Fabry Disease: Current and Novel Therapeutic Strategies. A Narrative Review.

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. OBJECTIVE: The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options. METHODS: A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment. RESULTS: A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms' stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile. CONCLUSION: The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.

Recommendations for the diagnosis and management of Fabry disease in pediatric patients: a document from the Rare Diseases Committee of the Brazilian Society of Nephrology (Comdora-SBN) / Recomendações para o diagnóstico e manejo de pacientes pediátricos com doença de Fabry: documento do comitê de doenças raras da Sociedade Brasileira de Nefrologia (Comdora-SBN)

Fabry disease (FD) is a genetic disease, with X-chromosome linked inheritance, due to variants in the GLA gene that encodes the α-galactosidase A (α-GAL) enzyme. The purpose of the present study was to create a consensus aiming to standardize the recommendations regarding the renal involvement of FD with guidelines on the diagnosis, screening, and treatment of pediatric patients. This consensus is an initiative of the Rare Diseases Committee (Comdora) of the Brazilian Society of Nephrology (SBN). Randomized controlled clinical studies and studies with real-life data added to the authors' experience were considered for this review. The result of this consensus was to help manage patient and physician expectations regarding treatment outcomes. Thus, this consensus document recommends the investigation of the pediatric family members of an index case, as well as cases with suggestive clinical signs. From the diagnosis, assess all possible FD impairments and grade through scales. From an extensive review of the literature including pediatric protocols and particularly evaluating pediatric cases from general studies, it can be concluded that the benefits of early treatment are great, especially in terms of neuropathic pain and renal impairment parameters and outweigh the possible adverse effects that were mainly manifested by infusion reactions.

A doença de Fabry (DF) é uma doença genética, com herança ligada ao cromossomo X, devido a variantes no gene GLA que codifica a enzima α-galactosidase A (α-GAL). O propósito do presente estudo foi criar um consenso objetivando padronizar as recomendações em relação ao acometimento renal da DF com orientações sobre o diagnóstico, rastreamento, e tratamento de pacientes pediátricos. Esse consenso é uma iniciativa do Comitê de Doenças Raras (Comdora) da Sociedade Brasileira de Nefrologia (SBN). Foram considerados para esta revisão estudos clínicos controlados randomizados e estudos com dados de vida real somados à experiência dos autores. O resultado desse consenso foi auxiliar no gerenciamento das expectativas de pacientes e médicos quanto aos resultados do tratamento. Assim, este documento de consenso recomenda a investigação dos familiares pediátricos de um caso índice, assim como de casos com clínica sugestiva. A partir do diagnóstico, avaliar todos os possíveis acometimentos da DF e graduar através de escalas. A partir de uma revisão extensa da literatura incluindo protocolos pediátricos e avaliando particularmente os casos pediátricos de estudos gerais, pode-se concluir que os benefícios do tratamento precoce são grandes, principalmente quanto aos parâmetros de dor neuropática e do acometimento renal, e suplantam os possíveis adversos que foram sobretudo manifestados por reações infusionais.

When Frequent (Pandemic) Occurs in a Non-Frequent Disease: COVID-19 and Fabry Disease: Report of Two Cases.

Fabry disease (FD), like COVID-19, can affect multiple organs, including the lungs. Patients with FD are expected to develop severe COVID-19, due to involvement of not only the lungs but also the kidneys and the presence of other comorbidities. We present 2 cases of mild COVID-19 in patients with FD who were infected with the COVID-19 virus. Although it is unknown whether the X chromosome mutation in patients with FD affects the development of severe COVID-19, it is suggested that it may play a protective role against COVID-19 infection. Based on these cases, we suggest that FD is not a risk factor for severe COVID-19.

Fabry disease: where are we now?

Fabry disease (FD) is a multisystemic X-linked disorder characterized by the accumulation of lysosomal globotriaosylceramide (Gb3) secondary to decreased activity of α-galactosidase in cells. Generally, males are more severely affected due to the X-linked inheritance pattern of the disease. However, females are asymptomatic or have a less severe pattern of disease. Enzyme replacement therapy (ERT) is the cornerstone of the treatment of FD. At present, there are two forms of ERT that can be applied to FD patients. Novel therapeutic approaches including chaperone therapy, substrate reduction therapy, and gene therapy have been introduced in the era of treatment of FD. In this review, we aimed to discuss the prevalence, clinical and genetic features, pathophysiology, diagnosis, and therapeutic options in FD patients with nephropathy.

Late-Onset Fabry Disease Presenting With Ventricular Tachycardia Originating From Typical Inferolateral Scar.

Late-onset cardiac Fabry disease is not uncommon among patients with unexplained left ventricular hypertrophy. Despite a less severe phenotype, life-threatening complications are possible in late-onset cardiac Fabry and may be the first presentation of the disease. Classical imaging features support the diagnosis; however, the presence of less common findings, such as ischemic features, should not lead to overlooking the diagnosis. Indeed, the coexistence of Fabry and ischemic heart disease is possible, even in the absence of obstructive coronary artery disease. Therefore, a high level of suspicion should be maintained, even in the presence of atypical presentations.

The Prevalence of Fabry Disease Among Turkish Patients with Non-Obstructive Hypertrophic Cardiomyopathy: Insights from a Screening Study

Aims: Fabry disease is an X-linked lysosomal storage disorder due to a deficiency of the α-galactosidase A enzyme. Cardiac involvement is present in over 60% of adult cases of Fabry disease. Hypertrophic cardiomyopathy without left ventricular outflow tract obstruction is the most common phenotype. The aim of the study was to screen adult patients with hypertrophic cardiomyopathy without left ventricular outflow tract. Methods: A total of 80 patients between the ages of 18 and 65 years old, were referred to a tertiary center for trans-thoracic echocardiography for various clinical indications. They were investigated for the presence of idiopathic left ventricular hypertrophy without resting or dynamic left ventricular outflow tract obstruction. Plasma α-galactosidase A enzyme activity and α-galactosidase GLA gene mutations were investigated. Results: The mean age was 41.5±12.7 years and 66.25% of patients were males. The mean echocardiographic parameters were as follows: left ventricular ejection fraction 60.7±7.4%, interventricular septum thickness 18.2±4.4 mm, left ventricular posterior wall 13.5±2.1 mm, left ventricular end-diastolic diameter 47.4±6.2 mm, left ventricular end-systolic diameter 27.8±6.5 mm, and left ventricular mass index 171.05±48.5 g/m². Hemizygous mutations associated with Fabry disease were detected in two male patients (2.50% of the screened population): NM_000169.2:c.334C>T(p.Arg112Cys), NM_000169.2:c.902G>A(p.Arg301Gln). Conclusion: Fabry disease should be considered in the differential diagnosis in a highly selected patient population with unexplained left ventricular hypertrophy. The cardiologist may play an important role in the screening and diagnosis of the disease.

Why systematic literature reviews in Fabry disease should include all published evidence.

Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies.

Inborn Errors of Metabolism and the Gastrointestinal Tract.

Inborn errors of metabolism (IEMs) are usually recognized by characteristic neurologic and metabolic manifestations and sometimes by dysmorphism. However, IEMs can present with a wide variety of gastrointestinal manifestations, whether as the primary or a minor clinical symptom. Regardless, gastrointestinal and hepatic manifestations of IEMs are important clinical features that can help identify an underlying defect; these disorders should be taken into consideration as part of a patient's clinical assessment. It is prudent to include metabolic disorders in the differential diagnosis because in some cases, gastrointestinal symptoms may be the only presenting feature in a patient with an underlying IEM.

Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation.

RATIONALE: A high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown. OBJECTIVE: Using FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC. RESULTS AND METHODS: The iPSC-differentiated cardiomyocytes derived from FC-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation. Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs. Meanwhile, IL-18 levels were found to be significantly elevated in the culture media of FC-iPSC-CMs and patients' sera. Notably, the serum IL-18 levels were highly paralleled with the progression of left ventricular hypertrophy in Fabry patients receiving ERT. Finally, using FC-iPSC-CMs as in vitro FC model, neutralization of IL-18 with specific antibodies combined with ERT synergistically reduced the secretion of IL-18 and the progression of cardiomyocyte hypertrophy in FC-iPSC-CMs. CONCLUSION: Our data demonstrated that cardiac IL-18 and circulating IL-18 are involved in the pathogenesis of FC and LVH. IL-18 may be a novel marker for evaluating ERT efficacy, and targeting IL-18 might be a potential adjunctive therapy combined with ERT for the treatment of advanced cardiomyopathy in FC patients with IVS4+919 G>A mutation.

Long-term enzyme replacement therapy for Fabry disease: efficacy and unmet needs in cardiac and renal outcomes.

Fabry disease is a progressive lysosomal storage disease caused by alpha-galactosidase A deficiency. This condition is characterized by progressive accumulation of glycosphingolipids with functional impairment in various organs, including the kidney, heart and cerebrovascular system. Enzyme replacement therapy (ERT) is essential because it attenuates the disease progression. The present study investigated the long-term efficacy of ERT in 19 Korean Fabry patients (11 adult males, 4 symptomatic female carriers and 4 pediatric males) who had received ERT for 8.1±2.2 years (range, 5.3-10.5 years). In the 11 adult males, the mean reduction in the estimated glomerular filtration rate (eGFR) was -3.8±4.5 ml-1 min 1.73 m-2. The rate of eGFR decline was significantly lower in patients with lower proteinuria (<1 g per day) before ERT. The left ventricular mass index decreased or was stable throughout the ERT in male patients with or without left ventricular hypertrophy before ERT initiation. In female carriers and pediatric male patients, renal and cardiac functions remained stable with ERT. Arrhythmias were observed in 10 adult males and 1 female patient before ERT and persisted during ERT. One pediatric patient newly developed arrhythmia despite ERT. In conclusion, long-term ERT has beneficial effects on the renal and cardiac outcomes of Fabry patients but has limited effect in patients with irreversible organ damage. Identification of patients in the early disease stage and rapid ERT initiation might be the best strategy to improve the natural course of the disease.

Gastrointestinal involvement in Fabry disease. So important, yet often neglected.

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A which causes accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. Gastrointestinal symptoms are due to intestinal dysmotility as well as impaired autonomic function, vasculopathy and myopathy. Since 2001, enzyme replacement therapy has been a mainstay in treatment of gastrointestinal symptoms of Fabry disease (FD), resulting in reduced gastrointestinal symptoms. Here, we report on four patients with Fabry disease (FD) who manifested early gastrointestinal involvement.

Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease.

BACKGROUND: Currently, no method is available to identify α-galactosidase A (agalA) mutations determining clinically relevant Fabry disease. In our largest European Fabry cohort, we investigated whether a biomarker, specific for the defect, could stratify persons at risk. METHODS AND RESULTS: A total of 124 individuals with agalA mutations were investigated with a comprehensive clinical workup, genetic analysis, and laboratory testing, including measurements of agalA activity and lyso-Gb3 (degradation product of the accumulating Gb3). Additionally, an extensive family screening with a clinical workup of relatives was performed. The patient population was divided into 2 samples: previously described mutations (n=72) and novel mutations (n=52). The patients with previously described mutations were subdivided into 2 groups: classical mutations, which were known to cause the classic type of Fabry disease with specific symptoms and a high risk for major events in all 3 main organs (heart, kidney, and central nervous system), and atypical mutations without the typical presentation. All patients with atypical mutations (n=17) had lower lyso-Gb3 levels than any of the patients with classical Fabry disease (n=55). A cutoff value of 2.7 ng/mL separated the 2 groups. Six out of 52 patients with novel mutations showed a lyso-Gb3 level <2.7 ng/mL. Clinical investigation, blinded to lyso-Gb3 results, revealed no classic organ involvement in these patients or their relatives. In contrast, the characterization of patients with lyso-Gb3≥2.7 ng/mL suggested classical Fabry mutations in most of the patients (93%). CONCLUSIONS: Our data show that the biomarker lyso-Gb3 may identify the clinically relevant agalA mutations leading to Fabry disease.

Utilidad del tratamiento de sustitución enzimática en la enfermedad de Fabry / Utility of enzyme replacement therapy in Fabry disease

Fundamento y objetivos: La enfermedad de Fabry (EF) es una enfermedad por depósito lisosomal de esfingolípidos secundaria al déficit de la enzima alfagalactosidasa A. El depósito a nivel endotelial de los vasa nervorum y de los axones de pequeño calibre resulta en la característica neuropatía dolorosa. Es nuestro objetivo presentar los resultados de la evaluación de la neuropatía antes y después de 18 meses de tratamiento de reemplazo enzimático con agalsidasa β. Materiales y método: Se trata de un estudio exploratorio realizado a 5 pacientes con EF. Se les realizó un estudio neurofisiológico con medición de velocidades de conducción y amplitudes motoras y sensitivas, y un test de cuantificación sensitiva así como medición del dolor por medio de escalas. Resultados: Previo al tratamiento no se encontraron anomalías en las velocidades de conducción ni en las amplitudes del potencial de acción muscular compuesto, el test de cuantificación sensitiva fue anormal en todos los pacientes. Luego del tratamiento se evidenció mejoría en las escalas de dolor y en el test de cuantificación sensitiva. Conclusiones: El tratamiento de reemplazo enzimático con agalsidasa-β demostró beneficio subjetivo y objetivo en relación con la neuropatía dolorosa de la EF (AU)

Background and Objective: The lysosomal deposit of sphingolipids secondary to alpha-galactosidase-A deficiency causes Fabry disease. The deposit in the endothelial cells of the vasa nervorum and the small caliber axons, among other structures, results in the characteristic painful neuropathy. It is our objective to present the findings of the neuropathy evaluation before and after 18 months of agalsidase beta enzyme replacement therapy. Materials and method: A neurological exam, a neurophysiological study measuring sensory and motor conduction velocities and amplitudes and a quantitative sensory testing were performed on 5 patients with confirmed Fabry disease; quantification on pain measurement scales was also done. Results; Prior to treatment, no anomalies were found in the conduction velocities or the compound muscular action potential amplitudes; the quantitative sensory test was abnormal in all patients. After treatment, improvement was seen in the pain scales and the quantitative sensory test. Conclusions: Enzyme replacement therapy with agalsidase beta demonstrated subjective and objective benefits related to the painful neuropathy of Fabry disease (AU)

To see a world in a grain of sand: elucidating the pathophysiology of Anderson-Fabry disease through investigations of a cellular model.

Thomaidis and colleagues have created a cellular model of Anderson-Fabry disease by 'silencing' alpha-galactosidase A (AGAL) activity in human tubular epithelial cells. Increased membrane globotriaosylceramide (Gb3/CD77) expression was observed; it is suggested that this finding may be potentially useful as a surrogate marker of disease severity. Decreased membrane Gb3/CD77 expression was observed following agalsidase-alpha treatment, providing evidence of changes in cellular phenotype in response to enzyme therapy.