Global reach of over 20 years of experience in the patient-centered Fabry Registry: Advancement of Fabry disease expertise and dissemination of real-world evidence to the Fabry community.

Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20 years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD.

Pregnancy Outcomes in Late Onset Pompe Disease.

There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated.

Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat.

Background: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes.

Methods: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations.

Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants.

Purpose: The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.

Methods: Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients.

Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: findings from the Fabry Registry.

Purpose: To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease.

Methods: The SF-36® Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.

A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1.

Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia.

Cardiovascular manifestations of Fabry disease: relationships between left ventricular hypertrophy, disease severity, and alpha-galactosidase A activity.

Aims: Fabry disease is a rare X-linked deficiency of alpha-galactosidase A (alphagal), which causes glycosphingolipid accumulation. This study analysed the cardiovascular manifestations of a cohort of Fabry patients, and sought to define relationships between disease severity, alphagal activity, and cardiac abnormalities.

Methods And Results: We prospectively analysed Fabry patients (139 subjects: 92 males and 47 females) undergoing screening for potential enzyme replacement therapy.

Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry.

Purpose: To evaluate life expectancy and cause of death among patients with Fabry disease, an X-linked lysosomal storage disorder.

Methods: Data from 2848 patients in the Fabry Registry were summarized using descriptive statistics. Life expectancy at birth was compared with that of the United States general population.

Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy.

Background: In Fabry disease, progressive glycolipid accumulation leads to organ damage and early demise, but the incidence of renal, cardiac and cerebrovascular events has not been well characterized.

Methods: We conducted a retrospective chart review of 279 affected males and 168 females from 27 sites (USA, Canada, Europe). The pre-defined study endpoints included progression of renal, cardiac and cerebrovascular involvement and/or death before the initiation of enzyme replacement therapy.

Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry.

Background And Purpose: Stroke is a common and serious clinical manifestation of Fabry disease, an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A activity. This study was undertaken to better understand the natural history of cerebrovascular manifestations of Fabry disease.

Methods: Data from 2446 patients in the Fabry Registry were analyzed to identify clinical characteristics of patients experiencing stroke during the natural history period (ie, before enzyme replacement therapy).

Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry.

Fabry disease is an X-linked lysosomal disease caused by deficiency of alpha-galactosidase A. Signs and symptoms of Fabry disease occurring during childhood and adolescence were characterized in 352 Fabry Registry patients. At enrollment (median age 12 year), 77% of males and 51% of females reported symptoms.

Home-based infusion therapy for patients with Fabry disease.

Fabry disease is an inherited, progressive, life-threatening disease; therefore, lifelong therapy is needed. By replacing the deficient enzyme, disease progression may be delayed or halted, thereby avoiding serious complications. Hospital-based agalsidase therapy is generally perceived as inconvenient and home-based infusion therapy is greatly appreciated by patients, their families and healthcare professionals.

Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry.

Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A deficiency. The Fabry Registry is a global clinical effort to collect longitudinal data on FD. In the past, most "carrier" females were usually thought to be clinically unaffected.

Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease.

Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart.

Fabry disease: clinical spectrum and evidence-based enzyme replacement therapy.

The clinical spectrum of Fabry disease, an X-linked lysosomal storage disorder due to alpha-galactosidase A (alpha-Gal A) deficiency, has been expanded beyond the classic phenotype to include the recently recognized later-onset "cardiac" and "renal" variants. The clinical manifestations in each of these disease subtypes are presented with particular emphasis on early recognition among pediatric patients as well as identification of unrecognized patients diagnosed as hypertrophic cardiomyopathy or in renal dialysis clinics. Previously, treatment of patients with Fabry disease was limited to palliative care of the excruciating pain, cardiac and cerebrovascular manifestations, and renal failure.

Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry.

The Fabry Registry is a global observational research platform established to define outcome data on the natural and treated course of this rare disorder. Participating physicians submit structured longitudinal data to a centralized, confidential database. This report describes the baseline demographic and clinical characteristics of the first 1765 patients (54% males (16% aged < 20 years) and 46% females (13% < 20 years)) enrolled in the Fabry Registry.

Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.

Background: Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement.

Objective: To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease.

Design: Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial.

Fabry disease: guidelines for the evaluation and management of multi-organ system involvement.

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A, and the subsequent accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Males with classical Fabry disease develop early symptoms including pain and hypohidrosis by the second decade of life reflecting disease progression in the peripheral and autonomic nervous systems. An insidious cascade of disease processes ultimately results in severe renal, cardiac, and central nervous system complications in adulthood.

Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome.

Background: Classic Fabry disease, an X-linked recessive lysosomal storage disease due to the deficient activity of alpha-galactosidase A, typically presents in early childhood with acroparesthesias, angiokeratomas, hypohidrosis, and corneal dystrophy. The neuropathic pain presumably results from glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers, and is treatable by enzyme replacement therapy. Later-onset variants with residual alpha-galactosidase A activity lack vascular endothelial involvement and classic symptoms, which lead to the development of cardiac and/or renal disease after the fourth decade of life.

Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy.

Gastrointestinal symptoms are often an early and prominent manifestation of Fabry disease, an X-linked inborn error of metabolism caused by the deficient activity of the lysosomal enzyme, alpha-galactosidase A. This enzyme deficiency results in the progressive accumulation of globotriaosylceramide and other glycosphingolipids in tissue lysosomes throughout the body. In classically affected patients, glycosphingolipid accumulation in the vascular endothelium eventually culminates in life-threatening renal, cardiac, and cerebrovascular disease.

Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.

Elsewhere, we reported the safety and efficacy results of a multicenter phase 3 trial of recombinant human alpha -galactosidase A (rh-alpha GalA) replacement in patients with Fabry disease. All 58 patients who were enrolled in the 20-wk phase 3 double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-alpha GalA (agalsidase beta, Fabrazyme, Genzyme Corporation) biweekly in an ongoing open-label extension study. Evidence of long-term efficacy, even in patients who developed IgG antibodies against rh- alpha GalA, included the continuously normal mean plasma globotriaosylceramide (GL-3) levels during 30 mo of the extension study and the sustained capillary endothelial GL-3 clearance in 98% (39/40) of patients who had a skin biopsy taken after treatment for 30 mo (original placebo group) or 36 mo (original enzyme-treated group).

Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes.

Objective: To describe the renal ultrasonography (US) and magnetic resonance imaging (MRI) findings in affected males and female carriers with the classic and cardiac variant phenotypes of Fabry disease (alpha-galactosidase A [alpha-Gal A] deficiency).

Methods: The renal US and MRI features of 76 classically affected males (aged 7-53 years), 40 female carriers from classically affected families (aged 18-66 years), and 6 males with the cardiac variant phenotype (aged 17-59 years) were reviewed by 3 blinded board-certified radiologists. The images were evaluated for the presence of cortical cysts, parapelvic cysts, renal atrophy, decreased cortical thickness, increased echogenicity (US only), and decreased corticomedullary differentiation (MRI only).

Enzyme replacement therapy for Fabry disease, an inherited nephropathy.

Fabry disease, an X-linked lysosomal storage disease, results from the deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids. In classically affected males with this inherited nephropathy, early and marked GL-3 deposition in the podocytes leads to proteinuria in childhood or adolescence. With increasing age, GL-3 deposition in renal microvascular endothelial cells, and to a lesser extent in interstitial and mesangial cells, leads to renal insufficiency in the third to fifth decades of life.