Cardiac Manifestations In Fabry Disease Research Articles

Incidence and risk factors for development of left ventricular hypertrophy in Fabry disease

Abstract Background Left ventricular hypertrophy (LVH) is the principal cardiac manifestation of Fabry disease (FD). This study aimed to determine the incidence and predictors of LVH development in a contemporary cohort of patients with FD and no LVH at baseline evaluation. Methods Consecutively referred adult (age ≥16 years) patients with FD were enrolled into an observational cohort study. Patients were prospectively followed in a specialist cardiomyopathy centre and the primary endpoint was the first detection of LVH (left ventricular mass index (LVMi) ≥115 g/m2 in men and ≥95 g/m2 in women). Results From a cohort of 393 patients, 214 (age 35.8 ±13.8 years; 61 [29%] males) had no LVH at first evaluation. During a median follow-up of 9.4 years (interquartile range [IQR] 4.7-12.7), 55 patients (24.6%) developed LVH. The estimated incidence of LVH was 11.3% (95% confidence interval [CI] 6.5-16.1) at 5 years, 29.1% (95%CI 21.5-36.7) at 10 years, and 45.0% (95%CI 33.8-62.4) at 15 years of follow-up. On multivariable analysis, independent predictors for LVH development were age (hazard ratio [HR] 1.04 [95%CI 1.02-1.06] per 1 year increase, p-value <0.001), male sex (HR 2.90 [95%CI 1.66-5.09], p-value <0.001), and an abnormal ECG (HR 3.10 [95%CI 1.72-5.57], p-value <0.001). The annual rate of change in LVMi was +2.77 (IQR 1.45-4.62) g/m2/year in males and +1.38 (IQR 0.09-2.85) g/m2/year in females (p-value <0.001). Conclusions Approximately one quarter of FD patients developed LVH during follow-up. Age, male sex, and ECG abnormalities were associated with a higher risk of developing LVH in patients with FD.Central Illustration

Cardiac manifestations of Fabry disease in G3Stg/GlaKO and GlaKO mouse models-Translation to Fabry disease patients.

Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by mutations in the GLA gene encoding alpha-galactosidase A (α-Gal). Loss of α-Gal activity leads to progressive lysosomal accumulation of α-Gal substrate, predominately globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (lyso-Gb3). FD manifestations include early onset neuropathic pain, gastrointestinal symptoms, and later onset life-threatening renal, cardiovascular and cerebrovascular disorders. Current treatments can preserve kidney function but are not very effective in preventing progression of cardiovascular pathology which remains the most common cause of premature death in FD patients. There is a significant need for a translational model that could be used for testing cardiac efficacy of new drugs. Two mouse models of FD have been developed. The α-Gal A-knockout (GlaKO) model is characterized by progressive tissue accumulation of Gb3 and lyso-Gb3 but does not develop any Fabry pathology besides mild peripheral neuropathy. Reports of minor cardiac function abnormalities in GlaKO model are inconsistent between different studies. Recently, G3Stg/GlaKO was generated by crossbreeding GlaKO with transgenic mice expressing human Gb3 synthase. G3Stg/GlaKO demonstrate higher tissue substrate accumulation and develop cellular and tissue pathologies. Functional renal pathology analogous to that found in early stages of FD has also been described in this model. The objective of this study is to characterize cardiac phenotype in GlaKO and G3Stg/GlaKO mice using echocardiography. Longitudinal assessments of cardiac wall thickness, mass and function were performed in GlaKO and wild-type (WT) littermate controls from 5-13 months of age. G3Stg/GlaKO and WT mice were assessed between 27-28 weeks of age due to their shortened lifespan. Several cardiomyopathy characteristics of early Fabry pathology were found in GlaKO mice, including mild cardiomegaly [up-to-25% increase in left ventricular (LV mass)] with no significant LV wall thickening. The LV internal diameter was significantly wider (up-to-24% increase at 9-months), when compared to the age-matched WT. In addition, there were significant increases in the end-systolic, end-diastolic volumes and stroke volume, suggesting volume overload. Significant reduction in Global longitudinal strain (GLS) measuring local myofiber contractility of the LV was also detected at 13-months. Similar GLS reduction was also reported in FD patients. Parameters such as ejection fraction, fractional shortening and cardiac output were either only slightly affected or were not different from controls. On the other hand, some of the cardiac findings in G3Stg/GlaKO mice were inconsistent with Fabry cardiomyopathy seen in FD patients. This could be potentially an artifact of the Gb3 synthase overexpression under a strong ubiquitous promoter. In conclusion, GlaKO mouse model presents mild cardiomegaly, mild cardiac dysfunction, but significant cardiac volume overload and functional changes in GLS that can be used as translational biomarkers to determine cardiac efficacy of novel treatment modalities. The level of tissue Gb3 accumulation in G3Stg/GlaKO mouse more closely recapitulates the level of substrate accumulation in FD patients and may provide better translatability of the efficacy of new therapeutics in clearing pathological substrates from cardiac tissues. But interpretation of the effect of treatment on cardiac structure and function in this model should be approached with caution.

Incidence and risk factors for development of left ventricular hypertrophy in Fabry disease

BackgroundLeft ventricular hypertrophy (LVH) is the principal cardiac manifestation of Fabry disease (FD). This study aimed to determine the incidence and predictors of LVH development in a contemporary cohort of...

Ambulatory electrocardiographic monitoring in patients with Fabry disease: study design and cohort characterization

Aim. To develop study design and analyze the characteristics of a cohort of patients with cardiac manifestations of Fabry disease (FD) in order to study the possibilities of electrocardiography (ECG) telemonitoring for screening for cardiac arrhythmias (CA), requiring a change in therapeutic tactics.Material and methods. This prospective cohort study included 11 patients (8 men and 3 women) with documented FD, with cardiac complaints and ECG signs of heart involvement. For ECG telemonitoring, non-invasive digital event recorders ECG Dongle (Nordavind-Dubna, Russia) were used. Primary endpoint was registration of CA requiring a change in therapeutic tactics (implantation of a pacemaker/defibrillator-cardioverter/prescribing anticoagulants). Secondary endpoint was dynamics of monitored parameters for operational correction of the therapeutic regimen.Results. The cohort of patients is predominantly male (73/27%; mean age, 41±13,7 years). At the time of inclusion, 8 (73%) patients received enzyme replacement therapy for 4-73 months. Most patients are active Internet users, are aware of telemedicine possibilities and are interested in remote monitoring. The main complaints were related to cardiac function interruptions, palpitations, and chest discomfort. Left ventricular hypertrophy was diagnosed on ECG in 7 (64%) patients. Echocardiography revealed symmetrical left ventricular hypertrophy in 5 patients, asymmetric interventricular septal hypertrophy in 2 patients. Other echocardiographic abnormalities included valvular heart disease (mitral and tricuspid valve prolapse with mitral and tricuspid regurgitation, presence of supplemental chords) and aortic root dilatation. Initially, the ECG was dominated by sinus rhythm (n=10); 1 patient had documented ventricular tachycardia, 4 patients had single and coupled ventricular premature contractions; supraventricular tachycardia and premature contractions in 2 patients. Four patients had a PR interval shortening without signs of accessory pathways, 1 patient — Wolff-Parkinson-White syndrome, 1 patient — prolonged QTc interval.Conclusion. For effective management of FD, additional multicenter studies are required to develop algorithms for making tactical decisions in the process of cardiac monitoring, taking into account the characteristics of the cardiovascular manifestations of this disease. The article proposes a technology for telemedicine cardiac monitoring using ECG event recorders for outpatient CA screening.

Validated Model for Prediction of Adverse Cardiac Outcome in Patients With Fabry Disease

BackgroundThe cardiac manifestations of Fabry disease are the leading cause of death, but risk stratification remains inadequate. Identifying patients who are at risk of adverse cardiac outcome may facilitate more evidence-based treatment guidance. Contemporary cardiovascular cardiac magnetic resonance biomarkers have become widely adopted, but their prognostic value remains unclear. ObjectivesThe objective of this study was to develop, internally validate, and evaluate the performance of, a prognostic model, including contemporary deep phenotyping, which can be used to generate individual risk estimates for adverse cardiac outcome in patients with Fabry disease. MethodsThis longitudinal prospective cohort study consisted of 200 consecutive patients with Fabry disease undergoing clinical cardiac magnetic resonance. Median follow-up was 4.5 years (IQR: 2.7-6.3 years). Prognostic models were developed using Cox proportional hazards modeling. Outcome was a composite of adverse cardiac events. Model performance was evaluated. A risk calculator, which provides 5-year estimated risk of adverse cardiac outcome for individual patients, including men and women, was generated. ResultsThe highest performing, internally validated, parsimonious multivariable model included age, native myocardial T1 dispersion (SD of per voxel myocardial T1 relaxation times), and indexed left ventricular mass. Median optimism-adjusted c-statistic across 5 imputed model development data sets was 0.77 (95% CI: 0.70-0.84). Model calibration was excellent across the full risk profile. ConclusionsThis study developed and internally validated a risk prediction model that accurately predicts 5-year risk of adverse cardiac outcome for individual patients with Fabry disease, including men and women, which could easily be integrated into clinical care. External validation is warranted.

CARS Imaging Advances Early Diagnosis of Cardiac Manifestation of Fabry Disease.

Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient’s prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90–96%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD.

Early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression.

Enzyme replacement therapy (ERT) slows disease progression of Fabry disease (FD), especially when initiated before the onset of irreversible organ damage. However, with the clinically asymptomatic progression of renal, cardiac and cerebral disease manifestations spanning decades, optimal timing of ERT initiation remains unclear. In this cross-sectional retrospective study, seven male FD patients with a classical disease phenotype (cFD) who started treatment with agalsidase-beta in childhood were evaluated after 10years of treatment (median age at evaluation 24years, range 14-26). Cardiac imaging (echocardiography and MRI), electrophysiological and biochemical data of these patients were compared to those of untreated male cFD patients (n=23, median age 22years, range 13-27). Albuminuria was less common and less severe in treated patients (albumin to creatinine ratio, ACR 0-8.8mg/mmol, median 0.4) compared to untreated patients (ACR 0-248mg/mmol, median 3.7, p=0.02). The treated group had a lower left ventricular mass, measured using echocardiography (median 80g/m2 versus 94g/m2, p=0.02) and MRI (median 53g/m2 versus 68g/m2, p=0.02). Myocardial fibrosis was absent in all included patients. eGFR was normal in all treated patients whereas 7/23 (30%) of untreated patients had abnormal eGFR. Cerebral manifestations did not differ. Start of treatment with ERT before age 16, in male cFD patients is associated with reduced occurrence of renal and cardiac manifestations of FD, as assessed by intermediate endpoints. Confirmation that this approach delays or even prevents renal failure and cardiac events requires another decade of follow-up.

Cardiac manifestations of fabry disease in female patients: a single centre experience

Abstract Introduction Fabry disease is a lysosomal storage disorder resulting in multisystemic effects due to deposition and accumulation of glycosphingolipids. Although an X linked disorder, it is recognised that female heterozygotes can express clinical manifestations. Cardiac expression in the female Fabry population remains incompletely understood. Data from the Fabry Outcome Survey suggests that up to a quarter of female patients demonstrate left ventricular hypertrophy (LVH) on echocardiography. Although LVH is the most commonly cited cardiac finding, other abnormalities from clinical surveillance can include electrocardiographic abnormalities, fibrosis and elevated troponin levels. Purpose To establish the prevalence and extent of cardiac involvement amongst our cohort of female Fabry patients. Methods Heterozygous females, confirmed by genetic testing, were identified in our single centre Fabry database. Data was collected retrospectively on their 12 lead ECG, high sensitivity troponin I level and echocardiography performed at their most recent cardiac Fabry clinic visit, along with the most recent cardiac magnetic resonance imaging (CMR). Values are expressed as mean ± SD. Results 51 female heterozygotes were identified, ranging from 23 to 83 years (mean age 49.3±15.4). 28 (54.9%) were established on enzyme replacement therapy. On echocardiography LVH of ≥13mm was identified in 14 (27.5%) patients (mean 14.6±1.9 mm). 44 patients had CMR and of these, 17 (38.6%) had findings in keeping with a Fabry cardiomyopathy (34.1% had fibrosis, 15.9% hypertrophy, 13.6% both). Of the 17 patients with abnormalities on CMR, 8 had normal left ventricular wall thickness on echocardiography. All patients had a high sensitivity troponin I measurement and this was above upper reference limits (>40ng/L) in 21 (41.1%) patients in the absence of chest pain. Of 21 patients with abnormal troponin I levels, 9 had normal left ventricular wall thickness on echocardiography. Abnormalities identified on 12 lead ECG are summarised in Table 1. All patients with ECG abnormalities listed in Table 1 had an abnormal troponin and/or abnormal imaging, except for 5 patients who had an isolated short PR interval. 6 patients had a permanent pacemaker and 1 had a primary prevention implantable cardioverter defibrillator. 25 (49%) of the 51 patients were classed as having cardiac involvement based on raised troponin levels and/or abnormal imaging findings. Conclusion Although Fabry disease is traditionally thought to be a male predominant disease, in our cohort nearly half of our female heterozygotes showed evidence of cardiac involvement. The use of CMR, cardiac biomarkers and 12 lead ECG are helpful adjuncts to identify cardiac involvement, which could otherwise be missed if stand-alone echocardiography was used. Timely identification and monitoring of cardiac involvement has clinical implication, especially with regards to prognosis and treatment. Funding Acknowledgement Type of funding sources: None.

2021 TSOC Expert Consensus on the Clinical Features, Diagnosis, and Clinical Management of Cardiac Manifestations of Fabry Disease.

Fabry disease (FD) is an X-linked, rare inherited lysosomal storage disease caused by α-galactosidase A gene variants resulting in deficient or undetectable α-galactosidase A enzyme activity. Progressive accumulation of pathogenic globotriaosylceramide and its deacylated form globotriaosylsphingosine in multiple cell types and organs is proposed as main pathophysiology of FD, with elicited pro-inflammatory cascade as alternative key pathological process. The clinical manifestations may present with either early onset and multisystemic involvement (cutaneous, neurological, nephrological and the cardiovascular system) with a progressive disease nature in classic phenotype, or present with a later-onset course with predominant cardiac involvement (non-classical or cardiac variant; e.g. IVS4+919G>A in Taiwan) from missense variants. In either form, cardiac involvement is featured by progressive cardiac hypertrophy, myocardial fibrosis, various arrhythmias, and heart failure known as Fabry cardiomyopathy with potential risk of sudden cardiac death. Several plasma biomarkers and advances in imaging modalities along with novel parameters, cardiac magnetic resonance (CMR: native T1/T2 mapping) for myocardial tissue characterization or echocardiographic deformations, have shown promising performance in differentiating from other etiologies of cardiomyopathy and are presumed to be helpful in assessing the extent of cardiac involvement of FD and in guiding or monitoring subsequent treatment. Early recognition from extra-cardiac red flag signs either in classic form or red flags from cardiac manifestations in cardiac variants, and awareness from multispecialty team work remains the cornerstone for timely managements and beneficial responses from therapeutic interventions (e.g. oral chaperone therapy or enzyme replacement therapy) prior to irreversible organ damage. We aim to summarize contemporary knowledge based on literature review and the gap or future perspectives in clinical practice of FD-related cardiomyopathy in an attempt to form a current expert consensus in Taiwan.

Narrative review on Morbus Fabry: diagnosis and management of cardiac manifestations.

Fabry disease (FD) is an X-linked lysosomal storage disorder due to reduced or undetectable α-galactosidase A (AGAL-A) enzyme activity caused by pathogenic variants in the AGAL-A gene (GLA). Tissue and organ changes are caused by widespread progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). The classical form of FD is multisystemic with cutaneous (angiokeratomas), neurological (peripheral neuropathy, premature stroke), renal (proteinuria and renal insufficiency), and cardiac involvement. Later onset variants may be limited to the heart. The objective of this review is to summarize the current knowledge on cardiac manifestations of FD and effects of targeted therapy. Cardiac involvement is characterized by progressive hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death (SCD). Targeted therapy is based on enzyme replacement therapy (ERT). Recently, small molecular chaperone, migalastat, became available for patients carrying amenable pathogenic GLA variants. The management of cardiac complications requires a complex approach. Several measures differ from standard clinical guidelines. Betablockers should be used with caution due to bradycardia risk, amiodarone avoided if possible, and anticoagulation used from the first appearance of atrial fibrillation. In Fabry cardiomyopathy SCD calculators are inappropriate. The awareness of FD manifestations is essential for early identification of patients and timely treatment initiation.

Screening for Fabry disease in patients with left ventricular noncompaction

Introduction and AimIt is unclear whether left ventricular noncompaction (LVNC) is a distinct cardiomyopathy or a morphologic manifestation of different cardiomyopathies. We previously reported a case of LVNC in a Fabry disease (FD) patient, but it remains to be clarified whether LVNC is a cardiac manifestation of FD, a coincidental finding or an overdiagnosis, which has major therapeutic implications. This study aims to determine the prevalence of FD among patients with LVNC. MethodsWe performed a retrospective study including all patients diagnosed with LVNC in eight hospital centers. Diagnosis of LVNC was based on at least one echocardiographic or cardiac magnetic resonance criterion. FD screening was performed by combined enzyme and genetic testing. ResultsThe study included 78 patients diagnosed with LVNC based on the Jenni (84.6%), Stöllberger (46.2%), Chin (21.8%), Petersen (83.8%) and Jacquier (16.2%) criteria. Left ventricular systolic dysfunction was present in 48.7%. Heart failure was found in 60.3%, ventricular dysrhythmias in 21.6% and embolic events in 11.5%. FD screening found no additional cases among patients with LVNC, besides the previously described case. ConclusionNo additional FD cases were found among patients with LVNC, which argues against the hypothesis that LVNC is a cardiac manifestation of FD.

2355Treatment of cardiac manifestations in Fabry disease with the oral drug Migalastat: First 12 months results from a cohort of amenable all-comers

2355Treatment of cardiac manifestations in Fabry disease with the oral drug Migalastat: First 12 months results from a cohort of amenable all-comers

A novel GLA mutation in a Korean boy with an early cardiac manifestation of Fabry disease

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by the deficiency of α-galactosidase A. Patients with classical FD present acroparesthesia, hypohidrosis, cornea verticillata, disseminated angiokeratoma, and microalbuminuria in childhood, and develop life-threatening renal, cardiac, and cerebrovascular complications typically after the fourth decade of life. To date, more than 700 mutations responsible for FD have been identified in the human GLA gene. Herein, we report a novel GLA mutation, c.1117_1141del25 (p.Gly373Profs*10), identified in an 11-year-old Korean boy with FD presenting early cardiac and neurologic manifestation and in other affected family members. The boy had acroparesthesia, hypohidrosis, cornea verticillata, and left ventricular hypertrophy. His mother and sister also had acroparesthesia. Two males on the mother’s side had similar pain and died of unknown causes. The plasma α-galactosidase A activity (4.1 nmol/hr/mg protein) of the patient was markedly lower than the mean value of the controls. The plasma level of globotriaosylsphingosine was elevated in the patient and all the carriers. We concluded the novel GLA mutation c.1117_1141del25 is a pathogenic mutation for FD, probably related to the early cardiac manifestation of FD.

Loss of base-to-apex circumferential strain gradient: A specific pattern of Fabry cardiomyopathy?

Cardiac manifestations in Fabry disease are mainly characterized by left ventricular hypertrophy (LVH). The aims of this study were (1) to describe the pattern of regional strain in patients with Fabry disease and (2) to assess whether this pattern may help differentiate patients with Fabry disease from patients with sarcomeric hypertrophic cardiomyopathy (HCM). Seventy-seven subjects were investigated: patients with Fabry disease ( n = 37; 57% with LVH), patients with HCM ( n = 21), and healthy controls ( n = 19). Global and segmental longitudinal and circumferential strain (CS) analyses were performed by two-dimensional speckle strain imaging. Base-to-apex longitudinal and CS gradient, defined as the peak gradient difference between averaged basal and apical strain, was calculated. Longitudinal strain gradient did not differ between controls and Fabry patients without hypertrophy (respectively: −10 ± 3.2 vs. −8 ± 4.3, P = 0.41) or between the HCM group and Fabry patients with hypertrophy (respectively: −7.5 ± 4.5 vs. −9 ± 4.5, P = 0.37). The CS gradient was lower in Fabry patients without hypertrophy compared to the controls (respectively: 1 ± 8 vs. 14.2 ± 9.5, P < 0.01), and lower in Fabry patients with hypertrophy compared to the HCM group (respectively: 0.5 ± 8 vs. 6 ± 9, P < 0.01). Base- to- apex CS gradient was lost in both Fabry groups. Loss of base-to-apex CS gradient may be a specific left ventricular deformation pattern of Fabry cardiomyopathy in patients with and without LVH.

Fabry disease.

Fabry disease resulting from a deficiency of α-galactosidase A leads to the accumulation of globotriaosylceramide in various organs. Because the disease is an X-linked recessive disorder, males tend to develop more symptoms and more severe symptoms than females. There are also some variants of Fabry disease, and cardiac variant (cardiac Fabry disease) has the dysfunctions only inheart. Cardiac manifestations in Fabry disease are initially symmetrical and concentric left ventricular hypertrophy, and later progressive cardiac dysfunction with localized thinning of the basal posterior wall. In recent years, enzyme replacement therapy has been performed as a treatment for Fabry disease, and the initiation of this therapy is expected before the cardiac fibrosis develops. Therefore, early diagnosis of Fabry disease is essential, and echocardiography is an indispensable tool for clinical practice of this disease. Then, it is necessary to remember this disease as a differential diagnosis when encountering unexplained left ventricular hypertrophy.

Loss of base-to-apex circumferential strain gradient: A specific pattern of Fabry cardiomyopathy?

Cardiac manifestations in Fabry disease are mainly characterized by left ventricular hypertrophy (LVH). The aims of this study were (1) to describe the pattern of regional strain in patients with Fabry disease and (2) to assess whether this pattern may help differentiate patients with Fabry disease from patients with sarcomeric hypertrophic cardiomyopathy (HCM). Seventy-seven subjects were investigated: patients with Fabry disease (n=37; 57% with LVH), patients with HCM (n=21), and healthy controls (n=19). Global and segmental longitudinal and circumferential strain (CS) analyses were performed by two-dimensional speckle strain imaging. Base-to-apex longitudinal and CS gradient, defined as the peak gradient difference between averaged basal and apical strain, was calculated. Longitudinal strain gradient did not differ between controls and Fabry patients without hypertrophy (respectively: -10±3.2 vs -8±4.3, P=.41) or between the HCM group and Fabry patients with hypertrophy (respectively: -7.5±4.5 vs -9±4.5, P=.37). The CS gradient was lower in Fabry patients without hypertrophy compared to the controls (respectively: 1±8 vs 14.2±9.5, P<.01), and lower in Fabry patients with hypertrophy compared to the HCM group (respectively: 0.5±8 vs 6±9, P<.01). Base-to-apex CS gradient was lost in both Fabry groups. Loss of base-to-apex CS gradient may be a specific left ventricular deformation pattern of Fabry cardiomyopathy in patients with and without LVH.

Cardiac Manifestation of Fabry Disease

Although Fabry disease was identified a century ago, it is still a challenging condition to diagnose and treat. Registries data suggest that at least 10% of patients may first present with a cardiac event and that cardiac disease is 1 of the 3 major causes of morbidity and mortality in affected males and females. Cardiac involvement in Fabry disease may be expressed as left ventricular hypertrophy (LVH), coronary disease, atrioventricular conduction disturbances, arrhythmias, and valvular involvement. The exact mechanism by which hypertrophy and fibrosis in the heart occur is not fully understood. Lysosomal globotriaosylceramide accumulation in the myocardium is responsible for only 3% of the mass in the hypertrophic heart, indicating that the LVH is not a direct result of substrate infiltration. One of the most important contributions that cardiologists can make is to consider the diagnosis of Fabry disease in patients with cardiac manifestations preceding the development of LVH and conduct family screen...

Keratan sulfate (KS) analysis in patients with Morquio syndrome type A: LC-MS/MS analysis of KS disaccharides demonstrates that urine is a better source than plasma to monitor dynamic change in KS

Fabry disease is a life-threatening X-linked genetic disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A. As a result of the enzyme deficiency, glycosphingolipids (GSLs)with terminal α-D-galactosyl moieties, primarily globotriaosylceramide (Gb3), accumulate leading to dysfunction of multiple cell/organ systems. Arrhythmias and left ventricle hypertrophy are the most prominent cardiac manifestations of Fabry disease, and can precipitate heart failure and cause the early death of the patients. The pathogenesis of the arrhythmias and cardiac hypertrophy in Fabry disease is unclear. The only available specific treatment for Fabry disease, enzyme replacement therapy (ERT) has limited effect on preventing or reversing cardiac manifestations, especially arrhythmias. Therefore, there is a demand for developing new therapeutic approaches. We generated induced pluripotent stem cell (iPSC) from classic male hemizygous Fabry patients and differentiated them into functional cardiomyocytes. These Fabry disease patient-derived cardiac cells showed slow spontaneous beating, mimicking bradycardia in the donor patients. Molecular analysis revealed upregulated expression of the membrane Ca2+ sensor L-type calcium channels (LTCC), hyperphosphorylation of ryanodine receptor (RyR2) and decreased expression of phospholamban in Fabry patient iPSCderived cardiomyocytes. Ca2+ imaging showed abnormal sarcoplasmic reticulum (SR) Ca2+ release and uptake in the Fabry patient cardiomyocytes. In addition, a LTCC inhibitor, verapamil improved the beating rate of Fabry disease patient cardiac clusters in vitro. We conclude that abnormal calcium (Ca2+) handing/homeostasis contributes to cardiac arrhythmia and possibly cardiac hypertrophy in Fabry disease and targeting the Ca2+ cycling pathway may be an effective treatment of heart disease in Fabry patients.

Abnormal intracellular calcium handling: a key pathogenic and therapeutic target of the cardiac manifestations in Fabry disease

Fabry disease is a life-threatening X-linked genetic disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A. As a result of the enzyme deficiency, glycosphingolipids (GSLs)with terminal α-D-galactosyl moieties, primarily globotriaosylceramide (Gb3), accumulate leading to dysfunction of multiple cell/organ systems. Arrhythmias and left ventricle hypertrophy are the most prominent cardiac manifestations of Fabry disease, and can precipitate heart failure and cause the early death of the patients. The pathogenesis of the arrhythmias and cardiac hypertrophy in Fabry disease is unclear. The only available specific treatment for Fabry disease, enzyme replacement therapy (ERT) has limited effect on preventing or reversing cardiac manifestations, especially arrhythmias. Therefore, there is a demand for developing new therapeutic approaches. We generated induced pluripotent stem cell (iPSC) from classic male hemizygous Fabry patients and differentiated them into functional cardiomyocytes. These Fabry disease patient-derived cardiac cells showed slow spontaneous beating, mimicking bradycardia in the donor patients. Molecular analysis revealed upregulated expression of the membrane Ca2+ sensor L-type calcium channels (LTCC), hyperphosphorylation of ryanodine receptor (RyR2) and decreased expression of phospholamban in Fabry patient iPSCderived cardiomyocytes. Ca2+ imaging showed abnormal sarcoplasmic reticulum (SR) Ca2+ release and uptake in the Fabry patient cardiomyocytes. In addition, a LTCC inhibitor, verapamil improved the beating rate of Fabry disease patient cardiac clusters in vitro. We conclude that abnormal calcium (Ca2+) handing/homeostasis contributes to cardiac arrhythmia and possibly cardiac hypertrophy in Fabry disease and targeting the Ca2+ cycling pathway may be an effective treatment of heart disease in Fabry patients.

Novel α-galactosidase A mutation in patients with severe cardiac manifestations of Fabry disease

Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of α-galactosidase A (α-gal A), a lysosomal hydrolase. This inactivation is responsible for the accumulation of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. Fabry is considered a rare disease, with an incidence of 1:40,000; however, there are good reasons to believe that it is often seen but rarely diagnosed. To date, more than 600 mutations have been identified in human GLA gene that are responsible for FD.We describe the case of a 54-year-old male patient, who presented with left ventricular hypertrophy, chronic renal failure and acroparaesthesias, which are considered to be specific features of FD. Clinical and instrumental investigations showed several cardiovascular manifestations. The molecular analysis of GLA gene revealed a novel mutation in the fifth exon, called N249K, and the enzymatic analysis showed no α-galactosidase A activity. Family screening detected the same mutation in some relatives and also the enzymatic analysis confirmed the diagnosis of FD.In conclusion, these data suggest that the N249K mutation may be associated with cardiac manifestations of FD combined with other classical features of the disease.