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The HTML version of this Article contained errors in Supplementary Figure S2 "Flowchart of the lyso-Gb3 screening and gene analysis in female patients", which have been detailed in the associated Correction.
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PURPOSE: Plasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and late-onset Fabry disease in males and females. METHODS: Between 1 July 2014 and 31 December 2015, we screened 2,359 patients (1,324 males) referred from 168 Japanese specialty clinics (cardiology, nephrology, neurology, and pediatrics), based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A (α-Gal A) activity, and analysis of the α-Gal A gene (GLA) for primary and secondary screens, respectively. RESULTS: Of 8 males with elevated lyso-Gb3 levels (≥2.0 ng ml-1) and low α-Gal A activity (≤4.0 nmol h-1 ml-1), 7 presented a GLA mutation (2 classic and 5 late-onset). Of 14 females with elevated lyso-Gb3, 7 displayed low α-Gal A activity (5 with GLA mutations; 4 classic and 1 late-onset) and 7 exhibited normal α-Gal A activity (1 with a classic GLA mutation and 3 with genetic variants of uncertain significance). CONCLUSION: Plasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands.
Subject(s)
Biomarkers/blood , Fabry Disease/blood , Genetic Testing , Glycolipids/blood , Sphingolipids/blood , Aged , Fabry Disease/genetics , Fabry Disease/pathology , Female , Galactosidases/blood , Galactosidases/genetics , Glycolipids/genetics , Humans , Male , Middle Aged , Mutation , Patient Selection , Risk Factors , Sphingolipids/geneticsABSTRACT
The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information.
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In the above article, we noticed that one female patient in the positive group (plasma lyso-Gb3 7.6 ng/ml, α-galactosidase A activity 4.9 nmol/h/ml) who presented at the neurology clinic was already diagnosed with Fabry disease before the current study. We excluded patients with a confirmed diagnosis of Fabry disease and those with relatives known to have Fabry disease. To accurately describe the information in the current study, we must exclude this patient from the analysis. We have accurately revised this information as follows.
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A main feature of Fabry disease is nephropathy, with polyuria an early manifestation; however, the mechanism that underlies polyuria and affected tubules is unknown. To increase globotriaosylceramide (Gb3) levels, we previously crossbred asymptomatic Glatm mice with transgenic mice that expressed human Gb3 synthase (A4GALT) and generated the GlatmTg(CAG-A4GALT) symptomatic Fabry model mice. Additional analyses revealed that these mice exhibit polyuria and renal dysfunction without remarkable glomerular damage. In the present study, we investigated the mechanism of polyuria and renal dysfunction in these mice. Gb3 accumulation was mostly detected in the medulla; medullary thick ascending limbs (mTALs) were the most vacuolated tubules. mTAL cells contained lamellar bodies and had lost their characteristic structure ( i.e., extensive infolding and numerous elongated mitochondria). Decreased expression of the major molecules-Na+-K+-ATPase, uromodulin, and Na+-K+-2Cl- cotransporter-that are involved in Na+ reabsorption in mTALs and the associated loss of urine-concentrating ability resulted in progressive water- and salt-loss phenotypes. GlatmTg(CAG-A4GALT) mice exhibited fibrosis around mTALs and renal dysfunction. These and other features were consistent with pathologic findings in patients with Fabry disease. Results demonstrate that mTAL dysfunction causes polyuria and renal impairment and contributes to the pathophysiology of Fabry nephropathy.-Maruyama, H., Taguchi, A., Nishikawa, Y., Guili, C., Mikame, M., Nameta, M., Yamaguchi, Y., Ueno, M., Imai, N., Ito, Y., Nakagawa, T., Narita, I., Ishii, S. Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.
Subject(s)
Fabry Disease/pathology , Kidney Diseases/pathology , Kidney Medulla/pathology , Animals , Disease Models, Animal , Fabry Disease/metabolism , Kidney Concentrating Ability/physiology , Kidney Diseases/metabolism , Kidney Medulla/metabolism , Male , Mice , Mice, Inbred C57BL , Polyuria/metabolism , Polyuria/pathology , Sodium/metabolism , Sodium-Potassium-Chloride Symporters/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Trihexosylceramides/metabolismABSTRACT
BACKGROUND: In Fabry disease, progressive glycolipid accumulation leads to damage in kidney and other organs. This study was designed to determine the prevalence rate of Fabry disease in Japanese dialysis patients. METHODS: All dialysis patients agreeing to Japan Fabry disease screening study (J-FAST) with informed consent were selected except for Fabry disease. The screening was performed by a method of measuring plasma and/or leukocytes lysosomal α-galactosidase A protein level and α-galactosidase A activity. If positive, genetic analysis was carried out upon patient's agreement. RESULTS: J-FAST dealt with 8547 patients (male 5408, female 3139). At the tertiary examination, 26 out of 8547 patients were found to be positive. Six out of 26 patients could not accept genetic analysis because of death. Remaining 20 patients agreed with genetic analysis; then 2 patients (male 2, female 0) had a variation of the α-Gal gene and 11 patients showed E66Q variations. Therefore, the frequency of Fabry disease in J-FAST was 0.04 % (2/5408) in males and 0 % (0/3139) in females, and then 0.02 % (2/8547) in all patients. The presumptive clinical diagnoses of end-stage kidney disease (ESKD) were 10 chronic glomerulonephritis, 7 diabetic nephropathy, 3 unknown etiology, 3 nephrosclerosis, 1 gouty nephropathy, 1 autosomal dominant polycystic kidney disease and 1 renal tuberculosis among 26 tertiary positive patients. Two male Fabry patients were initially diagnosed as nephrosclerosis and chronic glomerulonephritis. CONCLUSIONS: The prevalence rate of Fabry disease in J-FAST was 0.02 %. Moreover, Fabry disease could not be ruled out as the clinical diagnosis of ESKD.
Subject(s)
Fabry Disease/complications , Fabry Disease/epidemiology , Kidney Failure, Chronic/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Humans , Japan/epidemiology , Kidney Failure, Chronic/epidemiology , Mass Screening , Middle Aged , Young AdultABSTRACT
Objective To investigate the effects of fluvastatin on the tubulointerstitium damage in progressive diabetic kidney disease. Methods A rat model of type 2 diabetic nephropathy (DN) was developed successfully by combination of dietary induced insulin resistance and low dose STZ induced hyperglycemia after unilateral nephrectomy. Female SD rats were randomly divided into three groups: control rats, type 2 diabetic rats and type 2 diabetic rats treated with fluvastatin (2mg/kg/d). After 6 weeks, blood glucose, serum insulin, serum triglyceride and cholesterol, serum creatinine, and urinary protein were measured respectively. The protein expressions of c Jun and tansforming growth factor (TGF) ? 1 were studied by immunohistochemistry. TGF ? 1 gene expression was studied with a RT PCR technique. Results Fluvastatin at lower doses, which did not influence blood glucose and blood lipid level, significantly inhibited expression of c Jun protein(0 2536?0 0180 vs 0 5855?0 0314, P
