[Lysosomal storage disorders - Fabry disease and Gaucher disease]. / Lysosomale Speicherkrankheiten ­ Morbus Fabry und Morbus Gaucher.

Lysosomal storage disorders (LSD) are a heterogenous group of inborn errors of metabolism due to lysosomal malfunction. LSDs affect 1 in 5000 live births, albeit every LSD itself has a low incidence. The most common LSDs are Fabry disease and Gaucher disease. The underlying cause mainly is an enzyme deficiency but may also be due to defects in transport or activation proteins, which result in progressive intra- and extra-lysosomal accumulation of undegraded storage material. The lysosomes play a key role in degradation and cellular recycling of macromolecules. Besides disturbance of cellular function, substrate accumulation may result in secondary toxic and/or inflammatory processes. For treatment of Fabry and Gaucher disease, several therapeutic approaches are approved including enzyme replacement therapy, chaperon therapy for Fabry disease and substrate reduction therapy for Gaucher disease.

Resistive index of central retinal artery, aortic arterial stiffness and OCTA correlated parameters in the early stage of fabry disease.

This study aimed to evaluate the impact of Fabry disease (FD) on retinal microvasculature using optical coherence tomography angiography (OCTA), arterial stiffness, and the resistive index (RI) of the central retinal artery (CRA) in early disease stages. Twenty-nine genetically confirmed FD patients and twenty-six healthy controls were enrolled. Vessel density (VD) values of the superficial, deep, and choriocapillaris plexuses (SCP, DCP, and CC) were measured via OCTA. CRA RI was studied using color Doppler and grayscale sonography, and aortic pulse wave velocity (PWV) was assessed with the Complior method. CRA RI was significantly lower in the control group compared to the Fabry group (p < 0.001). Central VD was found to be significantly higher in the control group compared to the Fabry group in all the retinal layers (SCP (p < 0.001), DCP (p < 0.005), CC (p < 0.001)). PWV was significantly higher in the Fabry group than in the control group (p = 0.03). Fabry disease patients demonstrate elevated arterial stiffness, increased CRA RI, and diminished retinal microvascular density compared to healthy controls, indicating early ocular damage. Continuous monitoring and targeted screening for organ impairment are crucial in FD management. Identifying biomarkers for assessing ocular vascular involvement and treatment response is imperative. Further research is needed.

Evaluation of global and regional myocardial work by echocardiography in patients with Fabry disease.

BACKGROUND: This study aimed to quantitatively evaluate the left ventricular global and regional myocardial work of patients in Fabry disease (FD) by echocardiographic pressure-strain loop (PSL) analysis. RESULTS: The study included 48 patients with FD and 48 healthy controls matched for age and sex. According to the presence/absence of left ventricular hypertrophy (LVH), the patients with FD were divided into an LVH + group and an LVH- group. Left ventricular blood pressure was estimated noninvasively according to echocardiographic valvular events and systolic pressure in the brachial artery. Left ventricular myocardial work parameters were acquired by echocardiographic pressure-strain loop analysis. The FD groups had a significantly lower global longitudinal strain (GLS), global work index, global work efficiency (GWE), global constructive work and higher global waste work than the control group (P < .05). Regional analysis showed that all segmental myocardial waste work increased and myocardial work efficiency decreased in the LVH + group than in the LVH- group (P < .05). Segmental longitudinal strain, myocardial work index, and myocardial constructive work were markedly lower in the basal and middle segments (P < .05) and preserved in the apical segments. Multivariate analysis revealed that GWE and GLS were significant related to LVH. CONCLUSIONS: Myocardial work analysis can be used to assess global and regional myocardial work in patients with FD. In this study, GLS and GWE were reduced in patients with FD and associated with the presence of LVH. Basal and middle myocardial work decreased in relation to the LVH, while apical myocardial work remained, which added value to explore the distribution of myocardial impairment.

Fabry Disease Rat Model Develops Age- and Sex-Dependent Anterior Segment Ocular Abnormalities.

Purpose: Fabry disease is an X-linked lysosomal storage disorder that results in multi-systemic renal, cardiovascular, and neuropathological damage, including in the eyes. We evaluated anterior segment ocular abnormalities based on age, sex (male and female), and genotype (wild-type, knockout [KO] male, heterozygous [HET] female, and KO female) in a rat model of Fabry disease. Methods: The α-Gal A KO and WT rats were divided into young (6-24 weeks), adult (25-60 weeks), and aged (61+ weeks) groups. Intraocular pressure (IOP) was measured. Eyes were clinically scored for corneal and lens opacity as well as evaluated for corneal epithelial integrity and tear break-up time (TBUT). Anterior chamber depth (ACD) and central corneal thickness (CCT) using anterior segment-optical coherence tomography (AS-OCT). Results: The Fabry rats showed an age-dependent increase in IOP, predominantly in the male genotype. TBUT was decreased in both male and female groups with aging. Epithelial integrity was defective in KO males and HET females with age. However, it was highly compromised in KO females irrespective of age. Corneal and lens opacities were severely affected irrespective of sex or genotype in the aging Fabry rats. AS-OCT quantification of CCT and ACD also demonstrated age-dependent increases but were more pronounced in Fabry versus WT genotypes. Conclusions: Epithelial integrity, corneal, and lens opacities worsened in Fabry rats, whereas IOP and TBUT changes were age-dependent. Similarly, CCT and ACD were age-related but more pronounced in Fabry rats, providing newer insights into the anterior segment ocular abnormalities with age, sex, and genotype in a rat model of Fabry disease.

Inflammation, Oxidative Stress, and Endothelial Dysfunction in the Pathogenesis of Vascular Damage: Unraveling Novel Cardiovascular Risk Factors in Fabry Disease.

Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A (GLA) gene, disrupts lysosomal function, leading to vascular complications. The accumulation of globotriaosylceramide (Gb3) in arterial walls triggers upregulation of adhesion molecules, decreases endothelial nitric oxide synthesis, and induces reactive oxygen species production. This cascade results in fibrotic thickening, endothelial dysfunction, hypercontractility, vasospasm, and a pro-thrombotic phenotype. AFD patients display increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating heightened cardiovascular risk. Nailfold capillaroscopy (NFC) shows promise in diagnosing and monitoring microcirculatory disorders in AFD, though it remains underexplored. Morphological evidence of AFD as a storage disorder can be demonstrated through electron microscopy and immunodetection of Gb3. Secondary pathophysiological disturbances at cellular, tissue, and organ levels contribute to the clinical manifestations, with prominent lysosomal inclusions observed in vascular, cardiac, renal, and neuronal cells. Chronic accumulation of Gb3 represents a state of ongoing toxicity, leading to increased cell turnover, particularly in vascular endothelial cells. AFD-related vascular pathology includes increased renin-angiotensin system activation, endothelial dysfunction, and smooth muscle cell proliferation, resulting in IMT increase. Furthermore, microvascular alterations, such as atypical capillaries observed through NFC, suggest early microvascular involvement. This review aims to unravel the complex interplay between inflammation, oxidative stress, and endothelial dysfunction in AFD, highlighting the potential connections between metabolic disturbances, oxidative stress, inflammation, and fibrosis in vascular and cardiac complications. By exploring novel cardiovascular risk factors and potential diagnostic tools, we can advance our understanding of these mechanisms, which extend beyond sphingolipid accumulation to include other significant contributors to disease pathogenesis. This comprehensive approach can pave the way for innovative therapeutic strategies and improved patient outcomes.

How Do Physical Activity and Exercise Affect Fabry Disease? Exploring a New Opportunity.

BACKGROUND: Fabry disease (FD) is a multisystem, monogenic, X-linked storage disorder caused by mutations in the GLA gene, resulting in reduced alfa-galactosidase A enzyme activity. This effect leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide, in various tissues, including the heart, kidney, vasculature, smooth muscle, and peripheral nervous system. Hemizygous males are usually more severely affected than females, in whom random inactivation of an X chromosome may lead to variable phenotype. SUMMARY: Among the manifestations of FD, exercise intolerance is commonly diagnosed but often underestimated, even though it significantly limits quality of life, especially in young patients. This review primarily discusses the various pathophysiological mechanisms involved in exercise intolerance in FD patients, such as altered muscle composition, compromised cardiopulmonary framework, and peripheral neuropathy. Secondarily, it explores the potential effect of available therapy, including enzyme replacement therapy and chaperone therapy (migalastat), in reducing exercise intolerance while considering the potential impact of physical activity and exercise training as adjunctive treatments. CONCLUSION: Exercise intolerance has a major impact on the well-being of people with FD. Exercise training can play an important role in addition to drug therapy.

Oxidative stress and its role in Fabry disease.

Fabry disease is a rare X-linked disease characterized by deficient expression and activity of alpha-galactosidase A with consequent lysosomal accumulation of glycosphingolipids, particularly globotriaosylceramide in various organs. Currently, enzyme replacement therapy with recombinant human α-galactosidase is the cornerstone of the treatment of Fabry patients, although in the long term enzyme replacement therapy fails to halt disease progression, in particular in case of late diagnosis. This suggests that the adverse outcomes cannot be justified by the lysosomal accumulation of glycosphingolipids alone, and that additional therapies targeted at further pathophysiologic mechanisms might contribute to halting the progression of cardiac, cerebrovascular and kidney disease in Fabry patients. Recent evidence points toward the involvement of oxidative stress, oxidative stress signaling and inflammation in the pathophysiology of cardio cerebrovascular and kidney damage in Fabry patients. This review reports the current knowledge of the involvement of oxidative stress in Fabry disease, which clearly points toward the involvement of oxidative stress in the pathophysiology of the medium to long-term cardio-cerebrovascular-kidney damage of Fabry patients and summarizes the antioxidant therapeutic approaches currently available in the literature. This important role played by oxidative stress suggests potential novel additional therapeutic interventions by either pharmacologic or nutritional measures, on top of enzyme replacement therapy, aimed at improving/halting the progression of cardio-cerebrovascular disease and nephropathy that occur in Fabry patients.

Left ventricular hypertrophy: do not forget Fabry disease. Diagnostic work-up and differential diagnosis.

BACKGROUND: Left ventricular (LV) hypertrophy is a common clinical finding. Differential diagnosis includes Fabry disease, a rare and progressive, but treatable storage disease caused by deficiency of α-galactosidase A. However, diagnosis of Fabry is often hampered by its clinical heterogeneity, LV hypertrophy phenocopies and unawareness of the clinician. METHODS: This review summarises clinical data, family history, electrocardiogram (ECG) and imaging (echocardiogram and cardiovascular magnetic resonance (CMR)) characteristics to differentiate aetiologies of LV hypertrophy including clues for the diagnosis of Fabry. RESULTS: LV hypertrophy is a consequence of pressure overload mostly, but differential diagnosis includes hypertrophic cardiomyopathy and infiltrative diseases. Clinical data, ECG, type and degree of LV hypertrophy, functional and tissue characteristics differ among aetiologies. LV hypertrophy in Fabry is progressive and mostly concentric but may copy any hypertrophic cardiomyopathy. Dependent on residual alfa-galactosidase A enzyme activity, degree of LV hypertrophy in Fabry may vary. Initially, low myocardial CMR T1-map values are calculated. At a later stage, midwall late gadolinium enhancement of the inferolateral LV wall may occur. Global longitudinal strain may be depressed in the inferolateral wall. Voltage criteria for LV hypertrophy and short PQ interval are common. Right ventricular (RV) hypertrophy is frequent. In addition, multisystemic symptoms including neuropathic pain, hypohidrosis, proteinuria, renal insufficiency and familial young stroke are pointing to Fabry. CONCLUSIONS: LV hypertrophy should raise suspicion of Fabry disease, especially if LV hypertrophy is unexplained and/or associated with RV hypertrophy. In Fabry, LV hypertrophy may be heterogeneous and mimic any hypertrophic cardiomyopathy. ECG, multisystemic symptoms and imaging may provide clues for Fabry.

Prognostic Implications of Left Ventricular Hypertrophy and Mechanical Function in Fabry Disease: A Longitudinal Cohort Study.

BACKGROUND: The prognostic value of different grades of left ventricular hypertrophy (LVH) and left ventricular (LV) mechanical function in Fabry disease is unclear. We aimed to evaluate the association between the severity of LVH, LV mechanical function, and clinical outcomes in Fabry disease. METHODS: We conducted a retrospective cohort study from a single-center registry of adult patients with Fabry disease. Left ventricular mass index (LVMI) was measured by echocardiography. The severity of LVH was categorized by LVMI using the sex-specific cutoff values. Left ventricular mechanical function was measured as LV global longitudinal strain (GLS) by speckle-tracking analysis. The primary outcome was a composite of major adverse cardiovascular events (MACE) at 5 years, including heart failure hospitalization, sustained ventricular tachycardia, acute ischemic stroke, and all-cause mortality. RESULTS: The study included 268 patients (age 50.4 ± 15.4 years, men 46.6%) with Fabry disease (83.2% IVS4+919G > A mutation), and 106 patients (39.6%) had LVH. Patients with mild, moderate, or severe LVH had 5-year MACE rates of 7.4%, 10%, and 30.5%, respectively (P < .001). Moreover, patients with impaired LV GLS (<14.1%) had a higher 5-year MACE rate than those with preserved LV GLS (32.1% vs 2.4%, P < .001). Severe LVH was an independent predictor of MACE compared with absence of LVH (adjusted hazard ratio, 12.73; 95% CI, 1.3-124.71; P = .03), after adjusting for age, sex, hypertension, hyperlipidemia, atrial fibrillation, renal function, average E/e', enzyme replacement therapy, and LV GLS. Patients with severe LVH and impaired LV GLS had the highest incidence for MACE (log-rank P < .05), irrespective of sex, genotypes, and whether receiving enzyme replacement therapy or not. CONCLUSIONS: Sex-specific grading of LVH by LVMI is practical for risk stratification in patients with Fabry disease, and impaired LV GLS further refines the prognostication.

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

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 (aged ≥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 (aged 35.8±13.8 years; 61 (29%) males) had no LVH at first evaluation. During a median follow-up of 9.4 years (IQR 4.7-12.7), 55 patients (24.6%) developed LVH. The estimated incidence of LVH was 11.3% (95% CI 6.5% to 16.1%) at 5 years, 29.1% (95% CI 21.5% to 36.7%) at 10 years and 45.0% (95% CI 33.8% to 62.4%) at 15 years of follow-up. On multivariable analysis, independent predictors for LVH development were age (HR 1.04 (95% CI 1.02 to 1.06) per 1-year increase, p<0.001), male sex (HR 2.90 (95% CI 1.66 to 5.09), p<0.001) and an abnormal ECG (HR 3.10 (95% CI 1.72 to 5.57), p<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<0.001). CONCLUSIONS: Approximately one-quarter of patients with FD developed LVH during follow-up. Age, male sex and ECG abnormalities were associated with a higher risk of developing LVH in patients with FD.

Arrhythmogenesis in Fabry Disease.

PURPOSE OF REVIEW: Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate. RECENT FINDINGS: There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual's risk of arrhythmia in FD. In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.

Fabry disease Schwann cells release p11 to induce sensory neuron hyperactivity.

Patients with Fabry disease suffer from chronic debilitating pain and peripheral sensory neuropathy with minimal treatment options, but the cellular drivers of this pain are unknown. Here, we propose a mechanism we believe to be novel in which altered signaling between Schwann cells and sensory neurons underlies the peripheral sensory nerve dysfunction we observed in a genetic rat model of Fabry disease. Using in vivo and in vitro electrophysiological recordings, we demonstrated that Fabry rat sensory neurons exhibited pronounced hyperexcitability. Schwann cells probably contributed to this finding because application of mediators released from cultured Fabry Schwann cells induced spontaneous activity and hyperexcitability in naive sensory neurons. We examined putative algogenic mediators using proteomic analysis and found that Fabry Schwann cells released elevated levels of the protein p11 (S100A10), which induced sensory neuron hyperexcitability. Removal of p11 from Fabry Schwann cell media caused hyperpolarization of neuronal resting membrane potentials, indicating that p11 may contribute to the excessive neuronal excitability caused by Fabry Schwann cells. These findings demonstrate that sensory neurons from rats with Fabry disease exhibit hyperactivity caused in part by Schwann cell release of the protein p11.

A Case of a 49-Year-Old Man with Nonclassical Fabry Disease Diagnosed by Renal Biopsy.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficiency of α-GLA activity, leading to major organ failure and premature mortality. According to different disease courses, FD can be divided into classical and nonclassical phenotypes. The nonclassical FD phenotype is always absent of characteristic symptoms, which makes identifying it challenging. This article presents a 49-year-old man with a 10-year history of proteinuria and decreased glomerular filtration rate. An electrocardiogram showed a complete right bundle branch block and abnormal Q waves in high lateral, accompanied by dramatically elevated ST segment. Consequently, a renal biopsy was performed. Vacuolation was found in many podocytes in light microscopic examinations. Similarly, a myelin-like structure was detected by electron microscopy. Pathological findings were most consistent with FD. Consequently, genetic analysis, p.R301Q (c.902G>A [p.Arg301Gln]), confirmed the FD diagnosis. Angiotensin receptor blocker and traditional Chinese medicine, but not enzyme replacement therapy, were prescribed due to financial constraints. The patient had stabilization of kidney disease 6 months later. The case showed that renal biopsy should be performed in patients with cardiac and renal symptoms, which could contribute toward the correct diagnosis for nonclassical FD type.

Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation.

Fabry disease (FD) is an X-linked multisystemic lysosomal storage disease due to a deficiency of α-galactosidase A (GLA/AGAL). Progressive cellular accumulation of the AGAL substrate globotriaosylceramide (Gb3) leads to endothelial dysfunction. Here, we analyzed endothelial function in vivo and in vitro in an AGAL-deficient genetic background to identify the processes underlying this small vessel disease. Arterial stiffness and endothelial function was prospectively measured in five males carrying GLA variants (control) and 22 FD patients under therapy. AGAL-deficient endothelial cells (EA.hy926) and monocytes (THP1) were used to analyze endothelial glycocalyx structure, function, and underlying inflammatory signals. Glycocalyx thickness and small vessel function improved significantly over time (p<0.05) in patients treated with enzyme replacement therapy (ERT, n=16) and chaperones (n=6). AGAL-deficient endothelial cells showed reduced glycocalyx and increased monocyte adhesion (p<0.05). In addition, increased expression of angiopoietin-2, heparanase and NF-κB was detected (all p<0.05). Incubation of wild-type endothelial cells with pathological globotriaosylsphingosine concentrations resulted in comparable findings. Treatment of AGAL-deficient cells with recombinant AGAL (p<0.01), heparin (p<0.01), anti-inflammatory (p<0.001) and antioxidant drugs (p<0.05), and a specific inhibitor (razuprotafib) of angiopoietin-1 receptor (Tie2) (p<0.05) improved glycocalyx structure and endothelial function in vitro. We conclude that chronic inflammation, including the release of heparanases, appears to be responsible for the degradation of the endothelial glycocalyx and may explain the endothelial dysfunction in FD. This process is partially reversible by FD-specific and anti-inflammatory treatment, such as targeted protective Tie2 treatment.

Mechanisms of Neutralizing Anti-drug Antibody Formation and Clinical Relevance on Therapeutic Efficacy of Enzyme Replacement Therapies in Fabry Disease.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A (AGAL/GLA) gene. The lysosomal accumulation of the substrates globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) results in progressive renal failure, cardiomyopathy associated with cardiac arrhythmia, and recurrent strokes, significantly limiting life expectancy in affected patients. Current treatment options for FD include recombinant enzyme-replacement therapies (ERTs) with intravenous agalsidase-α (0.2 mg/kg body weight) or agalsidase-ß (1 mg/kg body weight) every 2 weeks, facilitating cellular Gb3 clearance and an overall improvement of disease burden. However, ERT can lead to infusion-associated reactions, as well as the formation of neutralizing anti-drug antibodies (ADAs) in ERT-treated males, leading to an attenuation of therapy efficacy and thus disease progression. In this narrative review, we provide a brief overview of the clinical picture of FD and diagnostic confirmation. The focus is on the biochemical and clinical significance of neutralizing ADAs as a humoral response to ERT. In addition, we provide an overview of different methods for ADA measurement and characterization, as well as potential therapeutic approaches to prevent or eliminate ADAs in affected patients, which is representative for other ERT-treated lysosomal storage diseases.

Pathogenesis and Molecular Mechanisms of Anderson-Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies.

Anderson-Fabry disease (AFD) is a rare disease with an incidenceof approximately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) is the element characterizing Fabry disease due to a hereditary deficiency α-galactosidase A (GLA) enzyme. The accumulation of Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition of sphingolipids occurs in the autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system cells, and myocardial cells, resulting in organ failure. This manuscript will review the molecular pathogenetic pathways involved in Anderson-Fabry disease and in its organ damage. Some studies reported that inhibition of mitochondrial function and energy metabolism plays a significant role in AFD cardiomyopathy and in kidney disease of AFD patients. Furthermore, mitochondrial dysfunction has been reported as linked to the dysregulation of the autophagy-lysosomal pathway which inhibits the mechanistic target of rapamycin kinase (mTOR) mediated control of mitochondrial metabolism in AFD cells. Cerebrovascular complications due to AFD are caused by cerebral micro vessel stenosis. These are caused by wall thickening resulting from the intramural accumulation of glycolipids, luminal occlusion or thrombosis. Other pathogenetic mechanisms involved in organ damage linked to Gb3 accumulation are endocytosis and lysosomal degradation of endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via a clathrin-dependent process. This process represents a crucial event in endothelial dysfunction. Several studies have identified the deacylated form of Gb3, globotriaosylsphingosine (Lyso-Gb3), as the main catabolite that increases in plasma and urine in patients with AFD. The mean concentrations of Gb3 in all organs and plasma of Galactosidase A knockout mice were significantly higher than those of wild-type mice. The distributions of Gb3 isoforms vary from organ to organ. Various Gb3 isoforms were observed mainly in the kidneys, and kidney-specific Gb3 isoforms were hydroxylated. Furthermore, the action of Gb3 on the KCa3.1 channel suggests a possible contribution of this interaction to the Fabry disease process, as this channel is expressed in various cells, including endothelial cells, fibroblasts, smooth muscle cells in proliferation, microglia, and lymphocytes. These molecular pathways could be considered a potential therapeutic target to correct the enzyme in addition to the traditional enzyme replacement therapies (ERT) or drug chaperone therapy.

Prompt Agalsidase Alfa Therapy Initiation is Associated with Improved Renal and Cardiovascular Outcomes in a Fabry Outcome Survey Analysis.

BACKGROUND: The timing of enzyme replacement therapy initiation in patients with Fabry disease is hypothesized to be critical. In this study, we used Fabry Outcome Survey data to assess the impact of prompt versus delayed initiation of treatment with agalsidase alfa on cardiovascular and renal events in patients with Fabry disease. METHODS: Available genetic data at baseline were used to define patients with mutations associated with classical versus late-onset Fabry disease. Time to cardiovascular or renal events, from treatment initiation until 120 months, was compared for patients in prompt versus delayed groups. "Prompt" was defined as treatment initiation <24 months from symptom onset (analysis A) or diagnosis (analysis B), and "delayed" was defined as ≥24 months from symptom onset (analysis A) or diagnosis (analysis B). Kaplan-Meier curves and Log rank tests compared event-free probabilities and time to first event. Multivariate Cox regression estimated hazard ratios (HRs). RESULTS: Analysis by time from symptom onset included 1374 patients (172 prompt, 1202 delayed). In a multivariate Cox regression analysis, prompt versus delayed treatment initiation significantly reduced the probability of cardiovascular (HR=0.62; P<0.001) and renal (HR=0.57; P=0.001) events. History of cardiovascular or renal events was associated with increased risk of respective events. Analysis by time from diagnosis included 2051 patients (1006 prompt, 1045 delayed). In a multivariate Cox regression analysis, prompt treatment initiation significantly reduced the probability of cardiovascular events (HR=0.83; P=0.003) after adjusting for history of cardiovascular events, sex, and age at treatment initiation. Univariate analysis showed that the probability of renal events was significantly lower in the prompt group (P=0.018); this finding was attenuated in the multivariate Cox regression analysis. CONCLUSION: This analysis suggests that prompt treatment initiation with agalsidase alfa provided better renal and cardiovascular outcomes than delayed treatment in patients with Fabry disease.

Altered pupillary light responses are associated with the severity of autonomic symptoms in patients with Fabry disease.

Symptoms of autonomic dysfunction are common in Fabry disease. In this study we aimed to evaluate alterations in the pupillary response to white light stimulation in patients with Fabry disease and their association with the severity of autonomic symptoms. Fourteen consecutive patients with Fabry disease and 14 healthy control participants were enrolled in this cross-sectional study. The Mainz Severity Score Index (MSSI) was used to measure the severity of Fabry disease and the Composite Autonomic Symptom Scale 31 (COMPASS 31) questionnaire was used to evaluate the severity of autonomic symptoms. The pupil light responses were assessed with an infrared dynamic pupillometry unit. There were significant reductions in the amplitude (P = 0.048) and duration (P = 0.048) of pupil contraction, and the latency of pupil dilation (P = 0.048) in patients with Fabry disease compared to control subjects. The total weighted COMPASS 31 score correlated with MSSI (r = 0.592; P = 0.026) and the duration of pupil dilation (ρ = 0.561; P = 0.037). The pupillomotor weighted sub-score of the COMPASS 31 correlated inversely with the duration of pupil contraction (r = - 0.600; P = 0.023) and latency of pupil dilation (ρ = - 0.541; P = 0.046), and directly with the duration of pupil dilation (ρ = 0.877; P < 0.001) and MSSI (r = 0.533; P = 0.049). In conclusion, abnormal pupillary function is demonstrated in patients with Fabry disease, which is associated with the severity of autonomic symptoms.