Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Dutra‐Clarke, Marina; Tapia, Daisy; Curtin, Emily; Rünger, Dennis; Lee, Grace K.; Lakatos, Anita; Alandy-Dy, Zyza; Freedkin, Linda; Hall, Kathy; Ercelen, Nesrin; Alandy-Dy, Jousef; Knight, Margaret; Pahl, Madeleine V.; Lombardo, Dawn; Kimonis, Virginia

doi:10.1016/j.ymgmr.2020.100700

Cited by 16 publications

(14 citation statements)

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“…The mechanism of AGALopathy being a lysosomal storage independent etiologic factor in FD could also explain why some patients with missense variants treated with recombinant AGAL do not respond to enzyme replacement therapy [3]. AGALopathy may also explain, why some patients treated with Migalastat experienced accelerated loss of kidney function [38].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…These individuals typically develop cardiac, kidney and neurologic complications in the 3 rd or 4 th decade of life [1]. Many, but not all, patients respond to enzyme replacement therapy with recombinant AGAL [2], though the response is sub-optimal [3]. Migalastat, a small-molecule chaperone that facilitates AGAL trafficking from the endoplasmic reticulum to lysosomes for certain (amenable) nontruncated enzymes, is also helpful in some cases [4].…”

Section: Introductionmentioning

confidence: 99%

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AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Živná

Dostálová

Barešová

et al. 2022

Preprint

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Background Classic Fabry disease (FD) is caused by GLA mutations that result in enzymatic deficiency of alpha-galactosidase A (AGAL), lysosomal storage of globotriaosylceramide, and a resulting multisystemic disease. In non-classic later-onset FD, patients have some preserved AGAL activity and a milder disease course, though female carriers may also be affected. While FD pathogenesis has been mostly attributed to catalytic deficiency of mutated AGAL, lysosomal storage and impairment of lysosomal functions, other pathogenic factors may be important, especially in non-classic later-onset FD. Methods We characterized the clinical, biochemical, genetic, molecular, cellular and organ pathology correlates of the p.L394P AGAL variant that was identified in six individuals with end-stage kidney disease by the Czech national screening program for FD and by further screening of 25 family members. Results Clinical findings revealed a milder clinical course with ~15% residual AGAL activity. Laboratory investigations documented intracellular retention of mutated AGAL with resulting ER stress and the unfolded protein response (UPR). Kidney biopsies did not show lysosomal storage. We observed similar findings of ER stress and UPR with several other classic and non-classic FD missense GLA variants. Conclusions We identified defective proteostasis of mutated AGAL resulting in chronic ER stress and UPR of AGAL expressing cells (hereafter referred to as AGALopathy) as an important contributor to FD pathogenesis. These findings provide insight into non-classic later-onset FD and may better explain clinical manifestations with implications for pathogenesis, clinical characterization and treatment of all FD forms.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Živná

Dostálová

Barešová

et al. 2022

Preprint

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“…23 There are two therapeutic enzymes available for intravenous administration: agalsidase α (Replagal) and agalsidase β (Fabrazyme), 4,19,24 of which only the latter is approved by the US Food and Drug Administration (FDA). 74 Replagal, manufactured by Shire Pharmaceuticals Ireland Limited, Ireland, and marketed by Shire Human Genetic Therapies AB, Sweden (https://www.ema.europa.eu/en/documents/productinformation/replagal-epar-product-information_en.pdf), is produced from human fibroblast cell lines. 25 Fabrazyme manufactured and distributed by Genzyme Corporation, Cambridge, MA, USA (https://www.accessdata.fda.gov/ drugsatfda_docs/label/2010/103979s5135lbl.pdf), is produced from Chinese hamster ovary cell lines.…”

Section: Enzyme Replacement Therapy For Fabry's Diseasementioning

confidence: 99%

“…Enzyme replacement therapy (ERT) with recombinant human α‐Gal A for treatment of Fabry's disease is in clinical use since 2001 23 . There are two therapeutic enzymes available for intravenous administration: agalsidase α (Replagal) and agalsidase β (Fabrazyme), 4,19,24 of which only the latter is approved by the US Food and Drug Administration (FDA) 74 . Replagal, manufactured by Shire Pharmaceuticals Ireland Limited, Ireland, and marketed by Shire Human Genetic Therapies AB, Sweden (https://www.ema.europa.eu/en/documents/product-information/replagal-epar-product-information_en.pdf), is produced from human fibroblast cell lines 25 .…”

Section: Biopharmaceutical Applications Of α‐Galactosidasesmentioning

confidence: 99%

Biopharmaceutical applications of α‐galactosidases

Anisha¹

2022

Biotech and App Biochem

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α‐Galactosidases are exoglycosidases that are active on galactose‐containing side chains in oligosaccharides, polysaccharides, glycolipids, and glycoproteins. α‐Galactosidases are gaining increased interest in human medicine, especially in the enzyme replacement therapy for Fabry's disease. α‐Galactosidases with regioselectivity toward α‐1,3‐linked galactose find application in xenotransplantation and blood group transformation. The use of α‐galactosidases as a therapeutic agent in alleviating the postprandial symptoms of irritable bowel syndrome is much acclaimed. The excellent therapeutic applications of α‐galactosidases have led to an upwelling of worldwide research interventions to identify novel α‐galactosidases with improved catalytic efficiency. In addition to these therapeutic applications, α‐galactosidases also have interesting applications in the industrial sectors like food, feed, probiotics, sugar, and paper pulp. The current review focuses on the diverse therapeutic applications of α‐galactosidases and their prospects.

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Missed diagnosis of Fabry disease: should we screen patients with multiple sclerosis?

et al. 2023

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Introduction Fabry disease (FD) can be undiagnosed in the context of multiple sclerosis (MS) due to similar clinical and paraclinical features. Our study aimed to determine the prevalence (and the necessity of screening) of FD among patients with possible or definite MS. Methods In this prospective monocentric observational study, we included consecutive patients enrolled between May 2017 and May 2019 after the first clinical event suggestive of MS. All patients underwent FD screening using dried blood spots in a stepwise manner combining genetic and enzyme testing. Patients were followed until May 2022. Results We included 160 patients (73.1% female, mean age 33.9 years). The 2017 revised McDonald’s criteria for definite MS were fulfilled by 74 (46.3%) patients at the time of study recruitment and 89 (55.6%) patients after 3–5 years of follow-up. None of the patients had a pathogenic GLA variant, and four (2.5%) had a variant of unknown significance (p.A143T, p.S126G, 2 × p.D313Y). In two of these patients, the intrathecal synthesis of oligoclonal bands was absent, and none had hyperproteinorachia or pleocytosis in cerebrospinal fluid. Detailed examination of FD organ manifestations revealed only discrete ocular and kidney involvement in two patients. Conclusion The prevalence of FD in the population of suspected or definite MS patients does not appear to be high. Our results do not support routine FD screening in all patients with a possible diagnosis of MS, but there is an urgent need to search for red flags and include FD in the differential diagnosis of MS.

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Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Cited by 16 publications

References 50 publications

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Biopharmaceutical applications of α‐galactosidases

Missed diagnosis of Fabry disease: should we screen patients with multiple sclerosis?

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