Treatment Of Fabry Disease Research Articles

Effectiveness and safety of enzyme replacement therapy in the treatment of Fabry disease: a Chinese monocentric real-world study.

To assess the effectiveness and safety of enzyme replacement therapy (ERT) for treating Fabry disease in clinical practice. The clinical data of patients with Fabry disease were retrospectively collected and screened according to inclusion and exclusion criteria. The effectiveness of ERT was evaluated by analyzing the improvement in renal dysfunction (decreased estimated glomerular filtration rate (eGFR) and proteinuria), cardiac system injury (mainly increased left ventricular mass index (LVMI)), and neuropathic pain after ERT treatment. The safety of ERT was measured by summarizing the occurrence of adverse events (AE) and adverse drug reactions (ADR) before and after ERT. Sixteen patients with Fabry disease who underwent ERT treatment 2-36 times over a period of 2-89weeks were enrolled in the study. Among them, 13 received symptomatic treatment based on the involvement of various organs, 14 were treated with anti-inflammatory and anti-allergic drugs, and 16 had no AE or ADR. After ERT, there was no significant difference in (eGFR, microalbumin (mALB), 24h urinary protein quantitation (24h PRO), urinary albumin/creatinine ratio (ACR), uric acid (UA), and β2 microglobulin (β2MG) (P > 0.05), and the renal function remained stable or improved; ERT could significantly reduce left ventricular mass index (LVMI) (P = 0.043) and lactate dehydrogenase (LDH) (P = 0.031), and other cardiac function indexes had an improvement trend or remained stable, but the difference was not significant (P > 0.05). After ERT, the degree of limb pain in three of the four minor patients improved. ERT could effectively stabilize or improve renal and cardiac function and relieve neuropathic pain in patients with Fabry disease, and no AE occurred during treatment, and the clinical effectiveness and safety were satisfactory.

Dirichlet latent modelling enables effective learning and sampling of the functional protein design space

Engineering proteins with desired functions and biochemical properties is pivotal for biotechnology and drug discovery. While computational methods based on evolutionary information are reducing the experimental burden by designing targeted libraries of functional variants, they still have a low success rate when the desired protein has few or very remote homologous sequences. Here we propose an autoregressive model, called Temporal Dirichlet Variational Autoencoder (TDVAE), which exploits the mathematical properties of the Dirichlet distribution and temporal convolution to efficiently learn high-order information from a functionally related, possibly remotely similar, set of sequences. TDVAE is highly accurate in predicting the effects of amino acid mutations, while being significantly 90% smaller than the other state-of-the-art models. We then use TDVAE to design variants of the human alpha galactosidase enzymes as potential treatment for Fabry disease. Our model builds a library of diverse variants which retain sequence, biochemical and structural properties of the wildtype protein, suggesting they could be suitable for enzyme replacement therapy. Taken together, our results show the importance of accurate sequence modelling and the potential of autoregressive models as protein engineering and analysis tools.

Experts' Opinion in Fabry Disease Management and the Unmet Medical Need: The Saudi Perspective.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-galactosidase A gene mutations. Its global incidence ranges from 1:40,000 to 1:170,000. This expert review evaluates the available guidelines, the status of diagnosed but untreated patients with FD, and the challenges in diagnosing and managing FD in the Kingdom of Saudi Arabia (KSA). An advisory board meeting (ABM) was conducted in two phases, with a survey that aimed to receive insights on the current unmet needs in the management of patients with FD in November 2022, and a second, offline meeting in February 2023. The goal of this ABM was to discuss current unmet needs in the management of Fabry patients in the Kingdom of Saudi Arabia. In the first ABM, experts opined on the best practices in the diagnosis, screening, and management of FD for healthcare professionals. These opinions on the management of FD relied on data from research and expert clinical judgments. In the second ABM, the same panel discussed different aspects of FD diagnosis, treatment, and management in the member countries of the Gulf Cooperation Council. The experts discussed the stigma associated with FD, patient awareness and knowledge, genetic screening, biomarkers, and home infusion therapy. They reviewed international guidelines and clinical criteria for enzyme replacement therapy (ERT). Furthermore, they also discussed the diagnosis of FD in men and women, the current guidelines followed for monitoring patients with FD, monitoring untreated patients with FD, Fabry Stabilization IndeX (FASTEX) as an assessment tool for the diagnosis of FD, FD management in KSA, challenges encountered while prescribing ERT in patients with FD, and the clinical criteria for starting ERT. The discussions led to the conclusion that currently, ERT is the only available therapy to manage FD and research should be focused on the early diagnosis and management of FD.

Gene therapy with lipid nanoparticles for Fabry disease: Leveraging E-selectin for targeted delivery to endothelial cells

Fabry disease (FD) is caused by deficiency of activity of the lysosomal enzyme α-Galactosidase A (α-Gal A) throughout the organism, and vascular dysfunction represents the main pathological event causing life-threatening complications. Therefore, endothelial cells (ECs) are currently receiving attention as potential targets for the development of innovative therapies for FD, including gene therapy. However, the difficulty of transfecting ECs poses a major challenge to the development of vascular endothelial-targeted nucleic acid delivery systems. In the present study, we have developed lipid nanoparticles (LNPs) coupled with antibodies against the E-selectin to deliver pDNA encoding α-Gal A specifically to activated ECs, which express E-selectin. Coupled LNPs showed significantly higher cell association than uncoupled LNPs in activated Human Umbilical Vein Endothelial Cells (HUVECs) and in a cellular model of FD (Immortalized Fabry Endothelial Cell Line-1 (IMFE-1)), and this was translated into a higher transfection efficacy. Additionally, in IMFE-1 cells, antibody-coupled LNPs increased α-Gal A activity to levels 6.5-fold higher than untreated cells. In conclusion, E-selectin-targeted LNPs encapsulating pDNA showed enhanced transfection efficacy in activated ECs and the ability to increase α-Gal A activity in an FD cellular model, opening the door to a new therapeutic strategy in the treatment of FD.

#3006 Therapeutic apheresis in Fabry disease

Abstract Background and Aims Fabry's disease (FD) is a rare lysosomal disorder linked to the X chromosome due to a mutation in the gene encoding alpha-galactosidase A (alpha-Gal A). This mutation leads to a defect in the metabolism of glycosphingolipids, causing the progressive accumulation of globotriaacylceramide (GB3) or LysoGB3 in cells, tissues, and organs. In the treatment of FD, we have enzyme replacement therapy (ERT) with Agalsidase-alfa (Replagal®), Agalsidase-beta (Fabrazyme®), and chaperones (Migalastat®). However, there are limitations such as disease progression and morbimortality. Regarding ERT, the development of circulating immunoglobulin G (IgG) antibodies against agalsidase (aGAL) in the long term appears to be associated with a loss of effectiveness. The use of Therapeutic Apheresis (TA), such as plasma exchange therapy (PE) and low-density lipoprotein apheresis (LDL-apheresis), is employed in the treatment of various pathologies due to its ability to eliminate plasma, antibodies, low-density lipoproteins, apolipoproteins, and the adaptability of therapy to the molecule to be removed. The aim was to demonstrate that LDL-apheresis and PE favor Lyso-Gb3 elimination, and PE also eliminates IgG-aGAL as an adjunctive treatment in FD and conducted a proof-of-concept study. Method Two branches of intervention were established, where patients were classified into two groups based on the presence or absence of anti-agalsidase IgG antibodies. If they have the presence of antibodies, they would be eligible for plasma exchanges with two objectives: removing pre-formed antibodies and eliminating Lyso-Gb3. Conversely, in the absence of pre-formed antibodies, LDL-apheresis is performed with the aim of eliminating Lyso-Gb3. The proof-of-concept study was done with two FD patients undergoing ERT were identified, one with IgG-aGAL and the other with very low levels. PE was performed on the first patient, and LDL-apheresis on the second. Lyso-Gb3 levels were titrated in blood before and after LDL-apheresis, and in the washout bag of the column. For antibodies, titration was done in pre and post PE blood and in the extracted plasma from PE. Results After applying TA techniques, we observed that PE reduces IgG-aGAL by 85%, and in the case of LDL-apheresis, there was a 28% reduction in IgG-aGAL. While the ability to eliminate LysoGb3 showed a reduction of 25.5% in PE and 39.7% for LDL-apheresis. To eliminate a potential confounding factor, LysoGb3 determination in albumin was within normal limits. Conclusion With these results, we confirm that PE is more efficient in removing IgG-aGAL but also eliminates LysoGb3, whereas LDL-apheresis is a very effective technique for removing Lyso-Gb3 but also contributes to antibody removal. Based on these findings, we consider TA to be an effective adjunctive tool for FD treatment, even as a standalone treatment. However, these are very preliminary results and should be reproduced with a larger number of patients.

#2401 Association of clinical characteristics with relative changes in plasma lyso-Gb3 levels by enzyme replacement therapy in patients with Fabry disease

Abstract Background and Aims Enzyme replacement therapy (ERT) is an established treatment for Fabry disease (FD), notably for its efficacy in reducing plasma globotriaosylceramide (Gb3) levels. FD is characterized by the accumulation of Gb3 in lysosomes, resulting in the formation of globotriaosylsphingosine (lyso-Gb3), a degradation product associated with disease severity. While numerous studies have demonstrated that ERT can reduce plasma lyso-Gb3 levels, these reductions are usually quantified in absolute terms. This study is the first to explore the relative changes in plasma lyso-Gb3 levels due to ERT and to investigate the association of these changes with patients' clinical characteristics through a retrospective analysis. Method This study included patients with FD who attended the division of Nephrology at our hospital. We excluded patients lacking sufficient clinical data or without plasma lyso-Gb3 measurements both before and after initiating ERT. We considered pre-ERT plasma lyso-Gb3 concentrations as the baseline and evaluated the relative changes at one year post-ERT and at the lowest recorded lyso-Gb3 level after ERT. These variations were compared across various clinical backgrounds to assess their correlation with clinical factors including age, gender, type of ERT medication (agalsidase α or β), and disease severity, as determined by the FASTEX score. Results This study included twelve patients with FD (5 males, 7 females). We observed significantly greater relative declining changes in plasma lyso-Gb3 concentration among males compared to females (one year: −71.9 ± 4.5% in males vs. −20.6 ± 13.7% in females, p < 0.01; minimum levels: −78.5 ± 8.9% in males vs. −48.4 ± 19.6% in females, p = 0.01). No significant difference emerged in lyso-Gb3 reduction between agalsidase α and β treatments over all. One year after treatment, the relative changes in the levels were −45.1 ± 32.6% for agalsidase α and −37.7 ± 24.2% for agalsidase β (p = 0.68). The minimum levels followed suit, with −59.4 ± 26.8% for agalsidase α and −63.2 ± 15.2% for agalsidase β (p = 0.78). Lastly, the relative changes in lyso-Gb3 one year after initiating ERT were significantly associated with age (r = −0.873, p < 0.001), FASTEX score (r = 0.814, p = 0.001), baseline α-galactosidase A activity (r = −0.833, p = 0.001), and baseline lyso-Gb3 levels (r = 0.877, p < 0.001). Additionally, at the lowest levels, the relative changes in lyso-Gb3 showed a significant association with baseline α-galactosidase A activity (r = −0.887, p < 0.001), and baseline lyso-Gb3 levels (r = 0.702, p = 0.011). Conclusion The findings of our study suggest that relative changes in lyso-Gb3 are more pronounced in male patients, those with lower baseline α-galactosidase A activity, and those with higher baseline plasma lyso-Gb3 levels. Patients exhibiting severe α-galactosidase A deficiency and more severe clinical symptoms may experience greater relative declines in plasma lyso-Gb3 concentration following ERT.

Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease.

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 2years showed that the intergroup difference [95%confidence interval] in the median slope was -0.36mL/min/1.73 m2/year [-2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of -3mL/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.

Targeting strategies with lipid vectors for nucleic acid supplementation therapy in Fabry disease: a systematic review

Fabry disease (FD) results from a lack of activity of the lysosomal enzyme α-Galactosidase A (α-Gal A), leading to the accumulation of glycosphingolipids in several different cell types. Protein supplementation by pDNA or mRNA delivery presents a promising strategy to tackle the underlying genetic defect in FD. Protein-coding nucleic acids in FD can be either delivered to the most affected sites by the disease, including heart, kidney and brain, or to specialized organs that can act as a production factory of the enzyme, such as the liver. Lipid-based systems are currently at the top of the ranking of non-viral nucleic acid delivery systems, and their versatility allows the linking to the surface of a wide range of molecules to control their biodistribution after intravenous administration. This systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines and provides an overview and discussion of the targeting ligands that have been employed so far to actively vectorize intravenously administered non-viral vectors based on lipid carriers to clinically relevant organs in the treatment of FD, for protein-coding nucleic acid (pDNA and mRNA) supplementation. Among the thirty-two studies included, the majority focus on targeting the liver and brain. The targeting of the heart has been reported to a lesser degree, whereas no articles addressing kidney-targeting have been recorded. Although a great effort has been made to develop organ-specific nucleic acid delivery systems, the design of active-targeted carriers with high quality, good clinical translation, and large-scale manufacturing capacity is still challenging.Graphical

Genotype-phenotype analysis of Fabry disease caused by GLA gene variation in a pedigree

Objective: To investigate the clinical phenotype and genetic characteristics of patients with Fabry disease caused by a GLA variant, IVS4+919G>A. Methods: It was a prospective study. Fabry disease screening was conducted among high-risk population in Ninghai from October 2021 to August 2023. Those children with decreased α-galactosidase enzyme activity<2.40 μmol/(L·h) or elavated Lyso-GL-3 level>1.10 μg/L in dried blood spot (DBS) method underwent GLA genetic testing for diagnosis confirmation. Meanwhile, family screening was carried out. A proband and his family members diagnosed with Fabry disease were research subjects. The clinical and genetic characteristics of patients with Fabry disease caused by the GLA variant (IVS4+919G>A) were analyzed. Results: The female proband aged 9.8 years with pain in both lower limbs as the initial symptom was found to have a heterozygous GLA variant IVS4+919G>A among 102 patients. In family screening, there were 4 family members (proband's father, elder sister, elder male cousin and elder female cousin) with Fabry disease and a family member (proband's fifth aunt) with a GLA variant. Among these 4 diagnosed family members, the elder male cousin of the proband, a boy aged 13.2 years had a heterozygous GLA variant, IVS4+919G>A with intermittent pain in both lower limbs as the initial symptom. The proband's father had knee joint pain. The proband's elder sister had decreased vision and his elder female cousin had no obvious symptoms. The proband's fifth aunt with a GLA variant had decreased vision. Conclusions: High-risk screening in children and family screening are helpful for early diagnosis and treatment of Fabry disease. Neuropathic pain may be a early symptom in children with Fabry disease caused by the GLA variant, IVS4+919G>A.

Newborn genetic screening for Fabry disease: Insights from a retrospective analysis in Nanjing, China

Fabry disease (FD), an X-linked disorder resulting from dysfunction of α-galactosidase A, can result in significant complications. Early intervention yields better outcomes, but misdiagnosis or delayed diagnosis is common, impacting prognosis. Thus, early detection is crucial in the clinical diagnosis and treatment of FD. While newborn screening for FD has been implemented in certain regions, challenges persist in enzyme activity detection techniques, particularly for female and late-onset patients. Further exploration of improved screening strategies is warranted. This study retrospectively analyzed genetic screening results for pathogenic GLA variants in 17,171 newborns. The results indicated an estimated incidence of FD in the Nanjing region of China of approximately 1 in 1321. The most prevalent pathogenic variant among potential FD patients was c.640-801G > A (46.15 %). Furthermore, the residual enzyme activity of the pathogenic variant c.911G > C was marginally higher than that of other variants, and suggesting that genetic screening may be more effective in identifying potential female and late-onset patients compared to enzyme activity testing. This research offers initial insights into the effectiveness of GLA genetic screening and serves as a reference for early diagnosis, treatment, and genetic counseling in FD.

Advances in Diagnosis and Treatment of Fabry Disease: A Review of Clinical Manifestations and Therapeutic Interventions

At present, early diagnosis of many orphan diseases is difficult due to their rare occurrence and insufficient knowledge of them. This article presents a review of the literature and our study of Fabry disease (FD), a rare genetic multisystem disease which belongs to the group of lysosomal storage diseases. This disease is based on a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to the progressive accumulation of glycolipid Gb3 in lysosomes in almost all cells of the body, causing extensive organ damage and an increase in plasma levels of globotriaosylsphingosine (lyso-Gb3 product of degradation of accumulated Gb3. Objective: The aim is to provide a comprehensive overview of modern knowledge and current research in the field of pathophysiology, diagnosis and treatment of heart damage in FD, to evaluate the characteristics of diagnosed patients living on the territory of the Moscow region, and to develop and propose for spreading an algorithm for the early detection of this pathology. Methods: A retrospective analysis of the medical records of 12 patients with an estab-lished diagnosis of Fabry disease was carried out. Data from 12 patients with FD, undergoing enzyme replacement therapy of varying durations were analyzed. All patients had left ventricular hypertrophy (LVH) and hypertrophic cardiomyopathy, with 9 having LVH diagnosed during a diagnosis. 7 patients get a cardioprotective therapy. All patients underwent molecular genetic testing. In 3 cases there was fa-tal case. Results: The data were analyzed and molecular genetic markers of FD were detected for the purpose of selective screening for FD in the study sample. Conclusion: An algorithm for the early diagnosis of FD has been developed and presented for distribution among general practitioners and cardiologists.

Fabry disease: integrative aspects from diagnosis to treatment

Aim: identify the main aspects of Fabry disease (FD) from clinical suspicion to diagnosis, its vascular and cellular effects, in addition to treatment. Methods: This study is an integrative review of the literature supported by the search for articles in databases, Pub Med, Lilacs, Scielo, journals, and websites, with the following descriptors “Fabry disease”, “Fabry Disease treatment”, “Agalsidase-β”, “Agalsidase-α”, “Migalatast”, “inflammatory biomarkers” and “oxidative stress”, using original research articles and reviews between the years 1991 and 2023. This bibliographic survey was carried out in the period 01/10/2022 to 20/04/2023. Results: From a total of 340 articles found, 85 articles were selected. Discussion: The natural history of FD appears to be very complex, with multisystemic involvement and phenotypic variability. The analysis of FD symptoms is essential to the early diagnosis, aiming for greater success in therapy and prognosis, ensuring better patients’ quality of life and survival. Conclusion: This review addresses the diagnosis and main therapeutic approaches to guide health professionals and researchers, and to stimulate the development of research on FD.

Modern Approach to Fabry Disease Diagnosis and Management in Children

Fabry disease (FD), or Andersen-Fabry disease, is a rare hereditary lysosomal disease (sphingolipids storage disease) characterized by progressive multisystem involvement. The major symptoms among children are neuropathic pain / acroparesthesia, angiokeratomas, hypo- or anhidrosis, vortex keratopathy. Biochemical tests, molecular genetic testing, and family screening play crucial role in the diagnosis of the disease. Specific pathogenetic treatment of FD includes enzyme replacement therapy (ERT) with recombinant medications of the lysosomal enzyme -galactosidase A. ERT initiation before the development of severe organs and systems’ damage contributes to its higher efficacy. This article covers various aspects of pathogenesis, clinical picture features in childhood, modern methods of diagnosis and management of FD according to literature data.

Evaluating the Metabolic Basis of α-Gal A mRNA Therapy for Fabry Disease.

mRNA injection-based protein supplementation has emerged as a feasible treatment for Fabry disease. However, whether the introduction of LNP-encapsulated mRNA results in the alteration of metabolomics in an in vivo system remains largely unknown. In the present study, α-galactosidase A (α-Gal A) mRNA was generated and injected into the Fabry disease mouse model. The α-Gal A protein was successfully expressed. The level of globotriaosylsphingosine (Lyso-Gb3), a biomarker for Fabry disease, as well as pro-inflammatory cytokines such as nuclear factor kappa-B (NF-κB), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α), were greatly decreased compared to the untreated control, indicating the therapeutic outcome of the mRNA drug. Metabolomics analysis found that the level of 20 metabolites was significantly altered in the plasma of mRNA-injected mice. These compounds are primarily enriched in the arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, and glycolysis/gluconeogenesis pathways. Arachidonic acid and 5-hydroxyeicosatetraenoic acid (5-HETE), both of which are important components in the eicosanoid pathway and related to inflammation response, were significantly increased in the injected mice, possibly due to the presence of lipid nanoparticles. Moreover, mRNA can effectively alter the level of metabolites in the amino acid and energy metabolic pathways that are commonly found to be suppressed in Fabry disease. Taken together, the present study demonstrated that in addition to supplementing the deficient α-Gal A protein, the mRNA-based therapeutic agent can also affect levels of metabolites that may help in the recovery of metabolic homeostasis in the full body system.

Development of a first-in-class autologous B cell therapy for the treatment of Fabry disease

Development of a first-in-class autologous B cell therapy for the treatment of Fabry disease

Impact of Nontreatment Duration and Keratopathy on Major Adverse Cardiovascular Events in Fabry Disease: A Nationwide Cohort Study.

Fabry disease (FD) is a rare inherited X-linked lysosomal storage disorder that results in the progressive accumulation of glycosphingolipids in multiple organs. Early FD-specific treatments may improve clinical outcomes; however, clinical evidence about early FD treatment is limited. We aimed to determine the cardiovascular outcomes of patients with FD who received enzyme replacement therapy. This nationwide observational study was conducted using the National Health Claims database of the Korean population with FD. The primary outcome was major adverse cardiovascular events (MACEs). MACE risk factors in FD were evaluated using time-dependent Cox regression. Between January 2007 and April 2022, 188 patients with FD were analyzed. Among them, 22 (11.7%) experienced MACE (males: 14/95 [14.7%]; females: 8/93 [8.6%]). The mean age at MACE diagnosis was 53.5 ± 11.0 years in all patients with FD, which was lower in males compared with in females (49.7 ± 9.6 vs. 60.0 ± 10.7 years, p = 0.030). Multivariate analysis (HR, 95% CI) revealed that age (1.042; 1.004-1.082) and duration of FD nontreatment (1.040; 1.003-1.078) were significant MACE risk factors in all patients. In males, age (1.080; 1.032-1.131), FD nontreatment duration (1.099; 1.048-1.152), and keratopathy (18.920; 4.174-85.749) were significant MACE risk factors in multivariate analysis. In females, the only significant MACE risk factor was a high Charlson comorbidity index score (1.795; 1.229-2.622). In conclusion, duration of FD nontreatment and keratopathy are significant MACE risk factors in males with FD. These findings suggest the importance of early initiation of FD-specific treatment and careful evaluation of keratopathy in males with FD.

Diagnosis and Treatment of Fabry Disease - A Review

Fabry disease is a rare lysosomal storage disease that is caused by the irregular degradation of a fatty acid. This disease causes a multisystem disorder affecting mainly the heart and kidneys due to the accumulation of the fatty acid Gb3. There is a classical presentation of Fabry, where patients show symptoms in childhood or early adolescence as well as late onset where patients show symptoms later in life in the third or fourth decade. Early diagnosis is imperative for the success of treatment. This review focuses on symptoms, diagnostic steps, treatment, and future research of Fabry disease.

C.376A>G, (p.Ser126Gly) Alpha-Galactosidase A mutation induces ER stress, unfolded protein response and reduced enzyme trafficking to lysosome: Possible relevance in the pathogenesis of late-onset forms of Fabry Disease

Fabry Disease (FD) (OMIM 301500) is a metabolic X-linked inherited lysosomal storage disorder that results from the deficient activity of Alpha-Galactosidase A (Alpha-Gal), a lysosomal hydrolase that cleaves neutral glycosphingolipids with terminal N-linked galactosyl moieties, mainly globotriaosylceramides (Gb3). The enzyme, encoded by a 12-kb gene mapping on the long arm (Xq22.1 region) of the X chromosome, is constituted by a glycosylated subunit of approximately 55 kD, synthesized as an inactive precursor that undergoes maturation in endoplasmic reticulum (ER) and Golgi apparatus before being delivered to the lysosome to form a functional dimer.The gene is comprised of seven exons and, so far, >1000 different mutations have been described as associated to FD (www.dbfgp.org/dbFgp/fabry/FabryGP.htm).Clinical phenotypes are divided in two main classes, classic or non-classic, based on clinical and biochemical findings. Non-classic FD, usually recognized as late-onset forms with oligosymptomatic phenotype, presents with symptoms restricted solely to cardiocytes, kidneys or brain associated to missense misfolding mutations. In the group of the non-classic FD, special attention should be given to patients carrying the c.376A > G (p.Ser126Gly) mutation. The lack of clear experimental evidences on its pathogenetic role, despite the clinical pictures of the patients with severe ischaemic lesions, renal involvement and acroparesthesias, led many authors to classify this mutation as inconsistent, non-pathogenetic, and consequently not eligible to the current pharmacological treatments for FD. To shed light on the cellular processes affected by this mutation and to assess if the biochemical pathways involved with, could really have a significant pathogenetic impact, we studied the mutation in silico and in COS-7 and HEK 293 cell models. We found p.Ser126Gly, even retaining both high degree of synthesis and residual activity, is mostly stacked into the ER inducing unfolded protein response (UPR) with reduced trafficking to the lysosome. These data strongly suggest that p.Ser126Gly could trigger a pathogenetic mechanism different from the classic and well assessed increased turnover with loss of biological activity described for other missense mutations. This mechanism seems mainly related to a negative gain of function, with ER retention and UPR activation and could lead, via inflammation and/or apoptosis, to irreversible cell damage.

Recent advances in the diagnosis and treatment of Fabry disease

Recent advances in the diagnosis and treatment of Fabry disease

Therapeutic Role of Pharmacological Chaperones in Lysosomal Storage Disorders: A Review of the Evidence and Informed Approach to Reclassification.

The treatment landscape for lysosomal storage disorders (LSDs) is rapidly evolving. An increase in the number of preclinical and clinical studies in the last decade has demonstrated that pharmacological chaperones are a feasible alternative to enzyme replacement therapy (ERT) for individuals with LSDs. A systematic search was performed to retrieve and critically assess the evidence from preclinical and clinical applications of pharmacological chaperones in the treatment of LSDs and to elucidate the mechanisms by which they could be effective in clinical practice. Publications were screened according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidelines. Fifty-two articles evaluating 12 small molecules for the treatment of seven LSDs are included in this review. Overall, a substantial amount of preclinical and clinical data support the potential of pharmacological chaperones as treatments for Fabry disease, Gaucher disease, and Pompe disease. Most of the available clinical evidence evaluated migalastat for the treatment of Fabry disease. There was a lack of consistency in the terminology used to describe pharmacological chaperones in the literature. Therefore, the new small molecule chaperone (SMC) classification system is proposed to inform a standardized approach for new, emerging small molecule therapies in LSDs.