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62 Alternative dosing regimens of agalsidase alfa (Replagal®) in Fabry disease
Abstracts / Molecular Genetics and Metabolism 92 (2007) S11–S34 of iduronate-2-sulfatase. Affected males present with dysostosis multiplex, short stature, hepatosplenomegaly, joint contractures, and cardiac abnormalities. A majority of patients have mental retardation with neurologic involvement (type A); however, milder forms exist with no neurologic dysfunction (type B). The gene (IDS) encoding iduronate-2-sulfatase has been localized to Xq28 and is composed of nine exons. Since 2003, we have performed molecular studies on 94 enzymatically diagnosed males from North America. Missense mutations were the most common lesion (50.0%) followed by mutations resulting in abnormal splicing (18.0%) while nonsense mutations and small insertions/deletions each comprised 10.7% of mutant alleles. The remaining changes consisted of rearrangements between IDS and the IDS-2 pseudogene (5.3%), large deletions (4.2%), and deletions in the IDS promoter (1.1%). While genotype/phenotype studies were limited, two changes were found in multiple patients with MPSIIB. Studies of 50 mothers of affected males determined that 80% were carriers while the remaining 20% did not carry the child’s mutation in their peripheral blood. Plasma iduronate-2-sulfatase activity is currently being evaluated in 24 confirmed carrier females to try to correlate enzyme activity with specific mutations. doi:10.1016/j.ymgme.2007.08.065
62 Alternative dosing regimens of agalsidase alfa (ReplagalÒ) in Fabry disease Joseph Clarke a, M. West b, J. Bultas c, M. Askari d, R. Schiffmann e, a Hospital For Sick Children, Toronto, Ont., Canada, b Queen Elizabeth II Hospital, Halifax, NS, Canada, c Charles University Hospital, Prague, Czech Republic, d National Institutes of Health, Bethesda, Maryland, USA, e National Institutes of Health, Bethesda, Maryland, USA Agalsidase alfa is used for enzyme replacement therapy (ERT) in Fabry disease at a dose of 0.2 mg/kg infused over 40 min every other week (EOW). This study was performed to determine the effect of alternative doses and/or dosing frequencies on plasma Gb3 levels, a marker of a metabolic effect of agalsidase alfa. In this open-label pharmacodynamic study, 18 ERT-naı¨ve adult males with Fabry disease were randomized to 1 of 5 dosing regimens for 10 weeks: 0.1 mg/kg weekly (n = 4), 0.2 mg/kg EOW (n = 4), 0.2 mg/ kg weekly (n = 4), 0.4 mg/kg EOW (n = 3), and 0.4 mg/kg weekly (n = 3). Pharmacokinetics of each dose were evaluated by measuring enzyme activity in serum at intervals for 24 h. Following the initial infusion, the area under the enzyme activity-time curves (AUC) was proportional to dose. Plasma half-life of infused agalsidase alfa was approximately 1 h (range, 56– 76 min) and was independent of dose. Baseline plasma Gb3 levels averaged 9.12 ± 0.62 nmol/mL (means ± SEM). After 10 weeks of treatment, mean plasma Gb3 had declined by about 50% with all five dosing regimens (48– 51%, P = NS between regimens). This magnitude of reduction is comparable to recently published values in patients treated with agalsidase beta infused at a dose of 1 mg/kg, EOW [W.R. Wilcox et al., Am. J. Hum. Genet. 75 (2004) 65–74]. Based on these observations, the currently recommended dose of agalsidase alfa, 0.2 mg/kg infused EOW, is sufficient to produce maximal reduction of plasma Gb3 in adult male patients with Fabry disease. doi:10.1016/j.ymgme.2007.08.067
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in all four quality of life domains including physical (p < 0.0001), emotional (p = 0.0014), social (p = 0.0053) and school functioning (p = 0.0001). Comparisons between male and female patients revealed significant differences with males more severely affected for physical (p = .0226), social (p = .0016), and school (p = .0372) subscales. Differences were not significant for the emotional subscale (p = .2455). Interestingly of the adolescent patients only one male was employed while more than 70% of females reported holding a job. Conclusion: Children and adolescents with Fabry disease have significantly lower quality of life scores than peers in the general population. Male patients appear to be more severely affected than females in childhood and adolescence. In contrast data from the Fabry registry indicate quality of life scores are similar between men and women over age 40. This implies a need to develop effective early treatment and monitoring for male and female patients with Fabry disease. doi:10.1016/j.ymgme.2007.08.069
65 Fabry disease female heterozygotes are not just ‘‘carriers’’, but have a significant burden of disease and impaired quality of life Raymond Wang a, Alicia Lelis b, James Mirocha c, William R. Wilcox d, a Cedars-Sinai Medical Center, Los Angeles, CA, USA, b Medical Genetics Institute,Cedars-Sinai Medical Center, c Biostatistics Core, Research Institute, Cedars-Sinai Medical Center, d Medical Genetics Institute, Cedars-Sinai Medical Center Purpose: To demonstrate significant symptomatology in women with heterozygous ±-galactosidase mutations. Methods: Data from medical records of the 44 heterozygous females followed at Cedars-Sinai Medical Center were compiled and analyzed for symptoms of Fabry disease. Quality of life data were also analyzed. Results: Seventy-six percent were referred due to an affected male relative; 76% reported acroparesthesias as their first symptom. A mean of 15.7 years elapsed from onset of first symptoms to the diagnosis. Twenty-four percent had experienced a stroke. Acroparesthesias were present in 65%. Electrocardiographic abnormalities were present in 75%, while echocardiography revealed 58% had valvular dysfunction and 24% had ventricular hypertrophy. Thirty-nine percent reported significant abdominal cramping and 43% had postprandial diarrhea. Sixty-three percent had reduced creatinine clearance; 13% had end-stage renal disease. Spirometry demonstrated evidence of obstructive pulmonary disease in 47%. Nearly 60% complained of fatigue and 82% of exercise intolerance. The presence of fatigue was associated with reduced maximum oxygen consumption (p = 0.049), and exercise intolerance with reduced maximal heart rate during exercise testing (p = 0.0089). Women diagnosed via family history experienced more angina (p = 0.035), decreased vibration sense (p = 0.026), and had worse % predicted FEF25-75 (p = 0.037) versus women diagnosed via symptoms. Quality of life, measured by the SF-36 survey, was globally reduced. Pain affected mood and enjoyment of life. Conclusions: This study indicates that the asymptomatic female ‘‘carrier’’ of Fabry disease is the exception, not the rule: heterozygotes suffer from significant multisystemic disease and reduced quality of life and must be monitored and treated accordingly.
64 Quality of life for pediatric patients with Fabry disease Robert Hopkin, Heather M. Taylor, Laurie A. Bailey, Michael S. Yi, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
doi:10.1016/j.ymgme.2007.08.070
Introduction: Quality of life has not been well documented in pediatric Fabry disease. This study tested the hypothesis that pediatric patients with Fabry disease have decreased quality of life when compared to controls in the general population. Methods: Study subjects were asked to complete the PedQL. Mean quality of life scores were compared to scores from general population. Results: Fifty-three participants completed the study. Quality of life scores were significantly lower in pediatric patients with Fabry disease
66 The incidence of depression and anxiety is increased in patients affected by Fabry disease Daniel Gruskin a, Dawn Laney b, Joe Cubells b, a Emory University, Decatur, GA, USA, b Human Genetics, Heather Hipp, BS (School of Medicine) Introduction: Fabry Disease (FD) is a progressive, multisystem, Xlinked lysosomal storage disorder caused by the deficiency of alpha-galactosidase A.
62 Alternative dosing regimens of agalsidase alfa (ReplagalÒ) in Fabry disease Joseph Clarke a, M. West b, J. Bultas c, M. Askari d, R. Schiffmann e, a Hospital For Sick Children, Toronto, Ont., Canada, b Queen Elizabeth II Hospital, Halifax, NS, Canada, c Charles University Hospital, Prague, Czech Republic, d National Institutes of Health, Bethesda, Maryland, USA, e National Institutes of Health, Bethesda, Maryland, USA Agalsidase alfa is used for enzyme replacement therapy (ERT) in Fabry disease at a dose of 0.2 mg/kg infused over 40 min every other week (EOW). This study was performed to determine the effect of alternative doses and/or dosing frequencies on plasma Gb3 levels, a marker of a metabolic effect of agalsidase alfa. In this open-label pharmacodynamic study, 18 ERT-naı¨ve adult males with Fabry disease were randomized to 1 of 5 dosing regimens for 10 weeks: 0.1 mg/kg weekly (n = 4), 0.2 mg/kg EOW (n = 4), 0.2 mg/ kg weekly (n = 4), 0.4 mg/kg EOW (n = 3), and 0.4 mg/kg weekly (n = 3). Pharmacokinetics of each dose were evaluated by measuring enzyme activity in serum at intervals for 24 h. Following the initial infusion, the area under the enzyme activity-time curves (AUC) was proportional to dose. Plasma half-life of infused agalsidase alfa was approximately 1 h (range, 56– 76 min) and was independent of dose. Baseline plasma Gb3 levels averaged 9.12 ± 0.62 nmol/mL (means ± SEM). After 10 weeks of treatment, mean plasma Gb3 had declined by about 50% with all five dosing regimens (48– 51%, P = NS between regimens). This magnitude of reduction is comparable to recently published values in patients treated with agalsidase beta infused at a dose of 1 mg/kg, EOW [W.R. Wilcox et al., Am. J. Hum. Genet. 75 (2004) 65–74]. Based on these observations, the currently recommended dose of agalsidase alfa, 0.2 mg/kg infused EOW, is sufficient to produce maximal reduction of plasma Gb3 in adult male patients with Fabry disease. doi:10.1016/j.ymgme.2007.08.067
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in all four quality of life domains including physical (p < 0.0001), emotional (p = 0.0014), social (p = 0.0053) and school functioning (p = 0.0001). Comparisons between male and female patients revealed significant differences with males more severely affected for physical (p = .0226), social (p = .0016), and school (p = .0372) subscales. Differences were not significant for the emotional subscale (p = .2455). Interestingly of the adolescent patients only one male was employed while more than 70% of females reported holding a job. Conclusion: Children and adolescents with Fabry disease have significantly lower quality of life scores than peers in the general population. Male patients appear to be more severely affected than females in childhood and adolescence. In contrast data from the Fabry registry indicate quality of life scores are similar between men and women over age 40. This implies a need to develop effective early treatment and monitoring for male and female patients with Fabry disease. doi:10.1016/j.ymgme.2007.08.069
65 Fabry disease female heterozygotes are not just ‘‘carriers’’, but have a significant burden of disease and impaired quality of life Raymond Wang a, Alicia Lelis b, James Mirocha c, William R. Wilcox d, a Cedars-Sinai Medical Center, Los Angeles, CA, USA, b Medical Genetics Institute,Cedars-Sinai Medical Center, c Biostatistics Core, Research Institute, Cedars-Sinai Medical Center, d Medical Genetics Institute, Cedars-Sinai Medical Center Purpose: To demonstrate significant symptomatology in women with heterozygous ±-galactosidase mutations. Methods: Data from medical records of the 44 heterozygous females followed at Cedars-Sinai Medical Center were compiled and analyzed for symptoms of Fabry disease. Quality of life data were also analyzed. Results: Seventy-six percent were referred due to an affected male relative; 76% reported acroparesthesias as their first symptom. A mean of 15.7 years elapsed from onset of first symptoms to the diagnosis. Twenty-four percent had experienced a stroke. Acroparesthesias were present in 65%. Electrocardiographic abnormalities were present in 75%, while echocardiography revealed 58% had valvular dysfunction and 24% had ventricular hypertrophy. Thirty-nine percent reported significant abdominal cramping and 43% had postprandial diarrhea. Sixty-three percent had reduced creatinine clearance; 13% had end-stage renal disease. Spirometry demonstrated evidence of obstructive pulmonary disease in 47%. Nearly 60% complained of fatigue and 82% of exercise intolerance. The presence of fatigue was associated with reduced maximum oxygen consumption (p = 0.049), and exercise intolerance with reduced maximal heart rate during exercise testing (p = 0.0089). Women diagnosed via family history experienced more angina (p = 0.035), decreased vibration sense (p = 0.026), and had worse % predicted FEF25-75 (p = 0.037) versus women diagnosed via symptoms. Quality of life, measured by the SF-36 survey, was globally reduced. Pain affected mood and enjoyment of life. Conclusions: This study indicates that the asymptomatic female ‘‘carrier’’ of Fabry disease is the exception, not the rule: heterozygotes suffer from significant multisystemic disease and reduced quality of life and must be monitored and treated accordingly.
64 Quality of life for pediatric patients with Fabry disease Robert Hopkin, Heather M. Taylor, Laurie A. Bailey, Michael S. Yi, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
doi:10.1016/j.ymgme.2007.08.070
Introduction: Quality of life has not been well documented in pediatric Fabry disease. This study tested the hypothesis that pediatric patients with Fabry disease have decreased quality of life when compared to controls in the general population. Methods: Study subjects were asked to complete the PedQL. Mean quality of life scores were compared to scores from general population. Results: Fifty-three participants completed the study. Quality of life scores were significantly lower in pediatric patients with Fabry disease
66 The incidence of depression and anxiety is increased in patients affected by Fabry disease Daniel Gruskin a, Dawn Laney b, Joe Cubells b, a Emory University, Decatur, GA, USA, b Human Genetics, Heather Hipp, BS (School of Medicine) Introduction: Fabry Disease (FD) is a progressive, multisystem, Xlinked lysosomal storage disorder caused by the deficiency of alpha-galactosidase A.