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Aortic root dilatation (47 mm) in a 51-year-old male patient with Fabry disease. 7 Courtesy: Olivier Dubourg and Dominique P Germain, University of Versailles, France.
Source publication
Fabry disease is an X-linked inherited condition due to the absence or reduction of alpha-galactosidase activity in lysosomes, that results in accumulation of globotriaosylceramide (Gb3) and related neutral glycosphingolipids. Manifestations of Fabry disease include serious and progressive impairment of renal and cardiac function. In addition, pati...
Context in source publication
Context 1
... appears to be positively correlated with the frequency of arrhythmia, valvular disease (mitral and aortic) and other cardiac signs and symp- toms, 92 including an increased intima-media thick- ness of the common carotid artery. 94 Aortic root dilatation is highly prevalent in male patients affected with Fabry disease (D.P. Germain, unpub- lished data) (Figure 4). 7 Cardiac symptoms can be detected in some chil- dren with Fabry disease. ...
Similar publications
Fabry disease is a rare X-linked inherited disorder due to deficient or absent lysosomal a-galactosidase A activity, resulting in an excessive glycosphingolipid deposit, mainly globotriaosylceramide (g13) and mortality due renal, cardiac and neurological cause. Current treatment available is enzyme replacement therapy, where the deficient enzyme is...
Background:
Fabry disease (FD) is a rare, lysosomal storage disorder caused by the absence or deficiency of the enzyme alpha-galactosidase A (α-Gal A) that leads to the abnormal accumulation of the lipid globotriaosylceramide (GB3) in a variety of cell types and tissues throughout the body. FD has an x-linked inheritance pattern. Previously though...
Fabry disease is a progressive X-linked disorder of glycosphingolipid metabolism caused by a deficiency of the α-galactosidase lysosomal enzyme. The partial or complete deficiency of the lysosomal enzyme leads to an accumulation of neutral glycosphingolipids in the vascular endothelium and visceral tissues throughout the body. In the heart, glycosp...
Citations
... This leads to widespread intracellular lysosomal accumulation of glycosphingolipids, namely, globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple organs. Accumulation causes intracellular and extracellular dysfunction by direct and indirect effects that lead to predominantly cardiac, renal, and cerebrovascular manifestations with significant associated morbidity and mortality [3]. ...
Purpose of Review
Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate.
Recent Findings
There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual’s risk of arrhythmia in FD.
Summary
In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.
... Fabry disease is an X-linked inherited disorder in which globotriaosylceramide and related neutral sphingolipids accumulate due to decreased lysosomal alpha-galactosidase activity. Symptoms of Fabry disease include progressive damage to the brain, kidneys, and heart [1]. The annual incidence of this disease is 1 in 100,000 [2]. ...
... The annual incidence of this disease is 1 in 100,000 [2]. Fabry disease is an X-linked genetic disorder, but it is also known to occur in women, despite being an X-linked disorder [1]. Fabry disease is rarely associated with malignant tumors. ...
... It has been reported that the incidences of acute myocardial infarction, ischemic heart disease, left coronary anterior descending stenosis, angina pectoris, pericarditis, and valvular heart disease are higher with left-sided irradiation than with right-sided irradiation [12]. Patients with Fabry disease are potentially at high risk for cardiac disease and cardiac dysfunction [1][2][3], and the cardiac risks associated with RT should be considered. However, there have been no reports of cardiac dysfunction in patients with Fabry disease undergoing RT. ...
Fabry disease is a metabolic disorder caused by a deficiency in lysosomal enzymes and is inherited as an X-chromosomal disorder. Patients with Fabry disease have a low incidence of cancer, and reports of malignant tumors, especially in the thoracic region, are rare. In this case report, we describe our experience with radiation therapy following breast-conserving surgery in a patient with left breast cancer and Fabry disease, and we review the existing literature. The patient, a woman in her 40s, required postoperative irradiation for left breast cancer (pT1N0M0). There were several patients with Fabry disease in her family, and the diagnosis of Fabry disease was made five years ago. Cardiac function evaluation revealed no significant abnormalities, but a myocardial biopsy had suggested the presence of Fabry disease. Due to the relatively preserved distance between the heart and the chest wall, the patient received heart-shielded three-dimensional conformal radiation therapy at a dose of 53.2 Gy in 20 fractions, without the use of deep-inspiration breath-hold or intensity-modulated radiotherapy. After treatment was completed, only mild radiation dermatitis was observed. Six months have passed since treatment, and there have been no serious adverse events.
... También como alternativa diagnóstica temprana, sustentado en cambios estructurales del riñón previa afectación de la función o signos de proteinuria (24). ...
Antecedentes: La enfermedad de Fabry (EF) es una enfermedad rara ligada a X secundaria al depósito lisosomal de glicoesfingolípidos debido a la deficiencia de la enzima alfa galactosidasa A (α-Gal A). A pesar de su baja frecuencia, es una condición que afecta la calidad de vida de los pacientes y disminuye su esperanza de vida. Objetivo: Generar recomendaciones informadas en evidencia para el diagnóstico y tratamiento de pacientes pediátricos (menores de 8 años) con EF. Métodos: Se realizó una revisión de literatura en bases de datos y literatura gris a partir del 2010, incluyendo guías de práctica clínica, revisiones sistemáticas, estudios primarios. La calidad de evidencia se evalúo de acuerdo con el tipo de evidencia. Las recomendaciones se sometieron a consenso de expertos a través de metodología Delphi modificada. El acuerdo se definió a partir del 80%. Resultados: A partir del análisis de la evidencia recolectada, se formularon un total de 45 recomendaciones para tamización, diagnóstico y tratamiento de paciente pediátrico con enfermedad de Fabry. El panel revisor estuvo conformado por once expertos en el tema. Las recomendaciones fueron aprobadas con puntuaciones entre 82.3% y 100%. Conclusiones: Las recomendaciones resultantes del consenso de expertos permitirán la toma de decisiones clínicas y estandarización de la práctica en la atención de pacientes pediátricos con EF a nivel nacional y regional; el diagnóstico temprano y oportuno garantiza una disminución del impacto en la calidad de vida de los pacientes y sus familiares. Palabras clave: Enfermedad de Fabry, niños, diagnóstico, terapeutica, biomarcadores
... Due to the progressive accumulation of glycosphingolipids in lysosomes diverse symptoms appear [3,6,15,16]. Specific to FD is that males are more severely affected than female heterozygotes, whose manifestation can range from as severely affected to, more frequently, asymptomatic depending on the random Xchromosomal inactivation [15,17,18]. FD is a multisystem disorder involving cardiac/renal disease, skin disorders (angiokeratoma), neurologic diseases (acroparesthesias, autonomic dysfunction and hypohidrosis), ocular abnormalities (cornea verticillata), sensorineural hearing loss and cerebrovascular diseases-stroke [3,6,19,20]. ...
... In GD and FD, the majority of patients develop gradually disease manifestations during childhood [7]. A swift diagnosis is often impeded by the rare nature of LSDs and their diverse clinical presentation associated with a rather poor awareness among clinicians [18]. The delayed diagnosis results in a delayed treatment, which is associated with increased disease complications [3,21]. ...
... Advanced complications, both mental as physical, jeopardize the overall benefit of treatment [3]. Timely initiation of effective treatments, such as enzyme replacement therapy (ERT), substrate reduction therapy (SRT) and chaperone therapy, are able to improve the disease status and outcome [9,18]. ...
Background:
Gaucher's and Fabry's disease are two of the most common treatable lysosomal storage diseases, and have a wide spectrum of clinical symptoms. Early detection is important, because timely initiation of treatments can improve the disease status and prevent complications. However disease manifestations develop in childhood, diagnosis is delayed until adulthood partly due to the limitations of the currently used diagnostic pathway. The aim of this research is to develop and validate a multiplex assay and defining reference ranges, which do not exist at this moment, to improve and facilitate the entire diagnostic work up and enable treatment in an earlier stage of disease.
Methods and findings:
Biomarkers glucosylsphingosine (GlcSph) and globotriaosylsphingosine (Lyso-Gb3) were detected and quantified using LC-MS/MS on dried blood spots. We developed an improved and new extraction method that allowed to measure GlcSph and Lyso-Gb3 in a multiplex analytical platform. After validation of the method, samples of 1480 individuals with normal enzymatic activity were collected to determine age and gender-related reference ranges.Our combination method showed a good linearity, precision, accuracy and limit of quantification with lack of carry-over following the specific international CLSI guidelines. The suggested protocol is robust, efficient, sensitive, specific, comprehensive and relatively cheap in order to accelerate the diagnostic process for both lysosomal storage diseases. The samples, with normal enzymatic activity, defined statistical relevant and clinical correct reference ranges for each specific age group by gender.
Conclusion:
We report a multiplex LC-MS/MS method and relevant reference ranges that are appropriate for the targeted screening, diagnosis and follow-up of Fabry and Gaucher disease.
... 2 Deposition of these complex sphingolipids leads to cellular dysfunction and subsequently life-threatening cardiovascular, renal and neurological complications. 3 Cardiovascular involvement includes progressive left ventricular hypertrophy (LVH), myocardial inflammation, fibrosis, congestive cardiac failure, arrhythmia and sudden death. 4 Gb3 and lysoGb3 accumulate in all cardiac cells including the conduction system, 5 triggering a cascade of cellular reactions leading to a pro-inflammatory microenvironment with local tissue injury and apoptosis. ...
Introduction
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme deficiency, leading to glycosphingolipid accumulation. Cardiac accumulation triggers local tissue injury, electrical instability and arrhythmia. Bradyarrhythmia and atrial fibrillation (AF) incidence are reported in up to 16% and 13%, respectively.
Objective
We conducted a systematic review evaluating AF burden and bradycardia requiring permanent pacemaker (PPM) implantation and report any predictive risk factors identified.
Methods
We conducted a literature search on studies in adults with FD published from inception to July 2019. Study outcomes included AF or bradycardia requiring therapy. Databases included Embase, Medline, PubMed, Web of Science, CINAHL and Cochrane. The Risk of Bias Agreement tool for Non-Randomised Studies (RoBANS) was utilised to assess bias across key areas.
Results
11 studies were included, eight providing data on AF incidence or PPM implantation. Weighted estimate of event rates for AF were 12.2% and 10% for PPM. Age was associated with AF (OR 1.05–1.20 per 1-year increase in age) and a risk factor for PPM implantation (composite OR 1.03). Left ventricular hypertrophy (LVH) was associated with AF and PPM implantation.
Conclusion
Evidence supporting AF and bradycardia requiring pacemaker implantation is limited to single-centre studies. Incidence is variable and choice of diagnostic modality plays a role in detection rate. Predictors for AF (age, LVH and atrial dilatation) and PPM (age, LVH and PR/QRS interval) were identified but strength of association was low. Incidence of AF and PPM implantation in FD are variably reported with arrhythmia burden likely much higher than previously thought.
PROSPERO database
CRD42019132045.
... Fabry disease (FD) is an ultra-rare genetic disorder with an incidence of 1:40,000 to 1:117,000, depending on the studied population [1]. It is caused by pathological variants of the alpha-galactosidase A gene (GLA) encoding lysosomal enzyme alpha-galactosidase A [2]. Lower activity of that enzyme leads to pathological accumulation of glycosphingolipids, such as globotriaosylceramides inside lysosomes, followed by cell degeneration, tissue inflammation, and organ impairment [3]. ...
... As mentioned, there were 92 patients with the risk factor ≥4. Among them, 80 patients were classified as FP and 12 were TP, which gave the ratio 1:7, while in the general population it is known to be 1:40,000 [1]. The obtained 1:7 ratio is 5714 times higher than the ratio represented within the general population. ...
In clinical practice, the consideration of non-specific symptoms of rare diseases in order to make a correct and timely diagnosis is often challenging. To support physicians, we developed a decision-support scoring system on the basis of retrospective research. Based on the literature and expert knowledge, we identified clinical features typical for Fabry disease (FD). Natural language processing (NLP) was used to evaluate patients’ electronic health records (EHRs) to obtain detailed information about FD-specific patient characteristics. The NLP-determined elements, laboratory test results, and ICD-10 codes were transformed and grouped into pre-defined FD-specific clinical features that were scored in the context of their significance in the FD signs. The sum of clinical feature scores constituted the FD risk score. Then, medical records of patients with the highest FD risk score were reviewed by physicians who decided whether to refer a patient for additional tests or not. One patient who obtained a high-FD risk score was referred for DBS assay and confirmed to have FD. The presented NLP-based, decision-support scoring system achieved AUC of 0.998, which demonstrates that the applied approach enables for accurate identification of FD-suspected patients, with a high discrimination power.
... 7 The prevalence of Fabry disease is estimated to be between 1 in 40 000 and 1 in 120 000 individuals. 8 These rates reflect clinically driven diagnoses; that is, testing is performed when symptoms are present or when the disease is suspected based on the familial pedigree. However, recent screening studies show that the prevalence of Fabry disease may be markedly higher than that previously estimated. ...
... In this retrospective cohort study of adults in Manitoba, we found an incidence of confirmed Fabry disease that is similar to clinical incidence rates that have been observed in other jurisdictions. 8 Throughout our study period, we found more than 1000 Manitobans at high risk who have not been screened for Fabry disease and had idiopathic hypertrophic cardiomyopathy, an ischemic stroke <45 years of age, kidney failure or proteinuria of unknown cause, or peripheral neuropathy without known contributing factors. This screening gap suggests a possibility, indicated by previous screening studies, that there may be a higher prevalence of Fabry disease in Manitoba than what is generally estimated based on the clinical diagnosis and pedigree analysis. ...
Background:
Fabry disease is a rare disorder caused by the deficient activity of α-galactosidase A (GLA) that often leads to organ damage. Fabry disease can be treated with enzyme replacement or pharmacological therapy, but due to its rarity and nonspecific manifestations, it often goes undiagnosed. Mass screening for Fabry disease is impractical; however, a targeted screening program for high-risk individuals may uncover previously unknown cases.
Objective:
Our objective was to use population-level administrative health databases to identify patients at high risk of Fabry disease.
Design:
Retrospective cohort study.
Setting:
Population-level health administrative databases housed at the Manitoba Centre for Health Policy.
Patients:
All residents of Manitoba, Canada, between 1998 and 2018.
Measurements:
We ascertained the evidence of GLA testing in a cohort of patients at high risk of Fabry disease.
Methods:
Individuals without a hospitalization or prescription indicative of Fabry disease were included if they had evidence of 1 of 4 high-risk conditions for Fabry disease: (1) ischemic stroke <45 years of age, (2) idiopathic hypertrophic cardiomyopathy, (3) proteinuric chronic kidney disease or kidney failure of unknown cause, or (4) peripheral neuropathy. Patients were excluded if they had known contributing factors to these high-risk conditions. Those who remained and had no prior GLA testing were assigned a 0% to 4.2% probability of having Fabry disease depending on their high-risk condition and sex.
Results:
After applying exclusion criteria, 1386 individuals were identified as having at least 1 high-risk clinical condition for Fabry disease in Manitoba. There were 416 GLA tests conducted during the study period, and of those, 22 were conducted in individuals with at least 1 high-risk condition. This leaves a screening gap of 1364 individuals with a high-risk clinical condition for Fabry disease in Manitoba who have not been tested. At the end of the study period, 932 of those individuals were still alive and residing in Manitoba, and if screened today, we expect between 3 and 18 would test positive for Fabry disease.
Limitations:
The algorithms we used to identify our patients have not been validated elsewhere. Diagnoses of Fabry disease, idiopathic hypertrophic cardiomyopathy, and peripheral neuropathy were only available via hospitalizations and not physician claims. We were only able to capture GLA testing processed through public laboratories. Patients identified to be at high risk of Fabry disease by the algorithm did not undergo GLA testing due to a clinical rationale that we were unable to capture.
Conclusions:
Administrative health databases may be a useful tool to identify patients at higher risk of Fabry disease or other rare conditions. Further directions include designing a program to screen high-risk individuals for Fabry disease as identified by our administrative data algorithms.
... Clinical symptoms are very variable, and the age of onset and rate of progression of symptoms may differ according to the patient. In this respect, the diagnosis may be delayed and irreversible damage may develop in the body in this process [15]. In general, proteinuria occurs in the 2nd decade, chronic renal failure, cerebral and cardiac symptoms appear in the 3rd decade. ...
Purpose:
In this prospective study we aimed to determine the rate of Fabry Disease (FD) in patients with left ventricular hypertrophy (LVH), and to evaluate the clinical presentations of patients with FD in a comprehensive manner. In addition, we aimed to raise awareness about this issue by allowing early diagnosis and treatment of FD.
Methods:
Our study was planned as national, multicenter, observational. Totally 22 different centers participated in this study. A total of 886 patients diagnosed with LVH by echocardiography (ECHO) were included in the study. Demographic data, biochemical parameters, electrocardiography (ECG) findings, ECHO findings, treatments and clinical findings of the patients were recorded. Dry blood samples were sent from male patients with suspected FD. The α-Gal A enzyme level was checked and genetic testing was performed in patients with low enzyme levels. Female patients suspected of FD were genetically tested with the GLA Gene Mutation Analysis.
Results:
FD was suspected in a total of 143 (16.13%) patients included in the study. The α-Gal-A enzyme level was found to be low in 43 (4.85%) patients whom enzyme testing was requested. GLA gene mutation analysis was positive in 14 (1.58%) patients. Male gender, E/e' mean ,and severe hypertrophy are important risk factor for FD.
Conclusion:
In daily cardiology practice, FD should be kept in mind not only in adult patients with unexplained LVH but also in the entire LVH population. Dry blood test (DBS) should be considered in high-risk patients, and mutation analysis should be considered in required patients.
... Due to the progressive accumulation of glycosphingolipids in lysosomes diverse symptoms appear [3,6,15,16]. Specific to FD is that males are more severely affected than female heterozygotes, whose manifestation can range from as severely affected to, more frequently, asymptomatic depending on the random Xchromosomal inactivation [15,17,18]. FD is a multisystem disorder involving cardiac/renal disease, skin disorders (angiokeratoma), neurologic diseases (acroparesthesias, autonomic dysfunction and hypohidrosis), ocular abnormalities (cornea verticillata), sensorineural hearing loss and cerebrovascular diseases-stroke [3,6,19,20]. ...
... In GD and FD, the majority of patients develop gradually disease manifestations during childhood [7]. A swift diagnosis is often impeded by the rare nature of LSDs and their diverse clinical presentation associated with a rather poor awareness among clinicians [18]. The delayed diagnosis results in a delayed treatment, which is associated with increased disease complications [3,21]. ...
... Advanced complications, both mental as physical, jeopardize the overall benefit of treatment [3]. Timely initiation of effective treatments, such as enzyme replacement therapy (ERT), substrate reduction therapy (SRT) and chaperone therapy, are able to improve the disease status and outcome [9,18]. ...
... This defect leads to the inability of the lysosomes to catabolize complex glycosphingolipids. As a result, FD is a progressive multisystem disease [1]. Disease symptoms develop in both hemizygous males and heterozygous female carriers. ...
Fabry disease (FD) is a rare X-linked disease due to a multiverse of disrupting mutations within the GLA gene encoding lysosomal α-galactosidase A (AGAL). Absent AGAL activity causes the accumulation of complex glycosphingolipids inside of lysosomes in a variety of cell types and results in a progressive multisystem disease. Known disease-associated point mutations in protein-coding gene regions usually cause translational perturbations and result in premature chain termination, punctual amino acid sequence alterations or overall altered sequence alterations downstream of the mutation site. However, nucleotide exchanges at the border between introns and exons can affect splicing behavior and lead to abnormal pre-mRNA processing. Prediction with the Human Splicing Finder (HSF) revealed an indication of a significant change in splicing-relevant information for some known FD-associated GLA mutations. To experimentally determine the extent of the change, we made use of a minigene reporter assay and verified alternative splicing events for the exonic mutations c.194G>T and c.358C>G, which led to the usage of alternative donor splice sites at exon 1 and exon 2, respectively. In addition, the mutations c.548G>T and c.638A>T led to significant exon 4 skipping. We conclude that splicing phenotype analysis should be employed in the in vitro analysis of exonic GLA gene mutations, since abnormal splicing may result in a reduction of enzyme activity and alter the amenability for treatment with pharmacological chaperone (PC).
