Mechanisms of Neutralizing Anti-drug Antibody Formation and Clinical Relevance on Therapeutic Efficacy of Enzyme Replacement Therapies in Fabry Disease

: 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.

Download Full-text

Fabry Cardiomyopathy: Current Practice and Future Directions

Cells ◽

10.3390/cells10061532 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1532

Author(s):

Jeffrey Yim ◽

Olivia Yau ◽

Darwin F. Yeung ◽

Teresa S. M. Tsang

Keyword(s):

Fabry Disease ◽

Early Stage ◽

Point Of Care ◽

Left Ventricular ◽

The Body ◽

Cardiac Biomarkers ◽

Dried Blood Spot ◽

Point Of Care Ultrasound ◽

Enzyme Replacement ◽

Blood Spot

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficient galactosidase A enzyme and subsequent accumulation of glycosphingolipids throughout the body. The result is a multi-system disorder characterized by cutaneous, corneal, cardiac, renal, and neurological manifestations. Increased left ventricular wall thickness represents the predominant cardiac manifestation of FD. As the disease progresses, patients may develop arrhythmias, advanced conduction abnormalities, and heart failure. Cardiac biomarkers, point-of-care dried blood spot testing, and advanced imaging modalities including echocardiography with strain imaging and magnetic resonance imaging (MRI) with T1 mapping now allow us to detect Fabry cardiomyopathy much more effectively than in the past. While enzyme replacement therapy (ERT) has been the mainstay of treatment, several promising therapies are now in development, making early diagnosis of FD even more crucial. Ongoing initiatives involving artificial intelligence (AI)-empowered interpretation of echocardiographic images, point-of-care dried blood spot testing in the echocardiography laboratory, and widespread dissemination of point-of-care ultrasound devices to community practices to promote screening may lead to more timely diagnosis of FD. Fabry disease should no longer be considered a rare, untreatable disease, but one that can be effectively identified and treated at an early stage before the development of irreversible end-organ damage.

Download Full-text

Considerations for Home-Based Treatment of Fabry Disease in Poland during the COVID-19 Pandemic and Beyond

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18168242 ◽

2021 ◽

Vol 18 (16) ◽

pp. 8242

Author(s):

Michał Nowicki ◽

Stanisława Bazan-Socha ◽

Mariusz Kłopotowski ◽

Beata Błażejewska-Hyżorek ◽

Mariusz Kusztal ◽

...

Keyword(s):

Fabry Disease ◽

Genetic Diseases ◽

Healthcare Providers ◽

Treatment Programs ◽

Current Therapy ◽

Term Care ◽

Pharmacological Chaperone ◽

Enzyme Replacement ◽

Home Based ◽

Rare Genetic Diseases

Current therapy for Anderson–Fabry disease in Poland includes hospital or clinic-based intravenous enzyme replacement therapy with recombinant agalsidase alpha or beta, or oral pharmacological chaperone therapy with migalastat. Some countries around the world offer such treatment to patients in the comfort of their own homes. The 2020–2021 COVID-19 pandemic has pushed global healthcare providers to evolve their services so as to minimize the risk of COVID-19 exposure to both patients and providers; this has led to advances in telemedicine services and the increasing availability of at-home treatment for various procedures including parenteral drug administration. A total of 80% of surveyed Anderson–Fabry disease patients in Poland would prefer home-based treatment, which would be a safe and convenient alternative to clinic-based treatment if patient selection is based on our proposed algorithm. Our recommendations for home-based treatments appear feasible for the long term care of Anderson–Fabry disease patients during the COVID-19 pandemic and beyond. This may also serve as a basis for home-based treatment programs in other rare and ultra-rare genetic diseases.

Download Full-text

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2020.12.069 ◽

2021 ◽

Vol 132 (2) ◽

pp. S36

Author(s):

Marina Dutra-Clarke ◽

Daisy Tapia ◽

Emily Curtin ◽

Dennis Ruenger ◽

Anita Lakatos ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Clinical Features ◽

Enzyme Replacement

Download Full-text

Fabry Disease Therapy: State-of-the-Art and Current Challenges

International Journal of Molecular Sciences ◽

10.3390/ijms22010206 ◽

2020 ◽

Vol 22 (1) ◽

pp. 206

Author(s):

Olga Azevedo ◽

Miguel Fernandes Gago ◽

Gabriel Miltenberger-Miltenyi ◽

Nuno Sousa ◽

Damião Cunha

Keyword(s):

Fabry Disease ◽

State Of The Art ◽

Large Body ◽

Real Life ◽

Clinical Manifestations ◽

Substrate Reduction Therapy ◽

Lysosomal Storage ◽

New Therapies ◽

Enzyme Replacement

Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the GLA gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Despite the large body of literature published about ERT over the years, many issues remain unresolved, such as the optimal dose, the best timing to start therapy, and the clinical impact of anti-drug antibodies. Migalastat was recently approved for FD patients with amenable GLA mutations; however, recent studies have raised concerns that “in vitro” amenability may not always reflect “in vivo” amenability, and some findings on real-life studies have contrasted with the results of the pivotal clinical trials. Moreover, both FD specific therapies present limitations, and the attempt to correct the enzymatic deficiency, either by enzyme exogenous administration or enzyme stabilization with a chaperone, has not shown to be able to fully revert FD pathology and clinical manifestations. Therefore, several new therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy. In this review, we provide an overview of the state-of-the-art on the currently approved and emerging new therapies for adult patients with FD.

Download Full-text

SUN-449 PATIENT WITH FABRY DISEASE IN CHRONIC HEMODIALYSIS FOR 7 YEARS AND 9 YEARS OF ENZYME REPLACEMENT THERAPY (ERT) IN TOTAL

Kidney International Reports ◽

10.1016/j.ekir.2020.02.990 ◽

2020 ◽

Vol 5 (3) ◽

pp. S381-S382

Author(s):

S. Fernandez ◽

P. Fernández ◽

S. Fernandez ◽

C.C. Fernández

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Chronic Hemodialysis ◽

Enzyme Replacement

Download Full-text

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Molecular Genetics and Metabolism Reports ◽

10.1016/j.ymgmr.2020.100700 ◽

2021 ◽

Vol 26 ◽

pp. 100700

Author(s):

Marina Dutra-Clarke ◽

Daisy Tapia ◽

Emily Curtin ◽

Dennis Rünger ◽

Grace K. Lee ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Clinical Features ◽

Enzyme Replacement

Download Full-text

Outcomes of Kidney Transplantation in Fabry Disease: A Meta-Analysis

Diseases ◽

10.3390/diseases9010002 ◽

2020 ◽

Vol 9 (1) ◽

pp. 2

Author(s):

Maria L. Gonzalez Suarez ◽

Charat Thongprayoon ◽

Panupong Hansrivijit ◽

Juan Medaura ◽

Pradeep Vaitla ◽

...

Keyword(s):

Kidney Transplantation ◽

Fabry Disease ◽

Kidney Transplant ◽

Allograft Rejection ◽

Graft Failure ◽

Current Therapy ◽

Transplant Recipients ◽

Lysosomal Storage ◽

Kidney Transplant Recipients ◽

Enzyme Replacement

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with progressive systemic deposition of globotriaosylceramide, leading to life-threatening cardiac, central nervous system, and kidney disease. Current therapy involves symptomatic medical management, enzyme replacement therapy (ERT), dialysis, kidney transplantation, and, more recently, gene therapy. The aim of this systematic review was to assess outcomes of kidney transplantation among patients with FD. Methods: A comprehensive literature review was conducted utilizing MEDLINE, EMBASE, and Cochrane Database, from inception through to 28 February 2020, to identify studies that evaluate outcomes of kidney transplantation including patient and allograft survival among kidney transplant patients with FD. Effect estimates from each study were extracted and combined using the random-effects generic inverse variance method of DerSimonian and Laird. Results: In total, 11 studies, including 424 kidney transplant recipients with FD, were enrolled. The post-transplant median follow-up time ranged from 3 to 11.5 years. Overall, the pooled estimated rates of all-cause graft failure, graft failure before death, and allograft rejection were 32.5% (95%CI: 23.9%–42.5%), 14.5% (95%CI: 8.4%–23.7%), and 20.2% (95%CI: 15.4%–25.9%), respectively. In the sensitivity analysis, limited only to the recent studies (year 2001 or newer when ERT became available), the pooled estimated rates of all-cause graft failure, graft failure before death, and allograft rejection were 28.1% (95%CI: 20.5%–37.3%), 11.7% (95%CI: 8.4%–16.0%), and 20.2% (95%CI: 15.5%–26.0%), respectively. The pooled estimated rate of biopsy proven FD recurrence was 11.1% (95%CI: 3.6%–29.4%), respectively. There are no significant differences in the risks of all-cause graft failure (p = 0.10) or mortality (0.48) among recipients with vs. without FD. Conclusions: Despite possible FD recurrence after transplantation of 11.1%, allograft and patient survival are comparable among kidney transplant recipients with vs. without FD.

Download Full-text

MO061IS THE PM290I MUTATION RELATED TO ORGAN INVOLVEMENT OF FABRY DISEASE?

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab080.0033 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Francisca Silva ◽

Nicole Pestana ◽

José Durães ◽

Nuno Guimarães Rosa ◽

Gil Silva

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Genetic Variant ◽

Clinical Manifestations ◽

Mutant Enzyme ◽

Enzyme Replacement ◽

Screening Study ◽

Gla Gene

Abstract Background and Aims Fabry disease (FD) is an X-linked hereditary disease. It results from mutations in the GLA gene, leading to deficient activity of the enzyme alpha-galactosidase A and progressive accumulation of undegraded glycosphingolipids in cell lysosomes. Enzyme replacement therapy improved the natural course of this disease, but an early diagnosis is crucial for a successful treatment. Method A screening study for GLA gene mutations was conducted for all patients under dialysis, from a single centre. All the probands with a detectable mutation were analysed individually. Data on the patient's family and personal pathological history were retrospectively collected, by consulting the clinical file. Results 35 years-old female diagnosed with chronic proteinuric kidney disease in the postpartum period. Despite optimal medical treatment the disease progressed, and she started renal replacement therapy with peritoneal dialysis. Five years later she was enrolled in a pilot screening study for FD and the heterozygous mutation c.870G>C (p.Met290Ile; M290I) in exon 6 of the GLA gene was found. The proband didn’t meet the criteria for a definitive FD diagnosis, but she remained under follow-up at our nephrology metabolic diseases consultation, as the mutation was described as pathogenic and associated with a classic FD phenotype. Later that same year, reassessment exams revealed a worsening left ventricle mass index, a new ischemic cerebral lesion and a substantial increase in serum globotriaosylsphingosine (LysoGb3) levels. These clinical changes led to the decision to initiate enzyme replacement therapy. Until now there are only a few descriptions of this genetic variant in the scientific literature. A Portuguese study analysed a total of 11 FD patients and described 2 patients with p.M290I mutation, without detectable Gb3 accumulation. Another study was designed to evaluate the genotype-phenotype relationship in 73 Chinese FD patients. Contrary to other reports, the p.M290I mutation was not associated to the classic FD phenotype. A Swiss investigation with a similar design analysed 69 FD patients during their routine annual examinations. M290I mutant enzyme was found in a 48-year-old heterozygous female with a classic FD phenotype but with a low serum LysoGb3. A Spanish newborn screening identified one male patient with FD and the p.M290I genetic variant but was unable to provide any information about the clinical expression of this mutation, since the diagnosis was made between the third and fifth days of life. The study describing the most patients carrying the M290I mutant enzyme is Brazilian and screened a total of 25,223 dialysis patients. Among 89 FD-positive patients, the p.M290I mutation was present in 22. However, the authors did not provide detailed information about the clinical manifestations or α-Gal A activity and LysoGb3 levels of these patients. Finally, a recent Portuguese screening of 150 hypertrophic cardiomyopathy patients found 25 patients with FD. Of these, one female carried the GLA gene variant p.M290I, with a non-detectable LysoGb3 plasma level. Conclusion We describe a case of FD due to a previously known but still poorly described GLA mutation, which offers strong evidence of its pathogenicity. To our knowledge, this is the first report of p.M290I mutation-associated disease activity evidenced by elevated levels of serum LysoGb3. Despite the absence of classic FD symptoms such as neuropathic pain, cornea verticillata and angiokeratoma, the presence of severe multiple organ evolvement, characterized by renal failure, cardiac disease and ischaemic stroke, strongly suggests a classic phenotype. Consequently, it is our opinion that the presence of a p.M290I GLA mutation should require a strict ongoing patient follow-up, as it may cause clinically significant disease.

Download Full-text