Anderson-Fabry Disease (AFD) is one of the rare lysosomal storage disorders for which a cause - specific therapy is available. Recently, a new specific drug has been marketed, namely Migalastat, a small-molecule pharmacological chaperone. The effect of Migalastat on cardiac involvement has been assessed so far by 2D echocardiography, demonstrating a significant reduction in left ventricular (LV) mass after 18 months of therapy. Calculation of LV mass by 2D echocardiography is limited by geometrical assumptions and quality of echocardiographic window, with a strong impact on accuracy. Cardiac Magnetic Resonance (CMR) overcomes these limitations, thus representing the gold standard technique for ventricular mass, volumes and function estimation. Moreover, CMR offers the unique possibility to perform a non-invasive tissue characterization, including the detection of both myocardial fibrosis by Late Gadolinium Enhancement and sphingolipid storage by T1 mapping. Beyond an accurate morphological description and a detailed tissue characterization, a complete cardiological assessment should also integrate functional data and bio-humoral profile.

This study is designed to provide a comprehensive evaluation of the therapeutic effect of Migalastat (123 mg every other day) on cardiac involvement after 18 months of therapy, integrating a morphological, functional and bio-humoral assessment.

Anderson-Fabry disease is a rare X-linked lysosomal disorder, mainly affecting cardiovascular, renal and nervous systems. Cardiac injury is the leading cause of death in these patients. Heart involvement is characterized by left ventricular hypertrophy (LVH), myocardial scarring and/or inflammation, Bradyarrhythmias or tachyarrhythmias, heart failure and represents the main cause of death in these patients. Since 2001, specific therapies (enzyme replacement therapy (ERT) first and pharmacological chaperone migalastat more recently) are available to treat these patients.

Migalastat is a small-molecule pharmacological chaperone stabilizing specific mutant forms of the enzyme (α-Gal ) and promoting its catabolic function. These mutant forms of α-Gal are defined as amenable to Migalastat. In patients with amenable mutations, orally administered Migalastat is a potential alternative treatment to intravenous ERT. Because of its chemical nature (small molecule) and route of administration (orally), Migalastat would avoid ERT-associated immunogenicity and infusion-associated reactions. Additionally, the higher volume of distribution of migalastat relative to ERT suggests enhanced penetration of organs and tissues. Theoretically, the chaperoning of α-Gal by Migalastat to lysosomes may better mimic natural enzyme trafficking and result in more constant α-Gal activity than biweekly ERT infusions.

Two main clinical studies have been published so far about safety and efficacy of Migalastat in AFD, demonstrating good safety, tolerability and comparable efficacy to ERT. These studies reported a significant decrease in LV mass index assessed by 2D echocardiography (-6,6 g/m2 in 33 patients after 18 months of therapy), mostly in patients with overt cardiac involvement and greater than the changes observed with ERT (-2 g/m2 in 16 patients after 18 months of therapy).

Calculation of LV mass by 2D echocardiography is based on the "Devereux formula", assuming that the LV is a prolate ellipsoid with a 2:1 long/short axis ratio and symmetric distribution of hypertrophy. This is not always the case in AFD Cardiomyopathy, showing a wide variety of hypertrophy patterns. Moreover, since linear measurements of LV wall thickness and diameters are cubed in this formula, even small measurement errors in dimensions or thickness have a strong impact on accuracy.

Cardiac magnetic resonance (CMR) represents the gold standard technique for ventricular mass, volumes and function estimation because of the possibility to directly measure these parameters without geometrical assumption. Therefore, CMR has an excellent inter-study reproducibility both in normal and in pathologic hearts, overcoming 2D echocardiography. Beyond its high reproducibility in LV mass measurement, CMR offers the unique possibility of non-invasive tissue characterization. This concept includes both detection and quantification of myocardial fibrosis by Late Gadolinium Enhancement images and application of new techniques, namely T1 mapping, detecting myocardial sphingolipid storage even before LVH occurs. Also, CMR allows a detailed characterization of myocardial deformation by feature tracking. Feature tracking CMR (FT-CMR) approximately applies the same principles of speckle tracking echocardiography (even though with differences methods of image acquisition and reconstruction) in order to measure global and segmental myocardial deformation. The strength of FT-CMR consists of its relatively unrestricted access to large fields of view, its high spatial resolution and its relatively high signal to noise and contrast to noise ratios.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level. MiRNAs have emerged as key regulators of several physiological and pathophysiological processes. Besides their intracellular function, recent studies demonstrated that miRNAs can be exported or released by cells and circulate in blood in a remarkably stable form. The discovery of circulating miRNAs opens the possibilities to use circulating miRNA patterns as biomarkers for several pathologies also for cardiovascular diseases. In a recent study, a common microRNA signature in AFD patients regardless of gender and age has been identified.15 miRNAs differentially expressed between 10 AFD subjects and 10 normal controls (NC) have been found. The levels of these 15 miRNAs in plasma sample of 10 subjects with LVH and no mutation in the Galactosidase Alpha (GLA) gene have also been studied. Among these 15 miRNAs, 3 discriminated AFD patients from subjects with LVH. In particular, 2 microRNAs (mir-199a-5p and mir126a-3p) were up-regulated and 1 miRNA (mir-423-5p) was down-expressed in AFD patients. Interestingly, in a recent study increased plasmatic levels of miR-126 and miR-199a were significantly associated with a lower major adverse Cardiovascular (CV) event rate in patients with coronary artery disease. Instead, elevated plasmatic levels of mir-423-5p is strongly related to the clinical diagnosis of Heart Failure. Several evidences indicate that the aberrantly expressed plasmatic miRNAs in AFD are linked to microvascular or macrovascular damage involved in the typical AFD vasculopathy and could be attractive as diagnostic markers as well as for the monitoring of the pharmacological treatment.

Integration of all these aspects allows a complete morpho-functional evaluation of cardiac involvement in AFD and a detailed monitoring of the effects of specific drugs.

This study is designed to provide a comprehensive evaluation of the therapeutic effect of Migalastat on cardiac involvement, integrating a morphological, functional and bio-humoral assessment of heart involvement. 15 patients with amenable mutation, clinical indication to Migalastat and signs of early or overt cardiac involvement with will undergo a complete cardiological evaluation before and 18 months after therapy with Migalastat. The cardiological assessment will include ECG, 2D echocardiography, CMR, cardio-pulmonary test, dosage of peripheral biomarkers (TnT High Sensitive; NT-proBNP, mir-199a-5p and mir126a-3p, mir-423-5p).

Inclusion Criteria:

• Genetic diagnosis of Fabry Disease and amenable mutation
• Clinical indication to Migalastat
• Signs of clinical or preclinical cardiac involvement (low T1 values with or without left ventricular hypertrophy)
• Age >16
• Ability to give a complete informed consent (for minor patients informed consent will be given by parents)

Exclusion Criteria:

• Contraindication to Migalastat (pregnancy, age <16, Glomerular Filtration Rate <30 ml/min, hypersensitivity to the active ingredient)
• Contraindication to CMR study (metallic fragment or foreign body, known claustrophobia, PaceMaker/Implantable Cardioverter Defibrillator not CMR conditional, electronic implant or device, eg, insulin pump or other infusion pump)

Between patients with genetic diagnosis of AFD referred for CMR at Policlinico San Donato, 15 patients with amenable mutation, clinical indication to Migalastat and signs of early or overt cardiac involvement (low myocardial native T1 value ± left ventricular hypertrophy) will be enrolled.