Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.
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ABSTRACT:
SUBMITTER: Maruyama H
PROVIDER: S-EPMC7609257 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
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Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.
Maruyama Hiroki H Miyata Kaori K Mikame Mariko M Taguchi Atsumi A Guili Chu C Shimura Masaru M Murayama Kei K Inoue Takeshi T Yamamoto Saori S Sugimura Koichiro K Tamita Koichi K Kawasaki Toshihiro T Kajihara Jun J Onishi Akifumi A Sugiyama Hitoshi H Sakai Teiko T Murata Ichijiro I Oda Takamasa T Toyoda Shigeru S Hanawa Kenichiro K Fujimura Takeo T Ura Shigehisa S Matsumura Mimiko M Takano Hideki H Yamashita Satoshi S Matsukura Gaku G Tazawa Ryushi R Shiga Tsuyoshi T Ebato Mio M Satoh Hiroshi H Ishii Satoshi S
Genetics in medicine : official journal of the American College of Medical Genetics 20190501 5
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. ...[more]
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Project description:PurposePlasma 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.MethodsBetween 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.ResultsOf 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).ConclusionPlasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands.
| S-EPMC6363642 | biostudies-literature
Project description:Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of α-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD.
| S-EPMC3589404 | biostudies-literature
Project description:Biomarkers useful for diagnosis and evaluation of treatment for patients with Fabry disease are urgently needed. Recently, plasma globotriaosylsphingosine (lyso-Gb3) and lyso-Gb3-related analogues have attracted attention as promising biomarkers of Fabry disease. However, the plasma concentrations of lyso-Gb3 and its analogues are extremely low or below the detection limits in some Fabry patients as well as in healthy subjects. In this paper, we introduce the novel application of a nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) system to the measurement of lyso-Gb3 and its analogues in plasma. Nano-LC-MS/MS requires smaller amounts of samples and is more sensitive than conventional techniques. Using this method, we measured the plasma concentrations of lyso-Gb3 and its analogues in 40 healthy subjects, 5 functional variants (males with E66Q), and various Fabry patients (9 classic Fabry males/9 mutations; 7 later-onset Fabry males/5 mutations; and 10 Fabry females/9 mutations). The results revealed that the mean lyso-Gb3 and lyso-Gb3(-2) concentrations in all the Fabry patient subgroups were statistically higher, especially in the classic Fabry males, than those in the functional variants and healthy subjects. The plasma concentrations of lyso-Gb3 and its analogues in healthy subjects, functional variants, and some Fabry patients with specific mutations (R112H and M296I) that cannot be established by conventional techniques were successfully determined by means of nano-LC-MS/MS. The lyso-Gb3 and lyso-Gb3(-2) concentrations in male patients with these mutations were lower than those in most Fabry patients having other mutations, but higher than those in the functional variants and healthy subjects. This new method is expected to be useful for sensitive determination of the plasma concentrations of lyso-Gb3 and its analogues. This study also revealed that not only lyso-Gb3 but also lyso-Gb3(-2) in plasma is a useful biomarker for the diagnosis of Fabry disease.
| S-EPMC4428877 | biostudies-literature
Project description:Globotriaosylsphingosine (lyso-Gb3) is a well-established biomarker for diagnosis and prognosis of Fabry disease. This biomarker is measured in biological samples by liquid chromatography-tandem mass spectrometry using an internal standard. The ideal internal standard is a variant of lyso-Gb3 substituted with heavy isotopes, but the total synthesis of such a compound is very labor intensive. In this report, we describe a simple, one-step synthesis of lyso-Gb3 labeled with carbon-13 in all of the galactosyl carbons.
| S-EPMC6239936 | biostudies-literature
Project description:BACKGROUND:Fabry disease (FD), an X-linked lysosomal storage disease, results from an ?-galactosidase A deficiency and altered sphingolipid metabolism. An accumulation of globotriaosylsphingosine (lyso-Gb3) likely triggers the pathological cascade leading to disease phenotype. The pathogenic significance of several Fabry mutations including the R118C ?-galactosidase (GLA) gene variant has been disputed. We describe three members of the same family with the R118C variant, each having documented clinical signs of FD, low residual enzyme levels, and an elevated lyso-Gb3 in one heterozygote.Determining the clinical significance of each GLA gene variant remains an ongoing challenge, with potential for inadequate treatment if the diagnosis of FD is missed. Elevated lyso-Gb3 has been shown to be the most reliable noninvasive marker of clinically relevant GLA variants. While the R118C variant will likely lead to a milder phenotype, additional genetic, epigenetic, and environmental factors can ameliorate or exacerbate the expression and impact on the resultant phenotype and associated complications. Patients affected with this variant warrant closer review and better management of disease risk factors.
| S-EPMC6336544 | biostudies-literature
Project description:Podocyturia in Fabry nephropathy leads to glomerulosclerosis and kidney disease progression. Integrins are involved in podocyte attachment to the glomerular basement membrane. We hypothesized that in Fabry nephropathy, lyso-Gb3 could modulate αvβ3 expression in podocytes. Together with UPAR, the αvβ3 integrin is a key mechanism involved in podocyte detachment and podocyturia. In cultured human podocytes stimulated with lyso-Gb3, the mRNA expression of the ITGAV and ITGB3 genes encoding integrins αv and β3, respectively, was analyzed by RT-qPCR. In cultured human podocytes, lyso-Gb3 at concentrations encountered in the serum of Fabry patients increased ITGAV and ITGB3 mRNA levels within 3 to 6 h. This pattern of gene expression is similar to that previously observed for PLAUR (UPAR) gene expression but is in contrast to the delayed (24 h) upregulation of other markers of podocyte stress and mediators of injury, such as CD80, TGFβ1, CD74, Notch1, and HES. Human podocyte stress in response to glycolipid overload in Fabry nephropathy, exemplified by lyso-Gb3, is characterized by an early increase in the expression of components of the αvβ3/UPAR system, which contrasts with the delayed rise in the expression of other mediators of podocyte injury. This suggests that the αvβ3/UPAR system may be a therapeutic target in Fabry nephropathy.
| S-EPMC7696179 | biostudies-literature
Project description:Fabry disease is an X-linked lysosomal storage disorder characterised by accumulation of glycosphingolipids, and accompanied by clinical manifestations, such as cardiac disorders, renal failure, pain and peripheral neuropathy. Globotriaosylsphingosine (lyso-Gb3), a deacylated form of globotriaosylceramide (Gb3), has emerged as a marker of Fabry disease. We investigated the link between Gb3, lyso-Gb3 and pain. Plantar administration of lyso-Gb3 or Gb3 caused mechanical allodynia in healthy mice. In vitro application of 100nM lyso-Gb3 caused uptake of extracellular calcium in 10% of sensory neurons expressing nociceptor markers, rising to 40% of neurons at 1?M, a concentration that may occur in Fabry disease patients. Peak current densities of voltage-dependent Ca(2+) channels were substantially enhanced by application of 1?M lyso-Gb3. These studies suggest a direct role for lyso-Gb3 in the sensitisation of peripheral nociceptive neurons that may provide an opportunity for therapeutic intervention in the treatment of Fabry disease-associated pain.
| S-EPMC4411215 | biostudies-literature
Project description:PurposeTo assess the utility of globotriaosylsphingosine (lyso-Gb3) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat.MethodsA post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb3 and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb3 and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb3 and kidney interstitial capillary (KIC) globotriaosylceramide (Gb3) inclusions was assessed in treatment-naive patients.ResultsNo significant correlations were identified between changes in lyso-Gb3 and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb3 levels nor the rate of change in lyso-Gb3 levels during treatment predicted FACE occurrences in all patients or those receiving migalastat for ≥24 months. Changes in lyso-Gb3 correlated with changes in KIC Gb3 inclusions in treatment-naive patients.ConclusionsAlthough used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb3 may not be a suitable biomarker for monitoring treatment response in migalastat-treated patients.
| S-EPMC7790748 | biostudies-literature
Project description:AimFabry disease is a lysosomal storage disorder leading to glycosphingolipid accumulation in different organs, tissues and biological fluids. The development of a Fabry disease gene therapy trial is underway in Canada. A tool to determine the distribution of Gb3 biomarkers in tissues of Fabry mice might be applicable to monitor the effect of gene therapy. Results & methodology: An ultra-performance LC-MS/MS (UPLC-MS/MS) method for the analysis of 22 Gb3 isoform/analogs in various Fabry mice tissues was developed and validated. Marked variation in biomarker organ distribution was found with higher levels in the spleen, followed by the small intestine, kidneys, lungs, heart, liver and brain.ConclusionThe devised method is sensitive and useful for the evaluation of biomarker profiles in Fabry mice.
| S-EPMC4992964 | biostudies-literature
Project description:BackgroundFabry disease (FD) is a rare lysosomal storage disorder caused by mutations in the GLA gene, resulting in reduced or lack of α-galactosidase A activity. This results in the accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in lysosomes causing cellular impairment and organ failures. While current therapies focus on reversing Gb3 accumulation, they do not address the altered cellular signaling in FD. Therefore, this study aims to explore Gb3-independent mechanisms of kidney damage in Fabry disease and identify potential biomarkers.MethodsTo investigate these mechanisms, we utilized a zebrafish (ZF) gla-/- mutant (MU) model. ZF naturally lack A4GALT gene and, therefore, cannot synthesize Gb3. We obtained kidney samples from both wild-type (WT) (n = 8) and MU (n = 8) ZF and conducted proteome profiling using untargeted mass spectrometry. Additionally, we examined mitochondria morphology and cristae morphology using electron microscopy. To assess oxidative stress, we measured total antioxidant activity. Finally, immunohistochemistry was conducted on kidney samples to validate specific proteins.ResultsOur proteomics analysis of renal tissues from zebrafish revealed downregulation of lysosome and mitochondrial-related proteins in gla-/- MU renal tissues, while energy-related pathways including carbon, glycolysis, and galactose metabolisms were disturbed. Moreover, we observed abnormal mitochondrial shape, disrupted cristae morphology, altered mitochondrial volume and lower antioxidant activity in gla-/- MU ZF.ConclusionsThese results suggest that the alterations observed at the proteome and mitochondrial level closely resemble well-known GLA mutation-related alterations in humans. Importantly, they also unveil novel Gb3-independent pathogenic mechanisms in Fabry disease. Understanding these mechanisms could potentially lead to the development of innovative drug screening approaches. Furthermore, the findings pave the way for identifying new clinical targets, offering new avenues for therapeutic interventions in Fabry disease. The zebrafish gla-/- mutant model proves valuable in elucidating these mechanisms and may contribute significantly to advancing our knowledge of this disorder.
| S-EPMC10478213 | biostudies-literature