Characterization of Early Disease Status in Treatment-Naive Male Paediatric Patients with Fabry Disease Enrolled in a Randomized Clinical Trial

Abstract

Trial DesignThis analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.MethodsMales aged 5–18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13–17 years), renal function, and glycolipid levels (plasma, urine).ResultsPlasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m2 (range 90.4–161.0 mL/min/1.73 m2) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0–27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.ConclusionsThese data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.Trial RegistrationClinicalTrials.gov NCT00701415

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study

“…The presence of early cerebrovascular disease in children with FD has been described in previous reports. 26,27 Other early findings may include subtle electrocardiography abnormalities, mild left ventricular hypertrophy, and mild albuminuria. [28][29][30] In conclusion, sex, phenotype, and plasma lysoGb3 concentrations are strongly associated with the rate of clinical events as well as cardiac, renal, and cerebral involvement.…”

Bedside Stereomicroscopy of Fabry Kidney Biopsies: An Easily Available Method for Diagnosis and Assessment of Sphingolipid Deposits

“…The important role of kidney biopsies in the diagnosis, classification and assessment of therapeutic efficacy in Fabry disease has recently been highlighted in several studies and case series [3,7,12,16,20], as well as in a recent KDIGO conference report [4]. There is increasing evidence that accumulation of Gb3 in podocytes is an early marker of potential progressive Fabry nephropathy, and several studies have shown that prominent histological changes appear far earlier than clinical renal symptoms or albuminuria [21,22]. Secondary changes in the filtration barrier may be a plausible mechanism for progressive structural and functional damage.…”

Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease

“…One further long-term and one small short-term study assessed skin Gb3 under ERT and showed partial clearance [10,30]. In a recent study using electron microscopy, Gb3 deposits were described and semiquantitatively assessed in treatment-naïve male pediatric FD patients [8]. Interestingly, Gb3 was found in superficial skin capillary endothelial cells and deep vessel endothelial cells of the majority of these young male patients, which is quantitatively similar to our findings with 53% male patients showing Gb3 deposits of >0.05% ROI in distal skin, however, with less spatial resolution as a disadvantage of the method.…”

“…In skin, Gb3 may accumulate in vascular endothelium, smooth muscles, fibroblasts, and eccrine sweat glands [2–8] and it has been localized to lysosomes using electron microscopy [9]. In a phase 3 clinical trial on enzyme replacement therapy (ERT), clearance of Gb3 was shown from vascular endothelium and to a lesser degree from dermal smooth muscle cells and perineurium [10].…”