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1. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Author

Mew, Nicholas Ah, Seminara, Jennifer, Burrage, Lindsay C., Berry, Gerard T., Breilyn, Margo, Schulze, Andreas, Harding, Cary O., Berry, Susan A., Wong, Derek, McCandless, Shawn E., Baumgartner, Matthias R., Konczal, Laura, Ficicioglu, Can, Diaz, George A., Coughlin, Curtis R., 2nd, Enns, Gregory M., Gallagher, Renata C., Lam, Christina, Stricker, Tamar, Wilkening, Greta, Dionisi-Vici, Carlo, Dobbelaere, Dries, Blasco-Alonso, Javier, Burlina, Alberto B., Freisinger, Peter, van Hasselt, Peter M., Skouma, Anastasia, Lund, Allan M., Vara, Roshni, Sarajlija, Adrijan, Morris, Andrew A., Chakrapani, Anupam, Barić, Ivo, Augoustides-Savvopoulou, Persephone, Chien, Yin-Hsiu, Cortès-Saladelafont, Elisenda, Eyskens, Francois, Gramer, Gwendolyn, Zeman, Jiri, Karall, Daniela, Couce, Maria L., Mühlhausen, Chris, Pedrón-Giner, Consuelo, Spiekerkoetter, Ute, Sykut-Cegielska, Jolanta, Wagenmakers, Margreet, Wijburg, Frits A., Posset, Roland, Garbade, Sven F., Gleich, Florian, Scharre, Svenja, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C.S., Druck, Ann-Catrin, Epp, Friederike, Hoffmann, Georg F., Kölker, Stefan, and Zielonka, Matthias

Published
2024
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4. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders—A successful strategy for clinical research of rare diseases

Author

Posset, Roland, Garbade, Sven F, Boy, Nikolas, Burlina, Alberto B, Dionisi‐Vici, Carlo, Dobbelaere, Dries, Garcia‐Cazorla, Angeles, de Lonlay, Pascale, Teles, Elisa Leão, Vara, Roshni, Mew, Nicholas Ah, Batshaw, Mark L, Baumgartner, Matthias R, McCandless, Shawn E, Seminara, Jennifer, Summar, Marshall, Hoffmann, Georg F, Kölker, Stefan, Burgard, Peter, Berry, Susan A, Burrage, Lindsay, Coughlin, Curtis, Diaz, George A, Gallagher, Renata C, Gropman, Andrea, Harding, Cary O, Lee, Brendan, Le Mons, Cynthia, Lawrence Merritt, J, Nagamani, Sandesh CS, Schulze, Andreas, Stricker, Tamar, Tuchman, Mendel, Waisbren, Susan, WeisfeldAdams, James, Wong, Derek, Yudkoff, Marc, Arnoux, JeanBaptiste, Barić, Ivo, Bosch, Annet M, Chabrol, Brigitte, Chakrapani, Anupam, CortèsSaladefont, Elisenda, Couce, Maria L, Eyskens, Francois, Laet, Corine, Meirleir, Linda, Freisinger, Peter, Gleich, Florian, Grünewald, Stephanie, Häberle, Johannes, Hwu, WuhLiang, Jalan, Anil, Karall, Daniela, Lindner, Martin, Lund, Allan M, Martinelli, Diego, Murphy, Elaine, Mühlhausen, Chris, Olivieri, Giorgia, Ottolenghi, Chris, Rodrigues, Esmeralda, Rubert, Laura, Sarajlija, Adrijan, Schiff, Manuel, Sokal, Etienne, SykutCegielska, Jolanta, Walter, John H, Williams, Monique, and Zeman, Jiri

Subjects
Clinical Research, Pediatric, Digestive Diseases, Neurodegenerative, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Cohort Studies, Data Analysis, Delayed Diagnosis, Europe, Female, Humans, Infant, Newborn, Male, Neonatal Screening, North America, Ornithine Carbamoyltransferase Deficiency Disease, Rare Diseases, Urea, Urea Cycle Disorders, Inborn, Urea cycle Disorders, international registry and database, diagnostic methods, Additional individual contributors of the UCDC and the E-IMD consortium, Clinical Sciences, Genetics & Heredity
Abstract

BACKGROUND:To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS:Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS:Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS:The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS:Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.

Published
2019

6. Fabry patient's experience of pegunigalsidase alfa monthly infusion: PEOPLE study

Author

Mehta, Ankit, primary, Eyskens, Francois J., additional, Pisani, Antonio, additional, Feldt-Rasmussen, Ulla, additional, Hughes, Derralynn, additional, Deegan, Patrick B., additional, Goker-Alpan, Ozlem, additional, Wallace, Eric, additional, Bernat, John, additional, Longo, Nicola, additional, Bianchi, Francesco, additional, Rocco, Rossana, additional, and Paleari, Ylenia, additional

Published
2024
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7. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Author

Posset, Roland, Garbade, Sven F., Gleich, Florian, Scharre, Svenja, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C.S., Druck, Ann Catrin, Epp, Friederike, Hoffmann, Georg F., Kölker, Stefan, Zielonka, Matthias, Mew, Nicholas Ah, Seminara, Jennifer, Burrage, Lindsay C., Berry, Gerard T., Breilyn, Margo, Schulze, Andreas, Harding, Cary O., Berry, Susan A., Wong, Derek, McCandless, Shawn E., Baumgartner, Matthias R., Konczal, Laura, Ficicioglu, Can, Diaz, George A., Coughlin, Curtis R., Enns, Gregory M., Gallagher, Renata C., Lam, Christina, Stricker, Tamar, Wilkening, Greta, Dionisi-Vici, Carlo, Dobbelaere, Dries, Blasco-Alonso, Javier, Burlina, Alberto B., Freisinger, Peter, van Hasselt, Peter M., Skouma, Anastasia, Lund, Allan M., Vara, Roshni, Sarajlija, Adrijan, Morris, Andrew A., Chakrapani, Anupam, Barić, Ivo, Augoustides-Savvopoulou, Persephone, Chien, Yin Hsiu, Cortès-Saladelafont, Elisenda, Eyskens, Francois, Wagenmakers, Margreet, Posset, Roland, Garbade, Sven F., Gleich, Florian, Scharre, Svenja, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C.S., Druck, Ann Catrin, Epp, Friederike, Hoffmann, Georg F., Kölker, Stefan, Zielonka, Matthias, Mew, Nicholas Ah, Seminara, Jennifer, Burrage, Lindsay C., Berry, Gerard T., Breilyn, Margo, Schulze, Andreas, Harding, Cary O., Berry, Susan A., Wong, Derek, McCandless, Shawn E., Baumgartner, Matthias R., Konczal, Laura, Ficicioglu, Can, Diaz, George A., Coughlin, Curtis R., Enns, Gregory M., Gallagher, Renata C., Lam, Christina, Stricker, Tamar, Wilkening, Greta, Dionisi-Vici, Carlo, Dobbelaere, Dries, Blasco-Alonso, Javier, Burlina, Alberto B., Freisinger, Peter, van Hasselt, Peter M., Skouma, Anastasia, Lund, Allan M., Vara, Roshni, Sarajlija, Adrijan, Morris, Andrew A., Chakrapani, Anupam, Barić, Ivo, Augoustides-Savvopoulou, Persephone, Chien, Yin Hsiu, Cortès-Saladelafont, Elisenda, Eyskens, Francois, and Wagenmakers, Margreet

Abstract

Purpose: Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed. Methods: We investigated the effects of LTx and MM on validated health-related outcome parameters, including the metabolic disease course, linear growth, and neurocognitive outcomes. Individuals were stratified into “severe” and “attenuated” categories based on the genotype-specific and validated in vitro enzyme activity. Results: LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts as reflected by the frequency of motor abnormality and cognitive standard deviation score at last observation. Conclusion: Whereas LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy and was associated with a more favorable growth outcome, LTx—as currently performed—was not associated with improved neurocognitive outcomes compared with long-term MM in the investigated urea cycle disorders.

Published
2024

8. Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase

Author

Warnock, David G, Bichet, Daniel G, Holida, Myrl, Goker-Alpan, Ozlem, Nicholls, Kathy, Thomas, Mark, Eyskens, Francois, Shankar, Suma, Adera, Mathews, Sitaraman, Sheela, Khanna, Richie, Flanagan, John J, Wustman, Brandon A, Barth, Jay, Barlow, Carrolee, Valenzano, Kenneth J, Lockhart, David J, Boudes, Pol, and Johnson, Franklin K

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Trials and Supportive Activities, Clinical Research, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 1-Deoxynojirimycin, Administration, Oral, Adult, Area Under Curve, Demography, Fabry Disease, Humans, Infusion Pumps, Isoenzymes, Male, Middle Aged, Recombinant Proteins, Skin, alpha-Galactosidase, General Science & Technology
Abstract

UnlabelledMigalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.Trial registrationClinicalTrials.gov NCT01196871.

Published
2015

9. Bone Health in Classic Galactosemia: Systematic Review and Meta-Analysis

Author

van Erven, Britt, Welling, Lindsey, van Calcar, Sandra C., Doulgeraki, Artemis, Eyskens, François, Gribben, Joanna, Treacy, Eileen P., Vos, Rein, Waisbren, Susan E., Rubio-Gozalbo, M. Estela, Bosch, Annet M., Baumgartner, Matthias R., Series editor, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Peters, Verena, Series editor, Morava, Eva, Editor-in-chief, Zschocke, Johannes, Series editor, and Baumgartner, Matthias, editor

Published
2017
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10. Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency

Author

Scharre, Svenja, Posset, Roland, Garbade, Sven F., Gleich, Florian, Seidl, Marie J., Druck, Ann‐Catrin, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C. S., Hoffmann, Georg F., Kölker, Stefan, Zielonka, Matthias, Ah Mew, Nicholas, Baumgartner, Matthias R., Berry, Gerard T., Berry, Susan A., Burrage, Lindsay, Diaz, George A., Ficicioglu, Can, Kisin, Genya, Konczal, Laura, Lam, Christina, McCandless, Shawn E., Merritt, J. Lawrence, Schulze, Andreas, Walter, Magdalena E., Wilson, Ashley, Wong, Derek, Arnaudo, Florence, Augoustides‐ Savvopoulou, Persephone, Barić, Ivo, Bosch, Annet M., Cano, Aline, Chien, Yin‐Hsiu, Dionisi‐Vici, Carlo, Dobbelaere, Dries, Eyskens, Francois, Freisinger, Peter, Garcia‐Cazorla, Angeles, Honzik, Tomas, Karall, Daniela, Lund, Allan M., Murphy, Elaine, Santer, René, Schiff, Manuel, Skouma, Anastasia, Sykut‐Cegielska, Jolanta, Wijburg, Frits A., Zeman, Jiri, for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group, VU University medical center, Paediatric Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and ARD - Amsterdam Reproduction and Development

Subjects
Male, Phenotype, ornithine transcarbamylase deficiency, disease severity, prediction, General Neuroscience, Humans, Hyperammonemia, Neurology (clinical), Severity of Illness Index, Ornithine Carbamoyltransferase Deficiency Disease
Abstract

Objective: Ornithine transcarbamylase deficiency (OTC-D) is an X-linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity-adjusted classification system based on in vitro residual enzymatic OTC activity. Methods: Applying a cell-based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC-D (mOTC-D) as reported in the UCDC and E-IMD registries. Results: Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC-D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Interpretation: Residual enzymatic OTC activity reliably predicts the disease severity in mOTC-D and could thus serve as a tool for severity- adjusted evaluation of therapeutic strategies and counselling patients and parents.

Published
2022
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11. Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients

Author

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

Published
2019
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12. Long-term safety and efficacy of pegunigalsidase alfa administered every 4 weeks in patients with Fabry disease:Two-year interim results from the ongoing phase 3 BRIGHT51 open-label extension study

Author

Bernat, John, Holida, Myrl D., Longo, Nicola, Goker-alpan, Ozlem, Wallace, Eric, Deegan, Patrick B., Tøndel, Camilla, Eyskens, Francois J., Feldt-rasmussen, Ulla, Hughes, Derralynn, Pisani, Antonio, Rocco, Rossana, Almon, Einat Brill, Alon, Sari, Chertkoff, Raul, Warnock, David G., Waldek, Stephen, Wilcox, William R., Bernat, John, Holida, Myrl D., Longo, Nicola, Goker-alpan, Ozlem, Wallace, Eric, Deegan, Patrick B., Tøndel, Camilla, Eyskens, Francois J., Feldt-rasmussen, Ulla, Hughes, Derralynn, Pisani, Antonio, Rocco, Rossana, Almon, Einat Brill, Alon, Sari, Chertkoff, Raul, Warnock, David G., Waldek, Stephen, and Wilcox, William R.

Abstract

Fabry disease (FD) is an inherited disorder caused by alpha-galactosidase-A deficiency leading to accumulation of globotriaosylceramide (Gb3), its metabolite lyso-Gb3, and other sphingolipids, resulting in impaired organ function. Current treatments include enzyme replacement therapies (ERTs) requiring infusions every 2 weeks (Q2W). Pegunigalsidase alfa (PA) is a PEGylated alpha-galactosidase-A enzyme with increased half-life compared with current ERTs, potentially allowing for dosing flexibility (1.0 mg/kg Q2W or 2.0 mg/kg every 4 weeks [Q4W]). BRIGHT51 (PB-102-F51, NCT03614234), an ongoing phase 3, open-label extension, evaluates the safety and efficacy of 2.0 mg/kg PA Q4W in adults with FD up to 4 years. Patients were eligible if they had completed BRIGHT, a 1-year switchover clinical trial for patients who previously received agalsidase alfa or agalsidase beta Q2W. For this interim analysis, safety and efficacy are reported from baseline in BRIGHT to ≥2 years of treatment. 29 adults (23 M:6F; mean age 40.9 years) were enrolled in BRIGHT51, with mean (range) PA exposure of 38.3 (25.3–44.8) person-months. 27/29 patients (93.1%) reported 339 treatment-emergent adverse events (TEAEs); 11/29 patients (37.9%) reported 46 PA-related TEAEs, of which none were serious/severe. 6/29 patients (20.7%, all males) experienced a total of 38 infusion-related reactions, all mild/moderate in intensity. Nine patients had antidrug antibodies (ADAs) at baseline; no de novo ADAs developed following the switch to PA for ≥2 years. At week 108, mean (SE) change from baseline of eGFR was −5.10 (1.96) mL/min/1.73m2; overall, the mean (SE) eGFR slope was −2.77 (0.54) mL/min/1.73m2/year (male: −3.03 [0.61] mL/min/1.73m2/year; female: -1.74 [1.21] mL/min/1.73m2/year). Mean (SE) plasma lyso-Gb3 was stable through week 108 (baseline: 19.36 [3.35] nmol/L; week 108: 22.98 [3.72] nmol/L). PA 2.0 mg/kg Q4W showed no new safety concerns during ≥2 years; additional analyses are needed to further eval

Published
2023

13. Long-term safety and efficacy of pegunigalsidase alfa administered every 4 weeks in patients with Fabry disease: Two-year interim results from the ongoing phase 3 BRIGHT51 open-label extension study

Author

Bernat, John, primary, Holida, Myrl D., additional, Longo, Nicola, additional, Goker-Alpan, Ozlem, additional, Wallace, Eric, additional, Deegan, Patrick B., additional, Tøndel, Camilla, additional, Eyskens, Francois J., additional, Feldt-Rasmussen, Ulla, additional, Hughes, Derralynn, additional, Pisani, Antonio, additional, Rocco, Rossana, additional, Almon, Einat Brill, additional, Alon, Sari, additional, Chertkoff, Raul, additional, Warnock, David G., additional, Waldek, Stephen, additional, and Wilcox, William R., additional

Published
2023
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15. P006: Long-term safety and efficacy of pegunigalsidase alfa administered every 4 weeks in Fabry disease: 2-Year interim results from BRIGHT51

Author

Bernat, John, primary, Holida, Myrl, additional, Longo, Nicola, additional, Goker-Alpan, Ozlem, additional, Wallace, Eric, additional, Deegan, Patrick, additional, Tondel, Camilla, additional, Eyskens, Francois, additional, Feldt-Rasmussen, Ulla, additional, Hughes, Derralynn, additional, Pisani, Antonio, additional, Linhart, Ales, additional, Rocco, Rossana, additional, Almon, Einat, additional, Alon, Sari, additional, Chertkoff, Raul, additional, Warnock, David, additional, Waldek, Stephen, additional, and Wilcox, William, additional

Published
2023
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17. Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young

Author

De Brabander, Isabel, Yperzeele, Laetitia, Ceuterick-De Groote, Chantal, Brouns, Raf, Baker, Robert, Belachew, Shibeshih, Delbecq, Jean, De Keulenaer, Gilles, Dethy, Sophie, Eyskens, François, Fumal, Arnaud, Hemelsoet, Dimitri, Hughes, Derralynn, Jeangette, Sandrine, Nuytten, Dirk, Redondo, Patricia, Sadzot, Bernard, Sindic, Christian, Sheorajpanday, Rishi, Thijs, Vincent, Van Broeckhoven, Christine, and De Deyn, Peter P.

Published
2013
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18. Peroxisome Mosaics

Author

Roels, Frank, Saudubray, Jean-Marie, Giros, Marisa, Mandel, Hanna, Eyskens, FranÇois, Saracibar, Nieves, Pueyo, BegoÑA Atares, Prats, Jose M., Prest, Betty De, Preter, Kathleen De, Pineda, Mercedes, Krystkowiak, Pierre, Gootjes, Jeannette, Wanders, Ronald J.A., Espeel, Marc, Poll-The, Bwee Tien, Roels, Frank, editor, Baes, Myriam, editor, and De Bie, Sylvia, editor

Published
2003
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19. Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway

Author

van Vliet, Kimber, primary, van Ginkel, Willem G., additional, Jahja, Rianne, additional, Daly, Anne, additional, MacDonald, Anita, additional, Santra, Saikat, additional, De Laet, Corinne, additional, Goyens, Philippe J., additional, Vara, Roshni, additional, Rahman, Yusof, additional, Cassiman, David, additional, Eyskens, Francois, additional, Timmer, Corrie, additional, Mumford, Nicky, additional, Gissen, Paul, additional, Bierau, Jörgen, additional, van Hasselt, Peter M., additional, Wilcox, Gisela, additional, Morris, Andrew A. M., additional, Jameson, Elisabeth A., additional, de la Parra, Alicia, additional, Arias, Carolina, additional, Garcia, Maria I., additional, Cornejo, Veronica, additional, Bosch, Annet M., additional, Hollak, Carla E. M., additional, Rubio‐Gozalbo, M. Estela, additional, Brouwers, Martijn C. G. J., additional, Hofstede, Floris C., additional, de Vries, Maaike C., additional, Janssen, Mirian C. H., additional, van der Ploeg, Ans T., additional, Langendonk, Janneke G., additional, Huijbregts, Stephan C. J., additional, and van Spronsen, Francjan J., additional

Published
2022
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20. Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria:A comparison between two genetic disorders affecting the same metabolic pathway

Author

van Vliet, Kimber, van Ginkel, Willem G., Jahja, Rianne, Daly, Anne, MacDonald, Anita, Santra, Saikat, De Laet, Corinne, Goyens, Philippe J., Vara, Roshni, Rahman, Yusof, Cassiman, David, Eyskens, Francois, Timmer, Corrie, Mumford, Nicky, Gissen, Paul, Bierau, Jörgen, van Hasselt, Peter M., Wilcox, Gisela, Morris, Andrew A.M., Jameson, Elisabeth A., de la Parra, Alicia, Arias, Carolina, Garcia, Maria I., Cornejo, Veronica, Bosch, Annet M., Hollak, Carla E.M., Rubio-Gozalbo, M. Estela, Brouwers, Martijn C.G.J., Hofstede, Floris C., de Vries, Maaike C., Janssen, Mirian C.H., van der Ploeg, Ans T., Langendonk, Janneke G., Huijbregts, Stephan C.J., van Spronsen, Francjan J., van Vliet, Kimber, van Ginkel, Willem G., Jahja, Rianne, Daly, Anne, MacDonald, Anita, Santra, Saikat, De Laet, Corinne, Goyens, Philippe J., Vara, Roshni, Rahman, Yusof, Cassiman, David, Eyskens, Francois, Timmer, Corrie, Mumford, Nicky, Gissen, Paul, Bierau, Jörgen, van Hasselt, Peter M., Wilcox, Gisela, Morris, Andrew A.M., Jameson, Elisabeth A., de la Parra, Alicia, Arias, Carolina, Garcia, Maria I., Cornejo, Veronica, Bosch, Annet M., Hollak, Carla E.M., Rubio-Gozalbo, M. Estela, Brouwers, Martijn C.G.J., Hofstede, Floris C., de Vries, Maaike C., Janssen, Mirian C.H., van der Ploeg, Ans T., Langendonk, Janneke G., Huijbregts, Stephan C.J., and van Spronsen, Francjan J.

Abstract

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine–tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal–Wallis tests with post-hoc Mann–Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions “working memory”, “plan and organize” and “monitor”, ASEBA dimensions “social problems” and “attention problems”, and for the SSRS “assertiveness” scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Published
2022

21. Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway

Author

Metabole ziekten patientenzorg, Child Health, Infection & Immunity, Integrale & Alg. Kindergen Patientenzorg, van Vliet, Kimber, van Ginkel, Willem G., Jahja, Rianne, Daly, Anne, MacDonald, Anita, Santra, Saikat, De Laet, Corinne, Goyens, Philippe J., Vara, Roshni, Rahman, Yusof, Cassiman, David, Eyskens, Francois, Timmer, Corrie, Mumford, Nicky, Gissen, Paul, Bierau, Jörgen, van Hasselt, Peter M., Wilcox, Gisela, Morris, Andrew A.M., Jameson, Elisabeth A., de la Parra, Alicia, Arias, Carolina, Garcia, Maria I., Cornejo, Veronica, Bosch, Annet M., Hollak, Carla E.M., Rubio-Gozalbo, M. Estela, Brouwers, Martijn C.G.J., Hofstede, Floris C., de Vries, Maaike C., Janssen, Mirian C.H., van der Ploeg, Ans T., Langendonk, Janneke G., Huijbregts, Stephan C.J., van Spronsen, Francjan J., Metabole ziekten patientenzorg, Child Health, Infection & Immunity, Integrale & Alg. Kindergen Patientenzorg, van Vliet, Kimber, van Ginkel, Willem G., Jahja, Rianne, Daly, Anne, MacDonald, Anita, Santra, Saikat, De Laet, Corinne, Goyens, Philippe J., Vara, Roshni, Rahman, Yusof, Cassiman, David, Eyskens, Francois, Timmer, Corrie, Mumford, Nicky, Gissen, Paul, Bierau, Jörgen, van Hasselt, Peter M., Wilcox, Gisela, Morris, Andrew A.M., Jameson, Elisabeth A., de la Parra, Alicia, Arias, Carolina, Garcia, Maria I., Cornejo, Veronica, Bosch, Annet M., Hollak, Carla E.M., Rubio-Gozalbo, M. Estela, Brouwers, Martijn C.G.J., Hofstede, Floris C., de Vries, Maaike C., Janssen, Mirian C.H., van der Ploeg, Ans T., Langendonk, Janneke G., Huijbregts, Stephan C.J., and van Spronsen, Francjan J.

Published
2022

23. eP149: Safety and efficacy of pegunigalsidase alfa, every 4 weeks, in Fabry disease: Results from the phase 3, open-label, BRIGHT study

Author

Bernat, John, primary, Holida, Myrl, additional, Longo, Nicola, additional, Goker-Alpan, Ozlem, additional, Wallace, Eric, additional, Deegan, Patrick, additional, Nedd, Khan, additional, Tondel, Camilla, additional, Eyskens, Francois, additional, Feldt-Rasmussen, Ulla, additional, Pisani, Antonio, additional, Rocco, Rossana, additional, Almon, Einat, additional, Alon, Sari, additional, Chertkoff, Raul, additional, Warnock, David, additional, Waldek, Stephen, additional, and Wilcox, William, additional

Published
2022
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25. Cystic fibrosis newborn screening (CF-NBS) start-up in Flanders (Belgium): report of first evaluation after 3 years

Author

Proesmans, Marijke, Régal, Luc, Eyskens, Francois, Roosens, L., Marcélis, Lionel, Seneca, Sara, Storm, Katrien, Colaert, Karen, De Wachter, Elke, Growth and Development, Pediatrics, Medical Genetics, Clinical sciences, Reproduction and Genetics, and Physiotherapy, Human Physiology and Anatomy

Abstract

In January 2019, CF-NBS was started in Flanders (Belgium) involving 2 screenings labs using an IRT-DNA algorithm with a limited CFTR mutation panel and an IRT/IRT failsafe. Diagnosis is confirmed by sweat chloride (SCl) and CFTR mutation analysis. Methods: IRT was measured in dried blood spots (DBS) collected 72–96 hours after birth. If IRT was above the P99 cut-off, 12 CFTR mutations were searched for. Screen positive newborns (IRT>P99 and 1 or 2 mutations) were referred to a CF centre for quantitative pilocarpine iontophoresis (QPI). For IRT >P99.9 with negative mutation screening, a failsafe is provided with repeat IRT before day 21 (IRT-D21). For meconium ileus (MI), CF diagnostics are done irrespective of NBS result. CF centres provided feedback to the screening labs after diagnostic assessment. Results: In 2019 and 2020 (analysis of 2021 ongoing), 125,732 newborns were screened (coverage 99.9%). Sixty-eight (0.056%) had raised IRT plus at least 1 mutation. Three babies were screen +ve from the failsafe arm (IRTIRT) and 5 were sent for a QPI after ultra-high IRT, no mutation but missing the repeat IRT-D2. This resulted in 76 referrals for QPI. CF was confirmed in 24/76 babies (23/68 and in 1/5 newborn after the failsafe net without repeat IRT-D21; 43 babies were carriers, 3 were CRMS/CFSPID (CF metabolic syndrome/CF screen positive inconclusive diagnosis), 6 no CF/ no carrier. Median age at initial visit in the CF centre was 20 days and 23 days at diagnosis. CF centres reported no missed cases so far. Only 1 baby with MI had a negative CF-NBS, however this was not considered as false negative as per protocol. Based on these results, sensitivity was 100%, PPV 0.31 (calculated without CFSPID), and CF/CFSPID ratio was 8. Discussion: Performance of the program has been in agreement with ECFS standards. By June 2022, results will be extended to 3 years of screening. Based on current results, the IRT cut-off will be adapted to P99.2 to further improve the PPV.

Published
2022

26. Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients

Author

van Kuilenburg, André B.P., Dobritzsch, Doreen, Meijer, Judith, Meinsma, Rutger, Benoist, Jean-François, Assmann, Birgit, Schubert, Susanne, Hoffmann, Georg F., Duran, Marinus, de Vries, Maaike C., Kurlemann, Gerd, Eyskens, François J.M., Greed, Lawrence, Sass, Jörn Oliver, Schwab, K. Otfried, Sewell, Adrian C., Walter, John, Hahn, Andreas, Zoetekouw, Lida, Ribes, Antonia, Lind, Suzanne, and Hennekam, Raoul C.M.

Published
2010
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27. NBS09 Newborn Screening for X-linked Adrenoleukodystrophy

Author

Orsini, Joseph J., Moser, A., Manning, Adrienne, Brown, Heather A., Eichler, Florian, Eyskens, Francois, Haynes, Christopher A., Kemp, Stephan, Lehtonen, Tero, Oladipo, Olajumoke, Schielen, Peter C., Singh, Rajendra, Taylor, Jennifer, Tortorelli, Silvia, Vogel, Beth, Orsini, Joseph, Laboratory Genetic Metabolic Diseases, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and Amsterdam Gastroenterology Endocrinology Metabolism

Abstract

NBS09 Newborn Screening for X-Linked Adrenoleukodystrophy

Published
2021

33. Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders

Author

Posset, Roland, Gropman, Andrea L., Nagamani, Sandesh C. S., Burrage, Lindsay C., Bedoyan, Jirair K., Wong, Derek, Berry, Gerard T., Baumgartner, Matthias R., Yudkoff, Marc, Zielonka, Matthias, Hoffmann, Georg F., Burgard, Peter, Schulze, Andreas, McCandless, Shawn E., Garcia‐Cazorla, Angeles, Seminara, Jennifer, Garbade, Sven F., Kölker, Stefan, Lee, Brendan, Harding, Cary O., Coughlin, Curtis R., Le Mons, Cynthia, Dobbelaere, Dries, Leão Teles, Elisa, Cortès‐Saladelafont, Elisenda, Gleich, Florian, Eyskens, Francois, Enns, Gregory, Wilkening, Greta N., Barić, Ivo, Lawrence Merritt, J., Heringer, Jana, Blasco‐Alonso, Javier, Zeman, Jiri, Häberle, Johannes, Sykut‐Cegielska, Jolanta, Djordjevic, Maja, Batshaw, Mark L., Summar, Marshall, Freisinger, Peter, Gallagher, Renata C., Berry, Susan A., Waisbren, Susan, Stricker, Tamar, and for the Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group

Subjects
0301 basic medicine, Adult, Glycerol, Male, Pediatrics, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Ornithine transcarbamylase, Liver transplantation, Asymptomatic, Article, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Cognition, Neonatal Screening, Intellectual disability, medicine, urea cycle disorders, diagnosis, therapy, cognitive function, Humans, Prospective Studies, Glycerol phenylbutyrate, Prospective cohort study, Child, Urea Cycle Disorders, Inborn, Newborn screening, business.industry, Infant, Newborn, Infant, medicine.disease, Mental Status and Dementia Tests, Phenylbutyrates, Liver Transplantation, 030104 developmental biology, Cross-Sectional Studies, Neurology, chemistry, Child, Preschool, Female, Neurology (clinical), medicine.symptom, business, Neurocognitive, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

OBJECTIVE Individuals with urea cycle disorders (UCDs) often present with intellectual and developmental disabilities. The major aim of this study was to evaluate the impact of diagnostic and therapeutic interventions on cognitive outcomes in UCDs. METHODS This prospective, observational, multicenter study includes data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow-up of 702 patient-years. RESULTS The mean cognitive standard deviation score (cSDS) was lower in symptomatic than in asymptomatic (p < 0.001, t test) individuals with UCDs. Intellectual disability (intellectual quotient < 70, cSDS < -2.0) was associated with the respective subtype of UCD and early disease onset, whereas height of the initial peak plasma ammonium concentration was inversely associated with neurocognitive outcomes in mitochondrial (proximal) rather than cytosolic (distal) UCDs. In ornithine transcarbamylase and argininosuccinate synthetase 1 deficiencies, we did not find evidence that monoscavenger therapy with sodium or glycerol phenylbutyrate was superior to sodium benzoate in providing cognitive protection. Early liver transplantation appears to be beneficial for UCDs. It is noteworthy that individuals with argininosuccinate synthetase 1 and argininosuccinate lyase deficiencies identified by newborn screening had better neurocognitive outcomes than those diagnosed after the manifestation of first symptoms. INTERPRETATION Cognitive function is related to interventional and non-interventional variables. Early detection by newborn screening and early liver transplantation appear to offer greater cognitive protection, but none of the currently used nitrogen scavengers was superior with regard to long-term neurocognitive outcome. Further confirmation could determine these variables as important clinical indicators of neuroprotection for individuals with UCDs. ANN NEUROL 2019.

Published
2018

34. Dietary practices in methylmalonic acidaemia: a European survey

Author

Pinto, Alex, primary, Evans, Sharon, additional, Daly, Anne, additional, Almeida, Manuela Ferreira, additional, Assoun, Murielle, additional, Belanger-Quintana, Amaya, additional, Bernabei, Silvia Maria, additional, Bollhalder, Sandra, additional, Cassiman, David, additional, Champion, Helena, additional, Chan, Heidi, additional, Corthouts, Karen, additional, Dalmau, Jaime, additional, Boer, Foekje de, additional, Laet, Corinne De, additional, Meyer, An de, additional, Desloovere, An, additional, Dianin, Alice, additional, Dixon, Marjorie, additional, Dokoupil, Katharina, additional, Dubois, Sandrine, additional, Eyskens, Francois, additional, Faria, Ana, additional, Fasan, Ilaria, additional, Favre, Elisabeth, additional, Feillet, François, additional, Fekete, Anna, additional, Gallo, Giorgia, additional, Gingell, Cerys, additional, Gribben, Joanna, additional, Hansen, Kit Kaalund, additional, Horst, Nienke Ter, additional, Jankowski, Camille, additional, Janssen-Regelink, Renske, additional, Jones, Ilana, additional, Jouault, Catherine, additional, Kahrs, Gudrun Elise, additional, Kok, Irene, additional, Kowalik, Agnieszka, additional, Laguerre, Catherine, additional, Verge, Sandrine Le, additional, Liguori, Alessandra, additional, Lilje, Rina, additional, Maddalon, Cornelia, additional, Mayr, Doris, additional, Meyer, Uta, additional, Micciche, Avril, additional, Och, Ulrike, additional, Robert, Martine, additional, Rocha, Júlio César, additional, Rogozinski, Hazel, additional, Rohde, Carmen, additional, Ross, Kathleen, additional, Saruggia, Isabelle, additional, Schlune, Andrea, additional, Singleton, Kath, additional, Sjoqvist, Elisabeth, additional, Skeath, Rachel, additional, Stolen, Linn Helene, additional, Terry, Allyson, additional, Timmer, Corrie, additional, Tomlinson, Lyndsey, additional, Tooke, Alison, additional, Kerckhove, Kristel Vande, additional, van Dam, Esther, additional, Hurk, Dorine van den, additional, Ploeg, Liesbeth van der, additional, van Driessche, Marleen, additional, van Rijn, Margreet, additional, Wegberg, Annemiek van, additional, Vasconcelos, Carla, additional, Vestergaard, Helle, additional, Vitoria, Isidro, additional, Webster, Diana, additional, White, Fiona, additional, White, Lucy, additional, Zweers, Heidi, additional, and MacDonald, Anita, additional

Published
2019
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36. Once every 4 weeks - 2 mg/kg of pegunigalsidase alfa for treating Fabry disease Preliminary results of a phase 3 study

Author

Holida, Myrl D., primary, Bernat, John, additional, Longo, Nicola, additional, Goker-Alpan, Ozlem, additional, Wallace, Eric, additional, Schiffmann, Raphael, additional, Deegan, Patrick, additional, Khan, Nedd, additional, Tøndel, Camilla, additional, Eyskens, Francois, additional, Hughes, Derralynn, additional, West, Michael, additional, Giraldo, Pilar, additional, Ezgu, Fatih, additional, Almon, Einat, additional, Alon, Sari, additional, Amit-Cohen, Bat-chen, additional, Szlaifer, Mali, additional, Chertkoff, Raul, additional, and Wilcox, William, additional

Published
2019
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38. Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients

Author

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

Published
2019

39. Raising Awareness of False Positive Newborn Screening Results Arising from Pivalate-Containing Creams and Antibiotics in Europe When Screening for Isovaleric Acidaemia

Author

Bonham, James, primary, Carling, Rachel, additional, Lindner, Martin, additional, Franzson, Leifur, additional, Zetterstrom, Rolf, additional, Boemer, Francois, additional, Cerone, Roberto, additional, Eyskens, Francois, additional, Vilarinho, Laura, additional, Hougaard, David, additional, and Schielen, Peter, additional

Published
2018
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41. Raising awareness of false positive newborn screening results arising from pivalate-containing creams and antibiotics in Europe when screening for isovaleric acidaemia

Author

Bonham, James R., Carling, Rachel S., Lindner, Martin, Franzson, Leifur, Zetterstrom, Rolf, Boemer, Francois, Cerone, Roberto, Eyskens, Francois, Vilarinho, Laura, Hougaard, David Michael, Schielen, Peter C. J. I., Bonham, James R., Carling, Rachel S., Lindner, Martin, Franzson, Leifur, Zetterstrom, Rolf, Boemer, Francois, Cerone, Roberto, Eyskens, Francois, Vilarinho, Laura, Hougaard, David Michael, and Schielen, Peter C. J. I.

Abstract

While the early and asymptomatic recognition of treatable conditions offered by newborn screening confers clear health benefits for the affected child, the clinical referral of patients with screen positive results can cause significant harm for some families. The use of pivalate-containing antibiotics and more recently the inclusion of neopentanoate as a component within moisturising creams used as nipple balms by nursing mothers can result in a significant number of false positive results when screening for isovaleric acidaemia (IVA) by measuring C5 acylcarnitine. A recent survey conducted within centres from nine countries indicated that this form of contamination had been or was a significant confounding factor in the detection of IVA in seven of the nine who responded. In three of these seven the prominent cause was believed to derive from the use of moisturising creams and in another three from antibiotics containing pivalate; one country reported that the cause was mixed. As a result, four of these seven centres routinely perform second tier testing to resolve C5 isobars when an initial C5 result is elevated, and a fifth is considering making this change within their national programme. The use of creams containing neopentanoate by nursing mothers and evolving patterns in the prescription of pivalate-containing antibiotics during pregnancy require those involved in the design and operation of newborn screening programmes used to detect IVA and the doctors who receive clinical referrals from these programmes to maintain an awareness of the potential impact of this form of interference on patient results.

Published
2018

43. Phase I/II Trial of Liver-derived Mesenchymal Stem Cells in Pediatric Liver-based Metabolic Disorders: A Prospective, Open Label, Multicenter, Partially Randomized, Safety Study of One Cycle of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in Urea Cycle Disorders and Crigler-Najjar Syndrome Patients

Author

Smets, Francoise MD, PhD, Dobbelaere, Dries MD, McKiernan, Patrick MD, Dionisi-Vici, Carlo MD, PhD, Broue, Pierre MD, Jacquemin, Emmanuel MD, PhD, Lopes, Ana Isabel MD, Goncalves, Isabel MD, Mandel, Hanna MD, PhD, Pawlowska, Joanna MD, PhD, Kaminska, Diana MD, PhD, Shteyer, Eyal MD, PhD, Torre, Giuliano MD, Shapiro, Riki MD, Eyskens, Francois MD, PhD, Clapuyt, Philippe MD, Gissen, Paul MD, PhD, Pariente, Daniele MD, PhD, Grunewald, Stephanie MD, PhD, and Yudkoff, Marc MD

Published
2019
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46. Dietary practices in methylmalonic acidaemia: a European survey

Author

Pinto, Alex, Evans, Sharon, Daly, Anne, Almeida, Manuela Ferreira, Assoun, Murielle, Belanger-Quintana, Amaya, Bernabei, Silvia Maria, Bollhalder, Sandra, Cassiman, David, Champion, Helena, Chan, Heidi, Corthouts, Karen, Dalmau, Jaime, Boer, Foekje de, Laet, Corinne De, Meyer, An de, Desloovere, An, Dianin, Alice, Dixon, Marjorie, Dokoupil, Katharina, Dubois, Sandrine, Eyskens, Francois, Faria, Ana, Fasan, Ilaria, Favre, Elisabeth, Feillet, François, Fekete, Anna, Gallo, Giorgia, Gingell, Cerys, Gribben, Joanna, Hansen, Kit Kaalund, Horst, Nienke Ter, Jankowski, Camille, Janssen-Regelink, Renske, Jones, Ilana, Jouault, Catherine, Kahrs, Gudrun Elise, Kok, Irene, Kowalik, Agnieszka, Laguerre, Catherine, Verge, Sandrine Le, Liguori, Alessandra, Lilje, Rina, Maddalon, Cornelia, Mayr, Doris, Meyer, Uta, Micciche, Avril, Och, Ulrike, Robert, Martine, Rocha, Júlio César, Rogozinski, Hazel, Rohde, Carmen, Ross, Kathleen, Saruggia, Isabelle, Schlune, Andrea, Singleton, Kath, Sjoqvist, Elisabeth, Skeath, Rachel, Stolen, Linn Helene, Terry, Allyson, Timmer, Corrie, Tomlinson, Lyndsey, Tooke, Alison, Kerckhove, Kristel Vande, van Dam, Esther, Hurk, Dorine van den, Ploeg, Liesbeth van der, van Driessche, Marleen, van Rijn, Margreet, Wegberg, Annemiek van, Vasconcelos, Carla, Vestergaard, Helle, Vitoria, Isidro, Webster, Diana, White, Fiona, White, Lucy, Zweers, Heidi, and MacDonald, Anita

Published
2020
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47. Mitochondrial mosaics in the liver of patients with Pearson and Alpers-Huttenlocher syndromes

Author

Roels, Frank, Verloo, P., Seneca, Sara, Meerschaut, V., Eyskens, Francois, Smet, Joél, Martin, Jean-Jacques, Praet, M., Van Coster, Rudy, and Department of Embryology and Genetics

Subjects
Alpers-Huttenlocher syndromes
Abstract

Mitochondrial heteroplasmy has previously been visualized by cytochrome oxidase staining (COX) in muscle, but not in liver. We studied 2 pts, a girl 2.5 year old with Pearson syndrome (PS) (pancytopenia and exocrine pancreatic failure), and a boy aged 14 months with Alpers-Huttenlocher syndrome (APS) (myoclonal epilepsy, onset at 11 months, and hepatic disease). Both patients showed mitochondria with weak or absent COX activity in many liver parenchymal cells that otherwise looked viable ; and strong mitochondrial staining in adjacent hepatocytes. COX activity was localized by DAB with and without cytochrome c after glutaraldehyde fixation, for light and electron microscopy. Mitochondrial staining was positive in bile duct epithelium, endothelium, Kupffer cells, vascular smooth muscle and neutrophils. In the Alpers pt mtDNA of skeletal muscle was depleted for 3/ 4 as seen by real time PCR. In blood of the girl with PS a deletion of 4091 bp located between positions 5969 and 10060 was found in 50% of the mtDNA. In her liver decreased protein and activity of complex IV, and subcomplexes of complex V were detected by blue native PAGE. Both pts had increased plasma lactate, but no ragged red fibers in muscle. OXPHOS activities were normal in muscle, fibroblasts and blood cells. Brain MRI of the PS pt demonstrated in the white matter of both frontal lobes a large cavitation with absence of the lactate MR spectrum. MRI of the AHS pt initially showed only slight diffuse cortical atrophy, which has become more obvious while convulsions persisted. These results demonstrate the merit of liver biopsies and COX staining for fast diagnosis of oxidative phosphorylation defects, and as a clue to their phenotype variation.

Published
2006

48. A phase 2a study to investigate the effect of a single dose of migalastat HCl, a pharmacological chaperone, on agalsidase activity in subjects with Fabry disease

Author

Warnock, David, primary, Bichet, Daniel, additional, Holida, Myrl, additional, Goker-Alpan, Ozlem, additional, Nicholls, Kathy, additional, Thomas, Mark, additional, Eyskens, Francois, additional, Shankar, Suma, additional, Dasouki, Majed, additional, Johnson, Franklin, additional, and Boudes, Pol, additional

Published
2013
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50. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study

Author

Hughes, Derralynn A, Nicholls, Kathleen, Shankar, Suma P, Sunder-Plassmann, Gere, Koeller, David, Nedd, Khan, Vockley, Gerard, Hamazaki, Takashi, Lachmann, Robin, Ohashi, Toya, Olivotto, Iacopo, Sakai, Norio, Deegan, Patrick, Dimmock, David, Eyskens, Francois, Germain, Dominique P, Goker-Alpan, Ozlem, Hachulla, Eric, Jovanovic, Ana, Lourenco, Charles M, Narita, Ichiei, Thomas, Mark, Wilcox, William R, Bichet, Daniel G, Schiffmann, Raphael, Ludington, Elizabeth, Viereck, Christopher, Kirk, John, Yu, Julie, Johnson, Franklin, Boudes, Pol, Benjamin, Elfrida R, Lockhart, David J, Barlow, Carrolee, Skuban, Nina, Castelli, Jeffrey P, Barth, Jay, and Feldt-Rasmussen, Ulla

Abstract

BackgroundFabry disease is an X-linked lysosomal storage disorder caused by GLAmutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.MethodsThe main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.ResultsFifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (−6.6 g/m2(−11.0 to −2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.ConclusionsMigalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.Trial registration number:NCT00925301; Pre-results.

Published
2017
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