Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort

Nowak, Albina; Huynh‐Do, Uyen; Krayenbuehl, Pierre-Alexandre; Beuschlein, Felix; Schiffmann, Raphael; Barbey, Frédéric

doi:10.1002/jimd.12167

Cited by 30 publications

(16 citation statements)

References 27 publications

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“…The first reports on real clinical cases suggest that the beneficial long terms effects of DGJ should be evaluated carefully. In fact, a raise in AGAL residual activity has been observed in the leucocytes in patients of a Swiss cohort but regrettably, it did not correlate with a decrease in lyso-Gb3 concentration measured in dried blood spots [43].…”

Section: Pharmacological Chaperones: the Quick Path To Success Is Notmentioning

confidence: 83%

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

Liguori

Monticelli

Allocca

et al. 2020

IJMS

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The term “pharmacological chaperone” was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.

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Section: Pharmacological Chaperones: the Quick Path To Success Is Notmentioning

confidence: 83%

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

Liguori

Monticelli

Allocca

et al. 2020

IJMS

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“…However, the biochemical responsiveness in the GLP assay was so low that it would have been considered non-amenable according to our criteria. A recent study revealed that a patient carrying the presumed amenable variant S276N had to be switched back to ERT due to biomarker escalation [25].…”

Section: Discussionmentioning

confidence: 99%

Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease

Lukáš

Cimmaruta

Liguori

et al. 2020

IJMS

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Fabry disease is one of the most common lysosomal storage disorders caused by mutations in the gene encoding lysosomal α-galactosidase A (α-Gal A) and resultant accumulation of glycosphingolipids. The sugar mimetic 1-deoxygalactonojirimycin (DGJ), an orally available pharmacological chaperone, was clinically approved as an alternative to intravenous enzyme replacement therapy. The decision as to whether a patient should be treated with DGJ depends on the genetic variant within the α-galactosidase A encoding gene (GLA). A good laboratory practice (GLP)-validated cell culture-based assay to investigate the biochemical responsiveness of the variants is currently the only source available to obtain pivotal information about susceptibility to treatment. Herein, variants were defined amenable when an absolute increase in enzyme activity of ≥3% of wild type enzyme activity and a relative increase in enzyme activity of ≥1.2-fold was achieved following DGJ treatment. Efficacy testing was carried out for over 1000 identified GLA variants in cell culture. Recent data suggest that about one-third of the variants comply with the amenability criteria. A recent study highlighted the impact of inter-assay variability on DGJ amenability, thereby reducing the power of the assay to predict eligible patients. This prompted us to compare our own α-galactosidase A enzyme activity data in a very similar in-house developed assay with those from the GLP assay. In an essentially retrospective approach, we reviewed 148 GLA gene variants from our former studies for which enzyme data from the GLP study were available and added novel data for 30 variants. We also present data for 18 GLA gene variants for which no data from the GLP assay are currently available. We found that both differences in experimental biochemical data and the criteria for the classification of amenability cause inter-assay discrepancy. We conclude that low baseline activity, borderline biochemical responsiveness, and inter-assay discrepancy are alarm signals for misclassifying a variant that must not be ignored. Furthermore, there is no solid basis for setting a minimum response threshold on which a clinical indication with DGJ can be justified.

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“…Currently, molecular analyses using these three approaches have several roles in LD diagnosis: (1) to confirm the final diagnosis, mainly in milder and atypical cases [ 29 ]; (2) to clarify borderline biochemical results in screening and enzymatic assays, as obtained in carriers and pseudodeficiency cases (when enzyme activity is decreased but with no clinical consequences) [ 30 ]; (3) to characterize a novel gene associated with a new type of LD, such as the cases of VPS33A in MPSPS [ 21 ] and DESG1 in leukodystrophy [ 31 ]; (4) for prenatal diagnosis [ 32 , 33 ]; (5) to predict disease severity [ 34 , 35 ]; (6) for the identification of patients with variants amenable to targeted therapy [ 36 , 37 ].…”

Section: Molecular Diagnosis Advances For Lysosomal Diseasesmentioning

confidence: 99%

Precision Medicine for Lysosomal Disorders

et al. 2020

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Precision medicine (PM) is an emerging approach for disease treatment and prevention that accounts for the individual variability in the genes, environment, and lifestyle of each person. Lysosomal diseases (LDs) are a group of genetic metabolic disorders that include approximately 70 monogenic conditions caused by a defect in lysosomal function. LDs may result from primary lysosomal enzyme deficiencies or impairments in membrane-associated proteins, lysosomal enzyme activators, or modifiers that affect lysosomal function. LDs are heterogeneous disorders, and the phenotype of the affected individual depends on the type of substrate and where it accumulates, which may be impacted by the type of genetic change and residual enzymatic activity. LDs are individually rare, with a combined incidence of approximately 1:4000 individuals. Specific therapies are already available for several LDs, and many more are in development. Early identification may enable disease course prediction and a specific intervention, which is very important for clinical outcome. Driven by advances in omics technology, PM aims to provide the most appropriate management for each patient based on the disease susceptibility or treatment response predictions for specific subgroups. In this review, we focused on the emerging diagnostic technologies that may help to optimize the management of each LD patient and the therapeutic options available, as well as in clinical developments that enable customized approaches to be selected for each subject, according to the principles of PM.

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Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort

Cited by 30 publications

References 27 publications

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease

Precision Medicine for Lysosomal Disorders

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