eliglustat-tartrate and Stroke

Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in Fabry disease, most severely the cardiac, kidney, and central nervous systems. In this brief review, we will focus on the kidney and central nervous system involvement.

Topics: alpha-Galactosidase; Enzyme Replacement Therapy; Fabry Disease; Genetic Predisposition to Disease; Humans; Isoenzymes; Mutation; Phenotype; Prognosis; Renal Insufficiency, Chronic; Stroke

Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency of the hydrolytic enzyme alpha galactosidase A, with consequent accumulation of globotrioasoyl ceramide in cells and tissues of the body, resulting in a multi-system pathology including end organ failure. In the classical phenotype, cardiac failure, renal failure and stroke result in a reduced median life expectancy. The current causal treatment for Fabry disease is the enzyme replacement therapy (ERT): two different products, Replagal (agalsidase alfa) and Fabrazyme (agalsidase beta), have been commercially available in Europe for almost 10 years and they are both indicated for long-term treatment. In fact, clinical trials, observational studies and registry data have provided many evidences for safety and efficacy of ERT in improving symptoms of pain, gastrointestinal disturbances, hypohidrosis, left ventricular mass index, glomerular filtration rate and quality of life. Few data are available on comparison of the two treatments and on the clinical course of the disease. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations.

Topics: Adult; alpha-Galactosidase; Clinical Trials as Topic; Enzyme Replacement Therapy; Fabry Disease; Female; Galactosidases; Heart Failure; Humans; Isoenzymes; Male; Recombinant Proteins; Renal Insufficiency; Stroke; Trihexosylceramides

Fabry disease, an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiovascular, and cerebrovascular disease, and premature death.. This longitudinal Fabry Registry study analyzed data from patients with Fabry disease to determine the incidence and type of severe clinical events following initiation of enzyme replacement therapy (ERT) with agalsidase beta, as well as risk factors associated with occurrence of these events. Severe events assessed included chronic dialysis, renal transplantation, cardiac events, stroke, and death.. The analyses included 969 male and 442 female Fabry patients. The mean age at first agalsidase beta infusion was 35 and 44, and median treatment follow-up 4.3years and 3.2years, respectively. Among males, cardiac events were the most common on-ERT events, followed by renal, stroke, and non-cardiac death. Among females, cardiac events were also most common followed by stroke and renal events. Patients with on-ERT events had significantly more advanced cardiac and renal disease at baseline as compared with patients without on-ERT events. Severe events were also associated with older age at ERT initiation (males and females), a history of pre-ERT events (females; approaching statistical significance in males), and a higher urinary protein/creatinine ratio (females). Approximately 65% of patients with pre-ERT events did not experience subsequent on-ERT events. Of patients without pre-ERT events, most (84% of males, 92% of females) remained event-free.. Patients with on-ERT severe events had more advanced Fabry organ involvement at baseline than those without such events and patients who initiated ERT at a younger age had less residual risk of on-ERT events. The observed patterns of residual risk may aid clinicians in multidisciplinary monitoring of male and female patients with Fabry disease receiving ERT, and in determining the need for administration of adjunctive therapies.

Topics: Adult; alpha-Galactosidase; Child; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Isoenzymes; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Registries; Risk Factors; Severity of Illness Index; Stroke

The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease.. A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain.. During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry.. Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.

Topics: Adult; alpha-Galactosidase; Cohort Studies; Death, Sudden, Cardiac; Disease Progression; Enzyme Replacement Therapy; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Isoenzymes; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Stroke; Time Factors; Treatment Outcome

Topics: alpha-Galactosidase; Death, Sudden, Cardiac; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Isoenzymes; Kidney Failure, Chronic; Male; Stroke

Several epidemiologic studies suggest that Fabry disease should be considered in young patients with cryptogenic stroke. We report a case of a young woman presenting with recurrent ischemic strokes who was finally diagnosed with Fabry disease after impaired kidney function had been identified. Fabry disease should be considered in unexplained cases of first or recurrent strokes in young patients disregarding the gender of the patient, especially when chronic kidney disease and/or proteinuria are present. Renal function should be closely monitored in patients with strokes and followed up after the event. In this case, intravenous thrombolysis was performed after the second ischemic event. No other case of thrombolysis for ischemic stroke in Fabry disease has been described in the literature.

Topics: Adult; alpha-Galactosidase; Brain Ischemia; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Isoenzymes; Kidney Function Tests; Paresis; Recurrence; Stroke; Thrombolytic Therapy; Tomography, X-Ray Computed

Fabry's disease (FD) an X-linked inherited lysosomal sphingolipidosis leads to a multisystemic disease. The efficacy of replacement enzyme therapy on the central nervous system manifestations has not been evaluated.. A 38-year-old patient suffered from a Fabry's disease diagnosed at the age of 10. Since the age of 26, he suffered from repeated ischemic strokes. Since the age of 34, he was treated by enzyme replacement therapy (agalsidase beta, 1 mg/kg/14 days). He had a cerebral MRI evaluation 1 year and 4 years after the initiation of the enzyme therapy. No new clinical event occurred during the follow-up and the imaging did not evidence new lesion.. We report the cerebral MRI follow-up under enzyme replacement therapy in a patient with Fabry's disease with central nervous system involvement. No new lesion appeared.. Enzyme replacement therapy seems beneficial in Fabry's disease with central nervous system involvement.

Topics: Adult; alpha-Galactosidase; Central Nervous System; Enzyme Replacement Therapy; Fabry Disease; Humans; Isoenzymes; Magnetic Resonance Imaging; Male; Secondary Prevention; Stroke; Treatment Outcome

We report a 35-year-old man with a stroke as the presenting feature of Fabry's disease. Cerebrovascular manifestation can be the first manifestation of this disease and must be systematically evoked by the neurologist. The neurological follow-up of these patients must be systematic.

Topics: Adult; alpha-Galactosidase; Biomarkers; Diagnosis, Differential; Fabry Disease; Follow-Up Studies; Genetic Testing; Humans; Isoenzymes; Male; Mutation; Risk Factors; Stroke; Treatment Outcome

Two different enzyme preparations, agalsidase alfa (Replagal(TM), Shire) and beta (Fabrazyme(TM), Genzyme), are registered for treatment of Fabry disease. We compared the efficacy of and tolerability towards the two agalsidase preparations administered at identical protein dose in a randomized controlled open label trial.. Thirty-four Fabry disease patients were treated with either agalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly. Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment. Other endpoints included occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine. After 12 and 24 months of treatment no reduction in left ventricular mass was seen, which was not different between the two treatment groups. Also, no differences in glomerular filtration rate, pain and decline in globotriaosylceramide levels were found. Antibodies developed only in males (4/8 in the agalsidase alfa group and 6/8 in the agalsidase beta group). Treatment failure within 24 months of therapy was seen in 8/34 patients: 6 male patients (3 in each treatment group) and 2 female patients (both agalsidase alfa). The occurrence of treatment failures did not differ between the two treatment groups; chi(2) = 0.38 p = 0.54.. Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatment with either agalsidase alfa or beta at a dose of 0.2 mg/kg biweekly. Treatment failure occurred frequently in both groups and seems related to age and severe pre-treatment disease.. International Standard Randomized Clinical Trial ISRCTN45178534 [http://www.controlled-trials.com/ISRCTN45178534].

Topics: alpha-Galactosidase; Antibodies; Cerebral Ventricles; Dose-Response Relationship, Drug; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Isoenzymes; Male; Pain Measurement; Patient Selection; Random Allocation; Recombinant Proteins; Stroke; Treatment Failure; Treatment Outcome