Fabry Disease in Women: Genetic Basis, Available Biomarkers, and Clinical Manifestations

Genes, Journal Year: 2023, Volume and Issue: 15(1), P. 37 - 37

Published: Dec. 26, 2023

Fabry Disease (FD) is a rare lysosomal storage disorder caused by mutations in the GLA gene on X chromosome, leading to deficiency α-galactosidase A (AGAL) enzyme activity. This leads accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), vital organs such as kidneys, heart, and nervous system. While FD was initially considered predominantly affecting males, recent studies have uncovered that heterozygous women, carrying single mutated gene, can manifest wide array clinical symptoms, challenging notion asymptomatic carriers. The mechanisms underlying diverse manifestations females remain not fully understood due X-chromosome inactivation (XCI). XCI also known “lyonization”, involves random one two chromosomes. process potential factor influencing phenotypic variation. review delves into complex landscape discussing its genetic basis, available biomarkers, manifestations, impact disease severity. Additionally, it highlights challenges faced both terms their burden interactions with healthcare professionals. Current treatment options, including replacement therapy, are discussed, along need for providers be well-informed about ultimately contributing improved patient care quality life.

Language: Английский

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Inflammation in Fabry disease: stages, molecular pathways, and therapeutic implications

Frontiers in Cardiovascular Medicine, Journal Year: 2024, Volume and Issue: 11

Published: June 12, 2024

Fabry disease, a multisystem X-linked disorder caused by mutations in the alpha-galactosidase gene. This leads to accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), culminating various clinical signs symptoms that significantly impact quality life. Although treatments such as enzyme replacement, oral chaperone, emerging therapies like gene therapy exist; delayed diagnosis often curtails their effectiveness. Our review highlights importance delineating stages inflammation disease enhance timing efficacy interventions, particularly before progression fibrosis, where treatment options are less effective. Inflammation is an important aspect pathogenesis disease. thought be predominantly mediated innate immune response, with growing evidence pointing towards potential involvement adaptive mechanisms remain poorly understood. Highlighted fact shares profiles systemic autoinflammatory diseases, blurring distinctions between these disorders highlighting need for nuanced understanding dynamics. insight crucial developing targeted improving administration current replacement. Moreover, our discusses complex interplay inflammatory processes treatments, challenges posed anti-drug antibodies. These antibodies can attenuate effectiveness therapies, necessitating more refined approaches mitigate impact. By advancing molecular changes, mediators causative factors drive we aim clarify role disease's progression. improved will help us see how fit into landscape Additionally, it guide development effective diagnostic therapeutic approaches, ultimately patient care.

Language: Английский

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Dapaglifozin on Albuminuria in Chronic Kidney Disease Patients with FabrY Disease: The DEFY Study Design and Protocol

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(11), P. 3689 - 3689

Published: May 26, 2023

Fabry disease (FD) is a rare genetic disorder caused by deficiency in the α-galactosidase A enzyme, which results globotriaosylceramide accumulation many organs, including kidneys. Nephropathy major FD complication that can progress to end-stage renal if not treated early. Although enzyme replacement therapy and chaperone are effective, other treatments such as ACE inhibitors angiotensin receptor blockers also provide nephroprotective effects when damage established. Recently, SGLT2 have been approved innovative drugs for treating chronic kidney disease. Thus, we plan multicenter observational prospective cohort study assess effect of Dapagliflozin, inhibitor, patients with (CKD) stages 1-3. The objectives evaluate Dapagliflozin primarily on albuminuria secondarily progression clinical stability. Thirdly, any association between SGT2i cardiac pathology, exercise capacity, inflammatory biomarkers, quality life, psychosocial factors will be evaluated. inclusion criteria age ≥ 18; CKD 1-3; despite stable treatment ERT/Migalastat ACEi/ARB. exclusion immunosuppressive therapy, type 1 diabetes, eGFR < 30 mL/min/1.73 m2, recurrent UTIs. Baseline, 12-month, 24-month visits scheduled collect demographic, clinical, biochemical, urinary data. Additionally, an capacity assessment performed. could new insights into using manifestations

Language: Английский

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Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1095 - 1095

Published: Jan. 6, 2023

Fabry disease is a lysosomal storage caused by mutations in the GLA gene that encodes alpha-galactosidase (AGAL). The causes abnormal globotriaosylceramide (Gb3) lysosomes. Variants responsible for genotypic spectrum of include abolish enzymatic activity and those cause protein instability. latter can be successfully treated with small molecules either bind stabilize AGAL or indirectly improve its cellular activity. This paper describes first attempt to reposition curcumin, nutraceutical, treat disease. We tested efficacy curcumin cell model found an improvement 80% mutant genotypes (four out five tested). fold-increase was dependent on ranged from 1.4 2.2. produced evidence supports co-chaperone role when administered pharmacological chaperones (1-deoxygalactonojirimycin galactose). combined treatment chaperone beneficial four mutants showed fold-increases ranging 1.1 2.3 DGJ 2.8 galactose. Finally, we long-term one (L300F) detected Gb3 clearance markers (LAMP-1 GAA). Altogether, our findings confirmed necessity personalized therapies patients paved way further studies trials treatments

Language: Английский

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Plasma and platelet lipidome changes in Fabry disease

Clinica Chimica Acta, Journal Year: 2024, Volume and Issue: 562, P. 119833 - 119833

Published: June 30, 2024

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by the progressive accumulation of globotriaosylceramide (Gb3) leading to systemic manifestations such as chronic kidney disease, cardiomyopathy, and stroke. There still a need for novel markers improved FD screening prognosis. Moreover, pathological mechanisms in FD, which also include inflammation fibrosis, are not yet fully understood.

Language: Английский

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Phase 1 Healthy Volunteer Study of AL01211, an Oral, Non‐brain Penetrant Glucosylceramide Synthase Inhibitor, to Treat Fabry Disease and Type 1 Gaucher Disease

Clinical Pharmacology in Drug Development, Journal Year: 2024, Volume and Issue: 13(6), P. 696 - 709

Published: Feb. 16, 2024

Abstract Glycosphingolipid (GSL) storage diseases are caused by deficiencies in the enzymes that metabolize different GSLs lysosome. Glucosylceramide synthase (GCS) inhibitors reduce GSL production and have potential to treat multiple diseases. AL01211 is a potent, oral GCS inhibitor being developed for treatment of Type 1 Gaucher disease Fabry disease. has minimal central nervous system penetration, allowing peripheral organs without risking CNS‐associated adverse effects. was evaluated Phase healthy volunteer study with single ascending dose (SAD) (MAD) arms, determine safety, pharmacokinetics including food effect, pharmacodynamic effects on associated GSLs. In SAD arm, showed Tmax approximately 3.5 hours, mean clearance (CL/F) 130.1 L/h, t 1/2 39.3 hours. Consuming high‐fat meal prior administration reduced exposures 3.5‐5.5‐fold, indicating effect. MAD had an 2‐fold accumulation, reaching steady‐state levels 10 days. Increasing exposure inversely correlated decrease plasma glucosylceramide globotriacylceramide reduction from baseline levels, 78% 52% day 14, respectively. generally well‐tolerated no serious events, thus supporting its further clinical development.

Language: Английский

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Inflammation, Oxidative Stress, and Endothelial Dysfunction in the Pathogenesis of Vascular Damage: Unraveling Novel Cardiovascular Risk Factors in Fabry Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8273 - 8273

Published: July 29, 2024

Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A

Language: Английский

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Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8632 - 8632

Published: May 11, 2023

Heart failure (HF) is a progressive chronic disease that remains primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number genes disorders linked to development constantly growing includes inherited metabolic (IMDs). Several IMDs various pathways have been reported presenting defects. Considering the pivotal role sugar metabolism in tissue, including energy production, nucleic acid synthesis glycosylation, it not surprising an increasing carbohydrate are described manifestations. In this systematic review, we offer comprehensive overview present cardiomyopathies, arrhythmogenic and/or structural We identified 58 complications: 3 sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 pentose phosphate pathway (G6PDH, TALDO); 9 diseases glycogen (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With review aim raise awareness about presentations draw attention pathogenic mechanisms may underlie complications.

Language: Английский

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GLA deficiency causes cardiac hypertrophy via enhanced autophagy

Science China Life Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Language: Английский

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Exome sequencing of a Portuguese cohort of early-onset Alzheimer’s disease implicates the X-linked lysosomal gene GLA

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 4, 2025

Cerebrovascular disease is a common comorbidity in patients with Alzheimer's (AD) and other dementias. Accumulating evidence suggests that dysfunction of the cerebral vasculature AD neuropathology interact multiple ways. Additionally, variants COL4A1 rare HTRA1, NOTCH3, COL4A1, CST3 have been associated pathogenesis. We aimed to search for genetic genes monogenic small vessel cohort Portuguese early-onset patients. performed whole-exome sequencing 104 thoroughly studied who lacked known pathogenic or frontotemporal dementia. searched (minor allele frequency < 0.001) non-synonymous disease: COL4A2, CSTA, GLA, TREX1. identified 12 18 (17.3% cohort). Three male carried GLA variant (p.Arg118Cys). One these had definite neuropathological study, confirming diagnosis showing concomitant Fabry pathology CA1-CA4 subiculum. also found several cSVD (NOTCH3, COL4A2 HTRA1), corroborating previous studies providing further support possibility may play role The presence same 3 patients, no cause disease, together colocalization areas relevant pathogenesis, suggest its pathophysiology, possibly parallel GBA Parkinson's meriting studies.

Language: Английский

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