Mutation-Specific Cardiomyocyte Lines from Patients with Fabry Disease: A Sustainable In Vitro Model to Investigate Structure, Function, and Disease Mechanisms

International Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 5(2), P. 15 - 15

Published: April 15, 2025

Background: Fabry disease (FD) results from pathogenic GLA variants, causing lysosomal α-galactosidase A (α-GalA) deficiency and sphingolipid ceramide trihexoside (Gb3 or THC) accumulation. Disease phenotype varies widely but cardiomyopathy is commonly life-limiting. As a multisystemic disorder, FD initiates at the cellular level; however, mechanism/s underlying Gb3-induced cell dysfunction remains largely unknown. This study established an in vitro mutation-specific model of using human-induced pluripotent stem (iPSC)-derived cardiomyocytes to explore pathology. Methods: Skin biopsies consenting patients normal control subjects were reprogrammed iPSCs then differentiated into cardiomyocytes. The mutations lines corrected CRISP-Cas9. Phenotypic characteristics, α-Gal activity, Gb3 accumulation, functional status, lipid analysis assessed. Cardiomyocytes derived two with severe clinical genotypes, GLAc.851T>C, GLAc.1193_1196del, their respective lines, GLAcorr c.851T>C, c.1193_1196del, selected for further studies. Results: individuals exhibited stable expression cardiomyocyte markers spontaneous contraction, morphological features FD, reduced accumulation Gb3. Lipidomic profiling revealed differences isoform profile between patient iPSC-derived Contraction strength was unchanged relaxation after contraction delayed, mimicking diastolic typical cardiomyopathy. Conclusions: provide useful aspects cardiomyopathy, including disruptions pathways, proteomics, multigene that together link genotype phenotype. platform potentially offers broad applicability across many genetic diseases prospect testing implementation individualised therapies.

Language: Английский

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Progress and Challenges in the Treatment of Fabry Disease

BioDrugs, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Fabry disease is a rare but life-threatening, X-linked, inherited lysosomal storage disorder in which globotriaosylceramide insufficiently metabolized because of reduced α-galactosidase A activity. Cellular accumulation causes multisystemic disease, which, if left untreated, reduces life expectancy female and male individuals by around 10 20 years, respectively, leading to progressive renal failure, hypertrophic cardiomyopathy, cardiac arrhythmia, premature cerebral infarction. The method choice for confirming the diagnosis determination activity leukocytes molecular genetic detection disease-causing mutation individuals. Current approved treatment includes enzyme replacement therapy (agalsidase alfa [0.2 mg/kg body weight], agalsidase beta or pegunigalsidase [both 1.0 weight]) every other week intravenously or, responding ('amenable') present, oral pharmacological chaperone (migalastat 123 mg, day). Future therapeutic options may include substrate reduction therapy, gene messenger RNA and/or vesicle-packaged therapy. This review presents current future with advantages disadvantages different options.

Language: Английский

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Long-Term Monitoring of Cardiac Involvement under Migalastat Treatment Using Magnetic Resonance Tomography in Fabry Disease

Life, Journal Year: 2023, Volume and Issue: 13(5), P. 1213 - 1213

Published: May 19, 2023

Background: Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was associated a stabilization of cardiac biomarkers reduction in mass index, as measured echocardiography. A recent study, using magnetic resonance (CMR) the gold standard, found stable course involvement after 18 months treatment migalastat. Our study aimed to provide long-term CMR data for Methods: total 11 females four males pathogenic amenable GLA mutations were treated migalastat underwent 1.5T imaging routine effect monitoring. The main outcome structural change, reflected CMR. Results: After initiation, end diastolic volume, interventricular septal thickness, posterior wall estimated glomerular filtration rate, plasma lyso-Gb3 remained during median follow-up time 34 (min.: 25; max.: 47). T1 relaxation times, reflecting glycosphingolipid accumulation subsequent processes up fluctuated over without clear trend. No new onset late gadolinium enhancement (LGE) areas, local fibrosis or scar formation myocardium, could be detected. However, patients initially present LGE showed increase percentage mass. α-galactosidase enzymatic activity increased from 37.3% (IQR 5.88-89.3) 105% 37.2-177) lower limit respective reference level (p = 0.005). Conclusion: confirms overall LVMi FD, individual may experience disease progression, especially those who myocardium already at therapy initiation. Thus, regular re-evaluation including needed optimal management each patient.

Language: Английский

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Renal and multisystem effectiveness of 3.9 years of migalastat in a global real‐world cohort: Results from the followME Fabry Pathfinders registry

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: 48(1)

Published: July 19, 2024

Abstract Fabry disease is a progressive, X‐linked lysosomal disorder caused by reduced or absent α‐galactosidase A activity due to GLA variants. The effects of migalastat were examined in cohort 125 patients with migalastat‐amenable variants the followME Pathfinders registry (EUPAS20599), an ongoing, prospective, patient‐focused evaluating outcomes for current treatments. We report annualised estimated glomerular filtration rate (eGFR) and Fabry‐associated clinical events (FACEs) who had received ≥3 years treatment real‐world setting. As August 2022, (60% male) mean exposure 3.9 years. At enrolment, median age was 58 (males, 57; females, 60) eGFR 83.7 mL/min/1.73 m 2 ( n = 122; males, 83.7; 83.8) left ventricular mass index 115.1 g/m 61; 131.2; 98.0). Mean (95% confidence interval) change overall 116) −0.9 (−10.8, 9.9) /year similar observed across varying levels kidney function at enrolment. Despite population baseline morbidity, 80% did not experience FACE during exposure. incidence renal, cardiac, cerebrovascular 2.0, 83.2, 4.1 per 1000 patient‐years, respectively. These data support role preserving renal multisystem effectiveness this population.

Language: Английский

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Fabry nephropathy: a treatable cause of chronic kidney disease

Rare Disease and Orphan Drugs Journal, Journal Year: 2024, Volume and Issue: 3(3)

Published: July 11, 2024

Fabry disease is a rare X-linked inborn error of metabolism that has high prevalence chronic kidney (CKD) and renal failure. It due to the deficiency α-galactosidase A (α-Gal) lysosomal enzyme with subsequent accumulation globotriaosylceramide (Gb3) in lysosomes. In kidney, podocyte main target this disease, although all cell types are involved. The podocyte, being terminally differentiated, does not replicate thus accumulates Gb3 throughout life. Podocytes injured by Gb3, leading their detachment from glomerular basement membrane loss urine. Albuminuria starts childhood progresses overt proteinuria teens 20 s. CKD ensues adults starting dialysis at an average age 42 years. Patients have stroke cardiomyopathy hypertrophic change, heart failure, dysrhythmias. Patient survival limited both genders. Diagnosis based on demonstration low α-Gal activity pathogenic GLA mutation. Clinical features highly variable, which makes recognition condition difficult. Treatment intravenous recombinant human replacement therapy (ERT) oral pharmacologic chaperone available. Control 0.5 g/day or less critical importance limit progression end-stage disease. Early initiation treatment gives best results, but optimal start uncertain. nephropathy remains challenge its multisystem nature, difficult diagnosis, complicated management. important as treatable cause CKD.

Language: Английский

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Treatment of Fabry Nephropathy: A Literature Review

Medicina, Journal Year: 2023, Volume and Issue: 59(8), P. 1478 - 1478

Published: Aug. 17, 2023

Fabry disease is an X-linked inherited lysosomal storage disorder with a deficiency of α-galactosidase A activity, which results in the intracellular accumulation globotriaosylceramide (Gb3) and related glycosphingolipids various organs. nephropathy one major complications disease, kidney damage often to cardiovascular mortality. The treatment thus helps prolong life expectancy. Two options for cardiopathy are now commercially available: enzyme replacement therapy (agalsidase α agalsidase β, biosimilar β) pharmacological chaperone (migalastat). In this review, we summarize efficacy these respect renal function, proteinuria, pathological findings. We also describe importance adjunctive nephropathy.

Language: Английский

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Systematic cascade screening in the Danish Fabry Disease Centre: 20 years of a national single-centre experience

PLoS ONE, Journal Year: 2022, Volume and Issue: 17(11), P. e0277767 - e0277767

Published: Nov. 16, 2022

The lysosomal storage disorder Fabry disease is caused by deficient or absent activity of the GLA gene enzyme α-galactosidase A. In present study we molecular and biochemical data Danish cohort report 20 years’ (2001–2020) experience in cascade genetic screening at National Disease Center. consisted 26 families, 18 index patients (9 males 9 females, no available for 8 index-patients) 97 family members with a pathogenic variant identified testing (30 67 females). Fourteen (5 females; mean age death 47.0 64.8 years respectively) died during follow-up. completeness patient identification country has resulted balanced genotypes according to gender (twice number females compared males), indicating that was not biased referral, further earlier diagnosis lower index-patients (mean diagnosis: 42.2 vs. 26.0 years). Six previously unreported disease-causing variants were discovered. nationwide registration families provide unique possibility establish complete advance current knowledge this inherited rare disorder.

Language: Английский

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Clinical outcomes in patients switching from agalsidase beta to migalastat: A Fabry Registry analysis

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: 47(5), P. 1080 - 1095

Published: July 4, 2024

Fabry Registry data were analyzed among 83 agalsidase beta-treated patients with disease who switched to migalastat. Outcomes (estimated glomerular filtration rate [eGFR], urine protein-creatinine ratio [UPCR], plasma globotriaosylceramide [GL-3], globotriaosylsphingosine [lyso-GL-3], interventricular septal wall thickness [IVST], left posterior [LPWT], ventricular mass index [LVMI]) assessed using linear mixed models estimate annual change over time in the pre- and postswitch periods. eGFR decreased throughout both periods (preswitch: -0.85 mL/min/1.73 m

Language: Английский

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c.640–814 T > C mutation in deep intronic region of alpha-galactosidase A gene is associated with Fabry disease via dominant-negative effect

Gene, Journal Year: 2024, Volume and Issue: 936, P. 149127 - 149127

Published: Nov. 28, 2024

Fabry disease (FD) is a lysosomal storage disorder resulting from mutations in the alpha-galactosidase A (GLA) gene, characterized by pain, skin lesions, renal failure, and cardiac disease. 60-year-old proband was hospitalized for recurrent atrial fibrillation (AF) that unresponsive to medication, with magnetic resonance imaging (CMRI) revealing left ventricular wall hypertrophy fat infiltration. Whole-exome sequencing (WES) did not reveal any suspicious pathogenic variants. To further assess diagnosis, endomyocardial biopsy (EMB) electron microscopy were performed, abundant zebra bodies cardiomyocytes, consistent FD. The diagnosis ultimately confirmed GLA enzyme activity analysis (<1.00). Further genetic investigations identified deep intronic variant (c.640-814T>C) within gene. Minigene experiments demonstrated this affected splicing of GLA, production truncated protein (p.Pro214SerfsTer10). Western blotting (WB) showed retained, while immunofluorescence (IF) indicated partial localization. In vitro assays retained non-functional exerted dominant-negative effect on normal protein. Molecular docking revealed could bind wild monomer, significantly reducing cellular activity. These findings indicate that, beyond being non-functional, c.640-814T>C mutation may also exerts impairs function results highlight importance recognizing treatment FD, contributing deeper understanding molecular mechanisms, enriching databases, providing insights into genotype-phenotype correlations.

Language: Английский

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Effects of Current Therapies on Disease Progression in Fabry Disease: A Narrative Review for Better Patient Management in Clinical Practice

Advances in Therapy, Journal Year: 2024, Volume and Issue: 42(2), P. 597 - 635

Published: Dec. 5, 2024

Fabry disease (FD) is a rare lysosomal storage disorder that characterized by renal, neurological, and cardiovascular dysfunction. Four treatments are currently available for patients with FD; three enzyme replacement therapies (ERTs; agalsidase alfa, beta, pegunigalsidase alfa) one pharmacological chaperone (migalastat). This review focuses on the evidence benefits of ERTs migalastat, provides an overview their impact manifestations quality life (QoL). Agalsidase beta associated benefits, may prevent renal progression. alfa stabilizing effects across all main organ systems, although minor sex-specific differences exist in more advanced baseline disease. The similar but depend extent Some data indicate be preferable over longer term. Both improved gastrointestinal pain symptoms, as well QoL. Patients end-organ damage tend not to respond optimally those who initiate before irreversible fibrosis develops, highlighting need early treatment initiation. Migalastat, which only approved amenable missense gene variants, generally stabilizes parameters benefits. Migalastat also improves diarrhea pain, QoL (although ERT effective management), neurological migalastat have been studied. Real-world raise concerns about vivo amenability some genetic variants. Future studies direct comparisons FD needed.

Language: Английский

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