#4043 FABRY DISEASE: A RARE ENTITY IN THE NEPHROLOGY SETTING

Rationale:Fabry disease (FD) is a rare, X-linked lysosomal deposition disease characterized by multi-system symptoms. The accumulation of globotriaosylceramide in various organs, such as the kidneys and heart, as well as the nervous system, has been speculated to be the mechanism involved in tissue damage, including vascular impairment with thrombotic events.Patient concerns:Here, we describe a 72-year-old male patient diagnosed with FD, who first presented with acute myocardial infarction, left ventricular thrombosis, and pericardial effusion, accompanied by cardiac hypertrophy.Diagnoses:A physical examination showed that he was hemodynamically stable and an electrocardiogram showed ventricular tachycardia (Fig. 1A). The single obvious abnormality was an ST segment depression with a preterminal negative T wave in leads I and aVL (Fig. 1B). Coronary angiography revealed regular findings (Fig. 2). Echocardiogram conducted at our hospital revealed hypertrophy, ejection fraction 40%, pericardial effusion (Fig. 3). Speckle tracking two-dimensional echocardiography strain analysis technology confirmed left ventricular thrombosis, and also revealed decreased movement of the inferior and posterior walls, the basal segment of the posterior wall was locally fibrotic (Fig. 4A and B). Further, myocardial contrast echocardiography confirmed left ventricular thrombosis (Fig. 4C). Cardiovascular magnetic resonance imaging indicated biventricular uneven hypertrophy, which was considered metabolic cardiomyopathy, with diffuse fibrosis of biventricular walls, apical thrombosis, and ischemic cardiomyopathy in the basal segment of the left ventricular lateral wall and left ventricular anterior wall (Fig. 5). Serum alpha-galactosidase concentration was 0.7 nmol/h/mgPr (normal range, 29.0–64.4 nmol/h/mgPr). Subsequent genetic testing revealed that he was hemizygous for a previously reported missense mutation (c.902G>A) inexon 6 of the GLA gene,[1] which induce p.R301Q (p.Arg301Gln), confirming a diagnosis of FD (Fig. 6).Interventions:Orally administered drugs included rivaroxaban, sacubitril valsartan, beta blockers, dapagliflozin, and mineralocorticoid receptor antagonist. Cardiac resynchronization therapy with an implanted defibrillator was implemented to prevent sudden death.Outcomes:At present, he is still in follow-up and there have been no adverse events.Conclusion:Our case suggests that clinicians should consider the possibility of FD in patients with acute myocardial infarction and cardiomyopathy. A detailed analysis of subtle historical clues would help promote earlier diagnosis of FD.

Fabry disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase A. This determines an accumulation of globotriaosylceramide within lysosomes. The clinical picture is highly variable and depends on cellular storage deposition. Renal, cardiac and nervous system are the most frequent organs involved. Gastrointestinal involvement is also present, associated with other clinical signs of Fabry disease and sometimes can be a prominent clinical manifestation. We describe a Fabry disease case in which gastrointestinal involvement was the first and the only clinical sign of Fabry disease and a diagnosis of Fabry disease was made by chance during a family screening. Enzyme replacement therapy was started and after 3 months, there was a complete disappearance of signs.

Background: Fabry disease (FD) is an X-linked disorder due to a pathogenic variant of the GLA gene that codes for the alpha-galactosidase enzyme. The reduced or absent activity of the enzyme results in lysosomal accumulation of globotriosylceramide and its derivative, globotriaosylsphingosine, in a variety of cells, leading to a variety of complications including cardiac, renal, and cerebrovascular disorders. Early diagnosis is critically important for the selection of therapeutic treatments, which are essential for improving outcomes. Here we present a case of FD diagnosed at the time of end-stage kidney disease presentation. Summary: A 40-year-old man with a history of seizures presented with increased serum creatinine, nephrotic rage proteinuria, and new-onset hypertension. A renal biopsy revealed numerous, whorled, and lamellated cytoplasmic inclusions in podocytes, glomerular peritubular capillary endothelial cells, mesangial cells, arterial myocytes, and interstitial macrophages. Ultrastructural analysis confirmed the presence of glycosphingolipid inclusions and enlarged lysosomes packed with multi-lamellated structures (“zebra” bodies). The findings were suggestive of a lysosomal storage disorder, and testing for alpha-galactosidase A levels revealed near-absent enzyme activity, confirming the diagnosis of advanced FD. Key Messages: The diagnosis of FD can be challenging as the manifestations of the disease are nonspecific, and patients can present early with classical symptoms or late with non-classical patterns of involvement. We will discuss strategies to identify the disorder early by reviewing the classical and non-classical presentations and further outline currently available and potential future treatment options.

Left ventricular myocardial work (LVMW) represents an innovative tool based on echocardiography designed to assess left ventricular (LV) performance in conjunction with LV pressure patterns. Although previous studies have compared differences in LVMW among patients with Fabry disease (FD), cardiac amyloidosis (CA), and hypertension at rest, there is limited research on the characteristics of LVMW in patients with FD during exercise. This study aims to explore the characteristics of LVMW at rest and during exercise in patients with FD and the value of LVMW combined with stress echocardiography for the early detection of impaired cardiac function in subclinical Fabry patients. This cross-sectional study included 54 participants, comprising 23 healthy individuals and 31 patients with FD. All participants underwent comprehensive two-dimensional echocardiography and semi-supine exercise stress echocardiography tests. At rest, individuals with FD exhibited markedly lower LV global longitudinal strain (LVGLS), LV global myocardial constructive work (LVGCW), LV global myocardial work efficiency (LVGWE), and LV global myocardial work index (LVGWI) compared to healthy controls. During exercise, LVGLS, LVGWI, LVGCW, and LV global wasted myocardial work (LVGWW) markedly increased in patients with FD and controls, while LVGWE decreased. However, across the four phases (rest, 25 W, peak, and recovery), patients with FD consistently demonstrated lower LVGLS, LVGWI, LVGWE, and LVGCW compared to controls. Moreover, the rise in LVGWI and LVGCW from the rest phase to the peak stage was markedly smaller in individuals with FD than in controls. A moderate correlation was found between LVGWI and LVGWE with LV mass index (LVMI) in individuals with FD (LVGWI: r = − 0.57, P < 0.05; LVGWE: r = − 0.68, P < 0.001). Additionally, individuals with FD with LV hypertrophy (LVH) exhibited lower LVGLS, LVGWE, and LVGCW from the rest to peak than those without LVH. Individuals with FD who had normal LVGLS at rest or those without LVH still showed markedly lower LVGWI than controls during the resting phase. Additionally, at peak exercise, LVGLS, LVGWI, and LVGCW were diminished significantly in the individuals with FD relative to the control cohort. ROC curve analysis in both resting and exercising states showed that LVGWI (rest: AUC 0.86, sensitivity 87%, specificity 74%; peak: AUC 0.94, sensitivity 71%, specificity 96%;) and LVGCW (rest: AUC 0.82, sensitivity 87%, specificity 70%; peak: AUC 0.92, sensitivity 84%, specificity 87%;) than LVGLS (resting: AUC 0.79, sensitivity 61%, specificity 87%; peak: AUC 0.88, sensitivity of 77%, and specificity of 87%) have a higher value in the diagnosis of FD. Patients with FD have markedly lower LVGWI, LVGWE, and LVGCW compared to the healthy controls, and these reductions are more prominent during exercise. Although LVGWI and LVGCW increase during exercise in patients with FD, the rate of increase is reduced, indicating impaired myocardial metabolism and energy utilization efficiency, especially in patients with FD with LVH. Additionally, LVMW combined with Stress Echocardiography allows early detection of impaired cardiac function in Fabry patients.

The incidence and predictive factors of arrhythmias and/or conduction abnormalities (ACAs) requiring cardiac device (CD) implantation are poorly characterized in Fabry disease (FD). The aim of our retrospective study was to determine the prevalence, incidence, and factors associated with ACA requiring CD implantation in a monocentric cohort of patients with confirmed FD who were followed up in a department of internal medicine and reference center for FD.Forty-nine patients (20M, 29F) were included. Nine patients (4M, 5F; 18%) had at least one episode of ACA leading to device therapy. Six patients (4M/2F) required a pacemaker (PM) for sinus node dysfunction (n = 4) or atrioventricular disease (n = 2). One female patient required an internal cardioverter-defibrillator (ICD) to prevent sudden cardiac death because of nonsustained ventricular tachycardia (nSVT). One female patient required PM-ICD for sinus node dysfunction and nSVT. One patient underwent CD implantation before the diagnosis of FD. The annual rate of CD implantation was estimated at 1.90 per 100 person years. On univariate analysis at the end of the follow-up period, the factors associated with ACAs requiring CD implantation were as follows: delayed diagnosis of FD, delayed initiation of enzyme replacement therapy, age at the last follow-up visit, and severe multiorgan phenotype (hypertrophic cardiomyopathy, chronic kidney disease, and/or sensorineural hearing loss). On multivariate analysis, age at diagnosis of FD and age at the last follow-up visit were independently associated with an increased risk of ACAs requiring CD (P < 0.05).Considering the high frequency of ACAs requiring CD implantation and the risk of sudden death in patients with FD, regular monitoring is mandatory, especially in patients with a late diagnosis of FD and/or with a severe phenotype. Regular Holter ECGs, therapeutic education of patients, and deliverance of an emergency card including a phenotype summary are crucial in the care of FD patients.Available guidelines for device therapy and the efficacy of enzyme replacement therapy for arrhythmias or conduction abnormalities are discussed.

In this issue, Banikazemi and colleagues' landmark trial on Fabry disease provides a crucial path toward lowering the morbidity of this disease. Among other findings, they determined that hemizygou...

Value of Electrocardiography to Distinguish Fabry Disease from Sarcomeric Hypertrophic Cardiomyopathy

Although Fabry disease was identified a century ago, it is still a challenging condition to diagnose and treat. Registries data suggest that at least 10% of patients may first present with a cardiac event and that cardiac disease is 1 of the 3 major causes of morbidity and mortality in affected males and females. Cardiac involvement in Fabry disease may be expressed as left ventricular hypertrophy (LVH), coronary disease, atrioventricular conduction disturbances, arrhythmias, and valvular involvement. The exact mechanism by which hypertrophy and fibrosis in the heart occur is not fully understood. Lysosomal globotriaosylceramide accumulation in the myocardium is responsible for only 3% of the mass in the hypertrophic heart, indicating that the LVH is not a direct result of substrate infiltration. One of the most important contributions that cardiologists can make is to consider the diagnosis of Fabry disease in patients with cardiac manifestations preceding the development of LVH and conduct family screen...

Fabry disease is an X-linked lysosomal storage condition caused by a deficiency of alpha-galactosidase A. In order to determine the average number of family members who are diagnosed with Fabry disease following the diagnosis of a proband, four lysosomal storage disease centers across the United States reviewed the completed pedigrees of their Fabry disease patients. In addition, data from three Fabry disease families from other centers were submitted by patients directly. The pedigree review found 74 probands (54 males and 20 females) who had 357 diagnosed family members, of which 223 were female (60.5%) and 146 were male (39.5%). Analysis found that, on average, there were five family members diagnosed with Fabry disease for every proband. Now that enzyme replacement therapy (ERT) is available for the treatment of Fabry disease, this finding emphasizes the need for all health care professionals to ensure a detailed pedigree has been constructed for each patient affected by Fabry disease and to encourage testing and evaluation of all at-risk family members.

BackgroundThe clinical diagnosis of Fabry Disease (FD) can be challenging due to the clinical heterogeneity, especially in females. Patients with FD often experience a prolonged interval between the onset of symptoms and receiving a diagnosis. Genetic testing is the gold standard for precise diagnosis of FD, however conventional genetic testing could miss deep intronic variants and large deletions or duplications. Although next-generation sequencing, which analyzes numerous genes, has been successfully used for FD diagnosis and can detect complex variants, an effective and rapid tool for identifying a wide range of variants is imminent, contributing to decrease the diagnostic delay.MethodsThe comprehensive Analysis of FD (CAFD) assay was developed for FD genetic diagnosis, employing long-range PCR coupled with long-read sequencing to target the full-length GLA gene and its flanking regions. Its clinical performance was assessed through a comparative analysis with Sanger sequencing.ResultsGenetic testing was performed on 82 individuals, including 48 probands and 34 relatives. The CAFD assay additionally identified variants in two probands: one had a novel and de novo pathogenic variant with a 1715 bp insertion in intron 4, and the other carried two deep intronic VUS variants in cis-configuration also in intron 4. In total, CAFD identified 47 different variants among 48 probands. Of these, 42 (89.36%, 42/47) were pathogenic, while 5 (10.64%, 5/47) were VUS. Sixteen (34.04%, 16/47) of the variants were novel, including 15 SNV/Indels and one large intronic insertion. Pedigree analysis of 21 probands identified four de novo disease-causing variants. Hence, FD exhibits not only variable clinical presentations but also a wide spectrum of variants. Utilizing a comprehensive testing algorithm for diagnosing FD, which includes enzyme activity, clinical features, and genetic testing, the diagnostic yield of CAFD is 97.92% (47/48), which is higher than that of conventional Sanger sequencing, at 95.83% (46/48).ConclusionThe duration between initial clinical presentation and diagnosis remains long and winding. CAFD provides precise diagnosis for a wide spectrum of GLA variants, promoting timely diagnosis and appropriate treatment for FD patients.

Background/Objectives: Fabry disease (FD) is a rare X-linked disease caused by the deficient activity of the enzyme α-galactosidase A. Cardiac involvement is particularly critical, often determining the disease prognosis. Epidemiological data on FD in Portugal are limited and inconsistent, highlighting the need for targeted screening. The F-CHECK study aimed to determine the prevalence of FD through the systematic screening of a Portuguese cohort of patients with unexplained cardiomyopathies. Methods: This multicenter observational study (NCT05409846) assessed the prevalence and clinical characteristics of FD in a Portuguese cohort (n = 409) of patients from 10 central hospitals who presented with unexplained cardiomyopathies, including idiopathic hypertrophic cardiomyopathy (HCM), left ventricular hypertrophy, dilated-phase HCM, and dilated cardiomyopathy with late gadolinium enhancement in the inferolateral segment. Screening was performed using dried blood spot assays to measure α-galactosidase A activity and/or by GLA gene sequencing in whole-blood samples. Results: FD was diagnosed in 14 patients, corresponding to a prevalence of 3.4%. FD diagnosis was significantly associated with systemic manifestations such as acroparesthesias (p = 0.027) and angiokeratomas (p = 0.003), as well as an increased risk of prior arrhythmic events (p = 0.021) and cerebrovascular disease (p = 0.016). Most FD patients (57%) presented a non-founder mutation in the GLA gene; however, they were pathogenically relevant. Conclusions: The observed 3.4% prevalence highlights the importance of systematic FD screening among Portuguese patients with unexplained cardiomyopathy, extending beyond classic hypertrophic presentations to dilated forms. Specific clinical signs, electrocardiogram findings, and cardiac imaging features can serve as valuable indicators to guide targeted genetic testing for FD.

Hypohidrosis is a frequent and early symptom in patients with Fabry disease. Studies have reported improved sweating in patients treated with enzyme-replacement therapy. A new method, Sudoscan, has been developed that is noninvasive, is quantitative, and can quickly evaluate sweat gland function. It is based on the electrochemical reaction between sweat chlorides and stainless-steel electrodes in contact with the palms and soles. The aim of our study was to evaluate the Sudoscan as a tool to assess sudomotor dysfunction in patients with Fabry disease. Consecutive patients were prospectively recruited who had a diagnosis of Fabry disease, which had been confirmed genetically and/or by measurement of α-galactosidase activity in leukocytes. Healthy controls, matched (1:1) for age and sex, were also enrolled. Test results were expressed immediately as electrochemical skin conductance (ESC, µS) for hands and feet. Sudomotor dysfunction was considered absent, moderate, or severe if the ESC measured on the feet was >60 µS, between 60 and 40 µS, or <40 µS, respectively. Among the 18 patients, 11 had hypohidrosis or anhidrosis. Hand and feet ESCs were significantly lower in patients compared to their controls (P=0.0015 and P=0.0047, respectively). Among patients, 8/18 (44.5%) had a sudomotor dysfunction, moderate in three and severe in five cases. Hand and feet ESCs were significantly lower in those with hypohidrosis/anhidrosis compared to those without (P=0.0014 and P=0.0056, respectively). This study showed that Sudoscan provided a quick, noninvasive, and quantitative measurement of sudomotor function in Fabry disease patients.

Fabry disease (FD, OMIM 301500) is an X-linked disorder of glycosphingolipid metabolism resulting from the deficient activity of alpha-galactosidase A, a lysosomal acid hydrolase, leading to progressive lysosomal accumulation of incompletely metabolized neutral glycosphingolipids. Cardiac involvement is frequent. The objective of this study was to characterize the cardiac abnormalities in male patients affected with classic Fabry disease and define the context in which the clinicians were able to make the diagnosis. Clinical evaluation, laboratory tests, electrocardiography (ECG) and echocardiography were performed in 20 hemizygous men (mean age 39 years, range 12-65 years). The context of diagnosis was obtained by review of patients' charts. Left ventricular hypertrophy (LVH) and/or concentric remodeling were found in 12 patients (60%). Structural changes in mitral and aortic valves were found in 25% and 10% of cases, respectively. The sensitivity of the ECG Romhilt-Estes score for LVH was high (80%). Short PR interval (40%), ST segment abnormalities and conduction delay were frequent on ECG. Left ventricular mass index, ECG scores for LVH and systolic pulmonary pressure correlated positively with age. There was no relation between classic vascular risk factors and coronary artery disease, transient ischemic attack (TIA) or stroke. Diagnosis of Fabry disease was frequently suggested by nephrologists, dermatologists or geneticists. Echocardiograph and ECG abnormalities are frequently observed in patients with Fabry disease. Cardiologists should be aware of the diagnosis of Fabry disease in patients presenting with LVH, concentric remodeling, mitral and aortic valve thickening on echocardiography, short PR interval and conduction defects on ECG.

It is generally accepted that Fabry disease (angiokeratoma corporis diffusum) is an X-linked disorder resulting from the deficient activity of the lysosomal enzyme alpha-galactosidase. In males, the enzymatic defect leads to accumulation of glycosphingolipids, particularly in the kidney which causes end-stage renal disease. We report here a woman who presented in 1987 with focal and segmental glomerulosclerosis and required hemodialysis 4 years later when her son was evaluated for proteinuria. In these patients morphologic, biochemical, and genetic investigations were performed to explore the possibility of a hereditary renal disorder. Ultrastructural examination of the son's renal biopsy specimen revealed lamellated osmiophilic inclusions in the glomeruli, typical of Fabry disease. Four months after kidney transplantation in the mother, a graft biopsy specimen also revealed dense lamellated inclusions on electron microscopy. The leukocyte alpha-galactosidase activity was 0.008 mumol/min.10(9) cells in the son and 0.070 in the mother (range 0.100-0.500 mumol/min.10(9) cells). The diagnosis of Fabry disease was confirmed in both patients by the identification by DNA sequencing of a novel mutation in the alpha-galactosidase gene: one single base pair deletion in exon 3 (7317delA). (1) end-stage renal disease may occur in heterozygous women with Fabry disease; (2) morphologic lesions due to glycosphingolipid accumulation may be observed in the renal allograft after transplantation, and (3) DNA analysis confirmed the diagnosis by demonstrating a frameshift mutation, which has as yet not been reported.

Introduction: Cardiac magnetic resonance(CMR), especially T1 mapping, has an important role in the diagnosis of Fabry disease, but the differential value in myocardial diseases with hypertrophic phenotype needs further study. More importantly, there has been no systematic study of the difference between different CMR techniques indistinguishing Fabry cardiomyopathy from hypertrophic cardiomyopathy (HCM). Hypothesis: Myomapping technology can be a parameter in distinguishing Fabry cardiomyopathy from HCM. Methods: We continuously included patients with clinically diagnosed hypertrophic cardiomyopathy, completed systematic magnetic resonance imaging, and used genetic testing as the diagnostic criteria. We reported the prevalence rate in the population of HCM, and deeply conducted comparative studies on the differences in magnetic resonance characteristics between Fabry disease and HCM. We also analyzed the diagnostic value of magnetic resonance imaging in distinguishing Fabry cardiomyopathy from HCM. Results: We continuously included patients diagnosed with hypertrophic cardiomyopathy at West China Hospital from 2012 to 2022 and completed systematic magnetic resonance imaging examinations. We reported the prevalence of Fabry cardiomyopathy in the population using genetic testing as the diagnostic criteria, and deeply conducted comparative studies on the differences in CMR features between Fabry disease and HCM. We also analyzed the diagnostic value of CMR in distinguishing Fabry cardiomyopathy from HCM. Conclusions: We found a prevalence of 13 (2.6%) cases of Fabry disease in the hypertrophic cardiomyopathy cohort (494 cases). Our further analysis found that there were no significant differences in the degree of hypertrophy, overall cardiac function and size of Fabry patients compared with patients with HCM, as well as strain analysis. NativeT1 was significantly reduced in Fabry disease, and segmental analysis found that the basal and middle ventricular septum and anterior wall were the most obvious. ECV differed significantly between the two groups. There was no difference in T2 between the two groups. ROC analysis showed that T1 had the most discriminating value