Search

BackgroundA small but significant reduction in left ventricular (LV) mass after 18 months of migalastat treatment has been reported in Fabry disease (FD). This study aimed to assess the effect of migalastat on FD cardiac involvement, combining LV morphology and tissue characterisation by cardiac magnetic resonance (CMR) with cardiopulmonary exercise testing (CPET).MethodsSixteen treatment-naïve patients with FD (4 women, 46.4±16.2 years) with cardiac involvement (reduced T1 values on CMR and/or LV hypertrophy) underwent ECG, echocardiogram, troponin T and NT-proBNP (N-Terminal prohormone of Brain Natriuretic Peptide) assay, CMR with T1 mapping, and CPET before and after 18 months of migalastat.ResultsNo change in LV mass was detected at 18 months compared to baseline (95.2 g/m2(66.0–184.0) vs 99.0 g/m2(69.0–121.0), p=0.55). Overall, there was an increase in septal T1 of borderline significance (870.0 ms (848–882) vs 860.0 ms (833.0–875.0), p=0.056). Functional capacity showed an increase in oxygen consumption (VO2) at anaerobic threshold (15.50 mL/kg/min (13.70–21.50) vs 14.50 mL/kg/min (11.70–18.95), p=0.02), and a trend towards an increase in percent predicted peak VO2(72.0 (63.0–80.0) vs 69.0 (53.0–77.0), p=0.056) was observed. The subset of patients who showed an increase in T1 value and a reduction in LV mass (n=7, 1 female, age 40.5 (28.6–76.0)) was younger and at an earlier disease stage compared to the others, and also exhibited greater improvement in exercise tolerance.ConclusionIn treatment-naïve FD patients with cardiac involvement, 18-month treatment with migalastat stabilised LV mass and was associated with a trend towards an improvement in exercise tolerance. A tendency to T1 increase was detected by CMR. The subset of patients who had significant benefits from the treatment showed an earlier cardiac disease compared to the others.Trial registration numberNCT03838237.

Objectives To elaborate an ECG-based nomogram estimating the probability to detect cardiac involvement by cardiac magnetic resonance (CMR) in Fabry Disease (FD). Methods 119 FD patients and 26 healthy controls underwent ECG and CMR. Test (n = 88, 60%) and validation cohorts (n = 57, 40%) were randomly derived. Cardiac involvement was defined as the presence of low myocardial T1 value, a CMR-surrogate of myocardial glycosphingolipid storage. ECG changes associated with low T1 value were identified in the test cohort, included in the nomogram and then tested in the validation cohort. Results Sokolow-Lyon index (AUC = 0.769), ratio between P-wave and PR-segment durations (Pwave/PRsegment) (AUC = 0.778), QRS duration (AUC = 0.703), QT (AUC = 0.769) duration were independently associated with the presence of low T1 on CMR at multivariate analysis. An ECG-based nomogram including these four parameters was accurate in identifying patients with CMR evidence of glycosphingolipid storage (c-index of the derived-nomogram = 0.90 in the test group; 0.81 in the validation group). Conclusion We propose a practical ECG-based nomogram accurately estimating the probability to detect low T1 values by CMR in FD patients. The application of this tool in clinical practice could improve early detection of FD cardiac involvement.

Objectives The search in the urinary sediment (U-sed) of fat particles with peculiar morphology is a simple and inexpensive tool for the diagnosis of Fabry disease (FD) nephropathy. In this study we investigated the morphology of a high number of such fat particles with the aim to obtain a morphological classification to be used for their identification. Methods Study of the morphology of fat particles in the U-sed of a cohort of FD patients using: bright field plus phase contrast microscopy (BF + PC), polarized light microscopy (POL), and transmission electron microscopy (TEM). Comparison of these results with those obtained for the fat particles seen in the U-sed of a control group (CG) of patients with non-FD glomerulopathies. Results FD: 18 U-sed from six patients (three samples/patient) were prospectively investigated and 506 fat particles identified. With BF + PC, these were classified in eight morphological categories (seven of which were confirmed by TEM), and with POL in 10 others. CG: eight U-sed from eight patients were investigated and 281 fat particles identified. These fell into four BF + PC morphological categories and into eight POL categories. While some categories were significantly more frequent in FD others were more frequent in the CG. Conclusions Our study demonstrates that 1. The morphology of fat particles found in the U-sed of FD patients is much wider and complex than that described so far 2. Several significant differences exist in the morphology of such fat particles between FD and CG patients.

Introduction Published data on hypertension incidence and management in Anderson–Fabry disease are scant and the contribution of elevated blood pressure to organ damage is not well recognized. Aim Therefore, we have assessed blood pressure values and their possible correlations with clinical findings in a well described cohort of Fabry patients. Methods Between January 2015 and May 2019, all adult Fabry patients (n = 24 females, n = 8 males) referred to our institute were prospectively enrolled. During the first examination patient’s genotype and clinical characteristics were recorded. Blood pressure data were obtained by standard observed office measurements followed, within 6 months, by ambulatory blood pressure monitoring and home self-recordings. Organ involvement, including kidneys, heart and brain, was monitored over time. Consequently, patients were defined as clinically stable or progressive through the Fabry Stabilization Index. Results The standard office measurements have diagnosed hypertension in three (9.37%) patients, but the ambulatory monitoring showed elevated blood pressure in six (18.75%) patients, revealing three cases of masked hypertension. All the hypertensive patients were females and, compared with normotensive subjects, they presented a lower glomerular filtration rate (p < 0.05) and a more advanced cardiac hypertrophy (p < 0.05). Four (66.7%) of them were diagnosed with a progressive form of the disease through the Fabry Stabilization Index while the majority of the normotensive group (84.6%, n = 19) was stable over time. No correlation was found between the prevalence of hypertension and the type of mutations causing Fabry disease. Conclusion Hypertension can be found in a restricted portion of clinically stable Fabry patients. In contrast, patients presenting with a progressive organ involvement, particularly renal impairment, have a major risk of developing uncontrolled blood pressure, and should be followed carefully. Moreover, the ambulatory blood pressure monitoring proved to be useful to reveal masked hypertension, which can contribute to the progressive worsening of the organ damage. Therefore, a proper diagnosis and therapy of hypertension may improve the outcome of Fabry patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40292-021-00450-0.

We present the case of a 76-year-old man with late-onset Fabry disease caused by the p.N215S missense mutation, with Fabry cardiomyopathy and nephropathy. In this case, the diagnosis of Fabry disease was incidental and followed minimal change disease (MCD) onset, with nephrotic syndrome and acute kidney injury requiring renal replacement therapy. Fabry nephropathy associated with the p.N215S mutation is becoming increasingly recognized among older patients. The importance of electron microscopy is herein highlighted and histological features common to Fabry nephropathy and MCD are discussed, along with the challenges associated with the diagnosis and clinical management.

Fabry disease is an X-linked inherited lysosomal disorder that causes accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and reduced life expectancy. It can affect both males and females and can be classified into classic or later-onset phenotypes. In classic Fabry disease, α-galactosidase A (α-Gal A) activity is absent or severely reduced and disease manifestations have an early onset that can affect multiple organs. In contrast, in later-onset Fabry disease, patients have residual α-Gal A activity and clinical features are primarily confined to the heart. Individualized therapeutic goals in Fabry disease are required due to varying phenotypes and patient characteristics, and the wide spectrum of disease severity. An international group of expert physicians convened to discuss and develop practical clinical recommendations for disease- and organ-specific therapeutic goals in Fabry disease, based on expert consensus and evidence identified through a structured literature review. Biomarkers reflecting involvement of various organs in adult patients with classic Fabry disease are discussed and consensus recommendations for disease- and organ-specific therapeutic goals are provided. These consensus recommendations should support the establishment of individualized approaches to the management of patients with classic Fabry disease by considering identification, diagnosis, and initiation of disease-specific therapies before significant organ involvement, as well as routine monitoring, to reduce morbidity, optimize patient care, and improve patient health-related quality of life.

Background Fabry disease (FD) is a rare x-linked lysosomal storage disease characterized by accumulation of glicosphingolipids in several organs, including the heart. Cardiac involvement manifests as left ventricular (LV) hypertrophy, often complicated by myocardial fibrosis. The impact of disease on functional capacity is not well defined, as well as the potential gender-related differences. Aim To evaluate the functional capacity in a cohort of FD patients with different degree of cardiac involvement. Methods Seventy-two patients were prospectively enrolled from March 2015 to December 2019. Patients underwent cardiac magnetic resonance (CMR) and cardiopulmonary exercise test (CPET) with cycle ergometer. In addition to standard CPET parameters, Chronotropic Index (CI) was calculated as (HR max − HR rest) / (HR max predicted − HR rest), adjusting with HR max predicted calculated as 119 + (HR rest/2) − (age/2) in case of beta-blockers treatment. Results CMR showed left ventricle (LV) hypertrophy (LV mass greater than normal reference value) in 36.1% of patients, LGE and reduced T1 values were detected in 30.6% and 59.7% of subjects respectively. Twenty-eight patients were males (39%), the median age was 40 (28–54) [median (25th–75th)] years and only 11 (15%) subjects were on beta-blockers. All subjects performed a maximal test [RQ max = 1.21 (1.14–1.26)] using a ramp protocol of 15 (15–20) Watt. The absolute peakVO2 was 18.2 (15.75–24.08) mL/min/kg, whilst the percentage of predicted peakVO2 was 67.7 (57.3–76.6)%. The chronotropic response of the overall population was characterized by reduced peak heart rate (HRmax) [80.3 (73.8–87.6)% of predicted], and diminished chronotropic index (CI) [0.67 (0.55–0.77) normal value: 0.80], but preserved heart rate reserve (HRR) [21 (12–28) bpm]. Ventilatory efficiency was preserved [VE/VCO2 = 25.70 (23.18–28.00)]. At gender analysis, men showed higher absolute peakVO2 [men vs females: 19.95 (17.20–28.28) vs 17.80 (15.50–21.28) mL/min/kg, p=0.02] but lower percentage of predicted [64.24 (52.58–70.61) vs 70.75 (59.05–78.02)%, p Conclusions This large cohort of FD patients with different degree of cardiac involvement showed a significantly impaired functional capacity, mainly characterized by relevant chronotropic incompetence (independent from the use of beta-blockers), consistent with systemic autonomic dysfunction. The degree of chronotropic incompetence was similar between the genders, but females showed higher predicted peakVO2 despite a lower peak O2 pulse. Funding Acknowledgement Type of funding sources: None.

Background Fabry Disease (FD) is a rare X-linked lysosomal storage disorder. Since 2016, pharmacological chaperone Migalastat has been approved for treatment of FD patients with amenable mutations to stabilize defective forms of the enzyme α-galactosidase A. A small but significant reduction in left ventricular (LV) mass after 18 months of Migalastat treatment has been previously reported by echocardiography. However, an integrated assessment of the effect of Migalastat on cardiac involvement, combining LV morphology and tissue composition by CMR with exercise capacity by cardiopulmonary test, is lacking. Purpose To determine the effects of 18 month treatment with Migalastat on LV mass, native T1 value and functional capacity in naïve patients with genetically confirmed FD cardiomyopathy. Methods Sixteen treatment naïve FD patients (4 females, mean age 46.4±16.2) with amenable mutations and signs of cardiac involvement underwent CMR with T1 mapping and cardio-pulmonary testing before and after 18 months of migalastat therapy as a part of MAIORA Study. Cardiac involvement was defined as presence of reduced native T1 values at CMR (a surrogate of myocardial glycosphingolipid storage) and/or LV hypertrophy (LVH). Nine patients (56%, 2 females, mean age 56.4±12.7 years) had LVH at baseline. Results Migalastat treatment was well tolerated in all patients, with no serious adverse event. No change in LV mass was detected at 18 months compared to baseline (95.2 (66.0–184.0) vs 103.0 (71.0–182.0) g/m2; p=0.5516). The same result was found after stratifying patients according to presence/absence of Late Gadolinium Enhancement (LGE) (LGE+ n=8, 2 females, mean age 56.2±13.1 years). There was a trend towards an increased native septal T1 value (870.0 (848–882) vs 860.0 (833.0–875.0) ms at baseline; p 0.056) with unchanged extracellular volume (ECV) (0.26 (0.23–0.028) vs 0.26 (0.22–0.29) at baseline; p 0.276) in the overall cohort. An improvement in functional capacity with a trend towards an increase in percent-predicted peak VO2 (72.0 (61.25–80.75) vs 67.0 (45.2–79.2) at baseline; p 0.056) and a significant increase in VO2 at anaerobic threshold (14.8 (12.6–20.0) vs 13.10 (6.8–18.6) ml/kg/min at baseline; p 0.004) was reported in the total population. Conclusion In treatment naïve FD patients with amenable mutations and signs of early or overt cardiac involvement, 18-month treatment with Migalastat stabilized LV mass both in patients with and without LGE and was associated with an improvement in exercise tolerance. The trend towards an increase in T1 value associated with unchanged ECV suggests partial clearance of cardiomyocyte glycoshingolipid storage. These real-world data are consistent with a beneficial impact of migalastat on the progression of cardiac involvement in FD. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amicus Therapeutics

Background The current study evaluates the application of histology and in situ proteomics (MALDI-MSI) in Fabry nephropathy (FN), showing investigative and classification role for this coupled approach. Methods A retrospective series of 14 formalin fixed paraffin embedded (FFPE) renal biopsies with diagnosis of FN and 1 biopsy from a patient bearing a galactosidase-alpha (GLA) genetic variant of unknown significance (GVUS, c.376A>G) have been classified for clinical characteristics. Groups were compared for histological differences (following the ISGFN scoring system). Moreover, renal biopsies from these cases have been analyzed with MALDI-MSI as previously described to find proteomic signatures among different mutations and phenotypes. Results Comparison of clinical features revealed lower mean 24 h proteinuria in females (225 mg/24 h) than in males (1477.5 mg/24 h, p = 0.006). As for clinical characteristics, females significantly differed from males only for lower arterial sclerosis, with a mean value of 0.82 vs. 1.05 (p = 0.001). Proteomic analysis demonstrated specific signatures in different subgroups of FN patients. Moreover, MALDI correctly classified cases with undetermined mutation or GVUS. Conclusions The present study demonstrated the feasible application of MALDI-MSI in the analysis of FN FFPE renal biopsies, allowing the detection of putative signatures for phenotypic distinction and demonstrating genetic classification capabilities.

Funding Acknowledgements Type of funding sources: None. Background Left ventricular (LV) diastolic dysfunction (DD) is a hallmark of hypertrophic cardiomyopathy (HCM) and its phenocopies, such as Fabry disease (FD). Together with left atrial (LA) size, LA function is emerging as a sensitive marker of the adaptive changes to backward transmission of LV cardiac filling pressure, thus implementing DD assessment. Additionally, both HCM and FD are characterized by a primitive atrial myopathy, but LA morpho-functional changes in HCM and FD have never been directly compared. More recently, LA strain by Cardiovascular Magnetic Resonance Feature Tracking (CMR-FT) has been demonstrated to be a feasible and reproducible tool to explore LA function. Purpose To compare LA morpho-functional changes in HCM and FD and to explore their correlation with tissue alterations. Methods 15 HCM and 15 sex-, age- and LV mass index-matched FD patients underwent CMR (Magnetom Aera 1.5T, Siemens) and Doppler Echocardiography for LV diastolic function assessment (E/e’ and DD grading from 0 to 3). LA phasic function was evaluated by CMR-FT strain (Qstrain Medis). The software output included passive (εe, conduit function), active (εa, booster pump function) and total strain (εs, reservoir function), along with LA volumes and ejection fraction (EF). Late gadolinium enhancement (LGE) was quantified as a percentage of LV mass using the standard deviations (SDs) method (≥ 5 SDs). Interstitial fibrosis was assessed by extracellular volume (ECV) quantification in remote myocardium. All patients were in sinus rhythm. Results In the HCM group, the proportion of patients with DD grade 2-3 was only slightly higher than in FD (p 0.26). Accordingly, no significant difference was found in E/e’ value (p 0.78). Compared to FD, HCM patients showed more severe LA morpho-functional changes, including larger LA end-systolic volume (ESV) (113 ± 35 vs 84 ± 23 ml), lower LA EF (37 ± 7 vs 44 ± 9 %) and a greater reduction of εs (-20 ± 5 vs -25 ± 6 %) and εa (-10 ± 4 vs -15 ± 4 %) (all p < 0.05). LV size and function and the burden of fibrosis (LGE quantification and ECV) were comparable between the two groups. Interestingly, in HCM population, unlike in FD, LA morpho-functional measurements significantly correlated with tissue characterization parameters (LA ESV with LGE, r 0.56, p 0.03; εs and εa with ECV, r -0.51, p 0.05 and r -0.59, p 0.02, respectively). Conclusions LA morpho-functional alterations are much more severe in HCM compared to FD with similar degree of LV hypertrophy. A more severe atrial myopathy or different mechanisms of atrial damage in the two cardiomyopathies may explain these findings. LA CMR-FT analysis may represent a sensitive tool to discriminate between HCM and FD, although larger studies are needed to confirm this finding and the possible correlation with the occurrence of atrial arrhythmias and thromboembolic risk.

Objectives Fabry disease (FD) is an X-linked lysosomal storage disorder, resulting from a deficiency of the enzyme α-galactosidase A, responsible for breaking down glycolipids such as globotriaosylceramide and its deacylated derivative, globotriaosylsphingosine (LysoGb3). Here, we compare the levels of LysoGb3 in dried blood spots (DBS) and plasma in patients with classic and late-onset phenotypes. Methods LysoGb3 measurements were performed in 104 FD patients, 39 males and 65 females. Venous blood was collected. A portion was spotted onto filter paper and another portion separated to obtain plasma. The LysoGb3 concentrations in DBS and plasma were determined by highly sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Agreement between different matrices was assessed using linear regression and Bland Altman analysis. Results The method on DBS was validated by evaluating its precision, accuracy, matrix effect, recovery, and stability. The analytical performances were verified by comparison of a total of 104 paired DBS and plasma samples from as many FD patients (representing 46 GLA variants). There was a strong correlation between plasma and the corresponding DBS LysoGb3 concentrations, with few exceptions. Discrepancies were observed in anemic patients with typically low hematocrit levels compared to the normal range. Conclusions The method proved to be efficient for the rapid analysis of LysoGb3. DBS provides a convenient, sensitive, and reproducible method for measuring LysoGb3 levels for diagnosis, initial phenotypic assignment, and therapeutic monitoring in patients with FD.

Nephropathy represents a major complication of Fabry Disease and its accurate characterization is of paramount importance in predicting the disease progression and assessing the therapeutic responses. The diagnostic process still relies on performing renal biopsy, nevertheless many efforts have been made to discover early reliable biomarkers allowing us to avoid invasive procedures. In this field, proteomics offers a sensitive and fast method leading to an accurate detection of specific pathological proteins and the discovery of diagnostic and prognostic biomarkers that reflect disease progression and facilitate the evaluation of therapeutic responses. Here, we report a review of selected literature focusing on the investigation of several proteomic techniques highlighting their advantages, limitations and future perspectives in their application in the routine study of Fabry Nephropathy.

Background Cardiac Magnetic Resonance (CMR) allows to detect progressive stages of cardiac involvement in Fabry Disease (FD). A systematic description of electrocardiographic (ECG) alterations occurring in FD is currently missing. Purpose To explore ECG changes in progressive stages of FD cardiomyopathy. Methods 71 FD patients and 17 healthy controls underwent CMR with T1 mapping and 12-lead ECG. ECG analysis included the duration of the P-wave and the interval between the end of P-wave and the beginning of QRS (PendQ). FD patients in the test cohort were divided into 3 groups with increasing severity of cardiac involvement: A) normal T1, no LVH; B) low T1, no LVH; C) low T1, LVH. Results An increase of Pwave/PendQ ratio was observed in Group A compared to Controls (1.08 vs. 0.75, p Conclusion FD is characterized by progressive ECG changes. The identification of ECG parameters able to predict a lowering of myocardial T1 values on CMR may promote early detection of cardiac involvement, helping to target the therapeutic approach. Progressive ECG and CMR changes in FD Funding Acknowledgement Type of funding source: Other. Main funding source(s): This study was partially supported by Ricerca Corrente funding from the Italian Ministry of Health to IRCCS Policlinico San Donato.

Background and Aims Anderson-Fabry disease (AFD) is a rare X-linked sphingolipid disorder caused by deficient activity of the enzyme α-galactosidase A leading to a progressive lysosomal accumulation of globotriaosylceramide and a consequent organ failure. Data on blood pressure (BP) values in AFD patients are scanty, however those available have revealed a significant prevalence of high blood pressure, especially in case of moderate to severe kidney impairment, becoming more prevalent with the progression of the renal disease. High blood pressure and hypertension major risk factors prevalence were analysed among a single Fabry cohort. Method Between January 2015 and May 2019, 32 AFD patients, 24 (75%) female and 8 (25%) male, referred to the Fabry Disease Unit, Nephrology Division of San Gerardo Hospital (Monza, Italy), were enrolled. All patients were Caucasian with an average age of 50±12.2 years old. Data regarding hypertension were obtained by 24h ambulatory blood pressure monitoring (ABPM), home self-monitoring, and repeated ambulatory measurements (Table 1). Patients were defined hypertensive according to 2018 ESC/ESH Guidelines. The severity and the stability of AFD were assessed in each patient with the Fabry Stabilization Index (FASTEX). Major risk factors for hypertension were also evaluated (Table 2). Results The 24h ABPM revealed uncontrolled high blood pressure in 6 (18.7%) patients with consensual home and office BP alterations. All patients were female with an average age of 58±9.9 years old. They had mostly a sedentary life-style, half of them had a diagnosis of dyslipidaemia and one was obese (BMI > 30). In the normotensive group, half of the patients were sedentary, less than a half of them was affected by dyslipidaemia and the average BMI was between the normal ranges. Other known risk factors for hypertension were scanty represented between the two groups. No one had history of transient ischemic attack or stroke. In the normotensive group the majority of patients had a normal or near-normal renal function, while in the hypertensive group one-third showed mild proteinuria and renal impairment with a moderate reduction in glomerular filtration rate. The FASTEX index showed that 84.6% of the normotensive group were stable, while 66.6% of the hypertensive group were not. In 9 (34.6%) patients of the normotensive group ACE-inhibitors/angiotensin-receptor blockers were previously introduced for the treatment of proteinuria in normal blood pressure values, while 2 (33.3%) patients of the hypertensive group received antihypertensive drugs. Conclusion In this observational study, the majority of AFD patients were normotensive. The prevalence of hypertensive patients was lower than 20%. Overall patients had a low prevalence of well-known risk factors associated with the development of hypertension. The link between AFD disease and the development of hypertension has not been fully studied yet. Hypertension in AFD patients might be due to Fabry associated vascular or renal disease or because of an associated essential hypertension. Arterial blood pressure seems to be relatively well controlled among AFD patients presenting with a low prevalence of risk factors for hypertension and a mild and stable organ involvement. In contrast, unstable patients with a high prevalence of well-known hypertension risk factors, particularly renal impairment, should be followed carefully, because they have a major risk of developing uncontrolled blood pressure. Further prospective studies with a larger sample size are needed to better investigate the pathophysiology of hypertension in AFD patients.

Aims Fabry cardiomyopathy is characterized by glycosphingolipid storage and increased myocardial trabeculation has also been demonstrated. This study aimed to explore by cardiac magnetic resonance whether myocardial trabecular complexity, quantified by endocardial border fractal analysis, tracks phenotype evolution in Fabry cardiomyopathy. Methods and results Study population included 20 healthy controls (12 males, age 32±9) and 45 Fabry patients divided into three groups: 15 left ventricular hypertrophy (LVH)-negative patients with normal T1 (5 males, age 28±13; Group 1); 15 LVH-negative patients with low T1 (9 males, age 33±9.6; Group 2); 15 LVH-positive patients (11 males, age 53.5±9.6; Group 3). Trabecular fractal dimensions (Dfs) (total, basal, mid-ventricular, and apical) were evaluated on cine images. Total Df was higher in all Fabry groups compared to controls, gradually increasing from controls to Group 3 (1.27±0.02 controls vs. 1.29±0.02 Group 1 vs. 1.30±0.02 Group 2 vs. 1.34±0.02 Group 3; P Conclusion Fabry cardiomyopathy is characterized by a progressive increase in Df of endocardial trabeculae together with shortening of T1 values. Myocardial trabeculation is increased before the presence of detectable sphingolipid storage, thus representing an early sign of cardiac involvement.

Background: In prehypertrophic Fabry disease, low myocardial T1 values, reflecting sphingolipid storage, are associated with early structural and ECG changes. The correlations between T1 values and functional parameters have not been explored. Furthermore, the potential prognostic role of T1 in predicting disease worsening is still unknown. Methods: ECG, 2D echocardiography, cardiopulmonary test, and cardiac magnetic resonance were performed in 44 Fabry patients without left ventricular hypertrophy (35.7±14.5 years, 68.2% females). After a 12-month follow-up, clinical stability was evaluated using Fabry Stabilization Index. Results: At baseline, T1 values showed a negative correlation with left ventricular mass ( r =−0.79; P r =−0.79; P r =−0.54; P r =−0.49; P r =−0.61; P 20%) at follow-up. Higher left ventricular wall thickness (odds ratio, 2.61; CI, 1.04–6.57; P =0.04), left atrial volume (odds ratio, 1.24; CI, 1.02–1.51; P =0.03), and lower T1 values (odds ratio, 0.98; CI, 0.96–0.99; P =0.03) at baseline were independently associated with clinical worsening at follow-up. Conclusions: In prehypertrophic Fabry disease, low T1 values correlate with early electrocardiographic, morphological cardiac changes, and worsening of global disease severity but are not associated with functional abnormalities. The presence of low T1 values is a risk factor for disease worsening, thus representing a potential new tool in prognostic stratification and therapeutic approach.

Lysosomal storage diseases (LSD) include a wide range of different disorders with variable degrees of respiratory system involvement. The purpose of this narrative review is to treat the different types of respiratory manifestations in LSD, with particular attention being paid to the main molecular pathways known so far to be involved in the pathogenesis of the disease. A literature search was conducted using the Medline/PubMed and EMBASE databases to identify studies, from 1968 through to November 2018, that investigated the respiratory manifestations and molecular pathways affected in LSD. Pulmonary involvement includes interstitial lung disease in Gaucher’s disease and Niemann-Pick disease, obstructive airway disease in Fabry disease and ventilatory disorders with chronic respiratory failure in Pompe disease due to diaphragmatic and abdominal wall muscle weakness. In mucopolysaccharidosis and mucolipidoses, respiratory symptoms usually manifest early in life and are secondary to anatomical malformations, particularly of the trachea and chest wall, and to accumulation of glycosaminoglycans in the upper and lower airways, causing, for example, obstructive sleep apnea syndrome. Although the molecular pathways involved vary, ranging from lipid to glycogen and glycosaminoglycans accumulation, some clinical manifestations and therapeutic approaches are common among diseases, suggesting that lysosomal storage and subsequent cellular toxicity are the common endpoints.

Enzyme Replacement Therapy for Fabry Disease Anderson-Fabry disease (FD) is a X-linked lysosomal storage disorder, which involves glycosphingolipids metabolism. Specific treatment for FD has been available in the last two decades, after the development and commercialization of recombinant human alfa-galactosidase A. Since then enzyme replacement therapy (ERT) has changed the natural history of the disease. Two different enzymatic formulations are available: agalsidase alfa and agalsidase beta at different dosages. The safety and efficacy profiles are similar. ERT induces Gb3 deposits reduction in renal and cardiac biopsies, improves quality of life, reduces pain and GI symptoms, decreases left ventricular mass and slows down renal function decline. In case of organ involvement, clinical evidence confirms the need to treat all patients with enzyme therapy, both male and female. In all other clinical settings, the decision to start ERT is controversial, because of the extremely variable clinical manifestations of FD. However, data suggest a greater response to ERT if started as early as possible in any patients. Timely treatment appears to be effective in stabilizing and possibly delaying FD progression. ERT infusion reactions due to allergic hypersensitivity or IgG antibody development could occur but can be easily managed. In-hospital and at home infusions are possible. The wide genetic and phenotypic heterogeneity observed in all FD patients requires a tailored approach to treatment options. Patients should be referred to an expert multidisciplinary team for the long term management of this challenging disease.

Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme &alpha, galactosidase A (&alpha, Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the &alpha, Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. &alpha, Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, &alpha, Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.

Author(s): Germain, Dominique P; Brand, Eva; Burlina, Alessandro; Cecchi, Franco; Garman, Scott C; Kempf, Judy; Laney, Dawn A; Linhart, Ales; Marodi, Laszlo; Nicholls, Kathy; Ortiz, Alberto; Pieruzzi, Federico; Shankar, Suma P; Waldek, Stephen; Wanner, Christoph; Jovanovic, Ana | Abstract: BackgroundThe p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease.MethodsTo expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events.ResultsIn p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%).Conclusionp.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.

Background Fabry's disease (FD) is a rare, multi-organ lysosomal disease, caused by the deficiency of the enzyme α-galactosidase A, and is difficult to diagnose. Although parapelvic cysts (PC) were previously associated with FD, their prevalence and significance are unclear. Methods The present study aimed to: (i) evaluate, by renal ultrasound, the real prevalence of PC and of their determinants in a multicentre, nationwide cohort of FD patients (n = 173, Study 1) and (ii) ascertain whether a greater accuracy of PC detection improved their identification, in FD patients from a single centre (n = 67, Study 2). In both studies, for each FD patient, an age- and renal function-matched subject was selected for comparison (1:1). Results In Study 1, PC were detected in 28.9% of FD subjects and in only 1.1% of control subjects (P

PURPOSE: Multiple sclerosis (MS) has been proposed as a possible differential diagnosis for Fabry disease (FD). The aim of this work was to evaluate the involvement of corpus callosum (CC) on MR images and its possible role as a radiological sign to differentiate between FD and MS. METHODS: In this multicentric study, we retrospectively evaluated the presence of white matter lesions (WMLs) on the FLAIR images of 104 patients with FD and 117 patients with MS. The incidence of CC-WML was assessed in the two groups and also in a subgroup of 37 FD patients showing neurological symptoms. RESULTS: WMLs were detected in 50 of 104 FD patients (48.1%) and in all MS patients. However, a lesion in the CC was detected in only 3 FD patients (2.9%) and in 106 MS patients (90.6%). In the FD subgroup with neurological symptoms, WMLs were present in 26 of 37 patients (70.3%), with two subjects (5.4%) showing a definite callosal lesion. CONCLUSION: FD patients have a very low incidence of CC involvement on conventional MR images compared to MS, independently from the clinical presentation and the overall degree of WM involvement. Evaluating the presence of CC lesions on brain MR scans can be used as a radiological sign for a differential diagnosis between MS and FD, rapidly addressing the physician toward a correct diagnosis and subsequent treatment options.

BACKGROUND AND PURPOSE: The pulvinar sign refers to exclusive T1WI hyperintensity of the lateral pulvinar. Long considered a common sign of Fabry disease, the pulvinar sign has been reported in many pathologic conditions. The exact incidence of the pulvinar sign has never been tested in representative cohorts of patients with Fabry disease. The aim of this study was to assess the prevalence of the pulvinar sign in Fabry disease by analyzing T1WI in a large Fabry disease cohort, determining whether relaxometry changes could be detected in this region independent of the pulvinar sign positivity. MATERIALS AND METHODS: We retrospectively analyzed brain MR imaging of 133 patients with Fabry disease recruited through specialized care clinics. A subgroup of 26 patients underwent a scan including 2 FLASH sequences for relaxometry that were compared with MRI scans of 34 healthy controls. RESULTS: The pulvinar sign was detected in 4 of 133 patients with Fabry disease (3.0%). These 4 subjects were all adult men (4 of 53, 7.5% of the entire male population) with renal failure and under enzyme replacement therapy. When we tested for discrepancies between Fabry disease and healthy controls in quantitative susceptibility mapping and relaxometry maps, no significant difference emerged for any of the tested variables. CONCLUSIONS: The pulvinar sign has a significantly lower incidence in Fabry disease than previously described. This finding, coupled with a lack of significant differences in quantitative MR imaging, allows hypothesizing that selective involvement of the pulvinar is a rare neuroradiologic sign of Fabry disease.

Importance Diagnostic screening for Anderson-Fabry cardiomyopathy (AFC) is performed in the presence of specific clinical red flags in patients with hypertrophic cardiomyopathy (HCM) older than 25 years. However, left ventricular outflow tract obstruction (LVOTO) has been traditionally considered an exclusion criteria for AFC. Objective To examine a series of patients diagnosed with HCM and severe basal LVOTO undergoing myectomy in whom the diagnosis of AFC was suspected by the cardiac surgeon intraoperatively and confirmed by histological and genetic examinations. Design, Setting, and Participants This retrospective analysis of patients undergoing surgical septal reduction strategies was conducted in 3 European tertiary referral centers for HCM from July 2013 to December 2016. Patients with a clinical diagnosis of obstructive HCM referred for surgical management of LVOTO were observed for at least 18 months after the procedure (mean [SD] follow-up, 33 [14] months). Main Outcomes and Measures Etiology of patients with HCM who underwent surgical myectomy. Results From 2013, 235 consecutive patients with a clinical diagnosis of HCM underwent septal myectomy. The cardiac surgeon suspected a storage disease in 3 patients (1.3%) while inspecting their heart samples extracted from myectomy. The mean (SD) age at diagnosis for these 3 patients was 42 (4) years; all were male. None of the 3 patients presented with extracardiac features suggestive of AFC. All patients showed asymmetrical left ventricular hypertrophy, with maximal left ventricular thickness in the basal septum (19-31 mm), severe basal LVOTO (70-120 mm Hg), and left atrial dilatation (44-57 mm). Only 1 patient presented with late gadolinium enhancement on cardiovascular magnetic resonance at the right ventricle insertion site. The mean (SD) age at surgical procedure was 63 (5) years. On tactile sensation, the surgeon felt a spongy consistency of the surgical samples, different from the usual stony-elastic consistency typical of classic HCM, and this prompted histological examinations. Histology showed evidence of intracellular storage, and genetic analysis confirmed a GLA A gene mutation (p.Asn215Ser) in all 3 patients. Conclusions and Relevance Screening for AFC should be performed even in the absence of red flags in patients with HCM older than 25 years.

Background: The FAbry STabilization indEX (FASTEX) is an innovative index allowing the assessment of clinical stability over time in Fabry disease patients. This index was developed in a population of 28 male patients with the classical form of Fabry disease. Objectives: The aim of the study was to test the accuracy of the FASTEX in evaluating Fabry disease stability in 132 male and female patients with classical and non-classical Fabry disease from nine Italian centres and it also aimed to define the sensitivity and specificity of this new tool. In particular, we aimed to investigate the correlation between the FASTEX and clinical judgement in a large-scale cohort of the study population. Methods: Statistical methods applied to this investigation included the calculation of accuracy, specificity and sensitivity, receiver operating characteristic (ROC) curves and Cohen’s j index related to the FASTEX and clinical judgement. Results: The patient population included 58 males (43.9%). The mean age of the overall population was 46.3 6 15. 1 years (range 31.2–61.4). The median interval between the two multidisciplinary evaluations used for FASTEX calculation was 398 days. Since no gold standard method is available to define the overall clinical condition of Fabry patients over time, the results of the FASTEX were compared with clinical judgements given by the physicians involved in this study. In this way, the FASTEX classified 121 of 132 (92%) patients correctly. In particular, the FASTEX correctly identified 93% (41/44) of clinically ‘unstable’ and 91% (80/88) of clinically ‘stable’ patients. The area under the curve of the ROC related to the FASTEX index cut-off (20) was equal to 0.967, very close to its theoretical maximum (1), which means that it is an excellent test for classifying patients as ‘stable’ or ‘unstable’ compared with clinical judgement. In addition, the FASTEX cut-off >20 provides themost acceptable balance between sensitivity and specificity. The Cohen’s j index value obtained in our study was 0.82, showing a highly statistically significant P-value

Ba ckground : Lysosomal storage diseases (LSDs) are a heterogeneous group of rare chronic genetic conditions. The standard-of-care treatment for LSDs is hospital-based infusion of enzyme replacement therapy (ERT), however, over time this can be stressful and inconvenient. The Italian TuTor program, established in 2011 by Sanofi Genzyme, is a professional nursing service providing home-based ERT to patients with LSDs. Objectives: The current questionnaire-based study was conducted to investigate the level of patient satisfaction with the TuTor program and to shed light on disease perception. Methods: Patients were enrolled in the TuTor program from 2011 onwards. The first 100 patients enrolled were interviewed at baseline with follow-up interviews conducted at 6, 12 and 18 months. R esults: Overall, 52 patients were female; 46 had Gaucher’s disease, 46 had Fabry disease and 8 had mucopolysaccharidosis type 1. Patients took on average >2 hours to receive hospital-based ERT, plus time associated with the infusion; 2 out of 3 patients needed a caregiver to travel to the hospital. After receiving home-based ERT for 6 months, 37% of patients considered their quality of life ‘greatly improved’ (60% at 18 months). Overall, 99% to 100% of patients rated the home-based nursing service as ‘positive’ or ‘very positive’ and reported that they would recommend the service to other patients with their condition. Conclusions: For patients with LSDs eligible for ERT, a disease-specific home-based nursing service increased their perception of quality of life over a hospital-based service and was advantageous in terms of their time and expenditure.

На сегодняшний день предложены 2 системы количественной оценки бремени гликогеноза с дефицитом α-галактозидазы: индекс оценки степени тяжести Майнца (MSSI) и система балльной оценки тяжести болезни Фабри (DS3). Сделана попытка разработать динамическую математическую модель FASTEX (от англ. FAbry STabilization indEX, индекс стабилизации Фабри) для оценки клинической стабильности состояния. Мультидисциплинарная группа экспертов по болезни Фабри впервые предложила новую шкалу оценки тяжести заболевания по предварительной оценке (от англ. raw score, RS), основанную на 3 доменах (домен нервной системы (боль, цереброваскулярные события), почечный домен (протеинурия, скорость клубочковой фильтрации), сердечный домен (параметры эхокардиографии, электрокардиографии и степень сердечной недостаточности по классификации Нью-Йоркской кардиологической ассоциации)) с небольшим числом пунктов в каждом из них и оценкой клинической стабильности во времени. RS протестирована на 28 пациентах (15 мужчин и 13 женщин) с классической формой болезни Фабри. Получена сильная корреляционная связь предложенной оценки RS и взвешенной оценки (от англ. weighted score, WS) с DS3 и MSSI (r2 = 0,914; 0,949; 0,910 и 0,938 соответственно). Для уточнения RS была рассчитана WS, выражаемая в процентах. WS была основана на относительной клинической значимости каждого пункта в пределах домена, при этом группа экспертов согласовывала присвоение разного веса клинического вреда конкретной системе органов. Для определения динамики тяжести заболевания RS была повторно определена через 1 год. Группа экспертов согласилась с пороговым ограничением в 20 % от исходного уровня в качестве клинической WS для определения клинической стабильности. Модель FASTEX показала хорошую корреляцию с клинической оценкой и клиническим изменением на протяжении времени у всех пациентов.

Anderson-Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations of the GLA gene that encodes alpha-galactosidase A. It is characterized by a multisystemic involvement: the renal, neurological, heart, cochleovestibular and cutaneous systems are the most damaged. Morbidity and mortality of Anderson-Fabry disease depend on renal insufficiency, heart failure and nervous system involvement. Left ventricular hypertrophy is the most common cardiac manifestation followed by conduction system disease, valve dysfunction, and arrhythmias. Mild to moderate left ventricular hypertrophy may simulate a non-obstructive hypertrophic cardiomyopathy. Management of Anderson-Fabry disease starting from the diagnosis of cardiac involvement, the prevention of complications, the therapeutic aspects, up to appropriate clinical follow-up, requires a multidisciplinary approach. According to recent management guidelines, only few evidence-based data are available to guide the clinical and therapeutic approach to this rare disease. An Italian Board, composed by nephrologists, cardiologists, geneticists, pediatricians and neurologists has been established in order to approve by consensus a diagnostic and therapeutic management protocol. The authors report the results of this cardiologic management consensus.

Fabry disease is a complex pathology, requiring a multidisciplinar approach both in the diagnostic workout and in the management of therapy. Clinical criteria able to predict its morbidity have not yet been found. The wide variability of clinical signs and symptoms requires an individual approach based on the single patient, in order to achieve an optimal management. Enzyme replacement therapy (ERT) has been introduced in the clinical setting for over ten years, but its ability to change the course of the disease has not yet been clearly proved. Recently the hypothesis that ERT may be ineffective in patients with severe organ involvement has emerged. The clinical course of Fabry disease is usually slower in eterozygous women than emizygous men, but can be frequently associated to severe organ failure and premature death in both cases. In this review we discuss the histological aspects of Fabry nephropathy in relation to diagnosis, prognosis, therapy and its effectiveness.

The occurrence of renal cell carcinoma (RCC) in Fabry disease (FD) is a rare event. We report a deep ultrastructural study of RCC in a patient with a previous histological diagnosis of FD. In order to highlight analogies and differences between the two histological samples, we used the nephrectomy specimen as a ‘repeat biopsy’, making a dynamic analysis of the evolution of the disease-related kidney damage. Secondly, a comparative ultrastructural analysis between non-neoplastic tissue and cancer demonstrated for the first time the presence of zebra bodies in the tumor cells. Finally, a hypothetical speculation about the relationship between the lysosomal accumulation, the oxidative damage and the genesis of the tumor was performed. The link connected the accumulation of glycosphingolipid globotriaosylceramide, characteristic of FD, with the expression of CD74 and macrophage migration inhibitory factor that may play an important role in tumorigenesis regulated by the Von Hippel-Lindau/hypoxia-inducible factor 1α pathway.