The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat

Elias, Benjamin; Valle, Maria Cecilia Della; Wu, Xiaoyang; Katz, Evan; Pruthi, Farhana; Bond, Sarah; Bronfin, Benjamin; Williams, Hadis; Yu, Julie; Bichet, Daniel G.; Germain, Dominique P.; Giugliani, Roberto; Hughes, D.A.; Schiffmann, Raphael; Wilcox, William R.; Desnick, Robert J.; Kirk, John; Barth, Jay; Barlow, Carrolee; Valenzano, Kenneth J.; Castelli, J.; Lockhart, David J.

doi:10.1038/gim.2016.122

Cited by 182 publications

(189 citation statements)

References 32 publications

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“…This variant was found to have high residual α-galactosidase A activity in the HEK-293 in vitro assay. 37 However, assaying the enzyme activity in peripheral white blood cells of males is required to confirm non-pathogenicity. The intronic variants we found were described in some patients and may lower enzyme activity to a certain extent, but not enough to typically cause Fabry disease on their own, and elevated Gb 3 was not present in skin biopsies (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Low frequency of Fabry disease in patients with common heart disease

Schiffmann

Swift

McNeill

et al. 2018

Genetics in Medicine

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Purpose: To test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease.Methods: Globotriaosylceramide in random whole urine using tandem mass spectroscopy, α-galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing.Results: We tested 2,256 consecutive patients: 852 women (median age 65 years (19-95)) and 1,404 men (median age 65 years (21-92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568). Urinary globotriaosylceramide was elevated in 15% of patients and 15 males had low α-galactosidase A activity. GLA variants found included R118C (n = 2), D83N, and D313Y (n = 7);

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Section: Discussionmentioning

confidence: 99%

Low frequency of Fabry disease in patients with common heart disease

Schiffmann

Swift

McNeill

et al. 2018

Genetics in Medicine

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“…Of the cell lines, 13 have GLA mutations that are associated with the classic Fabry phenotype. Three of the cell lines harbor a GLA mutation expected to have significant residual α-GalA activity (>5%) and be amenable to treatment with the pharmacological chaperone migalastat (28). Notably, cell line W4 is a compound heterozygote, with the migalastat amenable N139S variant on one allele and the migalastat non-amenable W236C variant on the other, a situation for which chaperoning has not been studied.…”

Section: Resultsmentioning

confidence: 99%

“…The cells with A143T and R301G had relatively high residual activity in the GLP-HEK assay (21.4% and 19.1%) (28), and agalsidase alfa had little effect on these cell lines, indicating that they probably had enough α-GalA activity to prevent relevant Gb3 accumulation. Notably, the pathogenicity of A143T is debated (53).…”

Section: Discussionmentioning

confidence: 99%

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Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

Welford

Mühlemann

Garzotti

et al. 2018

Human Molecular Genetics

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Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene coding for α-galactosidase A (α-GalA). The deleterious mutations lead to accumulation of α-GalA substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine. Progressive glycolipid storage results in cellular dysfunction, leading to organ damage and clinical disease, i.e. neuropathic pain, impaired renal function and cardiomyopathy. Many Fabry patients are treated by bi-weekly intravenous infusions of replacement enzyme. While the only available oral therapy is an α-GalA chaperone, which is indicated for a limited number of patients with specific ‘amenable’ mutations. Lucerastat is an orally bioavailable inhibitor of glucosylceramide synthase (GCS) that is in late stage clinical development for Fabry disease. Here we investigated the ability of lucerastat to lower Gb3, globotriaosylsphingosine and lysosomal staining in cultured fibroblasts from 15 different Fabry patients. Patients’ cells included 13 different pathogenic variants, with 13 cell lines harboring GLA mutations associated with the classic disease phenotype. Lucerastat dose dependently reduced Gb3 in all cell lines. For 13 cell lines the Gb3 data could be fit to an IC50 curve, giving a median IC50 [interquartile range (IQR)] = 11 μM (8.2–18); the median percent reduction (IQR) in Gb3 was 77% (70–83). Lucerastat treatment also dose dependently reduced LysoTracker Red staining of acidic compartments. Lucerastat’s effects in the cell lines were compared to those with current treatments—agalsidase alfa and migalastat. Consequently, the GCS inhibitor lucerastat provides a viable mechanism to reduce Gb3 accumulation and lysosome volume, suitable for all Fabry patients regardless of genotype.

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“…Recently, emphasis has been placed on understanding the clinical characteristics specific to a mutation, which might lead to a clinically relevant subclassification of FD into classic, non-classic, late onset or specific organ variants. Due to a significant variation of FD regarding clinical symptoms, there is a great interest in characterizing the impact of genotypes in order to understand and individualize therapy in addition to enzyme replacement therapy (ERT) [12].…”

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confidence: 99%

Diagnostic difficulties in chronic kidney disease – Is it or is it not Fabry disease?

Para¹,

Alexescu²,

Dronca³

et al. 2017

Balneo

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Introduction. Renal impairment and neurological symptoms are common manifestations of Fabry disease. Although rare, Fabry disease should be taken into consideration when consulting a patient who presents with neurological and renal impairment, acroparesthesia and fatigue. The aim of this paper is to discuss the case of a female patient presenting with mild systemic symptoms and consequent renal impairment. Case report. The female patient, aged 64, presented for a painful ankle swelling, acroparesthesias, nycturia and fatigue. We diagnosed a gout attack, but found that she had biological signs of renal impairment, aggravated by the use of non-steroidian anti-inflammatory drugs. The search for an etiology of her renal failure proved difficult because she refused the kidney biopsy. The positivity of pANCA antibodies added another potential cause of kidney disease. The mild deficiency of alphagalactosidase could not fully support the diagnosis of Fabry disease. Discussions and conclusions. In women, Fabry disease should be suspected even if the symptomatology is not typical and as severe as in men. It is difficult to diagnose the Fabry disease in a female patient with chronic kidney disease, because of its polymorphic manifestations and association with other comorbidities, in our case, pANCA vasculitis.

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The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat

Cited by 182 publications

References 32 publications

Low frequency of Fabry disease in patients with common heart disease

Low frequency of Fabry disease in patients with common heart disease

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

Diagnostic difficulties in chronic kidney disease – Is it or is it not Fabry disease?

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