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Enzyme replacement therapy (ERT) with recombinant α-galactosidase A (r-αGAL A) for the treatment of Fabry disease has been available for over 15 years. Long-term treatment may slow down disease progression, but cardiac, renal, and cerebral complications still develop in most patients. In addition, lifelong intravenous treatment is burdensome. Therefore, several new treatment approaches have been explored over the past decade. Chaperone therapy (Migalastat; 1-deoxygalactonojirimycin) is the only other currently approved therapy for Fabry disease. This oral small molecule aims to improve enzyme activity of mutated α-galactosidase A and can only be used in patients with specific mutations. Treatments currently under evaluation in (pre)clinical trials are second generation enzyme replacement therapies (Pegunigalsidase-alfa, Moss-aGal), substrate reduction therapies (Venglustat and Lucerastat), mRNA- and gene-based therapy. This review summarises the knowledge on currently available and potential future options for the treatment of Fabry disease., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the α-galactosidase A enzyme. This enzyme cleaves the last sugar unit of glycosphingolipids, including globotriaosylceramide (Gb 3 ), globotriaosylsphingosine (lyso-Gb 3 ), and galabiosylceramide (Ga 2 ). Enzyme impairment leads to substrate accumulation in different organs, vascular endothelia, and biological fluids. Enzyme replacement therapy (ERT) is a commonly used treatment. Urinary analysis of Gb 3 isoforms (different fatty acid moieties), as well as lyso-Gb 3 and its analogues, is a reliable way to monitor treatment. These analogues correspond to lyso-Gb 3 with chemical modifications on the sphingosine moiety (-C 2 H 4 , -C 2 H 4 +O, -H 2 , -H 2 +O, +O, +H 2 O 2 , and +H 2 O 3 ). The effects of sample collection time on urinary biomarker levels between ERT cycles were not previously documented. The main objective of this project was to analyze the aforementioned biomarkers in urine samples from seven Fabry disease patients (three treated males, three treated females, and one ERT-naïve male) collected twice a day (morning and evening) for 42 days (three ERT cycles). Except for one participant, our results show that the biomarker levels were generally more elevated in the evening. However, there was less variability in samples collected in the morning. No cyclic variations in biomarker levels were observed between ERT infusions.

Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene ( p = 0.05), higher plasma lysoGb3 at baseline ( p < 0.001) and agalsidase beta as first treatment ( p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.

Angiokeratomas are the cutaneous hallmark of Fabry disease. Although it is well established that enzyme replacement therapy (ERT) prevents or slows the progression of disease on target organs in the majority of patients, the long-term effect of ERT on angiokeratomas remains unknown. We present a patient diagnosed with Fabry disease at age 11, with rapid progression of new angiokeratomas in typical regions before beginning treatment with ERT. To date, our patient has been treated with ERT for 10 years. During the treatment period, new angiokeratomas have not arisen nor have existing ones enlarged during puberty, adolescence, and early adulthood. Furthermore, partial regression of the angiokeratomas has occurred in association with regression of left ventricular hypertrophy and anhidrosis. Overall, this case suggests that long-term ERT could stop the progression of angiokeratomas and induce their partial regression but does not produce complete resolution. Importantly, regression of angiokeratomas might be a marker of systemic target-organ efficacy of ERT.

α-Galactosidase, (E.C. 3.2.1.22) is an exoglycosidase that target galactooligosaccharides such as raffinose, melibiose, stachyose and branched polysaccharides like galactomannans and galacto-glucomannans by catalysing the hydrolysis of α-1,6 linked terminal galactose residues. The enzyme has been isolated and characterized from microbial, plant and animal sources. This ubiquitous enzyme possesses physiological significance and immense industrial potential. Optimization of the growth conditions and efficient purification strategies can lead to a significant increase in the enzyme production. To boost commercial productivity, cloning of novel α-galactosidase genes and their heterologous expression in suitable host has gained popularity. Enzyme immobilization leads to its greater reutilization, superior thermostability, pH tolerance and increased activity. The enzyme is well explored in food industry in the removal of raffinose family oligosaccharides (RFOs) in soymilk and sugar crystallization process. It also improves animal feed quality and biomass processing. Applications of the enzyme is in the area of biomedicine includes therapeutic advances in treatment of Fabry disease, blood group conversion and removal of α-gal type immunogenic epitopes in xenotransplantation. With considerable biotechnological applications, this enzyme has been vastly commercialized and holds greater future prospects., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Fabry disease. Fabry disease is an X-linked disorder in which lysosomal alpha-galactosidase A is lacking, leading to enzyme-substrate accumulation and tissues dysfunction. Acroparesthesia, angiokeratoma, familial nephropathy or hypertrophic cardiomyopathy should suggest Fabry disease. Enzymatic assay allows diagnosis in men but genetic assay is needed for women. Enzyme replacement therapy is available since 2001 and a pharmacologic chaperone since 2016., Competing Interests: B. Subran déclare n’avoir aucun lien d’intérêts. C. Montagner déclare avoir été prise en charge lors de congrès par Sanofi. J. London déclare avoir été pris en charge lors de congrès par Amicus. O. Lidove déclare des liens ponctuels (congrès et collaborations scientifiques) avec Amicus, Sanofi Genzyme et, Shire-Takeda. W. Mauhin déclare des liens ponctuels (congrès et/ou boards et présentations) avec Sanofi-Genzyme, Shire-Takeda et Amicus.

Fabry disease (FD) is a lysosomal storage disease, treatable by enzyme replacement therapy (ERT) that substitutes deficient α-galactosidase A (AGAL). The formation of neutralising anti-drug antibodies (ADA) inhibiting AGAL activity during infusion is associated with disease progression in affected male patients. In this study we analysed if ADAs also inhibit endothelial enzyme uptake as well as intracellular enzyme activity. Therefore, fluorescence-labelled AGAL in combination with ADA-positive sera from FD patients (n = 8) was used to analyse enzyme uptake in endothelial and FD-specific cells. Furthermore, immune adsorption and a comprehensive ADA epitope mapping were performed. Pre-incubation of AGAL with ADAs significantly inhibited intracellular enzyme activity, which was rescued by immune adsorption (both P < .01). ADAs from some patients also inhibited enzyme uptake. ADA epitope mapping identified an epitope at position 121 to 140 aa potentially responsible for uptake inhibition for these patients. Further analyses revealed the presence of stable AGAL/ADA-immune complexes at pH 4.5 and decreased intracellular enzyme activity in endothelial cells (P < .001). Finally, the pre-incubation of AGAL with ADAs resulted in a reduced depletion of intracellular globotriaosylceramide in patient-derived AGAL-deficient cells, demonstrating a direct negative impact of ADAs on intracellular clearance. Neutralising ADAs may not only inhibit infused AGAL activity, but according to their epitopes can also inhibit endothelial AGAL uptake. Indeed, internalised AGAL/ADA-complexes may not dissociate, underlining the importance of novel therapeutic approaches for ADA reduction and prevention to increase therapy efficiency in affected patients., (© 2019 SSIEM.)

Background: Two established scores, the Mainz Severity Score Index (MSSI) and Fabry Disease Severity Scoring System (DS3), quantify the disease burden in Fabry disease (FD), while the recent developed FAbry STabilization indEX (FASTEX) aims to detect disease progression., Objective: MSSI, DS3 and FASTEX were compared to evaluate disease stability or progression in a prospective cohort of Fabry patients under enzyme replacement therapy (ERT)., Methods: Disease load of 62 patients (28 [45%] females) treated with ERT (26 [42%] under agalsidase-alfa) was assessed using the current scores and re-assessed after 12 months of treatment. Fifteen (24%) patients were ERT-naïve at baseline., Results: All scores showed a correlation with each other, while MSSI and DS3 showed the strongest (Pearson r: 0.81, p < .0001). Plasma lyso-Gb3 levels in naïve patients correlated with increasing DS3 and MSSI scores (Pearson r: 0.60, p < .05; Pearson r: 0.64, p < .01; respectively), but not with the total weighted FASTEX score. Longitudinal analysis suggested a stable disease course using DS3 and MSSI. Only males long-term-treated with agalsidase-alfa presented with a slight increase of the general MSSI score (p = .0084). By contrast, the FASTEX score demonstrates that only 21 patients (33.9%) were stable, all other patients presented a disease progression. Patients with an unstable FASTEX mainly suffered from a significant loss of renal function (eGFR creat : -2.7 ± 7.3 ml/min/1.73 m 2 , p = .0298)., Conclusion: We conclude that the FASTEX seems to be a simple and user friendly, valuable tool to assess early changes in disease progression even in smaller patient cohorts and short term surveillance., Competing Interests: Disclosures Malte Lenders and Eva Brand received speaker fees and research grants from Takeda, Sanofi Genzyme, and Amicus Therapeutics. None of the funding companies had a role in writing or submission of this manuscript., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, predominantly globotriaosylsphingosine (Gb3) in lysosomes, as well as other cellular compartments of several tissues, causing multi-organ manifestations (acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement). Pathogenic mutations lead to a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA). In the presence of high clinical suspicion, a careful physical examination and specific laboratory tests are required. Finally, the diagnosis of Fabry's disease is confirmed by the demonstration of the absence of or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone. Future treatments are based on new strategic approaches such as stem cell-based therapy, pharmacological approaches chaperones, mRNA therapy, and viral gene therapy. This review outlines the current therapeutic approaches and emerging treatment strategies for Anderson-Fabry disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Mulberry cells are often present in the urinary sediments of patients with Fabry disease (FD). We herein report two patients with FD undergoing enzyme replacement therapy (ERT). A 41-year-old man was diagnosed based on lack of α-galactosidase A activity. ERT was subsequently administered. A 40-year-old woman was diagnosed based on urinary Mulberry cells and genetic testing, and ERT was initiated. While the renal function of the male patient deteriorated, the Mulberry cells disappeared in the female patient after ERT was administered. The detection of urinary Mulberry cells can contribute to the diagnosis as well as serve as a biomarker for the response to treatment.

Introduction: The lifespan of patients with Fabry disease (FD) is shorter than that seen in the general population. Leukocyte telomere length (LTL) and telomerase activity (TA) are potential markers of biologic aging. The aim of the current study was to determine the LTL and TA in FD patients and to assess the correlation between LTL and TA and renal involvement., Methods: We included 33 FD patients and 66 healthy matched controls. LTL and TA were measured using a quantitative PCR assay and gene expression assay. FD patients were stratified by renal function (estimated glomerular filtration rate [eGFR] higher or lower than 60 mL/min/1.73 m2) and proteinuria (urine protein creatinine ratio higher or lower than 0.5 g/g)., Results: LTL was significantly shorter (0.69 vs. 0.73, p = 0.015) and TA significantly higher (1.55 vs. 1.19, p = 0.047) in FD patients compared to controls. Males with FD had significantly shorter LTL (p = 0.020) and lower, but non-significant, TA compared to male controls (p = 0.333). Female FD patients had similar LTL (p = 0.285) but significantly higher TA compared to female controls (p = 0.005). LTL was not influenced by eGFR, but TA was significantly lower in the low eGFR group (p = 0.003)., Conclusions: FD patients have significantly shorter LTL, but significantly higher TA compared to healthy controls. Increased TA activity in FD patients could be the compensation mechanism to prevent LTL decrease (and accelerated ageing), which seems to be exhausted at the advanced stage of renal disease., (© 2019 S. Karger AG, Basel.)

Background: Cardiac response to enzyme replacement therapy (ERT) in Fabry disease is typically assessed by measuring left ventricular mass index using echocardiography or cardiovascular magnetic resonance, but neither quantifies myocardial biology. Low native T1 in Fabry disease represents sphingolipid accumulation; late gadolinium enhancement with high T2 and troponin elevation reflects inflammation. We evaluated the effect of ERT on myocardial storage, inflammation, and hypertrophy., Methods: Twenty patients starting ERT (60% left ventricular hypertrophy-positive) were compared with 18 patients with early disease and 18 with advanced disease over 1 year at 3 centers. Cardiovascular magnetic resonance (left ventricular mass index, T1, T2, global longitudinal strain, and late gadolinium enhancement) and biomarkers (high-sensitive troponin-T and NT-proBNP [N-terminal Pro-B-type natriuretic peptide]) at baseline (pre-ERT) and 12 months were performed. Early disease controls were stable, treatment-naïve patients (mainly left ventricular hypertrophy-negative); advanced disease controls were stable, established ERT patients (mainly left ventricular hypertrophy-positive)., Results: Over 1 year, early disease controls increased maximum wall thickness and left ventricular mass index (9.8±2.7 versus 10.2±2.6 mm; P =0.010; 65±15 versus 67±16 g/m 2 ; P =0.005) and native T1 fell (981±58 versus 959±61 ms; P =0.002). Advanced disease controls increased T2 in the late gadolinium enhancement area (57±6 versus 60±7 ms; P =0.023) with worsening global longitudinal strain (-13.2±3.4 versus -12.1±4.8; P =0.039). Newly treated patients had a small reduction in maximum wall thickness (14.8±5.9 versus 14.4±5.7 mm; P =0.028), stable left ventricular mass index (93±42 versus 92±40 g/m 2 ; P =0.186) and a reduction in T1 lowering (917±49 versus 931±54 ms; P =0.017)., Conclusions: Fabry myocardial phenotype development is different at different disease stages. After 1 year of ERT initiation, left ventricular hypertrophy-positive patients have a detectable, small reduction in left ventricular mass and storage.

Fabry's disease is a X-linked hereditary disease that causes the accumulation of glycosphingolipids in tissues and organs, including the kidneys and heart. This can result in both chronic kidney disease and cardiac dysfunction, including arrhythmias and heart failure. We describe a case of a 62-year-old male with Fabry's disease undergoing successful combined heart and kidney transplantation for chronic renal failure and low-output systolic heart failure. The patient has normal cardiac function and normal renal function 7 years after transplantation, while being maintained on enzyme replacement therapy with recombinant human alpha-galactosidase A. Fabry's disease is not a contraindication for organ transplantation, even in patients presenting with both renal failure and heart failure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Fabry disease is an X-linked deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal). This results in an accumulation of globotriaosylceramide (GL-3/Gb3) in a variety of cells with subsequent functional impairment. The continuous progress of FD often leads to decreased quality of life and premature death caused by multi-organic complications. The overall aim of our study was to determine the amount of circulating miRNAs in Fabry patients and to test whether ERT would alter the level of individual circulating miRNAs. We used miRNA sequencing by the HTG EdgeSeq System to identify the circulating miRNA pool from Fabry patients with and without enzyme replacement therapy (n = 6). In total, 296 miRNAs in serum of patients were identified. Among them 9 miRNAs were further evaluated in extra serum samples (n = 31) using real-time qPCR and 6 of them showed significant differential expression. The resulting miRNA pattern may help to better understand mechanisms involved in the beneficial effects of ERT and these new miRNA markers could help to estimate the efficacy of ERT or to identify Fabry patients with specific need for ERT.

Introduction: Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A. Symptoms include neuropathic pain and gastrointestinal problems, such as diarrhoea. To inform and support the design of a Phase III clinical trial for a new oral treatment for Fabry disease, this study evaluated patients' experiences of Fabry disease symptoms, the impact of symptoms on their quality of life, and their views on participating in clinical trials., Methods: An online survey questionnaire was distributed to patients with Fabry disease, through relevant patient organisations. The questionnaire consisted mainly of quantitative, closed questions with pre-defined response options. Fabry-specific pain intensity and its impact on quality of life were rated on a scale from 0 to 10., Results: In total, 367 patients completed the survey, of whom half reported frequent pain, moderate to severe pain, and pain in their hands and feet. Pain frequency, intensity and location were similar for males and females. There was no clear association between Fabry-specific pain and the use of enzyme replacement therapy (ERT), with moderate to severe pain reported by 80.4% of participants receiving ERT and by 75.0% of participants not receiving ERT. Of participants who were receiving ERT, 35.7% said they were willing to discontinue it to take part in a clinical trial testing a new oral drug for treating Fabry disease. Gastrointestinal symptoms were more heterogeneous in nature and frequency than Fabry-specific pain, but still affected a significant proportion of participants., Conclusions: Both male and female patients with Fabry disease experience significant Fabry-specific pain, which affects their quality of life. Furthermore, frequent diarrhoea affects many patients. The symptoms occur independently of the use of ERT. This suggests the healthcare needs of patients with Fabry disease are not being fully met, and additional treatments are required to improve symptoms and quality of life., Funding: This study was sponsored by Actelion Pharmaceuticals Ltd. Study sponsorship was transferred to Idorsia Pharmaceuticals Ltd in July 2018.

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 is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients., Methods: In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5-18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE)., Results: The mean age was 11.6 (range: 5-18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-agalsidase beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (-26.3%; P = .0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their agalsidase beta dose increased., Conclusions: Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5 years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved agalsidase beta dose of 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of α-galactosidase A in a Fabry disease mouse model, and find that an α2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.

Fabry disease is a rare X-linked inherited multisystem disorder resulting from deficiency of the lysosomal enzyme alpha-galactosidase A. Currently, specific therapies, including enzyme replacement therapies, are available for Fabry disease, but clinical trials provide limited information on long-term safety and effectiveness. Agalsidase alfa was approved in Japan in 2006. The post-marketing surveillance study of all patients receiving agalsidase alfa to evaluate its long-term safety and effectiveness as a mandatory condition for its approval had been conducted for 8 years (from February 2007 to March 2015). A total of 493 patients were included in this analysis of safety and effectiveness. The overall mean follow-up period was 3.5 years (range, 0.0-7.9 years). The percentage of patients with adverse drug reactions was 24.5% (121/493) and 12.6% had infusion-related reactions (62/493). In the 256 patients without prior enzyme replacement therapy whose IgG antibody data were available, 17 were IgG antibody positive (6.6%). However, the chronological correlation between seroconversion and the incidence of infusion-related reactions was not clear. The mean brief pain inventory score of the worst pain decreased in patients with moderate and severe pain at baseline. Plasma Gb 3 and urine sediment Gb 3 in males with classical Fabry disease without prior enzyme replacement therapy significantly decreased. The mean yearly changes in eGFR (mL/min/1.73 m 2 ) ranged from -2.88 to +1.00 in males with classical Fabry disease, from -2.04 to -0.95 in males with non-typical variant and from -2.64 to -1.02 in females. The lower eGFR or the more proteinuria at baseline, the faster the decrease in eGFR of the patients was observed. There was no substantial difference in cardiac parameters (left ventricular mass index, E/A wave ratio, ejection fraction, and QRS duration). In conclusion, agalsidase alfa, 0.2 mg/kg every other week, was well tolerated and controlled the progression of symptoms (especially renal and cardiac) of Fabry disease in adults. Enzyme replacement therapy should be started in Japanese patients before cardiac and/or renal symptoms of Fabry disease develop., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients., Methods: A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type., Results: Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease., Conclusions: This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease., Methods: A comprehensive systematic review of published literature on ERT in Fabry disease was conducted in January 2017. The literature analysis included all original articles reporting outcomes of ERT in paediatric patients., Results: Treatment-related outcomes in the paediatric population were reported in six publications derived from open-label clinical trials and in 10 publications derived from observational or registry-based studies. ERT was shown to significantly reduce plasma and urine GL-3 levels in paediatric patients with Fabry disease. The effect of ERT on GL-3 clearance from renal podocytes appeared to be agalsidase dose-dependent. ERT relieved pain and improved gastrointestinal symptoms and quality of life., Conclusions: Based on the published literature, the use of ERT in paediatric patients can significantly clear GL-3 accumulation, ameliorate the early symptoms of Fabry disease, and improve quality of life. Treatment with ERT in paediatric patients with Fabry disease may be important to prevent further disease progression and overt organ damage., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Treatment of Fabry disease (FD) with recombinant alpha-galactosidase A (r-αGAL A) is complicated by the formation of anti-drug antibodies in the majority of male patients with the classical disease phenotype. Detailed information regarding antibody subtypes, onset and persistence of antibody development and their effect on treatment efficacy is sparse., Methods: A retrospective study was carried out in 39 male patients with classical FD, treated with either agalsidase-alfa or agalsidase-beta (mean follow up of 10 years). With six to twelve months intervals plasma-induced in vitro inhibition of enzyme activity, lysoglobotriaosylsphingosine (lysoGb3) levels and renal function were assessed. In a subset of 12 patients, additionally anti- r-αGAL A IgM, IgA and IgG1, 2, 3 and 4 levels were analyzed., Results: In 23 out of 39 patients, plasma-induced in vitro inhibition of r-αGAL A activity was observed (inhibition-positive). The inhibition titer was strongly negatively correlated to the decrease in lysoGb3: agalsidase-alfa (FE log10(inhibition)  = -10.3, P ≤.001), agalsidase-beta (FE log10(inhibition)  = -4.7, P ≤.001). Inhibition-positive patients had an accelerated decline in renal function (FE = 1.21, p = .042). During treatment IgG1 anti-r-αGAL A levels increased only in inhibition-positive patients (p = .0045). IgG4 anti-r-αGAL A antibodies developed in 7 out of 9 inhibition-positive patients. Other antibody subclasses were either not present or too low to quantify., Conclusion: Development of inhibiting antibodies against r-αGAL A negatively affects the biochemical response to ERT and resulted in an accelerated decline in renal function. The presence of IgG1 and IgG4 anti-r-αGAL A antibodies is associated with in vitro αGAL A activity inhibition., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Anderson-Fabry disease is a rare X-linked lysosomal storage disease caused by α-galactosidase A (α-GalA) gene variants and characterized by a large genotypic and phenotypic spectrum. Enzyme replacement therapy (ERT) using recombinant α-GalA has been approved for > 10 years as a specific therapy for the disease. However, the long-term clinical efficacy for cardiac manifestations has been equivocal because it depends on several factors such as genotype, sex, age, and disease severity at the initiation of ERT. We report the differences in the clinical effects of ERT continued for > 10 years in three patients with the same genotype. Left ventricular hypertrophy and myocardial dysfunction progressed in the heterozygote proband even under ERT, although disease progression was prevented in two sons of Case 1.

The major cellular clearance pathway for organelle and unwanted proteins is the autophagy-lysosome pathway (ALP). Lysosomes not only house proteolytic enzymes, but also traffic organelles, sense nutrients, and repair mitochondria. Mitophagy is initiated by damaged mitochondria, which is ultimately degraded by the ALP to compensate for ATP loss. While both systems are dynamic and respond to continuous cellular stressors, most studies are derived from animal models or cell based systems, which do not provide complete real time data about cellular processes involved in the progression of lysosomal storage diseases in patients. Gaucher and Fabry diseases are rare sphingolipid disorders due to the deficiency of the lysosomal enzymes; glucocerebrosidase and α-galactosidase A with resultant lysosomal dysfunction. Little is known about ALP pathology and mitochondrial function in patients with Gaucher and Fabry diseases, and the effects of enzyme replacement therapy (ERT). Studying blood mononuclear cells (PBMCs) from patients, we provide in vivo evidence, that regulation of ALP is defective. In PBMCs derived from Gaucher patients, we report a decreased number of autophagic vacuoles with increased cytoplasmic localization of LC3A/B, accompanied by lysosome accumulation. For both Gaucher and Fabry diseases, the level of the autophagy marker, Beclin1, was elevated and ubiquitin binding protein, SQSTM1/p62, was decreased. mTOR inhibition did not activate autophagy and led to ATP inhibition in PBMCs. Lysosomal abnormalities, independent of the type of the accumulated substrate suppress not only autophagy, but also mitochondrial function and mTOR signaling pathways. ERT partially restored ALP function, LC3-II accumulation and decreased LC3-I/LC3-II ratios. Levels of lysosomal (LAMP1), autophagy (LC3), and mitochondrial markers, (Tfam), normalized after ERT infusion. In conclusion, there is mTOR pathway dysfunction in sphingolipidoses, as observed in both PBMCs derived from patients with Gaucher and Fabry diseases, which leads to impaired autophagy and mitochondrial stress. ERT partially improves ALP function., Competing Interests: Ozlem Goker-Alpan is affiliated with Consulting Shire and Sanofi Genzyme pharmacological companies. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background/aims: Fabry disease (FD) is a lysosomal storage disorder characterized by impaired alpha-galactosidase A (α-Gal A) enzyme activity due to mutations in the GLA gene. While virtually all tissues are affected, renal damage is particularly critical for the patients' outcome. Currently, powerful diagnostic tools and in vivo research models to study FD in the kidney are lacking, which is a major obstacle for further improvements in diagnosis and therapy. The present study focuses on the effects of enzyme replacement therapy on a previously established podocyte cell culture model of Fabry disease., Methods: We investigated the effect of in vitro application of α-Gal A on Fabry podocytes for 3 days, mimicking enzyme replacement therapy. We studied reduction of Gb3 levels and dysregulated molecular pathways such as autophagy, mTOR/AKT signaling and pro-fibrotic signaling by employing immunofluorescence, electron microscopy, tandem mass spectrometry and western blot., Results: We detected complete resolution of Gb3 accumulation in Fabry podocytes upon α-Gal A treatment. Despite robust Gb3 clearance, dysregulation of the signaling pathways investigated was not reversed., Conclusion: This study presents first evidence for Gb3-independent effects regarding dysregulation of signal transduction mechanisms in FD not recovering upon α-Gal A treatment. We assume that intracellular alterations observed in FD may have a point of no return after which a reversal of dysregulated cellular signal transduction by α-Gal A treatment is not effective, despite Gb3 clearance. Our observations suggest further research on signal transduction mechanisms altered in Fabry podocytes and on determining the appropriate time for initiation of Fabry therapy., Competing Interests: F. B. received travel support of Amicus Therapeutics. C. K. received travel support and speaker honoraria of Amicus Therapeutics, Sanofi-Genzyme and Shire and is an advisory board member of Amicus Therapeutics, Sanofi-Genzyme and Shire., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Introduction: Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). Reduced α-GAL activity leads to progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. The recent report of increased expression of CD77 in blood cells of patients with FD indicated that this molecule can be used as a potential marker for monitoring enzyme replacement therapy (ERT)., Objective: The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation)., Methods: We evaluated the fluctuations in PBMC (peripheral blood mononuclear cell) membrane CD77 expression in FD patients undergoing ERT and correlated these levels with those observed in different cell types., Results: A greater CD77 expression was found in phagocytes of patients compared to controls at baseline. Interestingly, the variability in CD77 levels is larger in patients at baseline (340 - 1619 MIF) and after 12 months of ERT (240 - 530 MIF) compared with the control group (131 - 331 MFI). Furthermore, by analyzing the levels of CD77 in phagocytes from patients throughout ERT, we found a constant decrease in CD77 levels., Conclusion: The increased CD77 levels in the phagocytes of Fabry carriers together with the decrease in CD77 levels throughout ERT suggest that measuring CD77 levels in phagocytes is a promising tool for monitoring the response to ERT in FD.

Background: Fabry disease is characterized by deficient expression/activity of α-GalA with consequent lysosomal accumulation in various organs of its substrate Gb3. Despite enzyme replacement therapy, Fabry disease progresses with serious myocardial, cerebral and renal manifestations. Gb3 accumulation may induce oxidative stress (OxSt), production of inflammatory cytokines and reduction of nitric oxide, which may impact on Fabry disease's clinical manifestations., Methods: OxSt status was characterized in 10 patients compared with 10 healthy subjects via protein expression of p22phox, subunit of NADH/NADPH oxidase, (Western blot), Heme oxygenase (HO)-1 levels (ELISA), antioxidant/anti-inflammatory, lipid peroxidation as malondialdehyde (MDA) production (colorimetric assay), phosphorylation state of Extracellular Signal Regulated Kinase (ERK)1/2 and Myosin Phosphatase Target Protein (MYPT)-1 (Western blot), marker of Rho kinase activation, both involved in OxSt signaling. Cardiac left ventricular (LV) mass was also evaluated (M-mode echocardiography)., Results: LV mass was higher in Fabry's males (123.72±2.03SEM g/m2) and females (132.09±6.72g/m2). p22phox expression was also higher in patients (1.04±0.09 d.u. vs 0.54±0.05 d.u. p<0.01) as well as MDA levels (54.51±3.97 vs 30.05±7.11 nmol/mL p = 0.01) while HO-1 was reduced (8.84±0.79 vs 14.03±1.23 ng/mL, p<0.02). MYPT-1's phosphorylation was increased in patients (0.52±0.11 d.u. vs 0.03±0.08 d.u., p<0.01) while phosphorylation of ERK1/2 was reduced (0.91±0.08 d.u. vs 1.53±0.17 d.u., p = 0.004)., Conclusions: This study documents OxSt activation and the altered reaction to it in Fabry patients. Cardiac remodeling, Rho kinase signaling activation and reduction of protective HO-1 might suggest that, in addition to enzyme replacement therapy, OxSt inhibition by either pharmacological or nutritional measures, is likely to prove useful for the prevention/treatment of Fabry patients' cardiovascular-renal remodeling., Competing Interests: This study was supported by an unrestricted grant from Sanofi- Genzyme. Linda Landini is employed by Sanofi-Genzyme. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Fabry disease (also known as Anderson-Fabry disease, angiocheratoma corporis diffusum, diffuse angiocheratoma) is a rare tesaurismosis linked to the deficiency of the lysosomal enzyme alpha-galactosidase A, required for the physiological catabolism of glycosphingolipids. The related clinical signs show a multisystemic feature and define a degenerative and disabling pathology, whose approach requires a close multidisciplinary specialist collaboration. Currently, the renewed interest in the disease is aimed at the need to provide an early diagnosis, in order to early begin the enzyme replacement therapy and to slow down or avoid the establishment of irreparable organ damage. For this reason, the diagnostic suspicion becomes crucial and arises from the careful observation and research of the symptoms, together with the anamnesis and the overall clinical evaluation of the patient., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

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.

Background: Fabry disease (FD) is a lysosomal storage disorder (LSD) that involves the cochleovestibular system. Tinnitus and progressive sensorineural hearing loss are frequent complains. A stabilization of hearing function has been reported with enzyme replacement therapy (ERT). This study aims to characterize the inner ear involvement, identify factors associated to hearing loss and evaluate the effect of ERT on the hearing function of FD patients., Methods: We reviewed the clinical records of patients with confirmed diagnosis of FD followed in a Reference Centre on LSD in the North of Portugal., Results: We included a total of 122 patients with a mean age of 47.1 ± 17.6 years and 48.3% males. Hearing loss was reported by 26.2% of the patients and 23.0% mentioned tinnitus. Pure tone audiometry revealed sensorineural hearing loss in 36.9% of the cases. FD patients presented worse age-adjusted hearing thresholds in all analysed frequencies compared to the normal population (p = .001). Patients with hearing loss presented a significantly higher value of microalbuminuria (p = .001) and a higher frequency of acroparesthesias (p = .032). Patients presented a comparable hearing level one year after starting ERT (p = .384)., Conclusions: In FD, hearing loss is common and age-matched hearing thresholds by frequency are worse than in the general population. Hearing loss was associated to the presence of acroparesthesias and higher values of microalbuminuria. Hearing loss stabilized in patients under ERT. A careful cochleo-vestibular evaluation should be part of the clinical assessment of FD., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Fabry disease (FD) is a rare X-chromosome-linked lysosomal storage disorder. Although initial expectations of enzyme replacement therapy (ERT) were high, it is now clear that real-world effectiveness is disappointing and evidence gathering has been inadequate. In retrospect, development of ERT for FD had several shortcomings. Little convincing evidence on the effectiveness existed at time of authorization. Also, post-marketing evaluation failed to generate sufficient and relevant data for adequate evaluation on effectiveness. Adaptive pathways might have benefitted ERT development by: (i) involving healthcare professionals, patients, health technology assessment bodies and payers in the development process; (ii) iterative development, starting with initial authorization in classical males; (iii) a clear real-world data collection plan; (iv) an independent disease registry; and (v) prescription control., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The current treatment of Fabry disease by enzyme replacement therapy with commercially available recombinant human α-Galactosidase A shows a continuous deterioration of the disease patients. Human recombinant α-Galactosidase A is a homodimer with noncovalently bound subunits and is expressed in the ProCellEx plant cell-based protein expression platform to produce pegunigalsidase alfa. The effect of covalent bonding between two α-Galactosidase A subunits by PEG-based cross-linkers of various lengths was evaluated in this study. The results show that cross-linking by a bifunctional PEG polymer of 2000 Da produces a more stable protein with improved pharmacokinetic and biodistribution properties. The chemical modification did not influence the tertiary protein structure but led to an increased thermal stability and showed partial masking of immune epitopes. The developed pegunigalsidase alfa is currently tested in phase III clinical trials and has a potential to show superior efficacy versus the currently used enzyme replacement therapies in the treatment of Fabry disease patients.

(1) Background: A high incidence of intervening sequence (IVS)4+919 G>A mutation with later-onset cardiac phenotype have been reported in a majority of Taiwan Fabry cohorts. Some evidence indicated that conventional biomarkers failed to predict the long-term progression and therapeutic outcome; (2) Methods: In this study, we constructed an induced pluripotent stem cell (iPSC)-based platform from Fabry cardiomyopathy (FC) patients carrying IVS4+919 G>A mutation to screen for potential targets that may help the conventional treatment; (3) Results: The FC-patient-derived iPSC-differentiated cardiomyocytes (FC-iPSC-CMs) carried an expected IVS4+919 G>A genetic mutation and recapitulated several FC characteristics, including low α-galactosidase A enzyme activity and cellular hypertrophy. The proteomic analysis revealed that arachidonate 12/15-lipoxygenase (Alox12/15) was the most highly upregulated marker in FC-iPSC-CMs, and the metabolites of Alox12/15, 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE), were also elevated in the culture media. Late administration of Alox12/15 pharmacological inhibitor LOXBlock-1 combined with α-galactosidase, but not α-galactosidase alone, effectively reduced cardiomyocyte hypertrophy, the secretion of 12(S)- and 15(S)-HETE and the upregulation of fibrotic markers at the late phase of FC; (4) Conclusions: Our study demonstrates that cardiac Alox12/15 and circulating 12(S)-HETE/15(S)-HETE are involved in the pathogenesis of FC with IVS4+919 G>A mutation.

Non-specific gastrointestinal symptoms, including pain, diarrhoea, nausea, and vomiting, can be the first symptoms of Fabry disease. They may suggest more common disorders, e.g. irritable bowel syndrome or inflammatory bowel disease. The confounding clinical presentation and rarity of Fabry disease often cause long diagnostic delays and multiple misdiagnoses. Therefore, specialists involved in the clinical evaluation of non-specific upper and lower gastrointestinal symptoms should recognize Fabry disease as a possible cause of the symptoms, and should consider Fabry disease as a possible differential diagnosis. When symptoms or family history suggest Fabry disease, in men, low alpha-galactosidase A enzyme levels, and in women, specific Fabry mutations confirm the diagnosis. In addition to symptomatic treatments, disease-specific enzyme replacement therapy with recombinant human alpha-galactosidase A enzyme or chaperone therapy (migalastat) in patients with amenable mutations can improve the disease, including gastrointestinal symptoms, and should be initiated as early as possible after Fabry disease has been confirmed; starting enzyme replacement therapy at as young an age as possible after diagnosis improves long-term clinical outcomes. Improved diagnostic tools, such as a modified gastrointestinal symptom rating scale, may facilitate diagnosing Fabry disease in patients with gastrointestinal symptoms of unknown cause and thus assure timely initiation of disease-specific treatment., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Fabry disease (FD) is an X-linked lysosomal storage disease and is the result of mutation in the α-Galactosidase A gene; such mutations cause a deficiency in α-Galactosidase A enzyme and an accumulation of glycosphingolipid in tissue. Affected males with classic FD have little or no enzyme activity and have an early onset of symptoms and signs, including acroparesthesias, hypohidrosis, angiokeratomas, gastrointestinal dysfunction and/or a characteristic corneal dystrophy during childhood/adolescence. Males with late-onset FD who have residual enzyme activity develop progressive multi-systemic involvement that leads to renal failure and hypertrophic cardiomyopathy, as well as cerebrovascular disease; these events mostly occur during the fourth to seventh decades of life. Heterozygous females can develop vital organ damage that in turn causes severe morbidity and mortality; these symptoms may be as severe as those in affected males. For the treatable disease, this review aims to raise awareness of early recognition and further management of FD based on newborn screening. As newborn screening for FD has been implemented worldwide, it allows the early detection of individuals with Fabry mutations. Based on screening studies, the prevalence of the later-onset type FD is much higher than that of classical type FD. Newborn screening studies have also revealed that patients with FD may develop insidious but ongoing irreversible organ damage. The timing of enzyme replacement therapy, which is able to stabilize the progression of disease, is important in order to prevent irreversible organ damage. Therapies that may become available in the future include pharmacological chaperones and substrate reduction therapy, both of which are still under investigation as ways of improving the health of individuals with FD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Enzymes are attractive as immunotherapeutics because they can catalyze shifts in the local availability of immunostimulatory and immunosuppressive signals. Clinical success of enzyme immunotherapeutics frequently hinges upon achieving sustained biocatalysis over relevant time scales. The time scale and location of biocatalysis are often dictated by the location of the substrate. For example, therapeutic enzymes that convert substrates distributed systemically are typically designed to have a long half-life in circulation, whereas enzymes that convert substrates localized to a specific tissue or cell population can be more effective when designed to accumulate at the target site. This Topical Review surveys approaches to improve enzyme immunotherapeutic efficacy via chemical modification, encapsulation, and immobilization that increases enzyme accumulation at target sites or extends enzyme half-life in circulation. Examples provided illustrate "replacement therapies" to restore deficient enzyme function, as well as "enhancement therapies" that augment native enzyme function via supraphysiologic doses. Existing FDA-approved enzyme immunotherapies are highlighted, followed by discussion of emerging experimental strategies such as those designed to enhance antitumor immunity or resolve inflammation.

Background: Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease-specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy., Methods: We studied a prospectively assembled consecutive cohort of 585 patients (71% male) from 2 hypertrophic cardiomyopathy tertiary referral centers by screening for low α-galactosidase A activity in dried blood spots. Male patients with low α-galactosidase A activity levels and all females were tested for mutations in the GLA gene., Results: In 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified 2 unrelated patients (0.34%), both with the GLA mutation encoding P.N215S, the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a man aged 53 years and a woman aged 69 years, and demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy. After family screening, a total of 27 new Fabry disease patients aged 2-81 years were identified in the 2 families, including 12 individuals who are now receiving enzyme replacement therapy., Conclusions: These observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease-affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Fabry's disease is a genetic disorder of X-linked inheritance caused by mutations in the alpha galactosidase A gene resulting in deficiency of this lysosomal enzyme. The progressive accumulation of glycosphingolipids, caused by the inadequate enzymatic activity, is responsible of organ dysfunction and thus of clinical manifestations. In the presence of a high clinical suspicion, a careful physical examination and specific laboratory tests are required, finally diagnosis of Fabry's disease is confirmed by the demonstration of absence or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females; in fact the performance of enzymatic activity assay alone in women is inconclusive. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. Because of its multisystemic involvement Fabry's disease may present a large spectrum of clinical manifestations as acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement (renal insufficiency, proteinuria, left ventricular hypertrophy, strokes). Enzyme replacement therapy with recombinant α- galactosidase A is actually the specific therapy for Fabry disease. Early beginning of this treatment has shown beneficial effects in particular in cardiac and renal disease, a less efficacy it has been reported in central nervous system involvement. ERT has shown to be associated to a significant reduction of Gb3 accumulation in several tissues, in particular heart and kidney; moreover it improves pain related quality of life. Next generation lysosomal storage disorder treatment is based on new strategic approaches as stem cell based therapy, pharmacological chaperones, viral gene therapy; concerning Fabry's disease, it has been recently addressed to great interest this last innovative method, that is to say viral gene therapy, for delivering recombination enzyme into main involved tissues; promising results have been reported in animal models. Great efforts have been made and are still required in this field in order to make available a more effective, safer, advantageous therapeutic strategy for patients with Fabry's disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objectives: Galacto-oligosaccharides (GOS) are dietary FODMAPs (fermentable carbohydrates) associated with triggering gastrointestinal symptoms in patients with irritable bowel syndrome (IBS). This randomized, double-blind, placebo-controlled, cross-over trial aimed to assess whether oral α-galactosidase co-ingestion with foods high in GOS and low in other FODMAPs would reduce symptoms., Methods: Patients meeting the Rome III criteria for IBS who were hydrogen-producers on breath testing were recruited. Participants were treated with full-dose (300 GALU (galactosidic units) α-galactosidase) and half-dose enzyme (150 GALU α-galactosidase), and placebo (glucose) in a random order with ≤14 days washout between arms. Following a 3-day low FODMAP run-in period, participants consumed provided diets high in GOS for a further 3-days. Gastrointestinal symptoms were measured daily using a 100 mm visual-analogue-scale, and breath samples taken hourly on the second last day with hydrogen content analysed as area-under-the-curve., Results: Thirty-one patients with IBS (20 IBS-D, 4 IBS-C, 7 IBS-M) completed the study. The addition of high GOS foods resulted in a significant increase in overall symptoms with 21 patients exhibiting GOS-sensitivity (>10 mm increase for overall symptoms). Of those, full-dose enzyme reduced overall symptoms (median 24. 5(IQR 17.5-35.8) vs. 5.5(1.5-15.0) mm; P=0.006) and bloating (20.5(9.5-42.0) vs. 6.5(2.0-15.8); P=0.017). Breath hydrogen production was minimal with no differences seen between placebo and full-dose (P=0.597)., Conclusions: Oral α-galactosidase taken with high GOS foods provides a clinically significant reduction in symptoms in GOS-sensitive individuals with IBS. This strategy can be translated into practice to improve tolerance to high GOS foods as an adjunct therapy to the low FODMAP diet.

Aim: Anderson-Fabry disease (AFD) is a hereditary disorder caused by a deficiency in the lysosomal enzyme α-galactosidase A which causes dysfunctions in multiple organ systems. Cardiac manifestation includes left ventricular hypertrophy, thickening of the valves, conduction disturbances and in the late phase, extensive areas of myocardial fibrosis with increased risk of sudden cardiac death. Case example: A case of AFD with exclusive cardiac involvement is described. During follow-up, due to the high risk of life-threatening arrhythmic events, implantation of an implantable cardioverter defibrillator is performed., Conclusion: AFD patients with advanced cardiac disease might represent a subgroup of patients who may require an implantable cardioverter defibrillator for primary prevention of sudden cardiac death.

Sphingolipidoses are genetically inherited diseases in which genetic mutations lead to functional deficiencies in the enzymes needed for lysosomal degradation of sphingolipid substrates. As a consequence, nondegradable lipids enrich in the lysosomes and lead to fatal pathological phenotypes in affected individuals. In this review, different drug-based treatment strategies including enzyme replacement therapy and substrate reduction therapy are discussed. A special focus is on the concept of pharmacological chaperones, one of which recently acquired clinical approval within the EU. On the basis of the different limitations for each approach, possible future directions of research are discussed.