BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disease resulting from pathogenic variants in the GLA gene coding α-galactosidase A (AGAL) and cleaving terminal alpha-linked galactose. Globotriaosylceramide (Gb3) is the predominantly accumulated sphingolipid. Gb3, deacylated-Gb3 (lysoGb3), and methylated-Gb3 (metGb3) have been suggested as FD biomarkers. MATERIALS AND METHODS: We developed a novel LC-MS/MS method for assessing lysoGb3 levels in plasma and Gb3 and metGb3 in urine and tested 62 FD patients, 34 patients with GLA variants of unknown significance (VUS) and 59 healthy controls. AGAL activity in white blood cells (WBCs) and plasma was evaluated in parallel. RESULTS: In males, lysoGb3 concentrations in plasma separated classic and late-onset FD patients from each other and from individuals carrying GLA VUS and healthy controls. Calculating AGAL activity/plasmatic lysoGb3 ratio allowed to correctly categorize all females with classic and majority of patients with late-onset FD phenotypes. Correlation of AGAL activity in WBCS with lipid biomarkers identified threshold activity values under which the biomarkers' concentrations increase. CONCLUSION: We developed a novel simplified LC-MS/MS method for quantitation of plasma lysoGb3. AGAL activity/plasma lysoGb3 ratio was identified as the best predictor for FD. AGAL activity correlated with plasma lysoGb3 and corresponded to individual FD phenotypes.

• MeSH
• alfa-galaktosidasa genetika   metabolismus   MeSH
• biologické markery krev   MeSH
• chromatografie kapalinová MeSH
• dospělí MeSH
• Fabryho nemoc * krev   diagnóza   moč   MeSH
• fenotyp MeSH
• glykolipidy krev   moč   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři MeSH
• sfingolipidy * krev   MeSH
• tandemová hmotnostní spektrometrie * MeSH
• trihexosylceramidy metabolismus   krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND AIMS: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by disease-associated variants in the alpha-galactosidase A gene (GLA). FD is a known cause of stroke in younger patients. There are limited data on prevalence of FD and stroke risk in unselected stroke patients. METHODS: A prospective nationwide study including 35 (78%) of all 45 stroke centers and all consecutive stroke patients admitted during three months. Clinical data were collected in the RES-Q database. FD was diagnosed using dried blood spots in a stepwise manner: in males-enzymatic activity, globotriaosylsphingosine (lyso-Gb3) quantification, if positive followed by GLA gene sequencing; and in females GLA sequencing followed by lyso-Gb3. RESULTS: 986 consecutive patients (54% men, mean age 70 years) were included. Observed stroke type was ischemic 79%, transient ischemic attack (TIA) 14%, intracerebral hemorrhage (ICH) 7%, subarachnoid hemorrhage 1% and cerebral venous thrombosis 0.1%. Two (0.2%, 95% CI 0.02-0.7) patients had a pathogenic variant associated with the classical FD phenotype (c.1235_1236delCT and p.G325S). Another fourteen (1.4%, 95% CI 0.08-2.4) patients had a variant of GLA gene considered benign (9 with p.D313Y, one p.A143T, one p.R118C, one p.V199A, one p.R30K and one p.R38G). The index stroke in two carriers of disease-associated variant was ischemic lacunar. In 14 carriers of GLA gene variants 11 strokes were ischemic, two TIA, and one ICH. Patients with positive as compared to negative GLA gene screening were younger (mean 60±SD, min, max, vs 70±SD, min, max, P = 0.02), otherwise there were no differences in other baseline variables. CONCLUSIONS: The prevalence of FD in unselected adult patients with acute stroke is 0.2%. Both patients who had a pathogenic GLA gene variant were younger than 50 years. Our results support FD screening in patients that had a stroke event before 50 years of age.

• MeSH
• alfa-galaktosidasa krev   genetika   MeSH
• cévní mozková příhoda krev   komplikace   epidemiologie   genetika   MeSH
• exprese genu MeSH
• Fabryho nemoc krev   komplikace   epidemiologie   genetika   MeSH
• genetické testování MeSH
• glykolipidy krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• prevalence MeSH
• prospektivní studie MeSH
• senioři MeSH
• sfingolipidy krev   MeSH
• test suché kapky krve MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

Fabryho nemoc je vzácná dědičná metabolická porucha ze skupiny lysozomálních střádavých onemocnění. Tato nemoc je léčitelná díky enzymové substituční terapii, v České republice dostupné od roku 2004. Vzhledem k dostupnosti terapie je důležité tyto pacienty, skrývající se pod nejrůznějšími diagnózami v mnoha ambulancích, správně a včas diagnostikovat.

Fabry disease is an X-linked lysosomal storage disease. Enzyme replacement therapy (ERT) is available in our country since 2004.The sooner diagnosis is made, the better ERT stabilizes the progression of Fabry disease. The timing of ERT is important in orderto prevent irreversible organ damage.

• MeSH
• alfa-galaktosidasa terapeutické užití   MeSH
• časná diagnóza MeSH
• diferenciální diagnóza MeSH
• enzymová substituční terapie ekonomika   metody   MeSH
• Fabryho nemoc * genetika   krev   terapie   MeSH
• Publikační typ
• přehledy MeSH

Blood group B glycosphingolipids (B-GSLs) are substrates of the lysosomal alpha-galactosidase A (AGAL). Similar to its major substrate-globotriaosylceramide (Gb3Cer)-B-GSLs are not degraded and accumulate in the cells of patients affected by an inherited defect of AGAL activity (Fabry disease-FD).The pancreas is a secretory organ known to have high biosynthesis of blood group GSLs. Herein, we provide a comprehensive overview of the biochemical and structural abnormalities in pancreatic tissue from two male FD patients with blood group B. In both patients, we found major accumulation of a variety of complex B-GSLs carrying predominantly hexa- and hepta-saccharide structures. The subcellular pathology was dominated by deposits containing B-glycoconjugates and autofluorescent ceroid. The contribution of Gb3Cer to the storage was minor. This abnormal storage pattern was specific for the pancreatic acinar epithelial cells. Other pancreatic cell types including those of islets of Langerhans were affected much less or not at all.Altogether, we provide evidence for a key role of B-antigens in the biochemical and morphological pathology of the exocrine pancreas in FD patients with blood group B. We believe that our findings will trigger further studies aimed at assessing the potential pancreatic dysfunction in this disease.

• MeSH
• ABO systém krevních skupin metabolismus   MeSH
• acinární buňky metabolismus   ultrastruktura   MeSH
• beta-buňky metabolismus   ultrastruktura   MeSH
• Fabryho nemoc krev   metabolismus   patologie   MeSH
• galaktosa analýza   metabolismus   MeSH
• glykosfingolipidy chemie   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• pankreas metabolismus   ultrastruktura   MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The aim of our study was to assess the possible relationships among heme oxygenase (HMOX), bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variations, serum bilirubin levels, and Fabry disease (FD). The study included 56 patients with FD (M : F ratio = 0.65) and 185 healthy individuals. Complete standard laboratory and clinical work-up was performed on all subjects, together with the determination of total peroxyl radical-scavenging capacity. The (GT)n and (TA)n dinucleotide variations in the HMOX1 and UGT1A1 gene promoters, respectively, were determined by DNA fragment analysis. Compared to controls, patients with FD had substantially lower serum bilirubin levels (12.0 versus 8.85 μmol/L, p = 0.003) and also total antioxidant capacity (p < 0.05), which showed a close positive relationship with serum bilirubin levels (p = 0.067) and the use of enzyme replacement therapy (p = 0.036). There was no association between HMOX1 gene promoter polymorphism and manifestation of FD. However, the presence of the TA7 allele UGT1A1 gene promoter, responsible for higher systemic bilirubin levels, was associated with a twofold lower risk of manifestation of FD (OR = 0.51, 95% CI = 0.27-0.97, p = 0.038). Markedly lower serum bilirubin levels in FD patients seem to be due to bilirubin consumption during increased oxidative stress, although UGT1A1 promoter gene polymorphism may modify the manifestation of FD as well.

• MeSH
• antioxidancia metabolismus   MeSH
• bilirubin krev   MeSH
• dospělí MeSH
• Fabryho nemoc krev   enzymologie   genetika   MeSH
• glukuronosyltransferasa genetika   MeSH
• hemoxygenasa-1 genetika   MeSH
• lidé MeSH
• polymorfismus genetický MeSH
• promotorové oblasti (genetika) MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Serum uric acid (UA) elevation is common in patients with cardiovascular, renal and metabolic diseases. However, no study to date has analysed the role of UA in Fabry disease (FD). OBJECTIVES: To evaluate the association between serum UA levels and mortality and morbidity in FD. MATERIALS AND METHODS: We conducted a post-hoc analysis of a prospectively followed-up cohort of 124 patients with genetically proven FD. Serum UA levels were acquired at baseline; clinical events and mortality were assessed during regular visits every 6 to 12 months. The primary endpoint was a composite of multiple secondary outcomes: all-cause mortality, adverse cardiovascular events, progression of renal dysfunction and stroke or transient ischaemic attack (TIA). Predictive value was assessed using the Cox proportional hazards model and the Kaplan Meyer estimator. RESULTS: During follow-up of 7.4 ± 3.7 years, 64 (52%) patients reached the primary combined endpoint. Overall, UA levels were significantly associated with combined outcome (p < 0.001) and remained independently associated after correcting for age, sex and estimated glomerular filtration rate (hazard ratio [HR] per 20 μmol/l increase 1.09, 95% confidence interval [95%CI] (1.00-1.19), p = 0.04). UA was associated with overall mortality in univariate analysis (p = 0.021); however, the association did not reach statistical significance after multivariate correction (HR per 20 μmol/l increase 1.07 95%CI 0.93-1.25, p = 0.32). Higher UA levels were also associated with cardiac adverse outcomes, progression of left ventricular hypertrophy and progression of renal dysfunction (ps < 0.001). No association was observed between UA levels and stroke or TIA (p = 0.323). CONCLUSION AND IMPLICATIONS: Increased serum UA levels may represent an independent risk factor for adverse clinical outcomes in Fabry patients and are associated with all-cause mortality. UA is a widely available and cheap biomarker that may improve risk stratification of Fabry patients in clinical practice.

• MeSH
• biologické markery krev   MeSH
• cévní mozková příhoda epidemiologie   MeSH
• dospělí MeSH
• Fabryho nemoc krev   epidemiologie   mortalita   MeSH
• hodnocení výsledků zdravotní péče metody   statistika a číselné údaje   MeSH
• Kaplanův-Meierův odhad MeSH
• kyselina močová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladý dospělý MeSH
• morbidita MeSH
• následné studie MeSH
• progrese nemoci MeSH
• proporcionální rizikové modely MeSH
• prospektivní studie MeSH
• tranzitorní ischemická ataka epidemiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články 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
• biopsie MeSH
• cévní endotel patologie   MeSH
• demografie MeSH
• dítě MeSH
• Fabryho nemoc krev   farmakoterapie   patofyziologie   moč   MeSH
• genotyp MeSH
• glykolipidy krev   MeSH
• hodnoty glomerulární filtrace MeSH
• johexol MeSH
• kůže krevní zásobení   MeSH
• kvalita života MeSH
• ledviny patologie   patofyziologie   ultrastruktura   MeSH
• lidé MeSH
• mladiství MeSH
• mozek patologie   MeSH
• mutace genetika   MeSH
• předškolní dítě MeSH
• sfingolipidy krev   MeSH
• trihexosylceramidy krev   genetika   moč   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

• MeSH
• časná diagnóza MeSH
• Fabryho nemoc genetika   krev   MeSH
• Gaucherova nemoc genetika   krev   MeSH
• genetické nemoci vázané na chromozom X * genetika   krev   MeSH
• lidé MeSH
• sfingolipidózy diagnóza   genetika   MeSH
• Check Tag
• lidé MeSH

BACKGROUND: Fabry disease (FD) is a genetic disorder characterized by accumulation of trihexosylceramide in lysosomes of various tissues leading to multiorgan manifestations, including progressive renal disease. Previous screening studies have shown that a non-neglectable proportion of haemodialysis(HD) patients have unsuspected FD. An extensive FD screening study, the largest to date, has been conducted in HD patients in Czech Republic. We aimed to uncover previously undiagnosed FD patients, to enable them to benefit from cause-specific therapeutic intervention with enzyme replacement therapy (ERT). METHODS: Large-scale screening was executed using a convenient automated enzymatic (alpha-galactosidose A, alpha-Gal A) dried blood spot on filter paper fluorescence method. RESULTS: In total, 3370 (45.1% males, 54.9% females) out of 4058 HD patients (83%) in Czech Republic participated in this blood spot screening (BSS) study. Abnormal low fluorescence readings were obtained in 117 patients (3.5%). Subsequent determination of plasma alpha-Gal A activity identified four males and three females with deficient plasma enzyme activity. Determination of alpha-Gal A activity in peripheral blood leucocytes and confirmatory molecular analysis resulted in four newly diagnosed Fabry males and one female. Subsequent family screening identified 10 family members with genotypically proven FD. Based on these screening results, ERT could be offered to five male FD patients. CONCLUSIONS: BSS represents a promising screening tool that has proven to be convenient and effective in uncovering unrecognized FD patients among the chronic HD population in Czech Republic.

• MeSH
• alfa-galaktosidasa chemie   MeSH
• dialýza ledvin metody   MeSH
• dospělí MeSH
• enzymoterapie MeSH
• enzymy MeSH
• Fabryho nemoc diagnóza   krev   terapie   MeSH
• financování organizované MeSH
• fluorescenční spektrometrie MeSH
• konformace proteinů MeSH
• lidé středního věku MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• rodokmen MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Geografické názvy
• Česká republika MeSH

• MeSH
• ABO systém krevních skupin krev   moč   MeSH
• chromatografie na tenké vrstvě MeSH
• Fabryho nemoc krev   moč   MeSH
• glykosfingolipidy analýza   chemie   imunologie   MeSH
• krční mandle chemie   MeSH
• lidé MeSH
• monoklonální protilátky imunologie   MeSH
• myši MeSH
• transplantace ledvin MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH