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Fabry disease (FD) is an X‐linked disease characterized by an accumulation of glycosphingolipids, notably of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) leading to renal failure, cardiomyopathy, and cerebral strokes. Inflammatory processes are involved in the pathophysiology. We investigated the immunological phenotype of peripheral blood mononuclear cells in Fabry patients depending on the clinical phenotype, treatment, Gb3, and lysoGb3 levels and the presence of anti‐drug antibodies (ADA). Leucocytes from 41 male patients and 20 controls were analyzed with mass cytometry using both unsupervised and supervised algorithms. FD patients had an increased expression of CD27 and CD28 in memory CD45‐ and CD45 + CCR7‐CD4 T cells (respectively p < 0.014 and p < 0.02). Percentage of CD45RA‐CCR7‐CD27 + CD28+ cells in CD4 T cells was correlated with plasma lysoGb3 (r = 0.60; p = 0.0036) and phenotype (p < 0.003). The correlation between Gb3 and CD27 in CD4 T cells almost reached significance (r = 0.33; p = 0.058). There was no immune profile associated with the presence of ADA. Treatment with agalsidase beta was associated with an increased proportion of Natural Killer cells. These findings provide valuable insights for understanding FD, linking Gb3 accumulation to inflammation, and proposing new prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA, leading to deficient lysosomal α-galactosidase A enzyme activity and multiorgan manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2 years showed that the intergroup difference [95%confidence interval] in the median slope was -0.36 mL/min/ 1.73 m²/year [-2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of -3 mL/min/1.73 m2/year and included zero. Despite challenges such as occasional hypersensitivity reactions and immunecomplex- mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective. [ABSTRACT FROM AUTHOR]

Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA, leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2 years showed that the intergroup difference [95%confidence interval] in the median slope was −0.36 mL/min/1.73 m2/year [−2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of −3 mL/min/1.73 m2/year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective.

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La maladie de Fabry est due à des mutations du gène GLA à l'origine d'un déficit de l'activité de l'enzyme lysosomale alpha-galactosidase A (α-gal A) et de l'accumulation intra-tissulaire de globotriaosylcéramide. Une nouvelle approche thérapeutique utilisant le chaperon pharmacologique migalastat a été récemment développée. Ce dernier se fixe, de manière spécifique et réversible, sur le site catalytique d'α-gal A mutées, mal conformées, afin d'éviter leur dégradation par le système contrôle-qualité du réticulum endoplasmique et leur permettre de cataboliser le globotriaosylcéramide dans les lysosomes. Ce traitement concerne environ 35 % des mutations du gène GLA reconnues comme sensible au migalastat selon un test pharmacogénétique in vitro. Deux études pivot de phase III, FACETS : migalastat vs. placebo et ATTRACT : migalastat vs. enzymothérapie ont analysé les effets in vivo du migalastat. Malgré certaines limitations méthodologiques, des résultats prometteurs ont été constatés. Le migalastat semble plus efficace que l'enzymothérapie à réduire l'indice de masse du ventricule gauche calculé par échocardiographie en cas d'hypertrophie cardiaque et présente des effets rénaux comparables. Ce traitement oral est le premier traitement personnalisé, axé sur le profil génétique du patient Fabry et ouvre une nouvelle ère dans la prise en charge des maladies conformationnelles. Fabry disease is due to mutations in the GLA gene that cause a deficiency of the activity of the lysosomal enzyme alpha-galactosidase A (α-gal A) resulting in intra-tissue accumulation of globotriaosylceramide. Recently, a novel therapeutic approach based on the pharmacological chaperone migalastat has been developed. It binds, in a specific and reversible manner, to the catalytic site of α-gal A mutants, to prevent their degradation by the quality control system of the endoplasmic reticulum and allow them to catabolize globotriaosylceramide in the lysosomes. This treatment concerns approximately 35% of the GLA gene mutations recognized as sensitive to migalastat according to an in vitro pharmacogenetic test. Two pivotal Phase III studies, FACETS: migalastat vs. placebo and ATTRACT: migalastat vs. enzyme replacement therapy analyzed the in vivo effects of migalastat. Despite some methodological limitations, promising results were found. Migalastat seems to be more effective than enzyme replacement therapy in reducing left ventricular mass index in case of cardiac hypertrophy and has comparable renal effects. This oral treatment is the first personalized treatment, based on the genetic profile of Fabry patients and opens a new era in the management of conformational diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes. Results Among the patients exposed to agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 μg/ml, interquartile range (IQR) [0.41–12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p

Fabry disease (FD) is an X-linked inborn error of glycosphingolipid metabolism due to the deficiency of α-galactosidase A. The progressive accumulation of globotriaosylceramide (Gb3), particularly in the vascular endothelium, leads to renal, cardiac, and cerebrovascular manifestations and early death. Clinical manifestations include the onset of pain and paresthesias in extremities, angiokeratoma and hypohidrosis during childhood or adolescence. Proteinuria and lymphedema occur with increasing age. Severe renal impairment leads to hypertension and uremia. Death usually occurs due to renal failure or cardiac or cerebrovascular disease. Disease presentation may be subtle, and its signs and symptoms are often discounted as malingering or are mistakenly attributed to other disorders, such as rheumatic fever, neurosis, multiple sclerosis, lupus, or petechiae. We present a 46-year-old man who since adolescence has suffered from painful acroparesthesia, disseminated skin angiokeratomas, hypohidrosis and heat intolerance. He was submitted to a thorough investigation with different specialists, but never reached a diagnosis. He started hemodialysis 3 years ago and at the moment is in standby for kidney transplantation. He was enrolled in a Brazilian FD screening and a reduced serum activity of α-galactosidase A (0.0027 nmol/h/mL – reference value 4-22) confirmed the diagnosis of FD. He has angiokeratoma at the bottom area, his echocardiogram demonstrated left ventricular hypertrophy and the family history is very rich, as the patient has 15 siblings. This case represents a very common story for FD patients. They usually spend most of their lives trying to find someone who could understand or explain their suffering. These results indicate that FD may be much more common among male dialysis patients than previously recognized. Subsequently, FD should be considered in every patient with unexplained renal disease, especially when cardiac or cerebral complications suggest an underlying multisystemic disorder. Early diagnosis of FD is important because it allows family studies to identify other affected relatives for genetic counseling and therapeutic intervention. Keywords: Chronic kidney disease; enzyme replacement therapy; fabry disease; angiokeratoma corporis diffusum; α-galactosidase; agalsidase; lysosomal diseases, renal dysfunction

Moss‐aGalactosidase A (moss‐aGal) is a moss‐derived version of human α‐galactosidase developed for enzyme replacement therapy in patients with Fabry disease. It exhibits a homogenous N‐glycosylation profile with >90% mannose‐terminated glycans. In contrast to mammalian cell produced α‐galactosidase, moss‐aGal does not rely on mannose‐6‐phosphate receptor mediated endocytosis but targets the mannose receptor for tissue uptake. We conducted a phase 1 clinical trial with moss‐aGal in six patients with confirmed diagnosis of Fabry disease during a 28‐day schedule. All patients received a single dose of 0.2 mg/kg moss‐aGal by i.v.‐infusion. Primary endpoints of the trial were safety and pharmacokinetics; secondary endpoints were pharmacodynamics by analyzing urine and plasma Gb3 and lyso‐Gb3 concentrations. In all patients, the administered single dose was well tolerated. No safety issues were observed. Pharmacokinetic data revealed a stable nonlinear profile with a short plasma half‐life of moss‐aGal of 14 minutes. After one single dose of moss‐aGal, urinary Gb3 concentrations decreased up to 23% 7 days and up to 60% 28 days post‐dose. Plasma concentrations of lyso‐Gb3 decreased by 3.8% and of Gb3 by 11% 28 days post‐dose. These data reveal that a single dose of moss‐aGal was safe, well tolerated, and led to a prolonged reduction of Gb3 excretion. As previously shown, moss‐aGal is taken up via the mannose receptor, which is expressed on macrophages but also on endothelial and kidney cells. Thus, these data indicate that moss‐aGal may target kidney cells. After these promising results, phase 2/3 clinical trials are in preparation. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked, lysosomal storage disease (OMIM: 301500), caused by α-galactosidase A deficiency, resulting in accumulation of its substrates, glycosphingolipids, primarily – globotriaosylceramide, in the lysosomes of multiple cell types with multi-system clinical manifestations, even within the same family, including abnormalities of the central and peripheral nervous system, kidneys, heart, gastrointestinal tract, lungs, organ of vision. Clinical heterogeneity is often the reason of the delayed diagnosis. Nowadays enzyme replacement therapy has proved its efficiency in the treatment of Fabry disease. Including Fabry disease in the differential diagnosis of a large range of disorders is important because of its wide clinical heterogeneity and the possibility of an earlier intervention with a beneficial treatment.

Background Fabry patients on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in estimated glomerular filtration rate (eGFR) and an increase of the Mainz Severity Score Index. Methods In this prospective observational study, we assessed end-organ damage and clinical symptoms in 112 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, who were (i) non-randomly assigned to continue this treatment regime (regular-dose group, n = 37); (ii) received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n = 38); or (iii) were re-switched to agalsidase-beta after receiving agalsidase-alfa for at least 12 months (re-switch group, n = 37) with a median follow-up of 53 (38–57) months. Results eGFR of patients in the regular-dose group remained stable. Patients in the switch group showed an annual eGFR loss of − 4.6  ±  9.1 mL/min/1.73 m2 (P < 0.05). Patients in the re-switch group also had an eGFR loss of − 2.2  ±  4.4 mL/min/1.73 m2 after re-switch to agalsidase-beta, but to a lower degree compared with the switch group (P < 0.05). Patients in the re-switch group suffered less frequently from diarrhoea (relative risk 0.42; 95% confidence interval 0.19–0.93; P = 0.02). Lyso-Gb3 remained stable in the switch (P = 0.97) and the regular-dose (P = 0.48) groups, but decreased in the re-switch group after change of the therapy regimen (P < 0.05). Conclusions After switch to agalsidase-alfa, Fabry patients experienced a continuous decline in eGFR, while this decline was attenuated in patients who were re-switched to agalsidase-beta. Decreasing lyso-Gb3 levels may indicate a better treatment response in the latter group. [ABSTRACT FROM AUTHOR]

A review was conducted to evaluate interventional therapy for Fabry disease. Fabry disease is a multisystemic X-linked storage disorder that affects the entire body and needs to be treated at an early age. The search was conducted using keywords such as "Fabry disease" and "Management" to review the databases. Seven studies were chosen from the 90 studies, and it was discovered that migalastat and enzyme replacement medication were successful in treating the condition, whereas agalsidase beta failed to have a positive effect on the patient. However, this analysis produced ambiguous conclusions. As only a small number of studies were included in the analysis, additional investigations and evaluations based on randomized controlled trials and case studies are required to determine potential drug-related outcomes. There is a need for future therapeutic research to cure genetically affected illnesses and diseases such as Fabry disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Besekar et al.)

Fabry disease (FD) is a progressive, multi-organ, lysosomal storage disease. Enzyme replacement therapy (ERT) is available for the treatment of the disease. While the reasons to initiate ERT have been frequently discussed, discontinuation of ERT is rarely reported. In this paper we describe our experiences with stopping ERT in FD. From 1999 through 2015, twenty-one patients discontinued ERT. These patients were generally older and more severely affected in comparison those who continued ERT. The reason to discontinue ERT switched from death or terminal illness in the first years towards treatment failure in more recent years. Three cases are described in more detail. We conclude that discontinuation of ERT should or may be considered in subgroups of FD patients although further studies on the effectiveness of ERT in subgroups of patients and the course of the disease after discontinuation of ERT are needed. [ABSTRACT FROM AUTHOR]

Abstract: Background: The Canadian Fabry disease initiative (CFDI) tracks outcomes of subjects with Fabry disease treated enzyme replacement therapy (ERT) given to subjects who meet evidence-based treatment guidelines and cardiovascular risk factor modification. Methods: We report 5year follow-up data on 362 subjects for a composite endpoint (death, neurologic or cardiovascular events, development of end-stage renal disease or sustained increase in serum creatinine of 50% from baseline). Results: At enrollment, 86 subjects had previously received ERT (Cohort 1a) and 67 subjects were newly started (Cohort 1b) and randomized to agalsidase alfa or agalsidase beta. 209 subjects did not initially meet ERT criteria (Cohort 1c), 25 of whom met ERT criteria in follow-up and were moved to Cohort 1b (total N=178 ERT treated subjects). Use of supportive therapies such as aspirin (78%), renin-angiotensin blockade (59%), and statins (55%) was common in ERT treated subjects. In Cohort 1a, 32 subjects met the composite endpoint with 8 deaths. In Cohort 1b, 16 subjects met the composite endpoint with 1 death. Cohort 1b had fewer clinical events than Cohort 1a (p=0.039) suggesting that the treatment protocol was effective in targeting subjects at an earlier stage. 19.4% of Cohort 1b subjects on agalsidase alfa and 13.3% on agalsidase beta had a clinical event (p=0.57). 10 Cohort 1c subjects had clinical events, none of which would have been prevented by earlier use of ERT. Conclusions: Cardiovascular risk factor modification and targeted use of ERT reduce the risk of adverse outcomes related to Fabry disease. [Copyright &y& Elsevier]

Abstract: Background: Enzyme replacement therapy for Fabry disease, consisting of biweekly infusions, interferes daily life. Home treatment proved beneficial. We evaluated a previously reported home treatment algorithm aiming to shorten the period of in-hospital infusions, while ascertaining patient safety. Methods: Retrospective analysis on clinical records of treated Fabry patients. Potentially predictive factors for infusion associated reactions (IARs) were studied: agalsidase antibodies, agalsidase product and dose, FOS-SSI scores, and GLA activity and mutation. A questionnaire evaluated patient satisfaction and compliance. Results: Seventy-nine patients were included (41 males, 46% agalsidase antibody positive (AB+)). 85% received home treatment. Home treatment complications were erroneous fast infusion rates (n=4) causing IARs and, rarely, venous access problems. The single SAE was unrelated to home treatment. IgG antibody status was significantly associated with IARs (89% vs. 26% p-value<0.01). Negative antibody status did not preclude IARs. Except for three AB+ patients, all first IARs occurred within 13 infusions. IARs occurred more frequently in patients using agalsidase beta 1.0mg/kg/eow than agalsidase alpha or beta 0.2mg/kg/eow, but the time to first IAR did not differ between groups. Four AB+ males experienced IARs after a dose increase. Compliance between home and in-hospital treatment was similar. Most patients preferred home treatment. Conclusion: In this study home therapy for Fabry disease was safe and improved patient satisfaction. We propose a revised algorithm which allows safe home-treatment in all male patients after 13 instead of 26 infusions, irrespective of ERT preparation or dose. Furthermore, AB+ patients with dosage increase may experience new or increased IARs, necessitating in-hospital observations. [Copyright &y& Elsevier]

Background. Few cases of Fabry disease, an X-linked lysosomal storage disorder, complicating pregnancy are reported. Case. A 36-year-old primigravida with known Fabry disease manifest with acroparesthesias, tinnitus, and hearing loss delivered a healthy unaffected infant at term. Conclusion. A symptomatic Fabry carrier may experience an otherwise uncomplicated pregnancy in the absence of vital organ involvement. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Fabry disease is an X-linked lysosomal storage disorder related to α-galactosidase A deficiency. • Two enzyme replacement therapies were approved by the European Medicines Agency in 2001: agalsidase-alfa and agalsidase-beta. • Patients with Fabry disease and treated with agalsidase-alfa or -beta can develop antibodies against the protein infused. • IgG antibodies against agalsidase-alfa and IgG and IgE antibodies against agalsidase-beta were previously described. WHAT THIS STUDY ADDS • Despite two successive treatments with agalsidase in our patient, kidney function declined. • Cross-reactivity between the two enzymes could be demonstrated. • Negative IgE antibodies and skin tests results do not necessarily equate with safety and the ability to continue with enzyme replacement therapies. AIMS To report a severe adverse event related to enzyme replacement therapy with agalsidase in an hemizygous male patient treated for Fabry disease. METHODS Retrospective analysis of clinical, radiological and biochemical data in a patient who suffered adverse events related to both agalsidase alfa and agalsidase beta treatments. RESULTS A hemizygous male patient was first treated for Fabry disease with agalsidase alfa. After more than 1 year of therapy, infusion-related symptoms necessitated systemic steroids and antihistaminic therapy. Decline in kidney function prompted a switch for agalsidase beta. Anaphylactoid shock occurred after the second infusion. No serum IgE antibodies were disclosed. Skin-test reactivity to agalsidase beta was negative. Following a published rechallenge infusion protocol, agalsidase beta was reintroduced, leading to a second anaphylactoid shock episode. Enzyme replacement therapy was stopped and the patient was treated with symptomatic therapy only. This case was referred to the pharmacovigilance department. CONCLUSION The negativity of immunological tests (specific anti-agalsidase IgE antibodies and skin tests) does not rule out the risk of repeated anaphylactoid shock following agalsidase infusion. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked lysosomal storage disorder that affects both sexes. Progressive cellular accumulation of glycolipids starts early in life and, if untreated, eventually leads to organ failure and premature death. The Fabry nephropathy is characterized by initial proteinuria in the second to third decades of life, and development of structural changes including glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Progressive kidney failure develops at a comparable rate as in diabetic nephropathy. First signs of kidney damage may arise in childhood, prior to first signs of overt renal dysfunction underscoring the key importance of early recognition and diagnosis. Globotriaosylceramide (GL-3) deposition is probably the initiating factor of the disease pathology and, with enzyme replacement therapy (ERT), clearance can be achieved in several cell types. However, some late-stage effects are not reversible. As there is growing evidence that renal outcomes are more directly related to the degree of fibrosis and scarring, preventing the development of these irreversible changes by early initiation of ERT may have the greatest impact on renal outcomes. Proteinuria should be rigorously monitored and aggressively treated with antiproteinuric therapy. This review describes the renal clinical features and histological changes, and outline options for therapeutic intervention that offer the best hope for patients affected by this life-threatening disorder.Kidney International (2008) 74, S29–S32. doi:10.1038/ki.2008.522 [ABSTRACT FROM AUTHOR]

Progressive loss of kidney function complicates Fabry disease, an X-linked lysosomal storage disorder that arises from deficiency of α-galactosidase activity. Heterozygous females with Fabry disease can be as severely affected as hemizygous males, who have the classic form of the disease. Enzyme-replacement therapy with recombinant human α-galactosidase clears the glycosphingolipid globotriaosylceramide from kidney cells, and can stabilize renal function in adults with mild to moderate Fabry nephropathy. However, adults with more advanced nephropathy and overt proteinuria do not respond as well. For these patients, antiproteinuric therapy given in conjunction with enzyme-replacement therapy might prevent further decline in kidney function. In this Review, we propose guidelines and recommendations for the diagnosis and management of Fabry nephropathy in adults, based on published data and on the consensus of opinion of participants in the 7th International Fabry Nephropathy Roundtable in 2007. These organ-specific guidelines could be easier to implement than general guidelines, provided they are used in the context of an overall multisystem care approach. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is an X-linked lysosomal disorder caused by mutations in GLA gene resulting in lack of or faulty α-galactosidase A (α-GalA) enzyme. Enzyme replacement therapy (ERT) with recombinant human α-GalA enzyme (agalsidase) is the standard treatment option for FD. Infusion-related reactions (IRRs), with symptoms ranging from rigors, to fever, pain, vomiting, angioedema and diarrhea, are often seen due to immune response against the exogenous enzyme. To elucidate the mechanisms causing the IRRs in FD, eight patients who developed IRRs were investigated. All, except one, tested negative for agalsidase-specific IgE and had normal tryptase levels. Circulating dendritic cells were drastically reduced during IRRs, suggesting possible sequestration to the sites of inflammation. An increase in NK cells and a decrease in T cells were also observed. Cytokines IL-4, IL-8 and TNF-α showed a significant increase, indicating nonspecific degranulation of mast cells. All IRRs were managed successfully using a combination of standard premedications and mast cell stabilizers without any interruption of therapy. Taken together, the results indicate crosstalk between immune cells resulting in IgE-independent mast-cell-specific allergic inflammation. Mast cell stabilizers could be used to control IRRs and for safe reintroduction of agalsidase in patients previously treated with ERT. [ABSTRACT FROM AUTHOR]

Fabry disease is due to mutations in the GLA gene that cause a deficiency of the activity of the lysosomal enzyme alpha-galactosidase A (α-gal A) resulting in intra-tissue accumulation of globotriaosylceramide. Recently, a novel therapeutic approach based on the pharmacological chaperone migalastat has been developed. It binds, in a specific and reversible manner, to the catalytic site of α-gal A mutants, to prevent their degradation by the quality control system of the endoplasmic reticulum and allow them to catabolize globotriaosylceramide in the lysosomes. This treatment concerns approximately 35% of the GLA gene mutations recognized as sensitive to migalastat according to an in vitro pharmacogenetic test. Two pivotal Phase III studies, FACETS: migalastat vs. placebo and ATTRACT: migalastat vs. enzyme replacement therapy analyzed the in vivo effects of migalastat. Despite some methodological limitations, promising results were found. Migalastat seems to be more effective than enzyme replacement therapy in reducing left ventricular mass index in case of cardiac hypertrophy and has comparable renal effects. This oral treatment is the first personalized treatment, based on the genetic profile of Fabry patients and opens a new era in the management of conformational diseases., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Fabry disease is a rare inborn error of the enzyme α-galactosidase (Α-Gal) and results in lysosomal substrate accumulation in tissues with a wide range of clinical presentations. The disease has attracted a lot of interest over the last years and several issues has been discovered up to now leading to increasing knowledge and awareness of the disease. However, several aspects are still unclear and under investigation. Thus, the new challenges that physicians encounter are the discovering of the pathogenic mechanisms, the neutralising antibodies to ERT, the long-term efficacy of therapies. In this article, we summarise and review the latest developments in the science community regarding diagnosis, management and monitoring of Fabry disease concerning in particular its physiopathology, novel biomarkers, antibodies development and novel treatment options., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Background: Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes.Results: Among the patients exposed to agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 μg/ml, interquartile range (IQR) [0.41-12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p < 0.0001), especially IgG4 (r = 0.75, p = 0.0005) and IgG2 (r = 0.72, p = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p = 0.04), which was correlated with IgG2 (r = 0.67, p = 0.017, n = 12) and IgG4 levels (r = 0.59, p = 0.041, n = 12). Plasma LysoGb3 levels were correlated with total IgG (r = 0.66, p = 0.001), IgG2 (r = 0.72, p = 0.004), IgG4 (r = 0.58, p = 0.03) and IgG1 (r = 0.55, p = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6-55.6] vs 12.5 [10.1-24.0], p = 0.005).Conclusion: Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies. [ABSTRACT FROM AUTHOR]

Résumé La maladie de Fabry, maladie lysosomale liée à l’X, résulte d’un déficit enzymatique (α-galactosidase A). Deux traitements enzymatiques recombinants différents (algalsidase alpha, agalsidase bêta) sont disponibles depuis 2001, pour traiter une maladie qui touche principalement les hommes, mais aussi les femmes. L’enzymothérapie substitutive favorise la clairance cellulaire du susbtrat et améliore, comparativement au placebo, certains paramètres cliniques (cœur, atteinte rénale, douleurs, qualité de vie). Cependant, il n’y a pas d’efficacité démontrée à ce jour sur l’atteinte du système nerveux central, sur la morbimortalité cardiaque, ni même sur l’atteinte rénale au-delà d’un certain stade (protéinurie supérieure à 1 g/j, débit de filtration glomérulaire estimé inférieur à 60 mL/min/1,73 m 2 ). Nous évoquons dans cette revue le bénéfice potentiel d’une intervention précoce, les mesures protectrices vasculaires devant être associées à l’enzymothérapie et leur rationnel, ainsi que les traitements alternatifs en cours de développement, tels que les molécules chaperons et les inhibiteurs de substrat. Fabry disease, an X-linked lysosomal storage disease, results from α-galactosidase A deficiency. Two different recombinant enzyme treatments (algalsidase alpha agalsidase beta) have been available since 2001 to treat a disease that affects not only men but also women. Enzyme replacement therapy promotes cell clearance of susbtrate, and improves some clinical parameters (heart, kidney damage, pain, quality of life). However, there is no proven efficacy to date on central nervous system lesions, on cardiac morbidity and mortality, nor on renal damage beyond a certain stage (proteinuria > 1 g/day and/or estimated glomerular filtration rate < 60 mL/min/1.73 m 2 ). In this review, we discuss the potential benefit of an early intervention, the vascular protective measures to be associated with enzyme therapy and their rationale, and some alternative treatments under development, such as chaperones and substrate molecules inhibitors. [ABSTRACT FROM AUTHOR]

Fabry disease, an X-linked lysosomal storage disease, results from α-galactosidase A deficiency. Two different recombinant enzyme treatments (algalsidase alpha agalsidase beta) have been available since 2001 to treat a disease that affects not only men but also women. Enzyme replacement therapy promotes cell clearance of susbtrate, and improves some clinical parameters (heart, kidney damage, pain, quality of life). However, there is no proven efficacy to date on central nervous system lesions, on cardiac morbidity and mortality, nor on renal damage beyond a certain stage (proteinuria>1g/day and/or estimated glomerular filtration rate<60mL/min/1.73m(2)). In this review, we discuss the potential benefit of an early intervention, the vascular protective measures to be associated with enzyme therapy and their rationale, and some alternative treatments under development, such as chaperones and substrate molecules inhibitors., (Copyright © 2016 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

Abstract: Fabry disease and cystinosis are both lysosomal diseases. Some clinical features (such as renal and corneal involvement) are shared by both diseases whereas many other features are different (mode of inheritance, rate of progression, mechanism of lysosomal storage, therapeutic modalities etc.). Intermediary mechanisms that lead from lysosomal overload to lesions and disease are still incompletely understood. [ABSTRACT FROM AUTHOR]

Abstract: Cardiac manifestations of Anderson-Fabry disease are usually part of a multiorgan involvement; they are frequently recognized in the young adult and increase morbidity and mortality. Cardiac complications, first hypertension and diastolic dysfunction, are observed in about half of patients and are accessible to the usual management of hypertension, heart failure, coronary artery disease, rhythm or conduction disturbances. However, the cardiac variant may present as an isolated or predominant cardiac involvement, with left ventricular hypertrophy being the most apparent sign, that could lead to the wrong diagnosis of « idiopathic » hypertrophic cardiomyopathy of sarcomeric origin (in 1–4% of cases, up to 6% in males before 40 years). However, in Fabry disease, hypertrophy is more often concentric without subaortic obstruction, while search for signs of Fabry disease (history of acroparesthesia or anhidrosis, renal dysfunction or stroke) should be systematic. Early identification of subjects with Fabry disease allows to check for target organ damage, family screening, genetic counseling and specific enzyme replacement therapy. The latter, in the absence of irreversible and extended myocardial fibrosis and/or severe renal dysfunction, is efficient on the progression of renal disease and cardiac hypertrophy and delayed in parallel the occurrence of a first renal, cardiac or neurologic event. [ABSTRACT FROM AUTHOR]