Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

Kok, Ken; Zwiers, Kimberley C.; Boot, Rolf G.; Overkleeft, Hermen S.; Aerts, Johannes M. F. G.; Artola, Marta

doi:10.3390/biom11020271

Cited by 74 publications

(65 citation statements)

References 159 publications

(211 reference statements)

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“…Fabry disease (FD, OMIM 301500) is an X-linked lysosomal disorder (LSD) caused by a deficiency of α-galactosidase A (α-GAL A) activity that results in the progressive accumulation of globotriaosylceramide (Gb 3 ) and related glycosphingolipids, particularly in cellular lysosomes and body fluids [1,2]. The clinical phenotype includes a broad spectrum of clinical severity ranging from classic to later-onset FD.…”

Section: Introductionmentioning

confidence: 99%

Newborn Screening for Fabry Disease in Northeastern Italy: Results of Five Years of Experience

Gragnaniello¹,

Polo²,

Giuliani³

et al. 2021

Biomolecules

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Fabry disease (FD) is a progressive multisystemic lysosomal storage disease. Early diagnosis by newborn screening (NBS) may allow for timely treatment, thus preventing future irreversible organ damage. We present the results of 5.5 years of NBS for FD by α-galactosidase A activity and globotriaosylsphingosine (lyso-Gb3) assays in dried blood spot through a multiplexed MS/MS assay. Furthermore, we report our experience with long-term follow-up of positive subjects. We screened more than 170,000 newborns and 22 males were confirmed to have a GLA gene variant, with an incidence of 1:7879 newborns. All patients were diagnosed with a variant previously associated with the later-onset phenotype of FD or carried an unclassified variant (four patients) or the likely benign p.Ala143Thr variant. All were asymptomatic at the last visit. Although lyso-Gb3 is not considered a reliable second tier test for newborn screening, it can simplify the screening algorithm when its levels are elevated at birth. After birth, plasma lyso-Gb3 is a useful marker for non-invasive monitoring of all positive patients. Our study is the largest reported to date in Europe, and presents data from long-term NBS for FD that reveals the current incidence of FD in northeastern Italy. Our follow-up data describe the early disease course and the trend of plasma lyso-Gb3 during early childhood.

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Section: Introductionmentioning

confidence: 99%

Newborn Screening for Fabry Disease in Northeastern Italy: Results of Five Years of Experience

Gragnaniello¹,

Polo²,

Giuliani³

et al. 2021

Biomolecules

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“…Pharmacological chaperones have become popular as potential treatments for several diseases, including lysosomal storage disorders, over the past 20 years, and the drug Migalastat, based on this approach, has been approved for treatment of Fabry disease (13)(14)(15). The drug binds the protein as an inhibitor (although non-inhibitory chaperones have also been proposed, which may overcome dosing complications introduced by inhibitory effects), assisting folding in the Endoplasmic Reticulum.…”

Section: Introductionmentioning

confidence: 99%

Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders

Woodard

Zheng

Zhang

2021

Preprint

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Three-dimensional structures of proteins can provide important clues into the efficacy of personalized treatment. We perform a structural analysis of variants within three inherited lysosomal storage disorders, comparing variants responsive to pharmacological chaperone treatment to those unresponsive to such treatment. We find that predicted ΔΔG of mutation is higher on average for variants unresponsive to treatment, in the case of datasets for both Fabry disease and Pompe disease, in line with previous findings. Using both a single decision tree and an advanced machine learning approach based on the larger Fabry dataset, we correctly predict responsiveness of three Gaucher disease variants, and we provide predictions for untested variants. Many variants are predicted to be responsive to treatment, suggesting that drug-based treatments may be effective for a number of variants in Gaucher disease. In our analysis, we observe dependence on a topological feature reporting on contact arrangements which is likely connected to the order of folding of protein residues, and we provide a potential justification for this observation based on steady-state cellular kinetics.Author summaryPharmacological chaperones are small molecule drugs that bind to proteins to help stabilize the folded state. One set of diseases for which this treatment has been effective is the lysosomal storage disorders, which are caused by defective lysosomal enzymes. However, not all genotypes are equally responsive to treatment. For instance, missense mutants that are particularly destabilized relative to WT are less likely to respond. The availability of datasets containing responsiveness data for large numbers of mutants, along with crystal structures of the protein involved in each disease, make machine learning methods incorporating sequence-based and structural data feasible. We hypothesize that data from two diseases, Fabry and Pompe disease, may be useful for predicting responsiveness of variants in the related Gaucher disease. Results suggest that many rare variants in Gaucher disease could be amenable to existing drugs. Results suggest that drug responsiveness depends on protein topology is such a way that mutations in early-to-fold residues are more likely to be non-responsive to pharmacological chaperone treatment, which is consistent with a simple kinetic model of stability rescue. This study provides an example of how machine learning can be used to inform further studies towards personalized treatment in medicine.

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“… 5 Lyso‐Gb3 destroys nociceptive neurons, leading to kidney fibrosis and inhibiting endothelial nitric oxide synthase. 6 Lyso‐Gb3 is strongly increased in plasma of classical FD male patients as well as in tissues and plasma of mice, but it does not correlate with the severity of the disease and cannot represent a valid surrogate biomarker. 7 , 8 …”

Section: Introductionmentioning

confidence: 99%

Current and experimental therapeutics for Fabry disease

et al. 2021

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Fabry (or Anderson‐Fabry) is a rare pan‐ethnic disease affecting males and females. Fabry is an X‐linked lysosomal storage disease, affecting glycosphingolipid metabolism, that is caused by mutations of the GLA gene that codes for α‐galactosidase A. Fabry disease (FD) can be classified into a severe, classical phenotype, most often seen in men with no residual enzyme activity, that usually appear before 18 years and a usually milder, nonclassical (later‐onset) phenotype that usually appear above 18 years. Affected patients show multifactorial complications, including renal failure, cardiovascular problems, and neuropathy. In this review, we briefly report the clinical trials so far performed with the available therapies, and then we focus on the in vitro and the in vivo experimental models of the disease, to highlight the relevance in improving the existing therapeutics and understand the mechanism of this rare disorder. Current available in vivo and in vitro models can assist in better comprehension of the pathogenesis and underlying mechanisms of FD, thus the existing therapeutic approaches can be optimized, and new options can be developed.

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Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

Cited by 74 publications

References 159 publications

Newborn Screening for Fabry Disease in Northeastern Italy: Results of Five Years of Experience

Newborn Screening for Fabry Disease in Northeastern Italy: Results of Five Years of Experience

Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders

Current and experimental therapeutics for Fabry disease

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