Involvement In Fabry Disease Research Articles

Myocardial determinants of Functional limitation in advanced Fabry cardiomyopathy

Abstract Background Cardiac involvement in Fabry Disease (FD) manifests as left ventricular hypertrophy (LVH) often complicated by myocardial fibrosis and/or inflammation. Both LVH and advanced tissue alterations can be non-invasively detected and quantified by cardiac magnetic resonance (CMR) with Late Gadolinium Enhancement (LGE). Impairment in functional capacity has been previously reported in FD patients. However, there is limited data regarding the determinants of myocardial alterations in exercise intolerance in FD. Methods Among 190 consecutive FD patients referred for CMR, 41 simultaneously performed a cardiopulmonary exercise test (CPET) to evaluate functional capacity. All patients underwent an extensive CMR protocol to provide a detailed evaluation of cardiac morphology and function, including multiparametric tissue characterization. CPET parameters were compared between patients with advanced Fabry cardiomyopathy (Group B), characterized by hypertrophy, inflammation, and fibrosis, and FD patients without irreversible cardiac damage (Group A). Results Group B patients were older compared to Group A (57.0 years vs 33.5 years, p<0.001), had a greater LVH (LVMI: 117 g/sqm vs 76.5 g/sqm, p<0.001; LVMWT 17 vs 10 mm, p<0.001). LV ejection fraction was preserved in both groups but Group B patients had a lower peak VO2 value compared to group A (17.8 ml/kg/min vs 21.9 ml/kg/min, p=0.025), a lower (but not significant) percent-predicted peak VO2. A negative linear correlation was identified between the LGE extension (expressed as % of LV mass) and peak VO2 (r=-0.553, p=0.014). This correlation remained consistent even after excluding patients under chronic beta-blocker therapy (r=-0.678, p=0.045). No significant correlation between LV mass and peak VO2 was found. Conclusions in patients with FD, the presence of advanced tissue alterations detected by LGE is associated with reduced functional capacity (low peak VO2) despite preserved LV ejection fraction, with a significant negative correlation.

NT-proBNP Reflects Left Ventricular Hypertrophy Rather than Left Ventricular Dilatation or Systolic Dysfunction in Patients with Fabry Disease

Background: The diagnosis and follow-up of cardiac involvement in Fabry disease constitutes an important challenge for clinicians caring for affected patients. Combining cardiac imaging with laboratory biomarkers appears most appropriate for longitudinal monitoring. Therefore, we examined the use of NT-proBNP and its association with imaging findings in patients with Fabry disease. Methods: We analysed cardiac MRI and echocardiography data, as well as laboratory results, from a single-centre prospective registry. Results: Repetitive follow-ups of 38 patients with Fabry disease, of whom 18 presented with left ventricular hypertrophy (LVH), revealed a correlation of NT-proBNP with left ventricular (LV) interventricular septal thickness, LV maximum wall thickness, LV and right ventricular (RV) mass index and trabecular mass in patients with LVH. Patients without LVH did not exhibit any tangible association between NT-proBNP and the mentioned parameters. Conversely, we could not detect an association of NT-proBNP with impairment of LV or RV ejection fraction or diastolic volume. Conclusions: NT-proBNP plays a pivotal role as a biomarker for cardiac involvement in patients with Fabry disease. Interestingly, in this specific population with mostly preserved ejection fraction, it seems to reflect ventricular hypertrophy rather than ventricular dysfunction or dilatation. While strong associations were found in hypertrophic patients, NT-proBNP’s prognostic value appears limited in non- or pre-hypertrophic stages.

Gastrointestinal involvement in Fabry disease

Fabry disease is an X-linked lysosomal storage disorder due to alpha-galactosidase A deficiency. This deficiency results in a progressive accumulation of globotriaosylceramide and related glycosphingolipids, particularly in vascular endothelial cells, renal cells, nerve cells, and cardiomyocytes. Gastrointestinal symptoms are frequent and can be extremely debilitating. It is known that most of the well-characterized gastrointestinal manifestations of Fabry disease are the result of the accumulation of glycosphingolipids, which causes vascular occlusion and malfunction of the peripheral and autonomic nervous system. Although improvement is noted in treating patients with enzyme replacement therapy and migalastat, some continue to experience symptoms after treatment; thus, it remains a significant cause of morbidity, necessitating concurrent adjuvant treatment. Current research is focused on clarifying the underlying dysmotility and further analyzing the correlation between the gut-brain axis, the histologic disease progression, and the clinical symptom presentation.

Assessing brain involvement in Fabry disease with deep learning and the brain-age paradigm.

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.

Serum Neopterin, Biopterin, Tryptophan, and Kynurenine Levels in Patients with Fabry Disease

Fabry disease is characterized by the accumulation of globotriaosylceramide. Substrate accumulation in lysosomes is thought to trigger an inflammatory response and is responsible for progressive organ damage through the induction of autoimmunity. The levels of pteridine and kynurenine pathway metabolites increase when immune activation is observed and are employed to monitor several diseases and determine prognosis. To elucidate the effects of immune activation on the pathophysiology of Fabry disease and to investigate the potential utility of pteridine and kynurenine metabolites. A prospective case-control study. In this study, 33 patients with Fabry disease and 33 age-and sex-matched healthy controls were included. Blood pteridine and kynurenine metabolites were studied in both groups. Organ involvement in Fabry disease and its correlation with the pteridine and kynurenine pathways were also investigated. The patients’ neopterin and biopterin levels and the tryptophan/kynurenine ratio were statistically higher than those of the healthy control group (p < 0.05). A statistically significant association was found between neopterin levels and hypertrophic cardiomyopathy, cardiac arrhythmias, and GFR values (p = 0.044, p = 0.021, and p = 0.030, respectively), tryptophan and corneal verticillate, hearing loss and tinnitus (p = 0.010, p = 0.009 and p = 0.046, respectively), and kynurenine levels and valvular heart disease (p = 0.020). From the onset of the disease, patients with Fabry disease exhibited elevated levels of inflammation and immune activation. Furthermore, inflammation and immune activation markers can be used as early disease biomarkers.

Clinical significance of small nerve fiber involvement in the early diagnosis and treatment of patients with Fabry disease

IntroductionPeripheral nervous system is early involved in Fabry disease (FD) and preferentially the small nerve fibers, causing the characteristic neuropathic pain crises usually beginning in childhood. Early detection of this likely underdiagnosed disease is an important approach because causal therapies are available. MethodsWe conducted a case-series study to investigate the small nerve fiber involvement in FD and its contribution to the diagnosis of the disease but also to the timely effective therapy administration. We used specific structured scales of symptoms and signs to detect peripheral neuropathy, as well as suitable functional and structural tests to diagnose the small fiber neuropathy (SFN). ResultsTwenty-seven consecutive patients (14 men, mean age 44.62 ± 10.70 years) with suspected FD were included in this study. Most of the patients presented symptoms of small nerve fiber involvement, which were accompanied by abnormal test results, fulfilling the criteria for SFN. The detection of SFN in our patients allowed the completion of the FD diagnostic criteria and thus the initiation of therapy. In five patients the SFN diagnosis determined the administration of therapy, whereas in two others it might be considered. ConclusionOur results further suggest the importance of early diagnosis of peripheral neuropathy, especially of small nerve fiber involvement, in patients with suspected FD as it contributes crucially not only to the diagnosis but also to the timely effective initiation of FD therapy.

Impact of kidney biopsy on deciding when to initiate enzyme replacement therapy in children with Fabry disease

BackgroundRecommendations on when to start enzyme replacement therapy (ERT) in children with Fabry disease (FD) differ between guidelines. In this study, kidney biopsies of a cohort of 14 untreated children and one treated child were analyzed for their morphologic changes to determine whether early initiation of ERT is indicated.MethodsAll pediatric FD patients (< 18 years old) diagnosed between 2003 and 2021 in our department who received a kidney biopsy were enrolled. Clinical symptoms; laboratory parameters regarding kidney function, such as eGFR, plasma urea, protein-creatinine, and albumin/creatinine ratio; and 14 kidney biopsies prior to ERT and one under treatment were retrospectively analyzed.ResultsA total of 14 patients were enrolled, including 9 male and 5 female children, aged 3–18 years (median age 11). Seven of the enrolled children were 10 years old or younger. Histological analysis of kidney biopsy samples revealed severe vacuolization and accumulation of inclusions in podocytes and renal tubules. The majority of cases had no FD-specific clinical or laboratory features independent of age, gender, or genotype. The youngest FD patient presenting with isolated abnormal kidney biopsy was 3 years old.ConclusionsWe demonstrate that histological lesions, typical for FD, can be observed in kidney biopsies at a very young age in patients without classical clinical symptoms or laboratory abnormalities. Thus, we recommend kidney biopsies as a possible tool for early diagnosis of renal involvement in FD. As a consequence of these early biopsy findings without a clinical correlate, an early initiation of ERT should be considered.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Exploring the prognostic value of myocardial inflammation in Fabry cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Background Cardiac involvement in Fabry Disease (FD) manifests as left ventricular hypertrophy (LVH) often complicated by myocardial fibrosis and/or inflammation. Indeed, glycosphingolipid storage does not explain the whole spectrum of FD pathophysiology. Lysosomal deposits of unmetabolized glycolipid substrates stimulate the activation of immunological pathways, taking to a chronic inflammatory process.1 In a subgroup of FD patients with late gadolinium enhancement (LGE), signs of myocardial inflammation can be detected by cardiac magnetic resonance (CMR) using T2-weighted (T2w) sequences and T2 mapping. T2 value in inferolateral wall (IL) has been described as the strongest predictor of increase in troponin level. 2 Aim The aims of the study were: 1) to compare CMR parameters in LVH and LGE positive FD patients with and without myocardial inflammation; 2) to verify if myocardial inflammation plays an incremental prognostic role in FD compared to LVH and LGE. Methods Among 190 consecutive FD patients referred for CMR, 47 patients with LVH and LGE were selected for this study. All patients underwent an extensive CMR protocol to provide a detailed evaluation of cardiac morphology and function, with multiparametric tissue characterization. Myocardial inflammation was detected by T2w and T2 mapping sequences. A comparison of CMR parameters between patients with and without inflammation was performed. A composite endpoint of cardiovascular (CV) events was used for survival analysis. Results No differences in age and Mainz Severity Score Index were found between LVH+/LGE+ FD patients with and without myocardial inflammation. Patients with inflammation showed significantly greater left ventricular mass index (LVMI) compared to patients without inflammation. Regarding tissue characterization, patients with myocardial inflammation had more extensive LGE and significantly higher ECV in IL wall. Native myocardial T1 was reduced in both groups without statistically significant difference. (Table 1) Myocardial inflammation always involved IL wall. During a median follow-up of 30 months, Kaplan-Meier curves showed similar event-free survival probability in patients with and without myocardial inflammation (Log-Rank p = 0,215, Figure 1). Conclusion In a population of LVH+/LGE+ FD patients, the presence of CMR signs of myocardial inflammation was associated with more severe LVH and more extensive LGE. However, the presence of myocardial inflammation did not showed an incremental prognostic value on CV outcomes on top of LVH and LGE. Larger studies are needed to verify this findings.

Increased cardiac involvement in Fabry disease using blood-corrected native T1 mapping

Fabry disease (FD) is a rare lysosomal storage disorder resulting in myocardial sphingolipid accumulation which is detectable by cardiovascular magnetic resonance as low native T1. However, myocardial T1 contains signal from intramyocardial blood which affects variability and consequently measurement precision and accuracy. Correction of myocardial T1 by blood T1 increases precision. We therefore deployed a multicenter study of FD patients (n = 218) and healthy controls (n = 117) to investigate if blood-correction of myocardial native T1 increases the number of FD patients with low T1, and thus reclassifies FD patients as having cardiac involvement. Cardiac involvement was defined as a native T1 value 2 standard deviations below site-specific means in healthy controls for both corrected and uncorrected measures. Overall low T1 was 135/218 (62%) uncorrected vs. 145/218 (67%) corrected (p = 0.02). With blood-correction, 13/83 previously normal patients were reclassified to low T1. This reclassification appears clinically relevant as 6/13 (46%) of reclassified had focal late gadolinium enhancement or left ventricular hypertrophy as signs of cardiac involvement. Blood-correction of myocardial native T1 increases the proportion of FD subjects with low myocardial T1, with blood-corrected results tracking other markers of cardiac involvement. Blood-correction may potentially offer earlier detection and therapy initiation, but merits further prospective studies.

Assessing small fiber neuropathy and subtle cardiac involvement in Fabry disease

Assessing small fiber neuropathy and subtle cardiac involvement in Fabry disease

Diagnosis of cardiovascular involvement in Fabry disease

Fabry disease is a rare X-linked genetic disorder, caused by partial or total loss of function of the lysosomal enzyme α-galactosidase A that induces glycosphingolipid accumulation in various organs and tissues, modifying their structure and function. Cardiovascular involvement in classic and late onset forms has emerged to be a major determinant of prognosis. In recent years, a constant evolution in imaging techniques and their mindful application has led to interesting results in the diagnostic workup, progressively reducing time required to recognize early signs of this disease. Owing to the growing awareness for diagnostic screening and the efficacy of the many therapeutic options currently available, the clinical history of Fabry patients has changed during the last decades. Therefore, an early diagnosis of Fabry disease and especially of cardiac involvement is essential to promptly adopt an adequate therapy.

Поражение сердца при болезни Фабри: особенности течения и диагностическое значение магнитно-резонансной томографии и speckle-tracking эхокардиографии

To evaluate the frequency and clinical features of heart involvement in Fabry disease (FD) and diagnostic value of cardiac MRI and speckle-tracking echocardiography.

Cardiac involvement in Fabry disease - A non-invasive assessment and the role of specific therapies.

Fabry disease is an X-linked inherited metabolic disorder due to the pathogenic mutation of the GLA gene, which codes lysosomal enzyme alpha-galactosidase A. The resultant accumulation of glycosphingolipids causes various systemic symptoms in childhood and adolescence, and major organ damage in adulthood. Cardiac involvement is important as the most frequent cause of death in Fabry disease patients. Progressive left ventricular hypertrophy with varying degrees of contractile dysfunction as well as conduction abnormalities and arrhythmias are typical cardiac features, and these findings can be evaluated in detail via non-invasive modalities, such as an electrocardiogram, echocardiography and cardiac magnetic resonance. In addition, specific therapies of enzyme replacement therapy and pharmacological chaperone therapy are available, and their beneficial effects on cardiac involvement have been reported. This minireview highlights recent evidence concerning non-invasive modalities for assessing cardiac involvement in Fabry disease and the effects of enzyme replacement therapy and pharmacological chaperone therapy on the findings of those modalities.

Structural disconnection and functional reorganization in Fabry disease: a multimodal MRI study.

Central nervous system involvement in Fabry disease, a rare systemic X-linked lysosomal storage disorder, is characterized by the presence of heterogeneous but consistent functional and microstructural changes. Nevertheless, knowledge about the degree and extension of macro-scale brain connectivity modifications is to date missing. In this work, we performed connectomic analyses of diffusion and resting-state functional MRI to investigate changes of both structural and functional brain organization in Fabry disease, as well as to explore the relationship between the two and their clinical correlates. In this retrospective cross-sectional study, 46 patients with Fabry disease (28F, 42.2 ± 13.2years) and 49 healthy controls (21F, 42.3 ± 16.3years) were included. All subjects underwent an MRI examination including anatomical, diffusion and resting-state functional sequences. Images were processed to obtain quantitative structural and functional connectomes, where the connections between regions of interest were weighted by the total intra-axonal signal contribution of the corresponding bundle and by the correlation between blood-oxygen level–dependent time series, respectively. We explored between-group differences in terms of both global network properties, expressed with graph measures and specific connected subnetworks, identified using a network-based statistics approach. As exploratory analyses, we also investigated the possible association between cognitive performance and structural and functional connectome modifications at both global and subnetwork level in a subgroup of patients (n = 11). Compared with healthy controls, patients with Fabry disease showed a significantly reduced global efficiency (P = 0.005) and mean strength (P < 0.001) in structural connectomes, together with an increased modularity (P = 0.005) in functional networks. As for the network-based statistics analysis, a subnetwork with decreased structural connectivity in patients with Fabry disease compared with healthy controls emerged, with eight nodes mainly located at the level of frontal or deep grey-matter areas. When probing the relation between altered global network metrics and neuropsychological tests, correlations emerged between the structural and functional disruption with results at verbal and working memory tests, respectively. Furthermore, structural disruption at subnetwork level was associated with worse executive functioning, with a significant moderation effect of functional changes suggesting a compensation mechanism. Taken together, these results further expand the current knowledge about brain involvement in Fabry disease, showing widespread structural disconnection and functional reorganization, primarily sustained by loss in axonal integrity and correlating with cognitive performance.

Mitochondrial microRNAs Are Dysregulated in Patients with Fabry Disease.

Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the gene for α-galactosidase A, inducing a progressive accumulation of globotriaosylceramide (GB3) and its metabolites in different organs and tissues. GB3 deposition does not fully explain the clinical manifestations of FD, and other pathogenetic mechanisms have been proposed, requiring the identification of new biomarkers for monitoring FD patients. Emerging evidence suggests the involvement of mitochondrial alterations in FD. Here, we propose mitochondrial-related microRNAs (miRs) as potential biomarkers of mitochondrial involvement in FD. Indeed, we demonstate that miRs regulating different aspects of mitochondrial homeostasis including expression and assembly of respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are consistently dysregulated in FD patients. Our data unveil a novel noncoding RNA signature of FD patients, indicating mitochondrial-related miRs as new potential pathogenic players and biomarkers in FD. SIGNIFICANCE STATEMENT: This study demonstrates for the first time that a specific signature of circulating mitochondrial miRs (mitomiRs) is dysregulated in FD patients. MitomiRs regulating fundamental aspects of mitochondrial homeostasis and fitness, including expression and assembly of the respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are significantly dysregulated in FD patients. Taken together, these new findings introduce mitomiRs as unprecedented biomarkers of FD and point at mitochondrial dysfunction as a novel potential mechanistic target for therapeutic approaches.

Cardiac Magnetic Resonance Features of Fabry Disease: From Early Diagnosis to Prognostic Stratification.

In the past few years, the wide application of cardiac magnetic resonance (CMR) significantly changed the approach to the study of cardiac involvement in Fabry Disease (FD). The possibility to perform non-invasive tissue characterization, including new sequences such as T1/T2 mapping, offered a powerful tool for differential diagnosis with other forms of left ventricular hypertrophy. In patients with confirmed diagnosis of FD, CMR is the most sensitive non-invasive technique for early detection of cardiac involvement and it provides new insight into the evolution of cardiac damage, including gender-specific features. Finally, CMR multiparametric detection of subtle changes in cardiac morphology, function and tissue composition is potentially useful for monitoring the efficacy of specific treatment over time. This paper aims to provide a comprehensive review of current knowledge regarding the application of CMR in FD cardiac involvement and its clinical implication.

Multi-Modality Cardiovascular Imaging Assessment in Fabry Disease

Fabry disease (FD) is a rare X-linked lysosomal storage disorder manifesting as progressive multi-organ accumulation of sphingolipids due to deficiency in the enzyme α-Galactosidase A. Sphingolipid accumulation can take place in all cardiac cell types which manifests as left ventricular hypertrophy, microvascular ischaemia, conduction abnormalities, arrhythmia, heart failure, and valvular disease. The use of advanced cardiovascular imaging techniques have enabled clinicians to stage and prognosticate the disease and guide therapy. Transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) in conjunction are the hallmark imaging modalities to allow for this assessment. Traditionally, the assessment of cardiac involvement in FD was based on the assessment of maximal wall thickness (MWT) and the development of left ventricular hypertrophy (LVH). It is now understood that sphingolipid accumulation takes place before the development of LVH. Advances in techniques within TTE and CMR, particularly that of strain assessment and T1/T2 mapping, have meant that Fabry cardiomyopathy (FCM) can be diagnosed earlier in the disease process. This potentially provides a window for initiation of enzyme replacement therapy (ERT) at a stage where it is likely to have the most beneficial effect in reducing the high mortality associated with FCM. This review outlines the advances in multimodality imaging in staging and prognosticating FCM, as well as the applications of cardiac imaging in assessing symptoms and complications of FCM.

Lyso-Gb3 as a biomarker for renal and cardiac involvement in Fabry disease: An analysis from the Fabry Outcome Survey (FOS)

Lyso-Gb3 as a biomarker for renal and cardiac involvement in Fabry disease: An analysis from the Fabry Outcome Survey (FOS)

Brazilian consensus recommendations for the diagnosis, screening, and treatment of individuals with fabry disease: Committee for Rare Diseases - Brazilian Society of Nephrology/2021.

Fabry disease (FD) is an X-linked inherited disorder caused by mutations in the GLA gene encoding enzyme alpha-galactosidase A (α-Gal A). The purpose of this study was to produce a consensus statement to standardize the recommendations concerning kidney involvement in FD and provide advice on the diagnosis, screening, and treatment of adult and pediatric patients. This consensus document was organized from an initiative led by the Committee for Rare Diseases (Comdora) of the Brazilian Society of Nephrology (SBN). The review considered randomized clinical trials, real-world data studies, and the expertise of its authors. The purpose of this consensus statement is to help manage patient and physician expectations concerning the outcomes of treatment. Our recommendations must be interpreted within the context of available evidence. The decisions pertaining to each individual case must be made with the involvement of patients and their families and take into account not only the potential cost of treatment, but also concurrent conditions and personal preferences. The Comdora intends to update these recommendations regularly so as to reflect recent literature evidence, real-world data, and appreciate the professional experience of those involved. This consensus document establishes clear criteria for the diagnosis of FD and for when to start or stop specific therapies or adjuvant measures, to thus advise the medical community and standardize clinical practice.

Effect of migalastat on cardiac involvement in Fabry disease: preliminary results from MAIORA study

Abstract 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