Paul R Harmatz1, Karl Eugen Mengel2, Roberto Giugliani3, Vassili Valayannopoulos4, Shuan-Pei Lin5, Rossella Parini6, Nathalie Guffon7, Barbara K Burton8, Christian J Hendriksz9, John J Mitchell10, Ana Maria Martins11, Simon A Jones12, Norberto Guelbert13, Ashok Vellodi14, Frits A Wijburg15, Ke Yang16, Peter Slasor16, Celeste Decker17. 1. UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA. 2. Villa Metabolica, Centre for Pediatric and Adolescent Medicine, MC University of Mainz, Mainz, Germany. 3. Medical Genetics Service/HCPA, Department of Genetics/UFRGS and INAGEMP, Porto Alegre, Brazil. 4. Reference Center for Inherited Metabolic Disease, Institut IMAGINE, Hôpital Universitaire Necker-Enfants Malades, Paris, France. 5. Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan. 6. Rare Metabolic Diseases Unit, Department of Pediatrics, San Gerardo University Hospital, Monza, Italy. 7. Hôpital Femme Mère Enfant, Lyon, France. 8. Ann and Robert H. Lurie Children's Hospital and Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 9. Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK. 10. McGill University Health Centre, Montreal, Canada. 11. Universidade Federal de São Paulo, São Paulo, Brazil. 12. Manchester Centre for Genomic Medicine, CMFT, University of Manchester, Manchester, UK. 13. Hospital de Niños de Cordoba, Cordoba, Argentina. 14. Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. 15. Academic Medical Center, Amsterdam, The Netherlands. 16. BioMarin Pharmaceutical Inc., Novato, CA, USA. 17. BioMarin Pharmaceutical Inc., Novato, CA, USA. Electronic address: cdecker@bmrn.com.
Abstract
OBJECTIVES: Baseline data from the Morquio A Clinical Assessment Program (MorCAP) revealed that individuals with Morquio A syndrome show substantial impairment in multiple domains including endurance and respiratory function (Harmatz et al., Mol Genet Metab, 2013). Here, 1- and 2-year longitudinal endurance and respiratory function data are presented. METHODS: Endurance was assessed using the 6-minute walk test (6MWT) and the 3-minute stair climb test (3MSCT). Respiratory function was evaluated by measuring forced vital capacity (FVC) and maximum voluntary ventilation (MVV). Data were analyzed using repeated measures ANCOVA models. Annualized estimates of change were determined using model estimates and interpolation. RESULTS: 353, 184, and 78 subjects were assessed at Year 0 (baseline), Year 1, and Year 2, respectively. The overall annualized estimate of change (SE) in 6MWT distance was -4.86±3.25m; a larger decline of -6.84±5.38m was observed in the subset of subjects meeting the inclusion/exclusion criteria of the Phase 3 clinical trial of elosulfase alfa (≥5years of age with baseline 6MWT distance ≥30 and ≤325m). In contrast, little change (-0.14±0.60stairs/min) was observed in 3MSCT. Annualized changes (SE) in FVC and MVV were 2.44±0.68% and 1.01±2.38%, respectively. FVC and MVV increased in patients aged ≤14years, but decreased in older patients. CONCLUSIONS: The natural history of Morquio A syndrome is characterized by progressive impairment of endurance as measured by the 6MWT. Longitudinal trends in FVC and MVV showing increase in younger patients, but decrease in older patients, are likely to be influenced by growth. Changes in 6MWT may represent a sensitive measure of disease progression in ambulatory Morquio A patients.
OBJECTIVES: Baseline data from the Morquio A Clinical Assessment Program (MorCAP) revealed that individuals with Morquio A syndrome show substantial impairment in multiple domains including endurance and respiratory function (Harmatz et al., Mol Genet Metab, 2013). Here, 1- and 2-year longitudinal endurance and respiratory function data are presented. METHODS: Endurance was assessed using the 6-minute walk test (6MWT) and the 3-minute stair climb test (3MSCT). Respiratory function was evaluated by measuring forced vital capacity (FVC) and maximum voluntary ventilation (MVV). Data were analyzed using repeated measures ANCOVA models. Annualized estimates of change were determined using model estimates and interpolation. RESULTS: 353, 184, and 78 subjects were assessed at Year 0 (baseline), Year 1, and Year 2, respectively. The overall annualized estimate of change (SE) in 6MWT distance was -4.86±3.25m; a larger decline of -6.84±5.38m was observed in the subset of subjects meeting the inclusion/exclusion criteria of the Phase 3 clinical trial of elosulfase alfa (≥5years of age with baseline 6MWT distance ≥30 and ≤325m). In contrast, little change (-0.14±0.60stairs/min) was observed in 3MSCT. Annualized changes (SE) in FVC and MVV were 2.44±0.68% and 1.01±2.38%, respectively. FVC and MVV increased in patients aged ≤14years, but decreased in older patients. CONCLUSIONS: The natural history of Morquio A syndrome is characterized by progressive impairment of endurance as measured by the 6MWT. Longitudinal trends in FVC and MVV showing increase in younger patients, but decrease in older patients, are likely to be influenced by growth. Changes in 6MWT may represent a sensitive measure of disease progression in ambulatory Morquio A patients.
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