ,[SDV]Life Sciences [q-bio] ,Mesomelic Dysplasia ,Transcriptome ,Mice ,Gene Frequency ,Missense mutation ,Child ,Zebrafish ,Genetics (clinical) ,Genetics ,Brain Diseases ,0303 health sciences ,biology ,Protein Stability ,030305 genetics & heredity ,AFF3 ,AFF4 ,horseshoe kidney ,intellectual disability ,mesomelic dysplasia ,Nuclear Proteins ,Syndrome ,Phenotype ,Ubiquitin ligase ,[SDV] Life Sciences [q-bio] ,Child, Preschool ,Female ,Transcriptional Elongation Factors ,Adolescent ,Mutation, Missense ,Osteochondrodysplasias ,Article ,Evolution, Molecular ,Young Adult ,03 medical and health sciences ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Fused Kidney ,030304 developmental biology ,Epilepsy ,Infant ,Horseshoe kidney ,biology.organism_classification ,medicine.disease ,biology.protein - Abstract
International audience; The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3-and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
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- 2021
32. Transcript analysis for variant classification resolution in a child with primary ciliary dyskinesia
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Alexander Ing, Erica Toledo, Theresa A. Laguna, Joel Charrow, Victoria R. Sanders, Kristina Firestein, Mary Kate McIntyre, Sabah Kadri, Dawn A. Kirschmann, Alissa Wlodaver, Joanne Salazar, Kai Lee Yap, and Christopher McCabe
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Research Report ,RNA Splicing ,Biology ,atrial situs inversus ,medicine.disease_cause ,Compound heterozygosity ,Exon ,pulmonary situs inversus ,medicine ,Coding region ,Humans ,RNA, Messenger ,Gene ,Loss function ,Genetics ,Mutation ,ciliary dyskinesia ,Gene Expression Profiling ,General Medicine ,Axonemal Dyneins ,Exons ,Stop codon ,Pedigree ,Child, Preschool ,RNA splicing ,Female ,Transcriptome ,Ciliary Motility Disorders - Abstract
Transcriptional analysis can be utilized to reconcile variants of uncertain significance, particularly those predicted to impact splicing. Laboratory analysis of the predicted mRNA transcript may allow inference of the in vivo impact of the variant and aid prediction of its clinical significance. We present a patient with classical features of primary ciliary dyskinesia (PCD) who was identified to have compound heterozygous variants in the DNAH11 gene (c.10691 + 2T > C, c.13523_13543dup21) via trio whole-exome sequencing in 2013. These variants were originally classified as Mutation and Likely Mutation. However, these variants were downgraded to variants of uncertain significance (VUSs) during reanalysis in 2016 because of uncertainty that they caused a loss of function of the gene. c.10691 + 2T > C is predicted to abrogate the canonical splice site and lead to the skipping of exon 65, but the adjoining of exon 64 and exon 66 in the DNAH11 transcript preserves the reading frame of the resultant protein. c.13523_13543dup21 is located in the last exon of the DNAH11 coding sequence, upstream of the canonical stop codon, which suggests a reduced likelihood to trigger nonsense-mediated decay (NMD). Transcriptional analysis was performed to characterize the impact of the variants, resulting in reclassification of c.10691 + 2T > C to Likely Pathogenic by providing evidence that it results in a deleterious effect and subsequent downstream reclassification of c.13523_13543dup21 to Likely Pathogenic as well. Our case illustrates the potential impact of transcriptional analysis on variant resolution, supporting its usage on variants that exert an unpredictable effect on splicing.
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- 2021
33. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial
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Stella Mazurová, John W. Day, Mazen M. Dimachkie, Sónia Tizon, Anna Kostera-Pruszczyk, Tahseen Mozaffar, Joel Charrow, Chafic Karam, Ricardo Maré, Jean-Baptiste Noury, Dewi Guellec, Jorge Alonso-Pérez, Acary Souza Bulle Oliveira, Loren D M Pena, Tianyue Zhou, Sergey Illarioshkin, Nathan Thibault, Marcelo Rugiero, Can Ebru Bekircan-Kurt, Lauren Chase, Monica Sciacco, Mamatha Pasnoor, Jenny Billy, Mark Tarnopolsky, Fabien Zagnoli, Marie Wencel, Sevim Erdem-Ozdamar, Erin Hatcher, Madoka Mori, Céline Tard, Nicolas Mavroudakis, Emmanuelle Salort-Campana, Antonio Toscano, Shafeeq Ladha, Angela Genge, Ans T. van der Ploeg, Michela Guglieri, Judith Johnson, Fanny Duval, Loïc Danjoux, Christopher Hug, Robert D. Henderson, Robert Neel, Luca Solera, Aleksandra Nadaj-Pakleza, Silvia Boschi, Nizar Chahin, Maurizio Gualtiero Moggio, Peter Young, Priya S. Kishnani, Yin-Hsiu Chien, Alexandra Kautzky-Willer, Claire Questienne, Francoise Bouhour, Gabriela A Niizawa, Ekaterina Fedotova, Tiziana Enrica Mongini, Harmke A. van Kooten, Vera Malinova, Sina Helms, Shahram Attarian, Patrick Deegan, Guilhem Sole, Hamilton Cirne, Ludwig Gutmann, Kenneth I. Berger, Laura Carrera Garcia, N A M E van der Beek, Stephanie Dearmey, Suzara Souto Lopes, Anna Potulska-Chromik, Joao Lindolfo Borges, Yesim Parman, Michaela Riedl, Sergey A. Klyushnikov, Olivier Huynh-Ba, Gauthier Remiche, Paula R. Clemens, Andrea Swenson, Stephan Wenninger, Miriam Hufgard-Leitner, Eugen Mengel, Kristina An Haack, Eve Gandolfo, David Reyes-Leiva, Jean-Baptiste Davion, Chester Whitley, Young Chul Choi, Patricia Altemus, Maria Judit Molnar, Perry B. Shieh, Matthias Vorgerd, Julia B Hennermann, Cheryl Smith, Volker Straub, Lauren Noll, Pascal Laforet, Andres Nascimento Osorio, Clarisa Maxit, Anne-Catherine Aubé-Nathier, Ozlem Goker-Alpan, Olimpia Musumeci, Louisa Müller-Miny, Tarekegn Hiwot, Jacqui Langton, Christopher Nance, Daniel Natera-de Benito, Jeffrey Statland, Nicola Longo, Vivien Pautot, Zoltan Grosz, Thomas Stulnig, Matthias Boentert, Anne-Katrin Guettsches, Chong Yew Tan, Erik Ortega, Derralynn Hughes, Hacer Durmus Tekce, Mark Roberts, Lenka Linková, Amel Karaa, Hani Kushlaf, Anthony Behin, Margarida Ramos Lopes, Jordi Diaz-Manera, Alessia Pugliese, Paulo Victor Sgobbi Souza, Carrie Bailey, Jennifer B Avelar, Hirofumi Komaki, Frederic Taithe, Benedikt Schoser, Sabine Specht, Kathryn E Brown, Gerson Carvalho, and Pediatrics
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medicine.medical_specialty ,Population ,Walking ,FEV1/FVC ratio ,stomatognathic system ,SDG 3 - Good Health and Well-being ,Double-Blind Method ,Internal medicine ,Statistical significance ,Child, Preschool ,Enzyme Replacement Therapy ,Humans ,Treatment Outcome ,Glycogen Storage Disease Type II ,alpha-Glucosidases ,medicine ,Respiratory function ,Adverse effect ,education ,Child ,Preschool ,Alglucosidase alfa ,education.field_of_study ,business.industry ,Standard treatment ,virus diseases ,Enzyme replacement therapy ,Neurology (clinical) ,business ,medicine.drug - Abstract
Summary Background Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease. Methods We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov , NCT02782741 . We report results of the 49-week primary analysis period. Findings Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI −0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]). Interpretation We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease. Funding Sanofi Genzyme.
- Published
- 2021
34. Gaucher disease type 1 patients from the ICGG Gaucher Registry sustain initial clinical improvements during twenty years of imiglucerase treatment
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Joel Charrow, José Simon Camelo, Pramod K. Mistry, Monica R. McClain, Nadia Belmatoug, and Neal J. Weinreb
- Subjects
0301 basic medicine ,Adult ,Male ,BAÇO ,medicine.medical_specialty ,Imiglucerase ,Adolescent ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Splenectomy ,Population ,030105 genetics & heredity ,Overweight ,Biochemistry ,Gastroenterology ,Body Mass Index ,03 medical and health sciences ,Hemoglobins ,Young Adult ,0302 clinical medicine ,Endocrinology ,Alglucerase ,Internal medicine ,Genetics ,Medicine ,Humans ,Enzyme Replacement Therapy ,Registries ,Bone pain ,education ,Child ,Molecular Biology ,education.field_of_study ,Gaucher Disease ,business.industry ,Platelet Count ,Infant ,Enzyme replacement therapy ,Middle Aged ,Child, Preschool ,Glucosylceramidase ,Female ,medicine.symptom ,business ,Body mass index ,030217 neurology & neurosurgery ,Spleen ,medicine.drug - Abstract
Background Alglucerase enzyme replacement therapy was approved for Gaucher disease (GD) in the United States in 1991; imiglucerase in 1994. We report hematologic, visceral, bone pain, bone crisis, height, weight, and Body Mass Index (BMI) outcomes in patients treated for 20 (±3) years with subset analyses based on pre-treatment severity, genotype, and age at treatment initiation. Methods GD type 1 (GD1) patients in the ICGG Gaucher Registry with complete sets of baseline, 10-year, and 20-year data are included (N = 475). Ten-year and 20-year data are compared to pre-treatment baseline, stratified by splenectomy status. Results Non-splenectomized patients: Improvements observed at 10 years were maintained at 20 years for most outcomes. Mean changes from baseline at 10 and 20 years, respectively, were: spleen volume: 18.2 multiples of normal (MN) to 5.1 MN and 4.2 MN; liver volume: 1.8 MN to 1.0 MN and 1.0 MN; hemoglobin: 11.4 g/dL to 13.7 g/dL and 13.8 g/dL; platelet count: 91.6 × 109/L to 168.0 × 109/L and 169.1 × 109/L; without bone crisis: 85.0% to 98.2% and 96.5%; without bone pain: 52.5% to 72.0% at 10 years, no significant change at 20 years (58.5%). Splenectomized patients: significant changes were observed in liver volume: 2.3 MN to 1.1 MN and 1.0 MN; hemoglobin: 11.7 g/dL to 13.3 g/dL and 13.4 g/dL; platelet count: 229.1 × 109/L to 288.1 × 109/L and 257.0 × 109/L; without bone crisis: 52.2% to 91.3% and 100%; without bone pain: 16.3% to 30.6% (not significant) and 46.9%. Similar results were found in each of the subset analyses. Patients who start treatment during childhood have normal weight and height in young adulthood. Many treated adult patients are overweight or obese; however, this is consistent with BMI trends observed in the general population. After 1–2 years, the average biweekly imiglucerase dose is ~40 units/kg body weight. Conclusion Imiglucerase is an effective, long-term treatment for GD1. In a long-term observational setting, improvements seen during early treatment years are sustained by continuing treatment for 20 years, except for bone pain in non-splenectomized patients. These results are consistent when analyzed by different patient subsets, including by disease severity.
- Published
- 2020
35. C-Type natriuretic peptide analogue therapy in children with achondroplasia
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Anu Cherukuri, Ming Liang Chan, Alice Huntsman Labed, Kala Jayaram, Kim Hanh Le Quan Sang, Carlos A. Bacino, Joel Charrow, Kevin Larimore, George Jeha, Jonathan Day, Natalie N. Owen, Bret L. Bostwick, Ravi Savarirayan, Valérie Cormier-Daire, Julie Hoover-Fong, Melita Irving, Paul Harmatz, Patricia I. Dickson, and John A. Phillips
- Subjects
musculoskeletal diseases ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,Body height ,medicine.drug_class ,Injections, Subcutaneous ,Growth ,030204 cardiovascular system & hematology ,Short stature ,Achondroplasia ,03 medical and health sciences ,0302 clinical medicine ,Osteogenesis ,Internal medicine ,Natriuretic peptide ,medicine ,Humans ,030212 general & internal medicine ,Growth Charts ,Child ,Endochondral ossification ,Cyclic GMP ,Dose-Response Relationship, Drug ,business.industry ,Genetic disorder ,Natriuretic Peptide, C-Type ,General Medicine ,medicine.disease ,Body Height ,Endocrinology ,C-type natriuretic peptide ,Dysplasia ,Child, Preschool ,Female ,Collagen ,medicine.symptom ,business ,Biomarkers - Abstract
Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification.In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months.During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months.In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).
- Published
- 2020
36. SAT-LB18 A Randomized Controlled Trial of Vosoritide in Children With Achondroplasia
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Klane K. White, Felipe Luna-Gonzáles, Antonio Leiva-Gea, Lynda E. Polgreen, Rosendo Ullot Font, Alice Huntsman-Labed, Donald Basel, Natsuo Yasui, Dania M Porco, Jonathan Day, Elena Fisheleva, Hiroshi Mochizuki, Melita Irving, Paul Harmatz, Keiichi Ozono, Daniel Hoernschmeyer, Yasemin Alanay, Julie Hoover-Fong, Joel Charrow, Kala Jayaram, Howard M. Saal, Frank Rutsch, Carlos A. Bacino, Klaus Mohnike, Ignacio Ginebreda, Paul Arundel, William R. Wilcox, Michael B. Bober, Ravi Savarirayan, Louise Tofts, and Shoji Kagami
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.disease ,law.invention ,Randomized controlled trial ,Pediatric Endocrinology ,law ,medicine ,Pediatric Growth and Adrenal Disorders ,Achondroplasia ,business ,AcademicSubjects/MED00250 ,Vosoritide - Abstract
Background: Achondroplasia is a disorder caused by specific mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) protein. Open-label, phase 2 trials in children with achondroplasia showed that administration of vosoritide, an analogue of C-natriuretic peptide, resulted in sustained increases in annualized growth velocity. Methods: This international, randomized, double-blind, phase 3 trial compared once-daily subcutaneous administration of vosoritide, at a dose of 15 μg per kg of body weight, with placebo in children with achondroplasia aged 5 to
- Published
- 2020
37. Neurofibromatosis Type 1-Associated Optic Pathway Glioma in Children: A Follow-Up of 10 Years or More
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Sharon Armarnik, Janice Lasky Zeid, Michael Kinori, Joel Charrow, and Robert Listernick
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Male ,Optic Nerve Glioma ,medicine.medical_specialty ,Visual acuity ,Neurofibromatosis 1 ,genetic structures ,Adolescent ,Optic Disk ,Vision Disorders ,Visual Acuity ,Antineoplastic Agents ,Ophthalmologic Surgical Procedures ,Asymptomatic ,Pallor ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Ophthalmology ,medicine ,Humans ,Neurofibromatosis ,Child ,030304 developmental biology ,Retrospective Studies ,0303 health sciences ,business.industry ,Optic Nerve Neoplasms ,Retrospective cohort study ,medicine.disease ,Combined Modality Therapy ,eye diseases ,Optic Chiasm ,Cohort ,030221 ophthalmology & optometry ,Optic nerve ,Female ,sense organs ,medicine.symptom ,Presentation (obstetrics) ,business ,Follow-Up Studies - Abstract
Purpose This study reports on neurofibromatosis type 1 (NF1)-associated optic pathway gliomas (OPGs) and a follow-up period of at least 10 years in a cohort of children. OPGs are a common manifestation of NF1 and can cause significant visual morbidity. Long-term follow-up in children with NF1-associated OPGs has not been reported previously. Design Retrospective observational case series. Methods This study included children with a documented follow-up of at least 10 years. Three final outcomes were evaluated: visual acuity (VA) per eye (i.e., in the more severely affected eye), VA per patient (i.e., VA when both eyes were open), and the presence of optic nerve head pallor. Results A total of 45 children were included, followed for a mean of 14 years (range, 10-21 years). At the end of follow-up, abnormal VA (considered moderate to severe impairment) in the more severely affected eye was present in 36% of the patients and in both eyes in 11%. Optic nerve head pallor of 1 or both nerves was present in 62%. In multivariate analysis, only initial VA and optic nerve head appearance at presentation were found to predict the final outcomes. All patients, except for 1, were asymptomatic at presentation and had normal VA and nerves that appeared normal, preserved their good vision in both eyes. Only 1 patient, who had normal VA and normal appearing nerves at presentation, had moderate to severe VA loss at long term follow-up. Conclusions In this study, children with NF1-associated OPG whose examination signs and symptoms were normal had a normal initial examination and excellent long-term visual and anatomical outcomes. VA and the appearance of the optic nerve head at presentation predict long-term outcome.
- Published
- 2020
38. Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants
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Pamela Smith, Rong Shao, Khaja Basheeruddin, Heather Shryock, Daniel Groepper, Joel Charrow, Lauren Hitchins, Barbara K. Burton, Katherine M. Christensen, George E. Hoganson, Stephen R. Braddock, Rachel Hickey, Dorothy K. Grange, and Julie Fleischer
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Newborn screening ,business.industry ,newborn screening ,lcsh:RJ1-570 ,Obstetrics and Gynecology ,pompe disease ,lcsh:Pediatrics ,Disease ,030105 genetics & heredity ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,Pediatrics, Perinatology and Child Health ,Pseudodeficiency alleles ,Medicine ,business ,030217 neurology & neurosurgery - Abstract
Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing.
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- 2020
39. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial
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Melita Irving, Klane K. White, Louise Tofts, Yasemin Alanay, Joel Charrow, Felipe Luna-González, William R. Wilcox, Frank Rutsch, Alice Huntsman-Labed, Paul Arundel, Dania M Porco, Lynda E. Polgreen, Michael B. Bober, Howard M. Saal, Daniel Hoernschemeyer, Carlos A. Bacino, Donald Basel, Elena Fisheleva, Shoji Kagami, Paul Harmatz, Jonathan Day, Klaus Mohnike, Rosendo Ullot Font, Keiichi Ozono, Julie Hoover-Fong, Kala Jayaram, Ignacio Ginebreda, Ravi Savarirayan, Hiroshi Mochizuki, Antonio Leiva-Gea, and Natsuo Yasui
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Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Injections, Subcutaneous ,030204 cardiovascular system & hematology ,Placebo ,Achondroplasia ,Growth velocity ,Double blind ,03 medical and health sciences ,0302 clinical medicine ,Absorptiometry, Photon ,Double-Blind Method ,Bone Density ,Osteogenesis ,Clinical endpoint ,medicine ,Humans ,030212 general & internal medicine ,Child ,Vosoritide ,business.industry ,Natriuretic Peptide, C-Type ,General Medicine ,medicine.disease ,Body Height ,Injection Site Reaction ,Child, Preschool ,Ambulatory ,Female ,Once daily ,business ,Biomarkers ,Collagen Type X - Abstract
BACKGROUND: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. METHODS: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 µg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. FINDINGS: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p
- Published
- 2020
40. Schaaf-Yang syndrome overview: Report of 78 individuals
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Christian P. Schaaf, Erin Kovar, Daryl A. Scott, John J. McCarthy, Bret L. Bostwick, Yves Lacassie, Joel Charrow, Tony Roscioli, Robert Smiegel, Philip J. Lupo, Megan E. Rech, Katerina Kraft, Edward J. Lose, and Samantha A. Schrier Vergano
- Subjects
Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Genetic counseling ,autism spectrum disorder ,Frameshift mutation ,MAGEL2 ,Young Adult ,03 medical and health sciences ,Neurodevelopmental disorder ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Allele ,Child ,Frameshift Mutation ,genotype–phenotype association ,Genetic Association Studies ,Research Articles ,Genetics (clinical) ,neurodevelopment ,business.industry ,Genetic disorder ,Infant ,Proteins ,Syndrome ,Schaaf‐Yang syndrome ,medicine.disease ,Phenotype ,030104 developmental biology ,Codon, Nonsense ,Neurodevelopmental Disorders ,Autism spectrum disorder ,Child, Preschool ,Cohort ,Female ,business ,Research Article - Abstract
Schaaf‐Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader‐Willi critical region 15q11‐15q13. SYS is a neurodevelopmental disorder that has clinical overlap with Prader‐Willi Syndrome in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence. Here, we describe the phenotype of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2. This cohort includes 43 individuals that have been reported previously, as well as 35 newly identified individuals with confirmed pathogenic genetic variants. We emphasize that intellectual disability/developmental delay, autism spectrum disorder, neonatal hypotonia, infantile feeding problems, and distal joint contractures are the most consistently shared features of patients with SYS. Our results also indicate that there is a marked prevalence of infantile respiratory distress, gastroesophageal reflux, chronic constipation, skeletal abnormalities, sleep apnea, and temperature instability. While there are many shared features, patients with SYS are characterized by a wide phenotypic spectrum, including a variable degree of intellectual disability, language development, and motor milestones. Our results indicate that the variation in phenotypic severity may depend on the specific location of the truncating mutation, suggestive of a genotype–phenotype association. This evidence may be useful in both prenatal and pediatric genetic counseling.
- Published
- 2018
41. Lifespan Development: Symptoms Experienced by Individuals with Neurofibromatosis Type 1 Associated Plexiform Neurofibromas from Childhood into Adulthood
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Sally E. Jensen, Jin Shei Lai, Joel Charrow, Robert Listernick, and Zabin S. Patel
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Adult ,Male ,Parents ,Neurofibromatosis 1 ,Adolescent ,Interviews as Topic ,Young Adult ,Age Distribution ,medicine ,Humans ,Neurofibromatosis ,Child ,Aged ,Social functioning ,Neurofibroma, Plexiform ,business.industry ,Chronic pain ,Erikson's stages of psychosocial development ,Secondary data ,Middle Aged ,medicine.disease ,Clinical Psychology ,Health psychology ,Family planning ,Child, Preschool ,Developmental Milestone ,Disease Progression ,Female ,Chronic Pain ,business ,Clinical psychology - Abstract
This secondary data analysis qualitatively identified salient concerns reported by individuals with Neurofibromatosis Type 1 (NF1)-associated plexiform neurofibromas (pNFs) at different stages of development. Past literature has focused on overall symptomatology, but has not examined nuances in how these symptoms are experienced across developmental phases. Therefore, we aimed to identify commonalities and differences in symptom experiences across age groups to better assist individuals to adjust to symptoms across the lifespan. Thirty-one children, adolescents, and adults (age ≥ 5 years old) and 15 parents participated in semi-structured interviews. Analyses focused on the following symptom categories: pain, social functioning, physical function impact, and stigma. Aspects of pain endorsed by all age groups included localized brief pain on contact with pNF and abnormal sensations; however, only adolescents and adults reported chronic pain and change in pain over time. Social functioning themes of limited activity participation, role limitations, and relationship impact were endorsed by all age groups, but differences emerged across age groups in the types of activity and role limitations, the type of relationship impact, and family planning concerns. All age groups described difficulty with mobility, but only parents reported problems with coordination and physical developmental milestones. While all age groups reported external stigma, internalized stigma was predominately endorsed by adults. While individuals in all age groups described pNF concerns related to pain, social function, physical function, and stigma, specific aspects of these symptoms differed across the developmental continuum. These findings can help assist individuals with pNF better transition to the next developmental phases.
- Published
- 2018
42. Newborn Screening for Lysosomal Storage Disorders in Illinois: The Initial 15-Month Experience
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Joel Charrow, Dorothy K. Grange, Rong Shao, Stephen R. Braddock, George Dizikes, Claudia Nash, Rebecca Barnett, Barbara K. Burton, Heather Shryock, George E. Hoganson, Brad T. Tinkle, Darrell J. Waggoner, Michael Schneider, and Khaja Basheeruddin
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Genotype ,Mucopolysaccharidosis ,Late onset ,Disease ,030105 genetics & heredity ,03 medical and health sciences ,Neonatal Screening ,Tandem Mass Spectrometry ,medicine ,Humans ,Newborn screening ,business.industry ,Incidence ,Incidence (epidemiology) ,Infant, Newborn ,Infant ,medicine.disease ,Fabry disease ,Dried blood spot ,Lysosomal Storage Diseases ,Pediatrics, Perinatology and Child Health ,Cohort ,Dried Blood Spot Testing ,Illinois ,business - Abstract
Objectives To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois. Study design Tandem mass spectrometry was used to assay for the 5 LSD-associated enzymes in dried blood spot specimens obtained from 219 973 newborn samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. Results The total number of cases with a positive diagnosis and the incidence for each disorder were as follows: Fabry disease, n = 26 (1 in 8454, including the p.A143T variant); Pompe disease, n = 10 (1 in 21 979); Gaucher disease, n = 5 (1 in 43 959); mucopolysaccharidosis (MPS) type 1, n = 1 (1 in 219 793); and Niemann-Pick disease type A/B, n = 2 (1 in 109 897). Twenty-two infants had a positive screen for 1 of the 5 disorders but could not be classified as either affected or unaffected after follow-up testing, including genotyping. Pseudodeficiencies for alpha-L-iduronidase and alpha-glucosidase were detected more often than true deficiencies. Conclusions The incidences of Fabry disease and Pompe disease were significantly higher than published estimates, although most cases detected were predicted to be late onset. The incidences of Gaucher disease, MPS I, and Niemann-Pick disease were comparable with previously published estimates. A total of 16 infants could not be positively identified as either affected or unaffected. To validate the true risks and benefits of newborn screening for LSD, long term follow-up in these infants and those detected with later-onset disorders will be essential.
- Published
- 2017
43. Newborn screening for mucopolysaccharidosis type II: a single center’s experience
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Barbara K. Burton, Rachel Hickey, Andrea Paras, Allegra M. Quadri, Joshua Baker, Joel Charrow, and Katherine H. Kim
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Newborn screening ,Pediatrics ,medicine.medical_specialty ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,Medicine ,Mucopolysaccharidosis type II ,business ,Single Center ,Molecular Biology ,Biochemistry - Published
- 2021
44. Transformation in pretreatment manifestations of Gaucher disease type 1 during two decades of alglucerase/imiglucerase enzyme replacement therapy in the International Collaborative Gaucher Group (ICGG) Gaucher Registry
- Author
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Joel Charrow, Manisha Balwani, Hans C. Andersson, Thomas A. Burrow, Barry E. Rosenbloom, Neal J. Weinreb, Edwin H. Kolodny, Aneal Khan, Priya S. Kishnani, Julie L. Batista, C. Ronald Scott, Pramod K. Mistry, and Paige Kaplan
- Subjects
Adult ,Male ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Imiglucerase ,medicine.medical_treatment ,Splenectomy ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Alglucerase ,Prevalence ,medicine ,Humans ,Enzyme Replacement Therapy ,Registries ,Research Articles ,Gaucher Disease ,business.industry ,nutritional and metabolic diseases ,Hematology ,Enzyme replacement therapy ,Middle Aged ,Glucosylceramidase ,Surgery ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Lower prevalence ,Female ,business ,Follow-Up Studies ,Research Article ,medicine.drug - Abstract
This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/imiglucerase‐treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (
- Published
- 2017
45. Home infusion of intravenous velaglucerase alfa: Experience from pooled clinical studies in 104 patients with type 1 Gaucher disease
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T. Andrew Burrow, Deborah Elstein, Joel Charrow, Atul Mehta, Hak Myung Lee, Gregory M. Pastores, Björn Mellgard, Pilar Giraldo, and Ari Zimran
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Male ,medicine.medical_specialty ,Pediatrics ,Home therapy ,Endocrinology, Diabetes and Metabolism ,Biochemistry ,Malaise ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Genetics ,Humans ,Medicine ,Enzyme Replacement Therapy ,In patient ,Prospective Studies ,Infusions, Intravenous ,Adverse effect ,Molecular Biology ,Gaucher Disease ,business.industry ,Velaglucerase alfa ,Type 1 Gaucher Disease ,Enzyme replacement therapy ,Surgery ,Clinical trial ,Treatment Outcome ,030220 oncology & carcinogenesis ,Glucosylceramidase ,Female ,medicine.symptom ,business ,030215 immunology ,medicine.drug - Abstract
The introduction of a home therapy option during clinical trials of velaglucerase alfa in patients with type 1 Gaucher disease marked the first time that home infusions have been permitted during a clinical trial for an investigational drug for Gaucher disease. Home infusions were an available option in 4 open-label velaglucerase alfa clinical studies to eligible patients who received their initial infusions at a clinic. Patients who participated in the home therapy option and received at least 10% of their infusions at home (n=100) received a range of 11.6%-100% of their scheduled infusions at home (median 87.5%), excluding infusions received at the clinic during protocol-mandated visits. The length of time over which individual patients received home therapy ranged from 13days to 4.56years (median 0.57years). During the time that home therapy was available, 2904 of 3572 (81.3%) infusions were administered at home. Ten patients experienced 62 infusion-related adverse events (IRAEs) during 38 home infusions, with malaise, pain, hypertension, fatigue, and headache being reported most frequently. No notable differences were found between the type and severity of IRAEs experienced at home and those experienced at the clinic. Home infusions administered by trained and qualified medical personnel were successfully introduced into the velaglucerase alfa clinical development program, and fewer than 10% of patients experienced IRAEs in the home setting. Local labeling and practice guidelines should be consulted for administration of velaglucerase alfa infusions at home.
- Published
- 2017
46. Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders
- Author
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Raymond Y. Wang, Elizabeth McCracken, George A. Diaz, J. Starr, Jaya Ganesh, Jose E. Abdenur, Joan Sanchez-de-Toledo, Gregory M. Enns, R. Conway, M. Eswara, Jerry Vockley, Deborah Marsden, and Joel Charrow
- Subjects
Male ,0301 basic medicine ,Resuscitation ,Endocrinology, Diabetes and Metabolism ,Metabolic disorders ,Cardiomyopathy ,Cardiovascular ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,Child ,Fatty acid oxidation disorders ,Pediatric ,Genetics & Heredity ,Clinical Trials as Topic ,Ejection fraction ,Inborn Errors ,Standard treatment ,Fatty Acids ,Triheptanoin ,Heart Disease ,Tolerability ,Child, Preschool ,Cardiology ,Female ,Cardiomyopathies ,Oxidation-Reduction ,medicine.medical_specialty ,Adolescent ,Clinical Sciences ,Article ,Lipid Metabolism, Inborn Errors ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,Genetics ,Humans ,Preschool ,Adverse effect ,Molecular Biology ,Triglycerides ,business.industry ,Infant, Newborn ,Infant ,Lipid Metabolism ,Newborn ,medicine.disease ,Surgery ,030104 developmental biology ,chemistry ,Heart failure ,Energy Metabolism ,business - Abstract
Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy were treated with triheptanoin under emergency treatment or compassionate use protocols. Case reports from 10 patients (8 infants) with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride (MCT) oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support (ventilation, ECMO, vasopressors) and, in some cases, resuscitation. The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction (EF) was assessed. EF was moderately to severely impaired prior to triheptanoin treatment, ranging from 12–45%. Improvements in EF began between 2 and 21 days following initiation of triheptanoin, and peaked at 33–71%, with 9 of 10 patients achieving EF in the normal range. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy. The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Two of the case histories illustrate that cardiomyopathy may also develop later in childhood and/or persist into adulthood. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD.
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- 2016
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47. Variants in the degron ofAFF3cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy
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David Kronn, Akemi J. Tanaka, Stefan Mundlos, Jennifer Norman, Crystle Lee, Delphine Héron, Elena L. Dadali, Anna Mikhaleva, Tomoko Uehara, Alexander Lavrov, Kenjiro Kosaki, Cecilie F. Rustad, Victoria R. Sanders, Heidi Taska-Tench, Ganka Douglas, Boris Keren, Nicolas Chatron, Ennio Del Giudice, E. Martina Bebin, Julien Delafontaine, Wendy K. Chung, Susan M. Hiatt, Olga Levchenko, Nicolas Guex, Jane Juusola, Tara Funari, Rhonda E. Schnur, Caroline Nava, Giuliana Giannuzzi, Binnaz Yalcin, Gregory M. Cooper, Dawn L. Earl, Sofia Douzgou, Kristian Tveten, Anna C.E. Hurst, Gerarda Cappuccio, Joel Charrow, Sinje Geuer, Alexandre Reymond, David J. Amor, Elin Tønne, Norine Voisin, Natasha J Brown, Alfredo Brusco, Dian Donnai, Giuseppina Vitiello, Sylvain Pradervand, Nicola Brunetti-Pierri, Else Merckoll, Fabio Sirchia, Toshiki Takenouchi, and Øystein L. Holla
- Subjects
Genetics ,Hypertrichosis ,0303 health sciences ,Mesomelic Dysplasia ,Horseshoe kidney ,Biology ,biology.organism_classification ,medicine.disease ,Phenotype ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Missense mutation ,Degron ,Zebrafish ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
The ALF transcription factor paralogs,AFF1, AFF2, AFF3andAFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe a new autosomal dominant disorder associated withde novomissense variants in the degron of AFF3, a nine amino acid sequence important for its degradation. Consistent with a causative role ofAFF3variants, the mutated AFF3 proteins show reduced clearance. Ten affected individuals were identified, and present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoeKIdney, NS forNievergelt/Savarirayan type of mesomelic dysplasia, S forSeizures, H forHypertrichosis, I forIntellectual disability and P forPulmonary involvement), partially overlapping theAFF4associated CHOPS syndrome. An eleventh individual with a microdeletion encompassing only the transactivation domain and degron motif ofAFF3exhibited overlapping clinical features. A zebrafish overexpression model that shows body axis anomalies provides further support for the pathological effect of increased amount of AFF3 protein.Whereas homozygousAff3knockout mice display skeletal anomalies, kidney defects, brain malformation and neurological anomalies, knock-in animals modeling the microdeletion and the missense variants identified in affected individuals presented with lower mesomelic limb deformities and early lethality, respectively.Transcriptome analyses as well as the partial phenotypic overlap of syndromes associated withAFF3andAFF4variants suggest that ALF transcription factors are not redundant in contrast to what was previously suggested
- Published
- 2019
48. Addendum to Letter to the Editor: Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1
- Author
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Marta Dragosky, Milan Petakov, Joel Charrow, Barry E. Rosenbloom, Ana Maria Martins, Sebastiaan J.M. Gaemers, Timothy M. Cox, Hadhami Ben Turkia, Hanna Rosenbaum, Priya S. Kishnani, Guillermo Drelichman, M. Judith Peterschmitt, T. Andrew Burrow, Amal El-Beshlawy, Evgueniy Hadjiev, Sumita Danda, Pramod K. Mistry, Cristina Fraga, Lisa H. Underhill, Manisha Balwani, Gregory M. Pastores, Selena Freisens, Hagit N. Baris, Elena Lukina, Pierre Maison-Blanche, and Gerald F. Cox
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Pediatrics ,medicine.medical_specialty ,Letter to the editor ,Pyrrolidines ,Treatment outcome ,MEDLINE ,Disease ,03 medical and health sciences ,0302 clinical medicine ,First line therapy ,Medicine ,Humans ,Enzyme Inhibitors ,Molecular Biology ,0303 health sciences ,Gaucher Disease ,business.industry ,030305 genetics & heredity ,Authorization ,Addendum ,Cell Biology ,Hematology ,Treatment Outcome ,Molecular Medicine ,business ,030217 neurology & neurosurgery ,Eliglustat - Published
- 2019
49. Vosoritide for children with achondroplasia: a 60-month update from an ongoing phase 2 clinical trial
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Melita Irving, Valérie Cormier-Daire, Paul Harmatz, Patricia I. Dickson, Elena Fisheleva, Joel Charrow, Julie Hoover-Fong, John D. Phillips, Kala Jayaram, Alice Huntsman Labed, Ravi Savarirayan, Jonathan Day, Lynda E. Polgreen, George Jeha, Carlos A. Bacino, and Kevin Larimore
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Phases of clinical research ,medicine.disease ,Biochemistry ,Endocrinology ,Genetics ,medicine ,Achondroplasia ,business ,Molecular Biology ,Vosoritide - Published
- 2021
50. Population-based newborn screening for mucopolysaccharidosis type II: A single center's experience
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Andrea Paras, Barbara K. Burton, Allegra M. Quadri, Rachel Hickey, Katherine H. Kim, Joel Charrow, and Joshua Baker
- Subjects
Newborn screening ,Pediatrics ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Population based ,Single Center ,Biochemistry ,Endocrinology ,Genetics ,medicine ,Mucopolysaccharidosis type II ,business ,Molecular Biology - Published
- 2021
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