Manifestations Of Fabry Disease Research Articles

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.

NEURO-MUSCULOSKELETAL MANIFESTATIONS IN FABRY DISEASE

Fabry Disease (FD) is a treatable lysosomal storage disorder. It is a genetic disease, diagnosis is often delayed or missed. FD is an inborn error of metabolism with clinical manifestations beginning from birth or observed much later, in adulthood. Identifying the disease as quickly as possible leads to a better clinical outcome. The objective of this review is to describe the neuro-musculoskeletal manifestations of FD, that can be easily confused with manifestations of other diseases. With this review, we want to draw attention to this condition, promote it, and succeed, we hope, in improving the speed of its diagnosis to obtain a better clinical outcome. An earlier diagnosis can lead to a better therapeutic intervention. Keywords: Fabry Disease (FD), α -galactosidase A, acroparesthesia, enzyme replacement treatment, musculo-skeletal symptoms.

Cerebrovascular disorders and Fabry disease

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding for alpha-galactosidase A. Renal, cardiac, and cerebrovascular involvement are the leading complications in early adulthood and are associated with severe morbidity and mortality. Cerebrovascular manifestations in FD manifest as ischemic stroke and transient ischemic attack and less frequently as hemorrhagic strokes. Many patients may develop their stroke not only before other major complications but also before the diagnosis of FD is made. This review will describe the frequency and characteristics of cerebrovascular disease in FD, the complex pathophysiological mechanisms, the neuroimaging findings, the value of screening studies in young patients with stroke, and the controversies regarding the beneficial effect of ERT for the prevention of cerebrovascular disease in FD.

Circulated TGF-β1 and VEGF-A as Biomarkers for Fabry Disease-Associated Cardiomyopathy.

Fabry disease (FD) is a lysosomal disorder caused by α-galactosidase A deficiency, resulting in the accumulation of globotriaosylceramide (Gb-3) and its metabolite globotriaosylsphingosine (Lyso-Gb-3). Cardiovascular complications and hypertrophic cardiomyopathy (HCM) are the most frequent manifestations of FD. While an echocardiogram and cardiac MRI are clinical tools to assess cardiac involvement, hypertrophic pattern variations and fibrosis make it crucial to identify biomarkers to predict early cardiac outcomes. This study aims to investigate potential biomarkers associated with HCM in FD: transforming growth factor-β1 (TGF-β1), TGF-β active form (a-TGF-β), vascular endothelial growth factor (VEGF-A), and fibroblast growth factor (FGF2) in 45 patients with FD, categorized into cohorts based on the HCM severity. TGF-β1, a-TGF-β, FGF2, and VEGF-A were elevated in FD. While the association of TGF-β1 with HCM was not gender-related, VEGF was elevated in males with FD and HCM. Female patients with abnormal electrocardiograms but without overt HCM also have elevated TGF-β1. Lyso-Gb3 is correlated with TGF-β1, VEGF-A, and a-TGF-β1. Elevation of TGF-β1 provides evidence of the chronic inflammatory state as a cause of myocardial fibrosis in FD patients; thus, it is a potential marker of early cardiac fibrosis detected even prior to hypertrophy. TGF-β1 and VEGF biomarkers may be prognostic indicators of adverse cardiovascular events in FD.

Ophthalmic Manifestations in Fabry Disease: Updated Review.

Fabry disease (FD) is an X-linked lysosomal storage disorder, causing Gb-3 (globotriaosylceramide) buildup in cellular lysosomes throughout the body, in particular in blood vessel walls, neuronal cells, and smooth muscle. The gradual accumulation of this glycosphingolipid in numerous eye tissues causes conjunctival vascular abnormalities, corneal epithelial opacities (cornea verticillata), lens opacities, and retinal vascular abnormalities. Although a severe vision impairment is rare, these abnormalities are diagnostic indicators and prognostics for severity. Cornea verticillata is the most common ophthalmic feature in both hemizygous men and heterozygous females. Vessel tortuosity has been linked to a faster disease progression and may be useful in predicting systemic involvement. New technologies such as optical coherence tomography angiography (OCTA) are useful for monitoring retinal microvasculature alterations in FD patients. Along with OCTA, corneal topographic analysis, confocal microscopy, and electro-functional examinations, contributed to the recognition of ocular abnormalities and have been correlated with systemic involvement. We offer an update regarding FD ocular manifestations, focusing on findings derived from the most recent imaging modalities, to optimize the management of this pathology.

Dapaglifozin on Albuminuria in Chronic Kidney Disease Patients with FabrY Disease: The DEFY Study Design and Protocol.

Fabry disease (FD) is a rare genetic disorder caused by a deficiency in the α-galactosidase A enzyme, which results in the globotriaosylceramide accumulation in many organs, including the kidneys. Nephropathy is a major FD complication that can progress to end-stage renal disease if not treated early. Although enzyme replacement therapy and chaperone therapy are effective, other treatments such as ACE inhibitors and angiotensin receptor blockers can also provide nephroprotective effects when renal damage is also established. Recently, SGLT2 inhibitors have been approved as innovative drugs for treating chronic kidney disease. Thus, we plan a multicenter observational prospective cohort study to assess the effect of Dapagliflozin, a SGLT2 inhibitor, in FD patients with chronic kidney disease (CKD) stages 1-3. The objectives are to evaluate the effect of Dapagliflozin primarily on albuminuria and secondarily on kidney disease progression and clinical FD stability. Thirdly, any association between SGT2i and cardiac pathology, exercise capacity, kidney and inflammatory biomarkers, quality of life, and psychosocial factors will also be evaluated. The inclusion criteria are age ≥ 18; CKD stages 1-3; and albuminuria despite stable treatment with ERT/Migalastat and ACEi/ARB. The exclusion criteria are immunosuppressive therapy, type 1 diabetes, eGFR < 30 mL/min/1.73 m2, and recurrent UTIs. Baseline, 12-month, and 24-month visits will be scheduled to collect demographic, clinical, biochemical, and urinary data. Additionally, an exercise capacity and psychosocial assessment will be performed. The study could provide new insights into using SGLT2 inhibitors for treating kidney manifestations in Fabry disease.

Clinical features and enzyme replacement therapy in 10 children with Fabry disease.

To summarize the clinical features, diagnosis and enzyme replacement therapy(ERT) of Fabry disease (FD) in children. The clinical data, laboratory tests, genetic variations and treatment of 10 FD children diagnosed in Shandong Provincial Hospital from September 2020 to June 2022 were retrospectively analyzed. Among the 10 cases from 6 families, 7 patients were boys of 4 to 13 years of age, and 3 were girls of 12 to 15 years of age. There were 7 symptomatic patients, including 6 boys and 1 girl. All 7 patients presented with acral neuralgia. Five patients had little or no sweating. Five patients presented with cutaneous angiokeratoma. Two patients had abdominal pain. One patient developed joint symptoms. Four patients had corneal opacity. One patient had hearing loss; one patient had short stature. One patient had mild proteinuria and 1 patient had dysplasia of the right kidney with decreased eGFR (55.28 ml/min.1.73 m2). The left ventricular mass index was slightly elevated in 1 patient. Three patients had mild obstructive ventilatory dysfunction; a small amount of effusion in the intestinal space of the lower abdomen or mild fatty liver was found in 2 patients. Partial empty sella turcica in 1 patient. A total of 6 GLA gene variants were detected in 10 children, among which C.1059_1061delGAT (p.met353del) was a newly discovered mutation. Five children received ERT, of which 4 were treated with agalsidase beta and 1 was treated with agalsidase alpha. Only 1 patient had anaphylaxis. Lyso-GL-3 levels decreased significantly in the first 3 months of ERT initiation and remained relatively stable thereafter in 3 patients. The Lyso-GL-3 level was decreased, but renal impairment continued to progress in 1 patient treated with agalsidase alpha. The clinical manifestations of FD in childhood are diverse, and it is necessary to make a definite diagnosis by combining family history, enzyme activity, biomarkers, gene testing and other indicators. Pedigree screening and high-risk population screening are helpful for early identification, early diagnosis and early treatment. No serious adverse reactions were found during the short-term treatment with agalsidase alpha and beta.

Fabry Disease, a Rare Disorder with Cardiac Manifestations. The Problem of Diagnosis and Treatment: a Literature Review

Fabry disease (FD) is an X-linked lysosomal storage disease caused by a mutation in the gene encoding α-galactosidase A and leads to reduced activity or complete absence of this enzyme, which causes the accumulation of globotriaosylceramide (Gb3) and its deacylated form (lyso-Gb3) in cells of the whole body. FD can occur both with multisystem manifestations, including damage to the nervous system, kidneys, and skin, and can affect only the heart. Cardiac involvement is a major cause of poor quality of life and death in patients with FD and an underrecognized cause of heart failure with preserved ejection fraction and ventricular arrhythmias in men over 30 years of age and women over 40 years of age. Cardiac damage begins at an early age, progresses subclinically until the appearance of significant symptoms, and usually manifests as leftventricular hypertrophy, mimicking hypertrophic cardiomyopathy.&#x0D; After the introduction of enzyme replacement therapy, early recognition of FD and differential diagnosis with other causes of leftventricular hypertrophy have become crucial to limit the progression of the disease. Recent advances in the understanding of cardiac pathophysiology and imaging have improved diagnostic and therapeutic approaches to the cardiac manifestations of this pathology.&#x0D; Modern achievements in the study of cardiac manifestations of FD have made it possible to significantly improve diagnostic and therapeutic approaches, in particular, in relation to the identification of pathogenetic mechanisms of organ damage and early disruption of their function. A better understanding of secondary pathogenic pathways, such as myocardial inflammation, may influence future therapeutic strategies and timely diagnosis of FD.&#x0D; Delay in diagnosis and untimely initiation of treatment remain critical problems for many patients with FD, especially for patients with late-onset cardiovascular manifestations, in whom treatment effects may be more limited and ineffective.&#x0D; Cooperation between specialists in genetic diseases and cardiologists remains important to identify patients before the appearance of cardiac symptoms in order to obtain maximum therapeutic effects.

D313Y Variant in Fabry Disease: A Systematic Review and Meta-analysis.

There is accumulating evidence in the literature indicating a strong correlation between Fabry disease (FD) phenotypes and specific sequence variations in the Galactosidase Alpha (GLA) gene. Among them, the potential pathogenicity and clinical relevance of D313Y variation in patients with FD remain debated. We performed a systematic review and meta-analysis of studies reporting D313Y as single occurring variant in the GLA gene and sought to evaluate (1) the prevalence of D313Y variation in different populations with or without clinical manifestations of FD, (2) the clinical FD phenotype in D313Y-positive patients, and (3) the proportion of D313Y-positive patients presenting abnormal laboratory findings (alpha-galactosidase-A deficiency or globotriaosylceramide accumulation). Forty cohorts comprising 211 individuals with D313Y variation among 42,723 participants with available GLA gene-sequencing data were included. Patients highly suspected for FD had a higher prevalence of D313Y variation (4.9%, 95% CI 1.6%-9.9%; I2 = 95.5%) compared with the general population (0%, 95% CI 0%-0.1%; I2 = 1.9%; p = 0.004). The prevalence of D313Y variation was 0.6% (95% CI 0.3%-1%; I2 = 74.1%), 0.4% (95% CI 0.2%-0.7%; I2 = 0%), and 0.3% (95% CI 0.2%-0.4%; I2 = 0%) in patients presenting with neurologic, cardiac, or renal manifestations, respectively. D313Y was associated with a milder, late-onset FD phenotype, as indicated by the mean patient age of 51 years (95% CI 44-59; I2 = 94%) and the evidence of alpha-galactosidase A deficiency and globotriaosylceramide accumulation in 26.7% (95% CI 15.3%-40%; I2 = 34%) and 16.2% (95% CI 8%-26.4%; I2 = 35%) of cases, respectively. D313Y-positive patients displayed predominantly neurologic FD manifestations (58.1%, 95% CI 37.7%-77.1%; I2 = 78%), with central and peripheral nervous system (CNS/PNS) involvement noted in 28.2% (95% CI 15.4%-43.2%; I2 = 51%) and 28.5% (95% CI 17.8%-40.5%; I2 = 61%) of cases, respectively. D313Y variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. Monitoring for CNS/PNS involvement is thus paramount to identify D313Y-positive patients with latent or early-FD pathology, which may qualify for enzyme-replacement therapy or chaperone treatment.

Neurological Manifestations of Fabry Disease: Literature Review

BACKGROUND: Fabry disease (FD) or Anderson FD is a hereditary disease belonging to the group of lysosomal storage diseases caused by decreased or absent activity of the enzyme α-galactosidase A. Enzyme deficiency leads to accumulation of glycospholipids in the lysosomes of cells of various organs, including the heart, kidneys, nervous system, and vascular endothelium. The complexity of the diagnosis of FD is due to the variety of its symptoms, the simultaneous involvement of many organs and systems. At present, possible pathogenetic treatment of the disease is enzyme replacement therapy, but its effectiveness is reduced in the later stages of the disease, when there are irreversible abnormal changes in vital organs and systems. In this regard, an urgent task is the early diagnosis of FD. AIM: Determination of neurological manifestations of FD as well as clinical criteria for screening for FD. MATERIALS AND METHODS: We analyzed cohort studies, randomized controlled trials, systematic reviews and meta-analyses, case-control studies, and case series from scientific medical databases: PubMed, Web of Science, Google Scholar in Russian, and English languages. CONCLUSION: The authors found that lesions of the nervous system in FD are detected in more than 80% of patients and can manifest as isolated or combined lesions of both the central and peripheral and autonomic nervous systems.

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.

Fabry disease - a genetically conditioned extremely rare disease with a very unusual course.

Fabry disease (FD) is a rare lysosomal storage disease. FD is caused by the presence of a deleterious mutation in the GLA gene encoding the enzyme alpha galactosidase A (αGAL A) on the X chromosome. The accumulation of Gb3 and lyso-GL-3 in nerve fiber cells, endothelium, vascular muscle cells, mesangial cells, podocytes, renal tubular epithelial cells and cardiomyocytes is the most important pathogenetic factor. The rate of disease progression depends on residual conserved enzymatic activity. In this article we present an example of a 25-year-old patient with FD with an initial asymptomatic course. The first manifestation of FD developed in the third decade of life. These include high blood pressure, urinary changes and grade V renal failure, requiring renal replacement therapy. The diagnosis was made very late, when renal failure and cerebro-cardiac complications occurred, including stroke and dangerous cardiac tamponade.

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.

High risk population screening for Fabry disease in hemodialysis patients in Vojvodina: Pilot study

Introduction/Objective. Fabry disease (FD) is an X-linked lysosomal storage disease that develops as a consequence of mutation in the alpha-galactosidase A (GLA) gene. There are more than 1080 known variants in the GLA gene. Some of them are pathogenic, but most of them are benign or represent the genetic change that can be classified as a genetic variant of unknown significance or simply be a representation of genetic polymorphism. There are two main features of FD, classic form and late-onset variants of disease. The main target organs in patients with FD are the kidneys, heart, and nervous system. Bearing in mind the fact that FD is a rare disease, the best way for active searching of patients is high-risk population screening, after which family screening for every proband case should be performed. Methods. In this paper, we present results of a multicentric pilot study that represents findings from the screening of hemodialysis patients for FD in six hemodialysis units in Vojvodina. Results. We have found one patient with benign mutation and 16 patients with genetic polymorphisms in GLA gene. We have learned that genetic changes in GLA gene can be frequent, but very rarely are of clinical significance and lead to manifestations of FD. Conclusion. Results of this screening study will give us important insights into our future work.

Beneficial screening of Fabry disease in patients with hypohidrosis.

Fabry disease (FD), which is a lysosomal storage disease resulting from a deficiency of α-galactosidase A, leads to the accumulation of globotriaosylceramide in various tissues and multiorgan impairment. Early diagnosis is important to improve long-term prognosis. Early clinical manifestations of FD include neuropathic pain, vascular skin lesions, and sweating abnormalities. Hypohidorosis is one of the clinical findings in the early stage of FD. However, there have been no studies on prospective screening of FD in patients with definitive diagnosis of hypohidrosis. We examined α-galactosidase A activity in white blood cells in 17 (one female and 16 male) patients with generalized hypohidorosis. Among 17 patients, one male patient (approximately 5.8%) had significantly reduced α-galactosidase A activity. He presented with a history of hypohidrosis with heat intolerance and neuropathic tingling pain in a warm environment from 6years ago. He had a few angiokeratoma on the trunk and extremities. Ultrastructural examination of skin biopsy from the angiokeratoma revealed lamellar inclusions in endothelial cells. Kidney biopsy revealed swollen podocytes and Gb3 deposition in the glomerulus, and urinalysis revealed mulberry bodies. He was finally diagnosed with FD and started on enzyme replacement therapy with agalsidase alpha in the early stage. In addition, his family screening led to find the patients of four additional FD. Screening for FD in patients with hypohidrosis may lead to efficient early detection of FD.

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 (&amp;gt;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.

High-Risk Screening for Fabry Disease: A Nationwide Study in Japan and Literature Review.

Fabry disease (FD) is an X-linked inherited disorder caused by mutations in the GLA gene, which encodes the lysosomal enzyme α-galactosidase A (α-Gal A). FD detection in patients at an early stage is essential to achieve sufficient treatment effects, and high-risk screening may be effective. Here, we performed high-risk screening for FD in Japan and showed that peripheral neurological manifestations are important in young patients with FD. Moreover, we reviewed the literature on high-risk screening in patients with renal, cardiac, and central neurological manifestations. Based on the results of this study and review of research abroad, we believe that FD can be detected more effectively by targeting individuals based on age. In recent years, the methods for high-risk screening have been ameliorated, and high-risk screening studies using GLA next-generation sequencing have been conducted. Considering the cost-effectiveness of screening, GLA sequencing should be performed in individuals with reduced α-Gal A activity and females with certain FD manifestations and/or a family history of FD. The findings suggest that family analysis would likely detect FD patients, although GLA sequencing of asymptomatic family members requires adequate genetic counseling.

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.

Fabry Cardiomyopathy: Current Practice and Future Directions.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficient galactosidase A enzyme and subsequent accumulation of glycosphingolipids throughout the body. The result is a multi-system disorder characterized by cutaneous, corneal, cardiac, renal, and neurological manifestations. Increased left ventricular wall thickness represents the predominant cardiac manifestation of FD. As the disease progresses, patients may develop arrhythmias, advanced conduction abnormalities, and heart failure. Cardiac biomarkers, point-of-care dried blood spot testing, and advanced imaging modalities including echocardiography with strain imaging and magnetic resonance imaging (MRI) with T1 mapping now allow us to detect Fabry cardiomyopathy much more effectively than in the past. While enzyme replacement therapy (ERT) has been the mainstay of treatment, several promising therapies are now in development, making early diagnosis of FD even more crucial. Ongoing initiatives involving artificial intelligence (AI)-empowered interpretation of echocardiographic images, point-of-care dried blood spot testing in the echocardiography laboratory, and widespread dissemination of point-of-care ultrasound devices to community practices to promote screening may lead to more timely diagnosis of FD. Fabry disease should no longer be considered a rare, untreatable disease, but one that can be effectively identified and treated at an early stage before the development of irreversible end-organ damage.

Abstract #1002422: Non Traumatic Fractures In Fabry Disease: A Case Report

Fabry disease (FD) is a rare X-linked inborn error of metabolism resulting from the deficiency of a- galactosidase A. It causes multi organ involvement including severe renal and cardiac manifestations. Bone involvement has been suggested in multiple studies, with osteoporosis being the leading bone manifestation in FD. We describe here a case of FD with multiple non traumatic fractures.