BACKGROUND:To prevent complications, uncontrolled movement of the guidewire during a coronary intervention should be avoided. Unintentional withdrawal of the wire can result in the inability to recross a lesion with the risk of myocardial infarction. On the other hand, unintended forward pushing can lead to a coronary perforation. Thus, interventionalists in training should practice keeping the coronary guidewire in a stable position to prevent complications. For this purpose, a skill trainer has been developed, which provides the possibility of unlimited practice outside of the cath lab.The purpose of this study was to assess the effectiveness and the validity of this skills trainer.METHODS:Ten novices and 10 participants with experience in diagnostic catheterization underwent training on the skills trainer consisting of 25 procedures. To assess the efficacy of the training module, the mean score of the first 3 procedures was compared with the final 3 procedures in the novice and the advanced group. To determine the construct validity of the simulator, a group of experts (E; performed >1000 percutaneous coronary interventions) also underwent evaluation on the skills trainer. For each procedure, the change in position of the guidewire as well as the time was determined and combined into a skills score with a maximum of 15 points.RESULTS:The novice and the advanced group improved significantly throughout the training on the simulator (N: 7.1 ± 2.6 to 12.2 ± 2.0, P = 0.007; A: 8.3 ± 2.0 to 13.2 ± 1.0, P = 0.005, Wilcoxon).The experts scored significantly higher than novices or the advanced participants during their first 3 procedures (E: 12.9 ± 1.0; N: 7.1 ± 2.6, P = 0.001; A: 8.3 ± 2.0, P = 0.001; Mann-Whitney U ).CONCLUSIONS:This low-cost task trainer is a valid and effective tool to train adequate balloon/stent exchange while keeping the guidewire in a stable position. Whether the skills acquired on the task trainer can be transferred to procedures performed on patients needs further investigation.

Fabry disease (OMIM 301500) is an X-linked (Xq22.1)lysosomal storage disorder leading to a progressive multisystem disease with high variability in both genotype and phenotype expression.The pathophysiological origin is found in an enzyme deficiency of the α-galactosidase A (enzyme commission no.3.2.1.22)leading to accumulation of globotriaosylceramides in all lysosome carrying tissue.Especially organ manifestations of the heart, kidneys and nervous system are of significant prognostic value and might complicate with Fabry-associated pain, young aged cryptogenic stroke, proteinuria, kidney failure, hypertrophic cardiomyopathy, heart failure, malign cardiac rhythm disturbances and eventually sudden cardiac death.Up to the introduction of the first enzyme replacement agent in 2001, patients faced the disease's natural course with no disease-specific therapies available.Today, two recombinant enzyme replacement agents (Fabrazyme ® , Sanofi Genzyme, Cambridge, MA, USA; Replagal ® , Takeda Pharmaceutical, Tokio, Japan) and one oral chaperone therapy (Migalastat ® , Amicus Therapeutics, USA) are available and well-established in daily clinical practice.Substrate reduction therapy, second-generation enzyme replacement agents and different gene therapy approaches are currently undergoing preclinical and clinical trial phases and aim to improve therapeutic success and long-term outcome of patients with Fabry disease.This narrative review summarizes the currently available therapeutic options and future perspectives in Fabry disease.

Abstract Background and Aims Patients with Fabry disease frequently develop cardiac hypertrophy and progressive Fabry nephropathy. The progress of cardiac hypertrophy can lead to replacement fibrosis and heart failure. Galectin-3 is expressed in the heart, kidneys, blood vessels, and macrophages. It marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Experimental data suggest that galectin-3 is involved in fibrosis and inflammation also associated with renal failure. Galectin-3 inhibitor therapy tested in a phase 2 clinical trial in chronic kidney disease lead to an improvement of the estimated glomerular filtration rate. Given the role of Galectin-3 in cardiac hypertrophy, heart and renal failure, we hypothesized that it may be of potential relevance particularly for Fabry disease patients. Method This study investigated the galectin-3 concentrations in 172 patients with genetically proven Fabry disease. We studied the association of galectin-3 concentrations with renal function, left ventricular mass, and adverse clinical symptoms in patients with Fabry disease. Galectin-3 was measured by FDA-approved ELISA. GFR was determined by DTPA clearance. Left ventricular mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analysis, associations with adverse clinical outcomes were determined by correlation analysis and linear and binary logistic regression analysis, respectively. Data was adjusted for age and sex. Results Patients had a mean age of 39±14 years and 41% were male. The mean galectin-3 concentration was 17±12 ng/mL (normal value is approx. 11 ng/mL). Patients had a mean BMI of 23.7±4.5 kg/m2 and a mean GFR of 92±38 ml/min. Galectin-3 was strongly correlated with GFR, creatinine and urea. With higher galectin-3 concentrations of the patients, their GFR was lower (r=-0.63, p<0.001) and creatinine and urea were higher (r=0.68 and r=0.53, respectively, both p<0.001). Furthermore, cardiac hypertrophy was significantly higher with higher concentrations of galectin-3. The correlation coefficient for septal hypertrophy was r=0.43 (p<0.001) and for posterior hypertrophy r=0.39 (p<0.001), respectively. Similarly, cardiac fibrosis was significantly higher with higher galectin-3 levels (r=0.34, p<0.001). Patients of the highest galectin-3 tertile furthermore had significantly higher risks of adverse clinical symptoms. The adjusted odds ratio to suffer from angina pectoris was increased > 6-fold and the odds ratio to suffer from neuropathic pain was increased > 3-fold for patients of the highest galectin-3 tertile as compared to patients of the lowest galectin-3 tertile. Conclusion Increased galectin-3 concentrations were strongly associated with cardiac hypertrophy, cardiac fibrosis, decreased renal function, and adverse clinical symptoms in patients with Fabry disease. Galectin-3 can be useful as biomarker for cardiac and renal complications in Fabry disease. Galectin-3 inhibitor treatment may reduce complications of Fabry disease, and requires a randomized controlled trial.

Abstract Background and Aims Patients with Fabry disease frequently develop progressive Fabry nephropathy, hypertrophic cardiomyopathy with arrhythmias and subsequent death, transient ischemic attacks and early cerebral stroke. Homoarginine is an amino acid derivative, mainly produced in the kidney from its precursor lysine. Homoarginine may increase nitric oxide availability, decrease the release of cytokines, modulate the renin-angiotensin-aldosterone system and improve cardiac contractility. We hypothesize that high homoarginine levels associate with less clinical symptoms and better renal function in patients with Fabry disease. Method This study investigated the homoarginin status and its association with renal function, left ventricular (LV) mass and adverse clinical symptoms in patients with Fabry disease. Homoarginine was measured by high-performance liquid chromatography in 162 patients who were genetically proven to have Fabry disease. GFR was determined by DTPA clearance. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, and BMI. Results Patients had a mean age of 39±14 years and 41% were male. The mean homoarginine concentration was 2.0±1.0 µmol/l. Patients had a mean BMI of 23.7±4.5 kg/m2 and a mean GFR of 93±37 ml/min. Homoarginine was significantly correlated with GFR and proteinuria. The better the homoarginine status of the patients, the higher was their GFR (r=0.20, p=0.04) and the lower proteinuria (r=-0.21, p=0.03). Furthermore, LV mass was significantly higher with lower homoarginine levels (r=-0.30, p<0.01). Patients of the lowest homoarginine tertile had a 4-fold higher risk of myocardial hypertrophy (OR 4.17, 95% CI 1.44-12.02), especially with septal and posterior hypertrophy, compared to those of the upper tertiles. Similarly, patients of the lowest homoarginine tertile had a higher rate of angina pectoris (OR 4.2, 95% CI 1.3-13.3) and chronic pain (OR 4.1, 95% CI 1.7-10.1), compared to patients of the upper tertiles. At lower homoarginine status, the median levels of proteinuria increased, as well as the prevalence rates of heart failure and the need for analgesic therapy. Conclusion In conclusion, low homoarginine status was strongly associated with cardiomyopathy, renal function and adverse clinical symptoms in patients with Fabry disease. Whether homoarginine supplementation improves complications of Fabry disease, requires a randomized controlled trial.

Long‐term effects of migalastat therapy in clinical practice are currently unknown. We evaluated migalastat efficacy and biomarker changes in a prospective, single‐center study on 14 patients with Fabry disease (55 ± 14 years; 11 men). After 1 year of open‐label migalastat therapy, patients showed significant changes in alpha‐galactosidase‐A activity (0.06–0.2 nmol/minute/mg protein; P = 0.001), left ventricular myocardial mass index (137–130 g/m2; P = 0.037), and serum creatinine (0.94–1.0 mg/dL; P = 0.021), accounting for deterioration in estimated glomerular filtration rate (87–78 mL/minute/1.73 m2; P = 0.012). The enzymatic increase correlated with myocardial mass reduction (r = −0.546; P = 0.044) but not with renal function (r = −0.086; P = 0.770). Plasma globotriaosylsphingosine was reduced in therapy‐naive patients (10.9–6.0 ng/mL; P = 0.021) and stable (9.6–12.1 ng/mL; P = 0.607) in patients switched from prior enzyme‐replacement therapy. These first real‐world data show that migalastat substantially increases alpha‐galactosidase‐A activity, stabilizes related serum biomarkers, and improves cardiac integrity in male and female patients with amenable Fabry disease mutations.

BACKGROUND:Fast progression of the transaortic mean gradient (P mean) is relevant for clinical decision making of valve replacement in patients with moderate and severe aortic stenosis (AS) patients. However, there is currently little knowledge regarding the determinants affecting progression of transvalvular gradient in AS patients. METHODS:This monocentric retrospective study included consecutive patients presenting with at least two transthoracic echocardiography examinations covering a time interval of one year or more between April 2006 and February 2016 and diagnosed as moderate or severe aortic stenosis at the final echocardiographic examination. Laboratory parameters, medication, and prevalence of eight known cardiac comorbidities and risk factors (hypertension, diabetes, coronary heart disease, peripheral artery occlusive disease, cerebrovascular disease, renal dysfunction, body mass index ≥30 Kg/m2, and history of smoking) were analyzed. Patients were divided into slow (P mean < 5 mmHg/year) or fast (P mean ≥ 5 mmHg/year) progression groups. RESULTS:A total of 402 patients (mean age 78 ± 9.4 years, 58% males) were included in the study. Mean follow-up duration was 3.4 ± 1.9 years. The average number of cardiac comorbidities and risk factors was 3.1 ± 1.6. Average number of cardiac comorbidities and risk factors was higher in patients in slow progression group than in fast progression group (3.3 ± 1.5 vs 2.9 ± 1.7; P=0.036). Patients in slow progression group had more often coronary heart disease (49.2% vs 33.6%; P=0.003) compared to patients in fast progression group. LDL-cholesterol values were lower in the slow progression group (100 ± 32.6 mg/dl vs 110.8 ± 36.6 mg/dl; P=0.005). CONCLUSION:These findings suggest that disease progression of aortic valve stenosis is faster in patients with fewer cardiac comorbidities and risk factors, especially if they do not have coronary heart disease. Further prospective studies are warranted to investigate the outcome of patients with slow versus fast progression of transvalvular gradient with regards to comorbidities and risk factors.

To the Editor: With great interest we have read the recent article by du Moulin et al, formally challenging the “low-pathogenicity hypothesis” of the D313Y genotype in Fabry disease. Most important, the authors report cerebrovascular events in 4 of 14 subjects. While these results indeed imply high prevalence of cerebrovascular complications in D313Y at first sight, a close look at some underlying numbers is needed to put these findings in context. First, prevalence of the D313Y genotype has long been substantially underestimated in screening studies, since findings were often based on measurements of enzyme activity, which is usually in normal range even in male D313Y gene carriers. Studies focusing on genetic testing have reported a D313Y genotype prevalence as high as 0.5% in the general population. Meanwhile, Baptista et al reported a D313Y prevalence of 1% in Portuguese patients with history of cryptogenic stroke. Despite overall low numbers, very simple math might therefore indicate: (1) generally no major impact of D313Y on risk of cerebrovascular events; (2) D313Y to generally increase (ie, roughly double) risk of cerebrovascular complications; or (3) D313Y to be a clinically relevant factor that—probably due to additional factors— subsequently leads to a clinically relevant increase of cerebrovascular complications not in all, but at least some gene carriers. The latter hypothesis might be supported by the finding that Lyso-Gb3, which is widely acknowledged as the most important Fabry biomarker, for example, in current consensus guidelines, is usually not elevated in D313Y gene carriers, but was found “mildly elevated in 2 females with cerebrovascular involvement” in the current study. Even though du Moulin et al reported “symptoms and organ manifestations compatible with Fabry disease” in 10 of 14 subjects, none showed cornea verticillata, angiokeratoma, cardiac or renal organ involvement, which is in line with earlier findings from our and other groups. In regard of “white matter lesions” found in brain magnetic resonance imaging (MRI), it should be noted that these are highly unspecific and have been shown related to many diseases with neurologic involvement—such as Alzheimer's disease—but are also frequent in the general population without clinical significance. In conclusion, complexity of both pathogenesis and organ involvement in Fabry disease as well as specific limitations in rare diseases still prohibit drawing simple conclusions. Clinicians should be careful not to overestimate unspecific symptoms being Fabry-associated. We clearly concur with du Moulin et al that mutations of unknown significance require an individual work-up to assess disease-severity in each individual patient, most important when taking into account specific treatment options.

ObjectivesCurrent guidelines highlight important therapy implications of cardiac fibrosis in patients with Fabry disease (FD). However, association between morphological and functional impairments with cardiac fibrosis in hereditary cardiomyopathies remains elusive. We investigated the association between echocardiography-determined cardiac dysfunction and cardiac MRI (cMRI)-detected myocardial fibrosis (late gadolinium enhancement, LE) in patients with FD with preserved left ventricular ejection fraction (≥50%).Methods146 patients with FD (aged 39±14 years, 57 men) were analysed, all receiving echocardiography and cMRI within a 1 week interval. Longitudinal systolic strain (LS_sys), strain rate (LSr_sys) and diastolic strain rate (LSr_E/LSr_A) were assessed using speckle-tracking imaging. Receiver operating characteristic (ROC) analysis was performed to identify the diagnostic performance of various markers for LE.ResultsLE was detected in 57 (39%) patients with FD. LV wall thickness, left atrial volume, septal E/e′, diastolic dysfunction grade, global LS_sys and E/LSr_E, mid-lateral LS_sys and LSr_E, as well as N-terminal pro-brain natriuretic peptide were all associated with LE independent of age, sex, body mass index, New York Heart Association functional class and kidney function. In ROC curve analysis, septal E/e′ performed best (area under the curve=0.86, 95% CI=0.79 to 0.92). Septal E/e′>14.8 was strongly associated with LE (specificity=97.8% and sensitivity=49.1%). In 9% of patients, localised LE was present even though no other cardiac or kidney abnormalities were detected.ConclusionsEchocardiography-derived diastolic dysfunction is closely linked to LE in FD. Septal E/e′ ratio is the best echocardiographic marker suggestive of LE. Diastolic dysfunction is not a prerequisite for LE in FD, since LE can be detected in the absence of measurable cardiac functional impairments.Trial registration numberClinicalTrials.gov Identifier (NCT03362164).

BackgroundTwo recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes.MethodsIn this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex.Results387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (β: −18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar.ConclusionsTreatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta.

Background: Fabry Disease (FD) is an X-linked hereditary lysosomal storage disorder which leads to a multisystemic intralysosomal accumulation of globotriaosylceramid (Gb3). Besides prominent renal and cardiac organ involvement, patients commonly complain about vestibulocochlear symptoms like high-frequency hearing loss, tinnitus and vertigo. However, comprehensive data especially on vertigo remain scarce. The aim of this study was to examine the prevalence and characteristics of vertigo and hearing loss in patients with FD, depending on renal and cardiac parameters and get hints about the site and the pattern of the lesions. Methods: Single-center study with 57 FD patients. Every patient underwent an oto-rhino-laryngological examination as well as videonystagmography and vestibular evoked myogenic potentials (VEMPs) and audiological measurements using pure tone audiometry and auditory brainstem response audiometry (ABR). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results: More than one out of three patients (35.1%) complained about hearing loss, 54.4% about vertigo and 28. 1% about both symptom. In 74% a sensorineural hearing loss of at least 25 dB was found, ABR could exclude any retrocochlear lesion. Caloric testing showed abnormal values in 71.9%, VEMPs were pathological in 68%. A correlation between the side or the shape of hearing loss and pathological vestibular testing could not be revealed. Conclusions: Hearing loss and vertigo show a high prevalence in FD. While hearing loss seems due to a cochlear lesion, peripheral vestibular as well as central nervous pathologies cause vertigo. Thus, both the site of lesion and the pathophysiological patterns seem to differ.

Lucerastat is a glucosylceramide synthase inhibitor aimed at reducing production of glycosphingolipids (GSLs), including those accumulating in Fabry disease. The safety, tolerability, pharmacodynamics, and pharmacokinetics of oral lucerastat were evaluated in an exploratory study in patients with Fabry disease. In this single‐center, open‐label, randomized study, 10 patients received lucerastat 1,000 mg b.i.d. for 12 weeks in addition to enzyme replacement therapy (ERT; the lucerastat group). Four patients with Fabry disease received ERT only. Eight patients reported 17 adverse events (AEs) in the lucerastat group. No clinically relevant safety abnormalities were observed. The mean (SD) levels of the plasma GSLs, glucosylceramide, lactosylceramide, and globotriaosylceramide, were significantly decreased from baseline in the lucerastat group (‐49.0% (16.5%), ‐32.7% (13.0%), and ‐55.0% (10.4%), respectively). Lucerastat 1,000 mg b.i.d. was well tolerated in patients with Fabry disease over 12 weeks. A marked decrease in plasma GSLs was observed, suggesting clinical potential for lucerastat in patients with Fabry disease.

BACKGROUND:This study aimed to explore the value of cardiac biomarker [serum high sensitive troponin T (hs-TNT) and N-terminal pro-brain natriuretic peptide (NT-proBNP)] measurement in the differential diagnosis of infiltrative cardiomyopathy patients [Friedreich's ataxia (FA), Fabry disease (FD) and light-chain (AL) cardiac amyloidosis (CA)] with preserved left ventricular (LV) systolic function. METHODS:Between 2012 and 2014, all consecutive patients presenting at our center with infiltrative cardiomyopathy and concomitant symmetrical LV hypertrophy as well as preserved LV systolic function were included in this study. Serum hs-TNT and NT-proBNP, morphologic and functional features derived from echocardiography and cardiac magnetic resonance imaging (cMRI) examinations were compared among these patients. RESULTS:A total of 57 patients (FA 20, FD 23 and CA 14) were included. Hs-TNT and NT-proBNP levels were significantly higher in the CA group [median: hs-TNT 98 pg/mL, NT-proBNP 4,110 pg/mL] than in the FA group [hs-TNT 14 pg/mL, NT-proBNP 40 pg/mL] and FD group [hs-TNT 18 pg/mL, NT-proBNP 131 pg/mL, both P<0.001]. There was a negative correlation between NT-proBNP and estimated glomerular filtration rate (eGFR) in CA patients (r=-0.72, P=0.012). Both hs-TNT >60 pg/mL (sensitivity 0.79, specificity 0.93) and NT-proBNP >1,000 pg/mL (sensitivity 0.91, specificity 0.93) excellently differentiated CA from FA and FD. CONCLUSIONS:Increased hs-TNT and NT-proBNP levels are suggestive of CA diagnosis among patients with infiltrative cardiomyopathy and preserved LV ejection fraction.

To evaluate potential risk factors for stroke or transient ischemic attacks (TIA) and to test the feasibility and efficacy of a Fabry-specific stroke risk score in Fabry disease (FD) patients without atrial fibrillation (AF).

Abstract Single nucleotide polymorphisms (SNPs) in the alpha-galactosidase A gene region (GLA) have been discussed as potential cause of symptoms and organ manifestations similarly to those seen in Fabry disease (FD). However, due to scarce data, clinical implications remain limited. The aim of the present study was to investigate the clinical impact of -10C>T SNP in the GLA. Prospective single-center observational study to determine the natural history and outcome of FD. Subjects initially referred to the Fabry Center for Interdisciplinary Therapy Würzburg (FAZIT) for management of suspected FD (11 women, 2 men, mean age 42 ± 10 years) who were tested negative for coding GLA mutations but positive for the noncoding -10C>T SNP underwent comprehensive characterization for therapy recommendation. All subjects reported at least 1 neurological, but no cardiac or renal symptoms. In 7 patients, pain of unknown etiology was reported and 3 patients had a history of cryptogenic stroke. In all patients, &agr;-GAL activity was at a lower limit, ranging between 0.27 and 0.45 nmol/min per mg protein (reference: 0.4–1.0), while plasma Lyso-Gb3 levels remained normal (range 0.39 ± 0.33; reference: ⩽0.9 ng/mL). For both hemizygous subjects investigated, brain magnetic resonance imaging revealed unspecific white matter lesions. One of these subjects had suffered from severe early-onset stroke, the other showed mild hypertrophic cardiomyopathy. Presence of isolated heterozygous -10C >T SNP is not associated with clinically relevant symptoms or organ manifestations as seen in FD. Respective polymorphisms might, however, play a role in modifying disease severity in FD. Great care has to be taken in respective subjects suspected to suffer from nonclassical FD in order to prevent unnecessary Fabry-specific therapy.

Background Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system. Besides prominent renal and cardiac organ involvement, cochlear symptoms like high-frequency hearing loss and tinnitus are frequently found with yet no comprehensive data available in the literature. Objective To examine hearing loss in patients with FD depending on cardiac and renal function. Material and methods Single-center study with 68 FD patients enrolled between 2012 and 2016 at the Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery of the University of Würzburg. Every subject underwent an oto-rhino-laryngological examination as well as behavioral, electrophysiological and electroacoustical audiological testing. High-frequency thresholds were evaluated by using a modified PTA6 (0.5, 1, 2, 4, 6, 8) and HF-PTA (6, 8 kHz). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results Sensorineural hearing loss was detected in 58.8% of the cohort, which occurred typically in sudden episodes and affected especially high frequencies. Hearing loss is asymmetric, beginning unilaterally and affecting the contralateral ear later. Tinnitus was reported by 41.2%. Renal and cardiac impairment influenced the severity of hearing loss (p < 0.05). Conclusions High frequency hearing loss is a common problem in patients with FD. Although not life-threatening, it can seriously reduce quality of life and should be taken into account in diagnosis and therapy. Optimized extensive hearing assessment including higher frequency thresholds should be used.

The progressive cardiomyopathy in patients with Fabry disease is often accompanied by angina pectoris and elevated levels of high-sensitive troponin T (hs-TnT), potentially mimicking acute coronary syndrome. Here, we present to representative cases with focus on clinical, diagnostic and therapeutic settings. An overview on the cardiomyopathy associated with Fabry disease and its role as differential diagnosis of acute coronary syndrome is provided. Fabry cardiomyopathy might exhibit similar clinical and biochemical constellations as seen in acute coronary syndrome. Thus, Fabry cardiomyopathy should be considered a differential diagnosis in acute coronary syndrome, particularly in patients demonstrating left ventricular hypertrophy of unknown origin.

Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR <90 ml/min/1.73m2 to 4 at eGFR <30, compared to patients with an eGFR >90. In addition, men with classical disease and a baseline eGFR <60 ml/min/1.73m2 had a faster yearly decline (-2.0 ml/min/1.73m2) than those with a baseline eGFR of >60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension.

In 2009, the agalsidase beta shortage resulted in switching to agalsidase alfa treatment for many Fabry disease patients, offering the unique opportunity to compare the effects of the two drugs. Because single studies describing effects of switching on the disease course are limited and inconclusive, we performed a systematic review and meta-analysis of existing data.Relevant studies were identified in the PubMed, Cochrane, ISI Web, and SCOPUS databases from July 2009 to September 2015. The following parameters were analyzed: clinical events, changes in organ function or structure, disease-related symptoms, lyso-Gb3 plasma levels, and adverse effects.The nine studies (217 patients) included in our systematic review showed only marginal differences in most of the evaluated parameters. Seven of these studies were included in the meta-analysis (176 patients). The pooled incidence rate of major adverse events was reported for five studies (150 patients) and was equal to 0.04 events per person-year. No significant change was observed after the shift in glomerular filtration rate, whereas left ventricular mass index, left ventricular posterior wall dimension, and ejection fraction were significantly reduced over time. Our data showed that the switch to agalsidase alfa was well tolerated and associated with stable clinical conditions.Genet Med 19 3, 275–282.

Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95% confidence interval, 3.17 to 10.00; P <0.001; hazard ratio for women, 2.88, 95% confidence interval, 1.54 to 5.40; P <0.001). Furthermore, men with classical Fabry disease had lower eGFR, higher left ventricular mass, and higher plasma globotriaosylsphingosine concentrations than men with nonclassical Fabry disease or women with either phenotype ( P <0.001). In conclusion, before treatment with enzyme replacement therapy, men with classical Fabry disease had a history of more events than men with nonclassical disease or women with either phenotype; women with classical Fabry disease were more likely to develop complications than women with nonclassical disease. These data may support the development of new guidelines for the monitoring and treatment of Fabry disease and studies on the effects of intervention in subgroups of patients.