BACKGROUND: The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. METHODS: To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. RESULTS: In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%). CONCLUSION: p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.

• Keywords
• GLA, Fabry disease, cardiac variant, p.Asn215Ser, p.N215S, phenotype,
• Publication type
• Journal Article MeSH

TRIAL DESIGN: This 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. METHODS: Males 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). RESULTS: Plasma 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 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) 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. CONCLUSIONS: These 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 REGISTRATION: ClinicalTrials.gov NCT00701415.

• MeSH
• Biopsy MeSH
• Endothelium, Vascular pathology   MeSH
• Demography MeSH
• Child MeSH
• Fabry Disease blood   drug therapy   physiopathology   urine   MeSH
• Genotype MeSH
• Glycolipids blood   MeSH
• Glomerular Filtration Rate MeSH
• Iohexol MeSH
• Skin blood supply   MeSH
• Quality of Life MeSH
• Kidney pathology   physiopathology   ultrastructure   MeSH
• Humans MeSH
• Adolescent MeSH
• Brain pathology   MeSH
• Mutation genetics   MeSH
• Child, Preschool MeSH
• Sphingolipids blood   MeSH
• Trihexosylceramides blood   genetics   urine   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• globotriaosyl lysosphingolipid MeSH Browser
• globotriaosylceramide MeSH Browser
• Glycolipids MeSH
• Iohexol MeSH
• Sphingolipids MeSH
• Trihexosylceramides MeSH