Lysosome function in glomerular health and disease

Cell and Tissue Research, Год журнала: 2021, Номер 385(2), С. 371 - 392

Опубликована: Янв. 12, 2021

Abstract The lysosome represents an important regulatory platform within numerous vesicle trafficking pathways including the endocytic, phagocytic, and autophagic pathways. Its ability to fuse with endosomes, phagosomes, autophagosomes enables break down a wide range of both endogenous exogenous cargo, macromolecules, certain pathogens, old or damaged organelles. Due its center position in intricate network events, has emerged as central signaling node for sensing orchestrating cells metabolism immune response, inter-organelle inter-cellular membrane repair. This review highlights current knowledge general function discusses these findings their implication renal glomerular cell types health disease involvement lysosomal storage diseases role lysosomes nongenetic injuries.

Язык: Английский

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CRISPR/Cas9-mediated A4GALT suppression rescues Fabry disease phenotypes in a kidney organoid model

Translational research, Год журнала: 2023, Номер 258, С. 35 - 46

Опубликована: Фев. 18, 2023

Язык: Английский

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Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

Journal of Clinical Medicine, Год журнала: 2021, Номер 10(8), С. 1664 - 1664

Опубликована: Апрель 13, 2021

Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations GLA gene, resulting gradual accumulation of globotriaosylceramide and other derivatives different tissues. Substrate promotes pathogenic mechanisms which several mediators could be implicated, inducing multiorgan lesions, mainly kidney, heart nervous system, clinical manifestations disease. Enzyme replacement therapy was shown delay progression, if initiated early. However, diagnosis early stages represents challenge, especially patients with non-classic phenotype, prompts search for biomarkers that help detect predict evolution We have reviewed involved were studied as potential can easily incorporated into practice. Some seem useful forms even improve female patients. The combination such some response biomarkers, may detection organ injury. incorporation practice increase capacity compared currently obtained established diagnostic markers provide more information on progression prognosis

Язык: Английский

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Early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression

Molecular Genetics and Metabolism, Год журнала: 2021, Номер 135(2), С. 163 - 169

Опубликована: Дек. 17, 2021

Enzyme replacement therapy (ERT) slows disease progression of Fabry (FD), especially when initiated before the onset irreversible organ damage. However, with clinically asymptomatic renal, cardiac and cerebral manifestations spanning decades, optimal timing ERT initiation remains unclear.In this cross-sectional retrospective study, seven male FD patients a classical phenotype (cFD) who started treatment agalsidase-beta in childhood were evaluated after 10 years (median age at evaluation 24 years, range 14-26). Cardiac imaging (echocardiography MRI), electrophysiological biochemical data these compared to those untreated cFD (n = 23, median 22 13-27).Albuminuria was less common severe treated (albumin creatinine ratio, ACR 0-8.8 mg/mmol, 0.4) (ACR 0-248 3.7, p 0.02). The group had lower left ventricular mass, measured using echocardiography 80 g/m2 versus 94 g/m2, 0.02) MRI 53 68 Myocardial fibrosis absent all included patients. eGFR normal whereas 7/23 (30%) abnormal eGFR. Cerebral did not differ.Start 16, is associated reduced occurrence renal FD, as assessed by intermediate endpoints. Confirmation that approach delays or even prevents failure events requires another decade follow-up.

Язык: Английский

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Clinical relevance of globotriaosylceramide accumulation in Fabry disease and the effect of agalsidase beta in affected tissues

Molecular Genetics and Metabolism, Год журнала: 2022, Номер 137(4), С. 328 - 341

Опубликована: Окт. 30, 2022

Fabry disease (FD) is a rare lysosomal storage disorder, characterized by reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) its metabolites cells various organs. Agalsidase beta, an replacement therapy (ERT), approved for use patients with FD Europe, Canada, Australia, South America, Asia, only ERT United States. In this review, we discuss clinical relevance GL3 accumulation, effect agalsidase beta on target tissues, association between treatment-related tissue clearance long-term structure, function, or outcomes. Accumulation kidney, heart, vasculature, neurons, skin, gastrointestinal tract auditory system correlates to cellular damage irreversible organ damage, as result sclerosis, fibrosis, apoptosis, inflammation, endothelial dysfunction. Damage leads renal dysfunction end-stage disease; myocardial hypertrophy heart failure arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia dysmotility; hearing loss. Treatment effective substantially clearing range from tissues affected FD. has also been shown slow decline lower overall risk progression, demonstrating indirect link stabilization

Язык: Английский

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Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry Registry

Molecular Genetics and Metabolism, Год журнала: 2022, Номер 138(2), С. 106967 - 106967

Опубликована: Ноя. 30, 2022

Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop adulthood. Outcomes Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes aged 5-30 years at initiation with agalsidase beta using data from the Registry (NCT00196742, sponsor: Sanofi).Reported GLA variants were predicted be associated phenotype or classified fabry-database.org. Linear mixed models conducted assess changes over ≥2-year follow-up estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined proteinuria/albuminuria levels), interventricular septal thickness (IVST) left ventricular posterior wall (LVPWT) Z-scores median age first treatment. Self-reports ('yes'/'no') abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), acute crises baseline compared reports after ≥0.5-year ≥2.5-year McNemar's test.Male (n = 117) female 59) LRI initiated a 19.9 23.6 years, respectively, followed for 6.3 5.0 respectively. The eGFR slopes -1.18 (Pfrom 0 <0.001) -0.92 mL/min/1.73 m2/year 0.040), Males HRI 23, UPCR 1.0 g/g), who started 26.7 had an slope -2.39 <0.001; Pdifference 0.055, as males) during 5.6 years. Echocardiographic variables stable males, regardless age, females (median >5.5 ≥4.5 respectively). Older (treatment 27.5 years) LVPWT 0.18/year 12, Pfrom 0.028), whereas IVST remained 13, 0.10/year, 0.304) ≥3.7 These did significantly differ younger females. Reports diarrhea females, reduced ≥4.0 After ≥5.4 all four symptoms decreased only decreased.During sustained unclassified similar characteristics, decline modest male LRI. greater older, proteinuric (i.e., HRI) males may suggest benefit earlier Overall, echocardiographic stable, particularly Significant reductions symptom occurred primarily longer less noticeable observed trends are suggestive overall improvement patients, but warrant larger longitudinal studies.

Язык: Английский

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Early Risk Stratification for Natural Disease Course in Fabry Patients Using Plasma Globotriaosylsphingosine Levels

Clinical Journal of the American Society of Nephrology, Год журнала: 2023, Номер 18(10), С. 1272 - 1282

Опубликована: Июль 27, 2023

Fabry disease is a very heterogeneous X-linked lysosomal storage disease. Disease manifestations in the kidneys, heart, and brain vary greatly, even between patients of same sex with classification (classical or nonclassical). A biomarker strong association development needed to determine need for Fabry-specific treatment appropriate frequency follow-up because clinical disorder may take decennia develop.

Язык: Английский

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Precision medicine in Fabry disease

Nephrology Dialysis Transplantation, Год журнала: 2021, Номер 36(Supplement_2), С. 14 - 23

Опубликована: Фев. 10, 2021

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A (GLA) gene, leading to deficiency A. The accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3), results progressive renal failure, cardiomyopathy associated with cardiac arrhythmia recurrent cerebrovascular events, significantly limiting life expectancy affected patients. In male patients, definitive diagnosis FD involves demonstrating GLA leucocytes. females, because potential high residual enzymatic activity, diagnostic gold standard requires molecular genetic analyses. current treatment options for include recombinant enzyme replacement therapies (ERTs) intravenous agalsidase-α (0.2 mg/kg body weight) or agalsidase-β (1 every 2 weeks as well an oral pharmacological chaperone (migalastat 123 mg other day) that selectively reversibly binds active sites amenable mutant forms enzyme. These facilitate cellular Gb3 clearance overall improvement burden. However, ERT can lead infusion-associated reactions, formation neutralizing anti-drug antibodies ∼40% all ERT-treated males, attenuation therapy efficacy. This article reviews clinical presentation, interdisciplinary management discusses therapeutic options, special focus on precision medicine, accounting individual variability mutations, lyso-Gb3 levels, allowing physicians predict more accurately which prevention strategy best patient.

Язык: Английский

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Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study

Frontiers in Medicine, Год журнала: 2023, Номер 10

Опубликована: Сен. 1, 2023

Objective Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition oral chaperone therapy migalastat available treatment options for not yet universally reflected in all guidelines. These consensus recommendations are intended provide guidance and monitoring patients receiving migalastat. Methods modified Delphi process was conducted determine on decisions multidisciplinary panel comprised 14 expert physicians across nine specialties two disease. Two rounds surveys were completed use biomarkers, monitoring, generated based statements that reached consensus. Results agreement 49 54 statements, including 16 round 1. Statements summarized baseline follow-up assessments frequency. All an amenable mutation may initiate if they have evidence Fabry-related symptoms and/or involvement. Treatment should include holistic assessment patient, considering involvement as well patient-reported outcomes patient preference. reliability α-Gal globotriaosylsphingosine pharmacodynamic response biomarkers remains unclear. Conclusion build previously published guidelines highlight importance holistic, migalastat, shared decision-making regarding treatments throughout journey.

Язык: Английский

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GLA Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease

Cells, Год журнала: 2024, Номер 13(5), С. 437 - 437

Опубликована: Март 1, 2024

Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the GLA gene leading to a deficiency of enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated FD, most notably kidney, heart, and central nervous system. In our previous study, we identified four from independent families with kidney or neuropathic pain: c.119C>A (p.P40H), c.280T>C (C94R), c.680G>C (p.R227P) c.801+1G>A (p.L268fsX3). To reveal molecular mechanism underlying predisposition mutations, analyzed effects these on protein structure α-galactosidase using bioinformatics methods. The results showed that have significant impact internal dynamics structures GLA, all altered amino acids close activity center lead significantly reduced activity. Furthermore, led accumulation autophagosomes impairment autophagy cells, which may turn negatively regulate slightly increasing phosphorylation mTOR. Moreover, overexpression mutants promoted expression lysosome-associated membrane 2 (LAMP2), resulting increased number lysosomes. Our study reveals pathogenesis FD provides scientific foundation for accurate diagnosis precise medical intervention FD.

Язык: Английский

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