Fabry Disease and the Heart: A Comprehensive Review

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene that result in a deficiency of the enzymatic activity of α-galactosidase A and consequent accumulation of glycosphingolipids in body fluids and lysosomes of the cells throughout the body. GB3 accumulation occurs in virtually all cardiac cells (cardiomyocytes, conduction system cells, fibroblasts, and endothelial and smooth muscle vascular cells), ultimately leading to ventricular hypertrophy and fibrosis, heart failure, valve disease, angina, dysrhythmias, cardiac conduction abnormalities, and sudden death. Despite available therapies and supportive treatment, cardiac involvement carries a major prognostic impact, representing the main cause of death in FD. In the last years, knowledge has substantially evolved on the pathophysiological mechanisms leading to cardiac damage, the natural history of cardiac manifestations, the late-onset phenotypes with predominant cardiac involvement, the early markers of cardiac damage, the role of multimodality cardiac imaging on the diagnosis, management and follow-up of Fabry patients, and the cardiac efficacy of available therapies. Herein, we provide a comprehensive and integrated review on the cardiac involvement of FD, at the pathophysiological, anatomopathological, laboratory, imaging, and clinical levels, as well as on the diagnosis and management of cardiac manifestations, their supportive treatment, and the cardiac efficacy of specific therapies, such as enzyme replacement therapy and migalastat.

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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.

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Cell Transplantation Combined with Recombinant Collagen Peptides for the Treatment of Fabry Disease

Cell Transplantation ◽

10.1177/0963689720976362 ◽

2020 ◽

Vol 29 ◽

pp. 096368972097636

Author(s):

Daisuke Kami ◽

Masashi Yamanami ◽

Takahiro Tsukimura ◽

Hideki Maeda ◽

Tadayasu Togawa ◽

...

Keyword(s):

Fabry Disease ◽

Cell Transplantation ◽

Financial Burden ◽

Kidney Injury ◽

The Body ◽

Term Survival ◽

Enzyme Replacement ◽

Continuous Release ◽

Alpha Galactosidase

Fabry disease is caused by a decrease in or loss of the activity of alpha-galactosidase, which causes its substrates globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) to accumulate in cells throughout the body. This accumulation results in progressive kidney injury due to glomerulosclerosis and in heart failure due to hypertrophy. Enzyme replacement therapy (ERT) has been used as the standard therapy for Fabry disease, but it causes a significant financial burden, and regular administration is inconvenient for patients. Because of the short half-life of alpha-galactosidase in vivo, therapeutic methods that can supplement or replace ERT are expected to involve continuous release of alpha-galactosidase, even at low doses. Cell transplantation therapy is one of these methods; however, its use has been hindered by the short-term survival of transplanted cells. CellSaic technology, which utilizes cell spheroids that form after cells are seeded simultaneously with a recombinant collagen peptide scaffold called a μ-piece, has been used to improve cell survival upon implantation. In this study, syngeneic murine embryonic fibroblasts were used to generate CellSaic that were transplanted into Fabry mice. These spheroids survived for 28 days in the renal subcapsular space with forming blood vessels. These results indicate CellSaic technology could be a platform to promote cellular graft survival and may facilitate the development of cell transplantation methods for lysosomal diseases.

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Enzyme Replacement Therapy in a Case of Anderson–Fabry Disease with Advanced Cardiac Involvement and Malignant Ventricular Arrhythmias

Heart Lung and Circulation ◽

10.1016/j.hlc.2012.05.149 ◽

2012 ◽

Vol 21 ◽

pp. S59

Author(s):

D. Korczyk ◽

J. Hill ◽

C. Denaro ◽

H. Finn

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Ventricular Arrhythmias ◽

Cardiac Involvement ◽

Enzyme Replacement

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Exosomes and cardiovascular cell–cell communication

Essays in Biochemistry ◽

10.1042/ebc20170081 ◽

2018 ◽

Vol 62 (2) ◽

pp. 193-204 ◽

Cited By ~ 14

Author(s):

Adam J. Poe ◽

Anne A. Knowlton

Keyword(s):

Biological Fluids ◽

Cell Communication ◽

Cell Types ◽

Cardiac Cells ◽

The Body ◽

Biologically Active ◽

Surrounding Tissue ◽

Intercellular Signaling ◽

Cardiac Damage ◽

Almost All

Exosomes have become an important player in intercellular signaling. These lipid microvesicles can stably transfer miRNA, protein, and other molecules between cells and circulate throughout the body. Exosomes are released by almost all cell types and are present in most if not all biological fluids. The biologically active cargo carried by exosomes can alter the phenotype of recipient cells. Exosomes increasingly are recognized as having an important role in the progression and treatment of cardiac disease states. Injured cardiac cells can release exosomes with important pathological effects on surrounding tissue, in addition to effecting other organs. But of equal interest is the possible benefit(s) conferred by exosomes released from stem cells for use in treatment and possible repair of cardiac damage.

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First two years of reimbursed enzyme replacement therapy in the treatment of Fabry disease in Poland

F1000Research ◽

10.12688/f1000research.55313.1 ◽

2021 ◽

Vol 10 ◽

pp. 841

Author(s):

Michał Nowicki ◽

Monika Komar ◽

Mariusz Kusztal ◽

Katarzyna Mizia-Stec ◽

Tomasz Liberek ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Clinical Symptoms ◽

Final Diagnosis ◽

The Body ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Number Of Patients ◽

Mean Time

Fabry disease (FD) is an ultra-rare genetic lysosomal storage disease caused by pathologic gene variants resulting in insufficient expression of α-galactosidase A. This enzyme deficiency leads to accumulation of globotriaosylceramide and globotriaosylsphingosine in plasma and in different cells throughout the body, causing major cardiovascular, renal, and nervous system complications. Until 2018, reimbursed enzyme replacement therapy (ERT) for FD was available in all European Union countries except Poland. We present the preliminary results of the first two years of reimbursed ERT in Poland. We obtained data from the seven largest academic centers in Katowice, Kraków, Wrocław, Poznań, Gdańsk, Warszawa, and Łódź. The questionnaire included the following data: number of patients treated, number of patients qualified for ERT, and patient characteristics. All centers returned completed questionnaires that included data for a total of 71 patients (28 men and 43 women) as of June 2021. Thirty-five patients with the diagnosis of FD confirmed by genetic testing (22 men and 13 women) had already qualified for reimbursed ERT. Mean (SD) age at the commencement of the ERT program was 39.6 (15.5) years (range 18-79 years). Mean time from the first clinical symptoms reported by the patients to the FD diagnosis was 21.1 (8.9) years, and the mean time from the final diagnosis of FD to the beginning of ERT was 4.7 (4.6) years. FD is still underdiagnosed in Poland. To identify undiagnosed FD patients and to ensure that patients in Poland benefit fully from ERT, implementation of an effective nationwide screening strategy and close cooperation with a network of rare disease centers is advised.

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Role of serial cardiac 18F-FDG PET-MRI in Anderson–Fabry disease: a pilot study

Insights into Imaging ◽

10.1186/s13244-021-01067-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Carmela Nappi ◽

Andrea Ponsiglione ◽

Antonio Pisani ◽

Eleonora Riccio ◽

Teodolinda Di Risi ◽

...

Keyword(s):

Fabry Disease ◽

Fdg Pet ◽

Cardiac Involvement ◽

Cardiac Injury ◽

Gadolinium Enhancement ◽

Enzyme Replacement ◽

Imaging Results ◽

Relationship Of

Abstract Aim We investigated the value of serial cardiac 18F-FDG PET-MRI in Anderson–Fabry disease (AFD) and the potential relationship of imaging results with FASTEX score. Methods and results Thirteen AFD patients underwent cardiac 18F-FDG PET-MRI at baseline and follow-up. Coefficient of variation (COV) of FDG uptake and FASTEX score were assessed. At baseline, 9 patients were enzyme replacement therapy (ERT) naïve and 4 patients were under treatment. Two patients presented a FASTEX score of 0 indicating stable disease and did not show any imaging abnormality at baseline and follow-up PET-MRI. Eleven patients had a FASTEX score > 20% indicating disease worsening. Four of these patients without late gadolinium enhancement (LGE) and with normal COV at baseline and follow-up had a FASTEX score of 35%. Three patients without LGE and with abnormal COV at baseline and follow-up had a FASTEX score ranging from 30 to 70%. Three patients with LGE and abnormal COV at baseline and follow-up had a FASTEX score between 35 and 75%. Finally, one patient with LGE and normal COV had a FASTEX score of 100%. Of the 12 patients on ERT at follow-up, FASTEX score was significantly higher in those 4 showing irreversible cardiac injury at baseline compared to 8 with negative LGE (66 ± 24 vs. 32 ± 21, p = 0.03). Conclusion 18F-FDG PET-MRI may be effective to monitor cardiac involvement in AFD.

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Enzyme Replacement Therapy in Fabry Disease: Influence on Cardiac Manifestations

Current Medicinal Chemistry ◽

10.2174/092986710791111297 ◽

2010 ◽

Vol 17 (16) ◽

pp. 1679-1689 ◽

Cited By ~ 6

Author(s):

L. Caballero ◽

V. Climent ◽

D. Hernandez-Romero ◽

M.A. Quintanilla ◽

G. de la Morena ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Enzyme Replacement ◽

Cardiac Manifestations

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A Case of a 50-Year-Old Woman with Typical Fabry Disease Who Showed Serial Electrocardiographic and Echocardiographic Changes over a 17-Year Period

Case Reports in Cardiology ◽

10.1155/2019/9385361 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7

Author(s):

Su Nam Lee ◽

Gee-Hee Kim ◽

Ki-Dong Yoo

Keyword(s):

Fabry Disease ◽

Ventricular Hypertrophy ◽

Cardiac Involvement ◽

Premature Death ◽

Vascular Wall ◽

Lag Time ◽

Left Ventricular ◽

The Body ◽

Lysosomal Storage ◽

Major Organ

Fabry disease (FD) is a progressive, X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A activity. Affected individuals accumulate globotriaosylceramide and glycosphingolipids in the lysosomes and cytoplasm of cells throughout the body, leading to major organ failure and premature death. Cardiac involvement includes left ventricular hypertrophy, arrhythmia, endothelial dysfunction at vascular wall, and cardiomyopathy. The diagnosis of FD can be difficult and there is often a long lag time between symptoms and diagnosis. Here, we present a case of a 50-year-old woman with typical Fabry disease who showed serial electrocardiographic and echocardiographic changes over 17 years prior to diagnosis with Fabry disease.

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109 Anderson Fabry disease in CMR: twins by traditional tissue characterization, different by parametric mapping

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jez319.028 ◽

2020 ◽

Vol 21 (Supplement_1) ◽

Author(s):

C Cavallaro ◽

A Barison ◽

N Martini ◽

A Meloni ◽

G Todiere ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Tissue Characterization ◽

Cardiac Involvement ◽

Genetic Test ◽

Lateral Wall ◽

Intracellular Accumulation ◽

Ssfp Cine ◽

Parametric Mapping ◽

Enzyme Replacement

Abstract Anderson Fabry disease (AFD) is an X-linked recessive lysosomal storage disease, caused by intracellular accumulation of glycosphingolipids due to deficiency of the enzyme α-galactosidase. The cardiac involvement carries a worse prognosis. Myocardial hypertrophy is the most common manifestation due to the intracellular accumulation of glycosphingolipids in myocytes. With disease progression the deposits are replaced by fibrosis although recent data suggest a chronic inflammation also independently to glycosphingolipids accumulation. Cardiac magnetic resonance (CMR) by tissue characterization using parametric mapping is a unique technique in evaluating AFD progression and in determining enzyme treatment indications and evolution under therapy. Heterozygous females are not asymptomatic carriers of the AFD mutation, they have a variable clinical presentation; disease expression in females is the result of random inactivation of the X chromosome. Female patients have a . This case provides an example of Fabry disease in a couple of sisters with a third sister with a diagnosis of AFD with cardiac, hepatic, and renal involvement. The youngest sister with a positive genetic test was symptomatic for chest pain, without any significant coronary arteries disease by coro CT. The ECG showed atrial fibrillation and sign for LVH confirmed by echocardiography. The traditional CMR study by SSFP cine images and LGE technique showed an increased thickness in the basal infero-lateral wall (15 mm) and the anterior interventricular septum (14 mm) with midwall fibrosis in the basal infero-lateral wall (Fig. 1 A, B). The oldest sister with a positive genetic test was asyntomatic in AF. ECG and ECOC were aspecific. The traditional CMR study by SSFP cine images and LGE technique showed the same finding of the youngest sister (Fig. 2 A, B) By T1 mapping based on the normal cut off values of the Lab the older sister reported a short T1 global value (915 ms) and short T1 values in all segment with exception of lateral wall, mid and distal inferior segments and distal septum (Figure 1 C). Despite the presence of positive LGE in the basal infero-lateral wall the T1 value was normal in this segment due to a pseudo normalization related to the sphingolipid accumulation. Based on the CMR report she started the enzyme replacement therapy and the CMR follow was planned at 1 year. Conversely, the younger woman reported a long T1 value only in the basal infero-lateral wall with normal T1 value in all the other segments (Figure 2 C). The positive LGE in the basal infero-later segment (oedema/fibrosis) justifies the long T1 value in this no thickness segment. Based on the CMR report she did not start enzyme replacement therapy. Conclusion The case of this family show how quantitative parametric mapping could be a unique tool for the clinicians to adjust the therapy and plan the follow up of patients affected by AFD with cardiac involvement. Abstract 109 Figure.

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