Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study.

BACKGROUND: Two 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. METHODS: In 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. RESULTS: 387 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 (ß: -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. CONCLUSIONS: Treatment 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.

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study.

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.

Echocardiographic Determinants of One-Year All-Cause Mortality in Patients With Chronic Heart Failure Complicated by Significant Functional Tricuspid Regurgitation.

BACKGROUND: Right ventricular (RV) dysfunction plays an important role in chronic heart failure (CHF). We evaluated the echocardiographic determinants of 1-year all-cause mortality in CHF patients with clinically relevant functional tricuspid regurgitation (TR). METHODS AND RESULTS: A total of 101 consecutive CHF patients (mean age 74 ± 10 years, 53% male) with moderate or severe functional TR were enrolled. Each patient underwent at least 2 echocardiography examinations in an interval of >6 months. Clinical follow-up was made after a median of 305 (interquartile range 164-365) days after the last echocardiography. The primary end point was all-cause mortality. Forty-two patients (42%) died during follow-up. Baseline right atrial (RA) area, TR volume increase and RV enlargement over time were significantly higher in nonsurvivors than survivors (all P < .05). Compared to baseline levels, systolic pulmonary artery pressure (sPAP) was significantly reduced in nonsurvivors during follow-up echocardiography (54 ± 19 vs 49 ± 21 mm Hg; P = .010), but significantly increased in survivors (48 ± 17 vs 54 ± 17 mm Hg; P = .001). Multivariable survival analysis suggested that baseline RA area ≥27 cm2 (hazard ratio [HR] 2.41, 95% confidence interval [CI] 1.21-4.80; P = .013), follow-up TR proximal isovelocity surface area regurgitant volume increase ≥15 mL (HR 2.27, 95% CI 1.20-4.31; P = .012), RV middle diameter increase ≥10 mm (HR 2.38, 95% CI 1.10-5.11; P = .027), and sPAP reduction ≥10 mm Hg (HR 3.04, 95% CI 1.51-6.13; P = .002) were determinants of 1-year all-cause mortality after the last echocardiography. Patients with 2 or 3 of these determinants were faced with significantly increased 1-year mortality (88% or 100%). CONCLUSIONS: Dynamic RV morphologic and functional changes during serial echocardiography are associated with significantly increased mortality risk in CHF patients with moderate or severe functional TR.

Case report of a 45-year old female Fabry disease patient carrying two alpha-galactosidase A gene mutation alleles.

BACKGROUND: X-chromosomal inheritance patterns and generally rare occurrence of Fabry disease (FD) account for mono-mutational hemizygous male and heterozygous female patients. Female mutation carriers are usually clinically much less severely affected, which has been explained by a suggested mosaicism in cell phenotype due to random allele shutdown. However, clinical evidence is scarce and potential additional effects in female gene carriers, which might account for specific clinical characteristics such as less severe chronic kidney disease, are yet unknown. CASE PRESENTATION: This article reports on a 45 year old female patient carrying the two alpha-galactosidase A gene mutations c.416A > G, p.N139S in exon 3 and c.708G > C, p.W236C in exon 5, but still showing only mild organ manifestations. CONCLUSION: This current case highlights the importance of careful clinical characterization in patients with Fabry disease, who may show additional rare constellations and, therefore, are in need of personalized medicine. The impact of potential additional protective effects exceeding the presence of a non-pathogenic GLA allele in female gene carriers requires further investigation.

A Skill Trainer for Balloon/Stent Exchange in Percutaneous Coronary Intervention-Concept and Evaluation.

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.

Contemporary therapeutics and new drug developments for treatment of Fabry disease: a narrative review.

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.

Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year.

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.

Lucerastat, an Iminosugar for Substrate Reduction Therapy: Tolerability, Pharmacodynamics, and Pharmacokinetics in Patients With Fabry Disease on Enzyme Replacement.

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.

Value of cardiac biomarker measurement in the differential diagnosis of infiltrative cardiomyopathy patients with preserved left ventricular systolic function.

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.

Association between Comorbidities and Progression of Transvalvular Pressure Gradients in Patients with Moderate and Severe Aortic Valve Stenosis.

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.

Characterization of vertigo and hearing loss in patients with Fabry disease.

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.

Association and diagnostic utility of diastolic dysfunction and myocardial fibrosis in patients with Fabry disease.

Objectives: Current 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%). Methods: 146 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. Results: LE 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. Conclusions: Echocardiography-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 number: ClinicalTrials.gov Identifier (NCT03362164).

Clinical impact of the alpha-galactosidase A gene single nucleotide polymorphism -10C>T: A single-center observational study.

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 ±â€Š10 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, α-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 ±â€Š0.33; 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.

Value of the CHA2DS2-VASc score and Fabry-specific score for predicting new-onset or recurrent stroke/TIA in Fabry disease patients without atrial fibrillation.

OBJECTIVES: 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). BACKGROUND: FD patients often experience cerebrovascular events (stroke/TIA) at young age. METHODS: 159 genetically confirmed FD patients without AF (aged 40 ± 14 years, 42.1% male) were included, and risk factors for stroke/TIA events were determined. All patients were followed up over a median period of 60 (quartiles 35-90) months. The pre-defined primary outcomes included new-onset or recurrent stroke/TIA and all-cause death. RESULTS: Prior stroke/TIA (HR 19.97, P < .001), angiokeratoma (HR 4.06, P = .010), elevated creatinine (HR 3.74, P = .011), significant left ventricular hypertrophy (HR 4.07, P = .017), and reduced global systolic strain (GLS, HR 5.19, P = .002) remained as independent risk predictors of new-onset or recurrent stroke/TIA in FD patients without AF. A Fabry-specific score was established based on above defined risk factors, proving somehow superior to the CHA2DS2-VASc score in predicting new-onset or recurrent stroke/TIA in this cohort (AUC 0.87 vs. 0.75, P = .199). CONCLUSIONS: Prior stroke/TIA, angiokeratoma, renal dysfunction, left ventricular hypertrophy, and global systolic dysfunction are independent risk factors for new-onset or recurrent stroke/TIA in FD patients without AF. It is feasible to predict new or recurrent cerebral events with the Fabry-specific score based on the above defined risk factors. Future studies are warranted to test if FD patients with high risk for new-onset or recurrent stroke/TIA, as defined by the Fabry-specific score (≥ 2 points), might benefit from antithrombotic therapy. Clinical trial registration HEAL-FABRY (evaluation of HEArt invoLvement in patients with FABRY disease, NCT03362164).

[The Fabry's Disease Cardiomyopathy as Differential Diagnosis of Acute Coronary Syndrome]. / Die Fabry-Kardiomyopathie als Differenzialdiagnose des akuten Koronarsyndroms.

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.

Cardiac and renal dysfunction is associated with progressive hearing loss in patients with Fabry disease.

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.

α-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease.

BACKGROUND: Hypertrophic cardiomyopathy is the most common type of cardiomyopathy, but many patients lack sarcomeric/myofilament mutations. We studied whether cardio-specific α-galactosidase A gene variants are misinterpreted as hypertrophic cardiomyopathy because of the lack of extracardiac organ involvement. METHODS AND RESULTS: All subjects who tested positive for the N215S genotype (n=26, 13 females, mean age 49±17 [range, 14-74] years) were characterized in this prospective monocentric longitudinal cohort study to determine genotype-specific clinical characteristics of the N215S (c.644A>G [p.Asn215Ser]) α-galactosidase A gene variant. All subjects were initially referred with suspicion of genetically determined hypertrophic cardiomyopathy. Cardiac hypertrophy (interventricular septum, 12±4 [7-23] mm; left ventricular posterior wall, 11±4 [7-21] mm; left ventricular mass, 86±41 [46-195] g/m2) was progressive, systolic function mainly preserved (cardiac index 2.8±0.6 [1.9-3.9] L/min per m2), and diastolic function mildly abnormal. Cardiac magnetic resonance imaging revealed replacement fibrosis in loco typico (18/26, 69%), particularly in subjects >50 years. Elderly subjects had advanced heart failure, and 6 (23%) were suggested for implantable cardioverter-defibrillator therapy. Leukocyte α-galactosidase A enzyme activity was mildly reduced in 19 subjects and lyso-globotriaosylceramide slightly elevated (median, 4.9; interquartile range, 1.3-9.1 ng/mL). Neurological and renal impairments (serum creatinine, 0.87±0.20; median, 0.80; interquartile range, 0.70-1.01 mg/dL; glomerular filtration rate, 102±23; median, 106; interquartile range, 84-113 mL/min) were discreet. Only 2 subjects developed clinically relevant proteinuria. CONCLUSIONS: α-Galactosidase A genotype N215S does not lead to the development of a classical Fabry phenotype but induces a specific cardiac variant of Fabry disease mimicking nonobstructive hypertrophic cardiomyopathy. The lack of prominent noncardiac impairment leads to a significant delay in diagnosis and Fabry-specific therapy.

Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors.

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.

Long Term Treatment with Enzyme Replacement Therapy in Patients with Fabry Disease.

Anderson-Fabry disease is a potentially life-threatening hereditary lysosomal storage disorder taking origin in over 1,000 known pathogenic mutations in the alpha-galactosidase A encoding gene. Over the past 15 years, intravenous replacement therapy of the deficient alpha agalsidase A enzyme has been well-established retarding the progression of a multisystemic disease and organ involvement. Despite this innovative treatment approach, premature deaths still do occur. The response to enzyme replacement therapy (ERT) varies considerably and appears to depend on gender, genotype (classic or later onset/non-classic), stage of disease or age and agalsidase inhibition by anti-agalsidase antibodies. Early ERT treatment at young age, a personalized approach, and adjunctive therapies for specific disease manifestations appear to impact on prognosis and are currently favored with the expectance of more effective intravenous and oral treatments in the short future.