Characterization of Fabry Disease in 352 Pediatric Patients in the Fabry Registry

Hopkin, Robert J.; Bissler, John J.; Banikazemi, Maryam; Clarke, Lorne A.; Eng, Christine M.; Germain, Dominique P.; Lemay, Roberta; Tylki‐Szymańska, Anna; Wilcox, William R.

doi:10.1203/pdr.0b013e318183f132

Cited by 247 publications

(283 citation statements)

References 21 publications

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“…In vitro studies suggest that these elevations trigger a cascade of pathological processes, including inflammatory and fibrotic responses that cause progressive damage to multiple organs (Germain 2010). In males with classic FD, early signs and symptoms, including neuropathic pain, hypohidrosis, and gastrointestinal dysmotility, usually appear in early childhood (Hopkin et al 2008), and life-threatening renal, cardiac, and cerebrovascular complications typically develop by the fourth or fifth decade of life (Germain 2010).…”

Section: Introductionmentioning

confidence: 99%

“…The optimal dose of agalsidase has long been a matter of debate (Desnick 2004), and identification of the biochemically and clinically most effective dose has been hampered by the slowly progressive nature of FD that lacks reliable, predictive biochemical or clinical surrogate end points. Additionally, the clinical presentation of FD is highly heterogeneous and the timing of symptom onset highly variable (Eng et al 2007;Hopkin et al 2008). There have been no randomized, double-blind trials of patients matched for sex, age, and disease severity to allow a direct comparison of the effectiveness of agalsidase beta and agalsidase alfa at their approved doses (Desnick and Schuchman 2012).…”

Section: Introductionmentioning

confidence: 99%

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Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Göker-Alpan

Gambello

Maegawa³

et al. 2015

JIMD Reports

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Introduction: Agalsidase alfa and agalsidase beta, recombinant enzyme preparations for treatment of Fabry disease (FD), have different approved dosing schedules: 0.2 mg/kg and 1.0 mg/kg every other week (EOW), respectively.Methods: This open-label, multicenter, exploratory phase 4 study evaluated plasma globotriaosylsphingosine (lyso-GL-3) and plasma and urine globotriaosylceramide (GL-3) levels at baseline and 2, 4, and 6 months after the switch from agalsidase alfa (0.2 mg/kg EOW for !12 months) to agalsidase beta (1.0 mg/kg EOW) in 15 male patients with FD. Immunoglobulin (Ig)G antidrug antibody titers were assessed, and safety was monitored throughout the study.Results: Plasma lyso-GL-3 concentrations decreased significantly within 2 months after switch and reductions continued through month 6 (mean absolute changes, À12.8, À16.1, and À16.7 ng/mL at 2, 4, and 6 months, respectively; all P < 0.001). The mean percentage reduction from baseline was 39.5% (P < 0.001) at month 6. For plasma GL-3, the mean absolute change from baseline (À0.9 mg/mL) and percentage reduction (17.9%) at month 6 were both significant (P < 0.05). Urine GL-3 measurements showed intra-patient variability and changes from baseline were not significant. No clinical outcomes were assessed in this 6-month study, and, therefore, no conclusions can be drawn regarding the correlation of observed reductions in glycosphingolipid concentrations with clinically relevant outcomes. There were no differences in IgG antidrug antibody titers between the two enzymes. The switch from agalsidase alfa to agalsidase beta was well tolerated.Conclusion: Plasma lyso-GL-3 and GL-3 levels reduced after switching from agalsidase alfa to agalsidase beta, indicating that agalsidase beta has a greater pharmacodynamic effect on these markers at the recommended dose. These data further support the use of agalsidase beta 1.0 mg/kg EOW as enzyme replacement therapy in FD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Göker-Alpan

Gambello

Maegawa³

et al. 2015

JIMD Reports

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“…The initial signs and symptoms of FD frequently include neuropathic pain in the extremities, hypohidrosis, angiokeratomas, and gastrointestinal discomfort. 3 Over a period of decades, the accumulation of glycosphingolipids impairs vital organ function, putting patients at risk of developing renal failure, stroke, and cardiovascular dysfunction. [4][5][6] Because it is an X-linked disorder, hemizygous males typically experience the most severe manifestations of FD, 1 but heterozygous females can also develop serious complications.…”

mentioning

confidence: 99%

Analysis of left ventricular mass in untreated men and in men treated with agalsidase-β: data from the Fabry Registry

Germain

Weidemann

Abiose

et al. 2013

Genetics in Medicine

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Fabry disease (FD) (OMIM 301500) is a rare disorder in which globotriaosylceramide and other glycosphingolipids accumulate within lysosomes because of insufficient activity of α-galactosidase A. 1,2 Over time, the glycosphingolipid substrate progressively accumulates within blood vessels and various other cell types throughout the body. The initial signs and symptoms of FD frequently include neuropathic pain in the extremities, hypohidrosis, angiokeratomas, and gastrointestinal discomfort. 3 Over a period of decades, the accumulation of glycosphingolipids impairs vital organ function, putting patients at risk of developing renal failure, stroke, and cardiovascular dysfunction. [4][5][6] Because it is an X-linked disorder, hemizygous males typically experience the most severe manifestations of FD, 1 but heterozygous females can also develop serious complications. [4][5][6][7] The cardiovascular manifestations of FD can include leftventricular hypertrophy (LVH), atrial and left-ventricular arrhythmias, heart block, valvular dysfunction, angina, and arterial wall thickening. 4,5,[8][9][10][11][12][13] As the disease progresses, the hypertrophy becomes more severe, including the development of myocardial fibrosis and serious cardiac events including cardiac-related death. 4,5,8,11 Agalsidase-β, a recombinant form of human α-galactosidase A (Fabrazyme, Genzyme a Sanofi Company, Cambridge, MA), is approved for use as enzyme replacement therapy (ERT) for FD. In clinical studies, agalsidase-β at a dose of 1 mg/kg/2 weeks cleared microvascular endothelial glycosphingolipid deposits from the heart, as well as from kidney and skin, within 5 months. 14 It also provided long-term stabilization of renal function in patients with mild renal involvement 15 and delayed time to renal, cardiovascular, and cerebrovascular events in patients with more advanced FD. 16 Because it is a rare disorder, the randomized clinical trials of agalsidase-β included a relatively limited number of subjects with FD. 14,16 Several prospective, observational studies have reported cardiac data from patients treated with agalsidase-β, but these also involved only small numbers of patients. 17,18 Purpose: The aim of this study was to evaluate the progression of left ventricular hypertrophy in untreated men with Fabry disease and to assess the effects of agalsidase-β (recombinant human α-galactosidase A) on left ventricular hypertrophy. Methods:Longitudinal Fabry Registry data were analyzed from 115 men treated with agalsidase-β (1 mg/kg/2 weeks) and 48 untreated men. Measurements included baseline left-ventricular mass and at least one additional left-ventricular mass assessment over ≥2 years. Patients were grouped into quartiles, based on left-ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression.Results: For men in whom treatment was initiated at the age of 18 to <30 years, mean left ventricular mass slope was −3.6 g/year (n = 31) compared with +9.5 g/year in untr...

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“…Our data, i.e., 90% of males and 47% of females reporting distal extremity pain, are in line with previously reported observations. Analyses of data from two Fabry's registries have shown that large proportions of children and adolescents (boys: 60 -80%, girls: 40 -60%) report neuropathic pain; boys often a few years earlier than girls (24,25). In many individuals, the pain had not been recognized as an early symptom of FD and correct diagnosis was delayed until well into adulthood.…”

Section: Discussionmentioning

confidence: 99%

Distal extremity pain as a presenting feature of Fabry's disease

Pagnini¹,

Borsini²,

Cecchi³

et al. 2011

Arthritis Care & Research

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Objective. Fabry's disease (FD) is an X-linked lysosomal storage disease. Distal extremity pain can be an early finding and renal, cardiac, and cerebrovascular complications may lead to complications and mortality. Treatment is now available for these patients, who may not be diagnosed correctly for years if the neuropathic nature of the pain is not recognized. The aim of our study was to describe early clinical features in a cohort of patients with FD and to emphasize the importance of distal extremity pain for early diagnosis. Methods. The medical charts of 35 patients with FD followed in a single center were reviewed. When data were incomplete, a detailed pain questionnaire was sent to patients. Nonresponders were contacted by telephone. Results. Distal extremity pain was present in the majority of cases (25 of 35). The mean age at diagnosis of FD was 43.5 years (range 5-77 years). Distal extremity pain was more prevalent in males than females and occurred mostly in childhood or adolescence. When present at onset, the disease progressed with subsequent organ system involvement. Misdiagnoses were frequent and included growing pains, juvenile idiopathic arthritis, connective tissue disease, and gout.

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Characterization of Fabry Disease in 352 Pediatric Patients in the Fabry Registry

Cited by 247 publications

References 21 publications

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Analysis of left ventricular mass in untreated men and in men treated with agalsidase-β: data from the Fabry Registry

Distal extremity pain as a presenting feature of Fabry's disease

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