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Background: The aim of our multicenter study was to investigate the implementation of the European Fabry guidelines on therapeutic recommendations in female patients with Fabry disease (FD) and to analyze the impact of enzyme replacement therapy (ERT) in treated and untreated females. Results: Data from 3 consecutive visits of 159 female FD patients from 6 Fabry centers were retrospectively analyzed. According to their treatment, patients were separated in 3 groups (untreated, n = 71; newly ERT-treated, n = 47; long-term ERT-treated, n = 41). Clinical presentation and laboratory data, including plasma globotriaosylsphingosine (lyso-Gb3) levels were assessed. The observation time ranged from 49 to 62 months. ∼90% of female patients treated with ERT presented with at least one organ manifestation justifying treatment according to current European guidelines. Untreated females showed a less severe disease load with less FD-typical organ damage. All groups presented with a stable cardiac status (all p > 0.05) over time. ERT-treated females presented with a slight yearly loss of estimated glomerular filtration (eGFR) over time (both p < 0.05), which was comparable to the natural decline for this age. Plasma lyso-Gb3 levels were higher in ERT-treated females and decreased by 0.95 [-4.44 to 4.08] ng/ml/year (p = 0.0002) in those who were newly ERT-treated. Conclusions: Severely affected females with FD who were treated with ERT, and less severely affected untreated females, showed a broadly stable disease course over 5 years. The treatment decisions were largely based on the European guidelines for FD. In untreated females, it is crucial to explore if organ involvement is FD-related in order to make the correct treatment decision. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) leads to significant morbidity and mortality, which may indicate accelerated ageing. However, it is still unclear whether there is a relationship between telomere length (TL), a marker of biological ageing, and disease outcome. We aimed to examine the relationship between leukocyte TL (LTL) dynamics and the presence of advanced disease stages and/or late complications of FD, including hypertrophic cardiomyopathy, nephropathy and stroke, both cross-sectionally and longitudinally. DNA was extracted from peripheral blood leukocytes and quantitative PCR was utilized to determine relative LTL in 99 Fabry patients. In the longitudinal analysis, we included 50 patients in whom at least three measurements were performed over a period of 5–10 years. The results showed a significant inverse correlation between LTL and age (ρ = −0.20, p = 0.05). No significant differences in LTL were found between females and males (p = 0.79) or between patients receiving disease-specific therapy and those without (p = 0.34). In a cross-sectional analysis, no association was found between the presence (p = 0.15) or number (p = 0.28) of advanced stages of the disease and/or late complications and LTL. Similarly, in a longitudinal analysis, no difference in LTL dynamics was found regarding the presence (p = 0.16) of advanced stage organ involvement and/or late complications or their number. These findings indicate that LTL dynamics in adulthood may not be a reliable indicator of disease outcomes in Fabry patients. Therefore, LTL may more accurately reflect the disease burden in early life, when TL is primarily determined. [ABSTRACT FROM AUTHOR]

The p.Arg301Gln variant in the α -galactosidase A gene (GLA) has been poorly described in the literature. The few reports show controversial information, with both classical and nonclassical Anderson–Fabry Disease (AFD) presentation patterns. The aim of this study was to analyze the penetrance, clinical phenotype, and biochemical profile of an international cohort of patients carrying the p.Arg301Gln genetic variant in the GLA gene. This was an observational, international, and retrospective cohort case series study of patients carrying the p.Arg301Gln variant in the GLA gene associated with AFD disease. Forty-nine p.Arg301Gln GLA carriers, 41% male, were analyzed. The penetrance was 63% in the entire cohort and 1.5 times higher in men. The mean age of symptoms onset was 41 years; compared to women, men presented symptoms earlier and with a shorter delay to diagnosis. The typical clinical triad—cornea verticillate, neuropathic pain, and angiokeratomas—affected only 20% of the cohort, with no differences between genders. During follow-up, almost 20% of the patients presented some type of nonfatal cardiovascular and renal event (stroke, need for dialysis, heart failure, and arrhythmias requiring intracardiac devices), predominantly affecting men. Residual levels were the most common finding of α-GAL A enzyme activity, only a few women had a normal level; a small proportion of men had undetectable levels. The incidence of combined outcomes including all causes of death was 33%, and the cumulative incidence of all-cause mortality was 9% at the follow-up. Patients carrying the p.Arg301Gln GLA variant have a high penetrance, with predominantly cardiorenal involvement and clinical onset of the disease in middle age. Only a small proportion showed the classic clinical presentation of AFD. As in other X-linked diseases, males were more affected by severe cardiovascular and renal events. This genotype–phenotype correlation could be useful from a practical clinical point of view and for future decision making. [ABSTRACT FROM AUTHOR]

The assessment of late gadolinium enhancement (LGE) and left ventricular hypertrophy (LVH) by cardiac magnetic resonance (CMR) as diagnostic and prognostic maker in Fabry disease is advancing. We aimed to investigate the impact of clinical characteristics and CMR findings on cardiac outcome in patients with FD. In this study 55 patients with genetically confirmed FD and available CMR imaging were included. The primary endpoint was defined as a composite of cardiac events including cardiac death, new occurrence of atrial fibrillation, heart failure, ventricular tachycardia and bradycardia requiring device insertion. During a median follow-up of 4.9 years (IQR 3.7–5.9), 9 patients (16.3%) reached the primary cardiac end point. The global amount of LGE was associated with an increased risk for primary endpoint in the univariate analysis (HR 1.4 per 10% increase in LGE, p = 0.002). However maximal wall thickness (MWT) was the sole independent predictor of the primary endpoint in a stepwise logistic regression model (HR 9.8 per mm increase in MWT, p < 0.0001). Kaplan-Meier analysis revealed significant difference in event free survival rate between patients with and without LVH (Long-rank p = 0.006) and in patients with and without LGE (Long-rank p < 0.001). Patients without LVH and LGE were free of adverse cardiac events. LVH and LGE detected by CMR were associated with adverse cardiac events in FD. In particular maximal wall thickness can be useful in cardiac risk stratification of FD patients. • In Fabry disease CMR findings can be used to identify patients with cardiac involvement. • Left ventricular hypertrophy and late gadolinium enhancement are associated with adverse cardiac events in Fabry disease. • Maximal wall thickness is a strong predictor of cardiac outcome in our study [ABSTRACT FROM AUTHOR]

Background: Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was associated with a stabilization of cardiac biomarkers and a reduction in left ventricular mass index, as measured by echocardiography. A recent study, using cardiac magnetic resonance (CMR) as the gold standard, found a stable course of myocardial involvement after 18 months of treatment with migalastat. Our study aimed to provide long-term CMR data for the treatment with migalastat. Methods: A total of 11 females and four males with pathogenic amenable GLA mutations were treated with migalastat and underwent 1.5T CMR imaging for routine treatment effect monitoring. The main outcome was a long-term myocardial structural change, reflected by CMR. Results: After migalastat treatment initiation, left ventricular mass index, end diastolic volume, interventricular septal thickness, posterior wall thickness, estimated glomerular filtration rate, and plasma lyso-Gb3 remained stable during the median follow-up time of 34 months (min.: 25; max.: 47). The T1 relaxation times, reflecting glycosphingolipid accumulation and subsequent processes up to fibrosis, fluctuated over the time without a clear trend. No new onset of late gadolinium enhancement (LGE) areas, reflecting local fibrosis or scar formation of the myocardium, could be detected. However, patients with initially present LGE showed an increase in LGE as a percentage of left ventricular mass. The median α-galactosidase A enzymatic activity increased from 37.3% (IQR 5.88–89.3) to 105% (IQR 37.2–177) of the lower limit of the respective reference level (p = 0.005). Conclusion: Our study confirms an overall stable course of LVMi in patients with FD, treated with migalastat. However, individual patients may experience disease progression, especially those who present with fibrosis of the myocardium already at the time of therapy initiation. Thus, a regular treatment re-evaluation including CMR is needed to provide the optimal management for each patient. [ABSTRACT FROM AUTHOR]

Background: Fabry disease (FD) is a potentially lethal lysosomal disorder with systemic vascular changes. Previous studies demonstrated retinal vascular involvement using optical coherence tomography angiography (OCTA) in affected patients; Aim: To analyze and quantify the retinal vasculature measuring vessel density (VD), vessel length density (VLD), and the ratio of VD to VLD (VD/VLD) in superficial capillary plexuses (SCP) and deep capillary plexuses (DCP) using OCTA in patients with FD and to show whether they differ from healthy controls (HC); Patients and methods: Single-center, retrospective, consecutive cohort study of patients with genetically proven FD. Patients underwent an ophthalmological examination including OCTA. VD, VLD, foveal avascular zone (FAZ), and the VD/VLD were compared to an HC group using a linear mixed model; Results: A statistically significant difference in the VLD and VD/VLD of DCP was observed between the two groups (p < 0.001). Using ROC curves with AUC and Youden's Index, a cut-off value for differentiating both groups using VD/VLD in DCP FD with high specificity and high sensitivity was established; Conclusions: FD and HC groups seem to be separable using the VD/VLD ratio in DCP. This new biomarker might differentiate changes in the retinal microvasculature that are not detectable by VD or VLD alone. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene leading to deficiency of α-galactosidase A (α-gal A). This results in progressive multisystemic glycosphingolipid accumulation, especially globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). Enzyme replacement therapy with two recombinant enzymes, agalsidase-α and –β is approved for two different dosages. However, little is known about which enzyme is more effective in decreasing the metabolite load in male and female patients with the classic form of the disease. In this prospective observational study, 14 consecutive adult Fabry patients (10 males) with a classic GLA -mutation, were switched from agalsidase–α to agalsidase–β at the respective licensed doses. Lyso-Gb3 levels were measured before the switch and for a period of 12 months after the switch in dried blood spots by tandem mass spectrometry. Mean age at start of the switch was 36.7 ± 14 years. Plasma Lyso-Gb3 levels decreased from 27.2 ± 17.9 ng/mL before the switch to 16.8 ± 10.5 ng/mL after the switch (mean reduction of 30.1%; p = 0.004). The decrease was maximal in the subgroup of 7 male patients with no or very low residual enzyme activity (mean reduction of 40.4%). However, two females with high residual enzyme activity also showed a reduction >30% after the switch. In male patients, the reduction of plasma Lyso-Gb3 correlated negatively with the residual α-gal A activity: r = −0.803; p = 0.009. Agalsidase-β at licensed dose is significantly more effective than agalsidase-α to reduce Lyso-Gb3 levels in classic Fabry patients, and should be used as first line therapy in classic males with no residual enzyme activity. [ABSTRACT FROM AUTHOR]

Treatment with agalsidase alfa in patients with Fabry disease is most effective when initiated early in the disease course; however, the clinical benefits in elderly patients are less well established. This analysis assesses outcomes in patients aged 65 years or older from the Fabry Outcome Survey (FOS) who were treated with agalsidase alfa. FOS data were extracted for adult patients aged 65 years or older who received agalsidase alfa, had baseline data and at least 3 years of post-baseline data, and had undergone no renal transplantation and/or dialysis before treatment. The data of patients who had undergone renal transplantation and/or dialysis during follow-up were excluded from estimated glomerular filtration rate (eGFR) analysis after the date of the renal transplantation and/or dialysis. Adult patients were stratified into two groups: those who started treatment before 65 years of age and who were still being treated when aged 65 years or older (group A), and those who started treatment when aged 65 years or older (group B). Mean annual changes in left ventricular mass index (LVMI), eGFR and proteinuria were assessed in group A (before and after the age of 65 years to understand if there was an age-related effect once patients turned 65 years of age) and in group B. Estimated mean (standard error [SE]) annual changes in LVMI were 0.46 (0.26) g/m2.7 and 0.21 (0.42) g/m2.7 in patients in group A when they were younger than 65 years and when they were aged 65 years or older, respectively, and 0.12 (0.65) g/m2.7 in patients in group B. For eGFR, mean (SE) annual changes were 0.83 (2.12) mL/min/1.73 m2 and 2.64 (2.18) mL/min/1.73 m2 in patients in group A when they were younger than 65 years and when they were aged 65 years or older, respectively, and 2.31 (1.44) mL/min/1.73 m2 in patients in group B. Proteinuria remained relatively stable in both subgroups of group A (before and after the age of 65 years) and group B. Continuation and initiation of agalsidase alfa treatment in patients aged 65 years or older with Fabry disease were associated with stabilization of proteinuria and minimal increases in cardiac (LVMI) and renal (eGFR) outcomes. • The effect of ERT on elderly patients with FD still needs to be better elucidated. • Cardiac and renal function with agalsidase alfa were stable in elderly patients. • Agalsidase alfa provides sustained benefits in elderly patients. [ABSTRACT FROM AUTHOR]

Patients suffering from Fabry disease (FD) have an increased risk of developing neuropsychiatric symptoms (NPS), mostly impairment in cognitive performance and depression. Single cases of psychosis have been reported, however, their association with FD can be coincidental. Furthermore, deficits in social functioning and adaptation as well as specific coping styles in FD patients were observed. Recent studies focused on a longitudinal course of the disease and identified risk factors associated with specific NPS. Since 2001, enzyme replacement therapy (ERT) has been available and in preliminary studies seems to improve cognitive impairment and adaptive skills. In this systematic review, we analyze the available literature on the NPS in FD and investigate if there are any differences in their distribution between males and females, children/adolescents and adults, and individuals treated with ERT and untreated. We discuss the role of the psychological, environmental, and molecular alterations and their correlation to psychiatric manifestations in FD. Finally, we would like to increase awareness of the spectrum of NPS in FD. [ABSTRACT FROM AUTHOR]

Background: Variable disease progression confounds accurate prognosis in Fabry disease. Evidence supports the long-term benefit of early intervention with disease-specific therapy, but current guidelines recommend treatment initiation based on signs that may present too late to avoid irreversible organ damage. Findings from the 'PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease' (PREDICT-FD) initiative included expert consensus on 27 early indicators of disease progression in Fabry disease and on drivers of and barriers to treatment initiation in Fabry disease. Here, we compared the PREDICT-FD indicators with guidance from the European Fabry Working Group and various national guidelines to identify differences in signs supporting treatment initiation and how guidelines themselves might affect initiation. Finally, anonymized patient histories were reviewed by PREDICT-FD experts to determine whether PREDICT-FD indicators supported earlier treatment than existing guidance.Results: Current guidelines generally aligned with PREDICT-FD on indicators of renal involvement, but most lacked specificity regarding cardiac indicators. The prognostic significance of neurological indicators such as white matter lesions (excluded by PREDICT-FD) was questioned in some guidelines and excluded from most. Some PREDICT-FD patient-reported signs (e.g., febrile crises) did not feature elsewhere. Key drivers of treatment initiation in PREDICT-FD were: (A) male sex, young age, and clinical findings (e.g., severe pain, organ involvement), (B) improving clinical outcomes and preventing disease progression, and (C) a family history of Fabry disease (especially if outcomes were severe). All guidelines aligned with (A) and several advocated therapy for asymptomatic male patients. There was scant evidence of (B) in current guidance: for example, no countries mandated ancillary symptomatic therapy, and no guidance advocated familial screening with (C) when diagnosis was confirmed. Barriers were misdiagnosis and a lack of biomarkers to inform timing of treatment. Review of patient histories generally found equal or greater support for treatment initiation with PREDICT-FD indicators than with other guidelines and revealed that the same case and guideline criteria often yielded different treatment recommendations.Conclusions: Wider adoption of PREDICT-FD indicators at a national level could promote earlier treatment in Fabry disease. Clearer, more concise guidance is needed to harmonize treatment initiation in Fabry disease internationally. [ABSTRACT FROM AUTHOR]

More than 900 variants have been described in the GLA gene. Some intronic variants and copy number variants in GLA can cause Fabry disease but will not be detected by classical Sanger sequence. We aimed to design and validate a method for sequencing the GLA gene using long-read Oxford Nanopore sequencing technology. Twelve Fabry patients were blindly analyzed, both by conventional Sanger sequence and by long-read sequencing of a 13 kb PCR amplicon. We used minimap2 to align the long-read data and Nanopolish and Sniffles to call variants. All the variants detected by Sanger (including a deep intronic variant) were also detected by long-read sequencing. One patient had a deletion that was not detected by Sanger sequencing but was detected by the new technology. Our long-read sequencing-based method was able to detect missense variants and an exonic deletion, with the added advantage of intronic analysis. It can be used as an efficient and cost-effective tool for screening and diagnosing Fabry disease. [ABSTRACT FROM AUTHOR]

Background Fabry disease (FD), an X-linked lysosomal storage disorder, results from the deficient activity of α-galactosidase A (α-Gal A) and the accumulation of its substrates, globotriaosylceramide (Gb3) and its deacylated derivative, globotriaosyl-sphingosine (Lyso-Gb3). Here, we compared the levels of Lyso-Gb3 in dried blood spots (DBS) and sera in affected males and heterozygotes with the “Classic” and “Later-Onset” phenotypes. Methods The Lyso-Gb3 concentrations in DBS and sera from 56 FD patients were determined by highly sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Results The serum Lyso-Gb3 levels in 18 and 5 affected males with the Classic and Later-Onset phenotypes, were 61 ± 38 and 14 ± 12 ng/mL, respectively. Lyso-Gb3 levels in 30 females from Classic families and three females from Later-Onset families were 10 ± 5.4 and 2.4 ± 1.0 ng/mL, respectively. The linear regression model with serum Lyso-Gb3 as the dependent variable and DBS Lyso-Gb3 an independent variable was described by the function y = − 1.83 + 1.68 ∗ x and showed a high coefficient of determination, R 2 = 0.976. The overall correlation between the Lyso-Gb3 levels in DBS and sera was high (R = 0.99; p < 0.001). Conclusion DBS provides a convenient, sensitive, and reproducible source to measure Lyso-Gb3 levels for diagnosis, initial phenotypic assignment, and therapeutic monitoring in patients with Fabry disease. [ABSTRACT FROM AUTHOR]

Introduction: Fabry disease (FD) is a lysosomal storage disorder leading to decreased α-galactosidase A enzyme activity and subsequent abnormal accumulation of glycosphingolipids in various organs. Although histological evidence of lung involvement has been demonstrated, the functional impact of these changes is less clear. Materials and methods: Adult patients with FD who had yearly pulmonary function tests (PFT) at two centers from 1999 thru 2015 were eligible for this observational study. Primary outcome measures were the change in forced expiratory volume in the first second (FEV1) and FEV1/FVC over time. As secondary outcome we investigated sex, smoking, enzyme replacement therapy (ERT), residual enzyme activity, and Mainz Severity Score Index as possible predictors. Results: 95 patients (41% male, 38.2 ± 14.5 years) were included. The overall prevalence of bronchial obstruction (BO, (FEV1/FVC < 70%)) was 46%, with male sex, age and smoking as significant predictors. FEV1 decreased 29 ml per year (95% CI -36, -22 ml, p<0.0001). FEV1 decline was significantly higher in males (p = 0.009) and in patients on ERT (p = 0.004). Conclusion: Pulmonary involvement seems to be a relevant manifestation of Fabry disease, and routine PFTs should therefore be included in the multidisciplinary follow-up of these patients. [ABSTRACT FROM AUTHOR]

Background/Aims: Fabry disease (FD) is a rare inherited lysosomal storage disease with common and serious kidney complications. Enzyme replacement therapies (ERT) with agalsidase-α and -β were investigated to characterize their therapeutic effect on kidney function in FD patients with Classic phenotype. Methods: The prospective FD cohort consisted of 98 genetically confirmed patients (females, n = 61, males, n = 37). The median [interquartile range] follow-up time (time difference from first to last visit) was 9 [6, 12] years. The median age of ERT start was 36 [21 - 54] years for females and 39 [28 - 49] years for males. Results: A disease progression model was developed to (i) characterize the time course of estimated glomerular filtration rate (eGFR) and (ii) evaluate therapeutic effects of ERT on kidney function. Change in eGFR over time was best described by the linear model. Females had stable kidney function with and without ERT (eGFR slopes of -0.07 ml/min/1.73m^2 per year and 0.52 ml/min/1.73m^2 per year, respectively). Males with ERT showed an eGFR decrease of -3.07 ml/min/1.73m^2 per year. Conclusion: Mathematical disease progression modeling indicates that there is no clear therapeutic effect of ERT on kidney function in adult patients with Classic Phenotype of FD. Interpretation of these findings should take into account that the study is not randomized and lacks a placebo controlled group. Further investigations are warranted to clarify whether earlier ERT initiation before 18 years of age, higher ERT dose or more intensive therapies can preserve kidney function. [ABSTRACT FROM AUTHOR]

Background Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the α-galactosidase A gene ( GLA ) that result in absent or markedly reduce α-galactosidase A (α-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40–50% of GLA -mutation confirmed heterozygotes have normal or only slightly decreased leukocyte α-GalA activities. Recently, LysoGb3 has been appreciated as a novel FD biomarker, especially for therapeutic monitoring. Methods Among our GLA -mutation proven FD patients, we screened 18 heterozygotes whose leukocyte α-GalA activity was determined at initial diagnosis. For these females, we measured their serum LysoGb3 levels using highly-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Results We identified three unrelated females in whom the accumulating LysoGb3 was increased, whereas their leukocyte α-GalA activities were in the normal range. Conclusion LysoGb3 serves as an useful biomarker to improve the diagnosis of FD heterozygotes and for therapeutic evaluation and monitoring. [ABSTRACT FROM AUTHOR]

Objective: Best treatment outcomes in Fabry disease (FD) associated cardiomyopathy can be obtained when treatment is started as early as possible. The rationale of this study was to assess the role of ECG changes for identification of cardiac involvement and patients at an earlier stage of the disease more likely deriving a benefit from enzyme replacement therapy (ERT).Methods: A retrospective analysis of patient data was performed from an observational, longitudinal, prospective cohort. Treatment response was defined as absence or presence of disease progression, defined as new onset or increase in left ventricular (LV) mass >10%. Demographic, clinical, ECG and echocardiographic parameters at baseline were tested for their value in determining absence or presence of disease progression under ERT at 5-year follow-up.Results: The study population consisted of a total of 38 patients (25 men, mean age 36±13 years, overall median follow-up duration 6.4±1.2 years). Patients in the progression group (14 men, 4 women) had a longer QRS duration (99±11 ms vs 84±13 ms, p<0.05 for men, 93±9 years vs 81±5 years, p<0.05 for women) and QTc interval (401±15 ms vs 372±10 ms, p<0.005 for men) and a higher amount of ECG abnormalities (86% vs 18%, p<0.005 for men and 100% vs 0%, p<0.005 for women) at the time of ERT initiation. An abnormal baseline ECG was significantly associated with disease progression (sensitivity 94.1%, specificity 88.9%, positive likelihood ratio of 8.47, p<0.005).Conclusions: An abnormal ECG at the time of treatment initiation is significantly associated with cardiac disease progression in FD. This effect seems to be independent of age, gender or LV mass at baseline and suggests maximal treatment benefit when ERT is initiated before ECG abnormalities develop. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the α-galactosidase A gene (GLA) that result in deficiency of α-galactosidase A (α-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates accumulate in plasma, urine and tissue lysosomes. There are two major phenotypes, classic and later-onset. Males with the more severe, classic phenotype have an α-Gal A activity of <1% and suffer early symptoms including acroparesthesias, angiokeratoma, corneal opacities and hypohidrosis, culminating in cardiomyopathy, kidney disease, and premature strokes in adults. The less severe, later-onset phenotype is characterized by an α-Gal A activity of >1%, asymptomatic childhood, but a progressive heart or kidney disease in adult males. The two phenotypic entities require different diagnostic and therapeutic strategies. Results: A total of 164 patients from 44 independent pedigrees, 61 affected males and 103 heterozygous individuals, have been diagnosed with FD in Switzerland since the year 1958. The ratio classic to later-onset phenotype was 3:1. Overall, 49% of the patients had amenable mutations, of those, 24% had classic and 25% later-onset phenotype. All patients with the later-onset phenotype had amenable missense mutations. While screening programs for FD have never been performed in Switzerland, mainly classic mutations were diagnosed in the past, later-onset mutations only being increasingly diagnosed recently. Conclusions Although the later-onset phenotype naturally occurs 10-20 times more frequently than the classic one, as shown in newborns screening studies, in our population, the prevalence of classic was considerably higher than later-onset phenotype, most likely because systematic screening for FD have never been performed in Switzerland. However, an increasing number of later-onset phenotype patients has been diagnosed in the recent time, due to increasing awareness of FD. Screening studies would help identify many so far undiagnosed later-onset patients. [ABSTRACT FROM AUTHOR]

Background: To date, there are no studies associating the dried blood spot (DBS) levels of globotrioasylsphingosine (lysoGb3) with quantitative optical coherence tomography angiography (OCTA) parameters in Fabry disease (FD) patients. Here, we aimed to investigate the association between OCTA vessel density (VD), vessel length density (VLD) with DBS lysoGb3. Methods: A retrospective, single center analysis of all consecutive FD patients enrolled at the Department of Ophthalmology of the University Hospital of Zurich from 1 December 2017 to 9 September 2020. An association between VD and VLD detected by OCTA and lysoGb3 was investigated using a linear mixed model. Results: A total of 57 FD patients (23 male, 34 female; 109 eyes) were included. Forty-one patients suffered from the classic phenotype and 16 from the later-onset phenotype. LysoGb3 inversely correlated with VD and VLD in both the superficial (VD: p = 0.034; VLD: p = 0.02) and deep capillary plexus (VD: p = 0.017; VLD: p = 0.018) in the overall FD cohort. Conclusions: Our study shows an association between lysoGb3 and OCTA VD and VLD. This supports the hypothesis that quantitative OCTA parameters might be useful as diagnostic biomarkers for evaluating systemic involvement in FD, and possibly other diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fabry Disease (FD) manifestations include organ damage, systemic inflammation, and fibrosis. • Lipidome changes possibly reflect systemic and cellular responses to FD. • Plasma ceramide ratios used in cardiovascular risk assessment were increased in FD. • Platelets accumulated lyso-Gb3, but not Gb3 in FD patients. • Identified lipids may serve as potential new screening and prognostic markers for FD. Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by the progressive accumulation of globotriaosylceramide (Gb3) leading to systemic manifestations such as chronic kidney disease, cardiomyopathy, and stroke. There is still a need for novel markers for improved FD screening and prognosis. Moreover, the pathological mechanisms in FD, which also include systemic inflammation and fibrosis, are not yet fully understood. Plasma and platelets were obtained from 11 ERT (enzyme–replacement therapy)-treated symptomatic, 4 asymptomatic FD patients, and 13 healthy participants. A comprehensive targeted lipidomics analysis was conducted quantitating more than 550 lipid species. Sphingadiene (18:2;O2)-containing sphingolipid species, including Gb3 and galabiosylceramide (Ga2), were significantly increased in FD patients. Plasma levels of lyso-dihexosylceramides, sphingoid base 1-phosphates (S1P), and GM3 ganglioside were also altered in FD patients, as well as specific plasma ceramide ratios used in cardiovascular disease risk prediction. Gb3 did not increase in patients' platelets but displayed a high inter-individual variability in patients and healthy participants. Platelets accumulated, however, lyso-Gb3, acylcarnitines, C16:0-sphingolipids, and S1P. This study identified lipidome changes in plasma and platelets from FD patients, a possible involvement of platelets in FD, and potential new markers for screening and monitoring of this disease. [ABSTRACT FROM AUTHOR]

Background Fabry disease (FD), an X-linked lysosomal storage disorder, results from α-galactosidase A gene (GLA) mutations causing deficient α-galactosidase A (α-GalA) activity. There are two major subtypes: early-onset Type 1 "Classic" and Type 2 "Later-Onset" phenotypes. Type 1 males have essentially no α-GalA activity, marked microvascular endothelial globotriaosylceramide (Gb3) accumulation, and childhood/adolescent onset characterized by acroparesthesias, angiokeratoma, corneal opacities, and hypohidrosis. With age, progressive Gb3 deposition in microvascular endothelial cells, renal podocytes, and cardiomyocytes, leads to renal insufficiency/failure, cardiomyopathy, and cerebrovascular disease. Type 2 males have residual α-GalA activity, no microvascular Gb3 accumulation, lack Type 1 early manifestations, and present in adulthood with progressive cardiac and/or renal disease. Previously, FD prevalence was estimated at ~1 in 40,000-119,000 males. However, the incidence is unknown it is best estimated by newborn screening (NBS) of male newborns, as enzyme screening does not reliability identify female heterozygotes. Methods Online databases were searched for FD NBS studies those with GLA sequencing were reanalyzed for pathogenic mutations and phenotype. Results In 15 NBS studies reporting mutations, 1,566,931 newborns were screened. Of the seven studies that reported 247,286 males, 0.0546% had pathogenic mutations. Among these studies, the incidence of Caucasian and Asian males was ~1:4,000 and ~1:1,400, respectively, with Types 1 to 2 phenotype ratios of 1:20 and 1:13, respectively. Conclusions The estimated FD male incidence was markedly more frequent than the previously estimated prevalence, primarily since Type 2 males were previously under-diagnosed. In X-linked diseases, expected heterozygotes number twice the newborn males. For Type 1 males, NBS facilitates early treatment. For Type 2 males, NBS presents ethical issues, since manifestations develop in adulthood. Screening Types 1 and 2 at-risk family members will identify older previously undiagnosed affected family members for medical management including enzyme replacement or pharmacologic chaperone therapy. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of α-galactosidase-A, which results in accumulation of the glycosphingolipid (GSL) globotriaosylceramide (Gb 3). Gb 3 and globotriaosylsphingosine (lyso-Gb 3) levels in plasma and urine are used routinely for diagnosis and treatment monitoring. FD female patients are problematic to diagnose and to predict when to begin treatment. Further biomarkers are needed to detect pre-symptomatic females that will develop the chronic symptoms associated with FD. A LC-MS/MS glycosphingolipidomic assay was developed to measure lyso-Gb 3 and GSLs from the lysosomal GSL degradation pathway, including globoside (Gb 4), Gb 3 , ceramide dihexosides (CDH) and ceramide monohexosides (CMH). We analysed plasma and urine from a cohort of Fabry patients, grouped according to clinical symptoms and independent of treatment status (asymptomatic females n = 18, symptomatic females n = 18, males n = 27 and control urines n = 16 and control plasmas n = 58). Multivariate and subsequent univariate analysis showed urine GSLs which had highest significance in identifying asymptomatic females were total levels of CDH, in particular the long chain isoforms C22:1,C22:0,C22:1-OH,C22:0-OH,C24:2,C24:0,C24:2-OH,C24:1-OH,C24:0-OH,C26:0 which likely represent Galabiosylceramide (Ga 2) and not lactosylceramide. These long chain Ga 2 isoforms were found to be 5-fold elevated and more statistically significant (p < 0.0001) than plasma lyso-Gb 3 (p < 0.01) in identifying asymptomatic Fabry female patients. Receiver operating characteristic curve analysis gave an area under the curve of 0.82 (p = 0.001) for lyso-Gb 3 and 0.88 (p = 0.0006) for long-chain CDH isoforms indicating the long chain CDH isoforms were as, if not more, a better biomarker for the identification of female FD patients. Unlabelled Image • Ceramide dihexoside (CDH) is the predominant glycosphingolipid in females. • Plasma ceramide monhexoside is increased in Fabry disease. • Urinary long-chain CDH isoforms are better than lyso-Gb3 to distinguish Fabry females. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. In order to improve health care of FD-patients, knowledge of its predictors is important. The aim of our study was to evaluate health-related quality of life (HrQol) in FD and to identify its independent determinants by exploring a wide range of demographic, social and clinical parameters. In this cross-sectional multicenter study, 135 adult patients with FD were recruited at three specialized European centers in Germany and Switzerland. Demographics, social status and clinical parameters as well as data on HrQol (EQ5D, EQ VAS) and depression were collected by means of self-reporting questionnaires and confirmed by medical records. HrQol and its predictors were evaluated by univariate and multivariate regression analyses. The study population consisted of 78 female and 57 male FD patients (median age 48 yrs) of whom 80.7% (N = 109) were on enzyme replacement therapy (ERT) and 10.4% (N = 14) were on chaperone treatment. Univariate analysis revealed various factors reducing HrQol such as age > 40 years, classic phenotype, organ involvement (kidney and heart disease, stroke/ transient ischemic attack (TIA) , gastrointestinal disturbances), depression, and burning limb pain. However, only the following factors were identified as independent predictors of decreased HrQol: classic phenotype, kidney and heart disease, stroke/TIA, depression, and burning limb pain. ERT and chaperone therapy were independent determinants of increased HrQol. Modifiable factors, such as burning limb pain and depression, identified as independent predictors of HrQol-deterioration should be addressed in programs aiming to improve HrQol in FD. A multidisciplinary approach is essential in FD-patients since diverse organ involvement prominently compromises HrQol in affected patients. Our findings showed that the classic phenotype is a strong predictor of worsening HrQol. [ABSTRACT FROM AUTHOR]

Background Fabry disease, an inherited lysosomal storage disorder, causes multi-organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease. The impact of therapy depends upon patient- and disease-specific factors and timing of initiation. Methods A European panel of experts collaborated to develop a set of organ-specific therapeutic goals for Fabry disease, based on evidence identified in a recent systematic literature review and consensus opinion. Results A series of organ-specific treatment goals were developed. For each organ system, optimal treatment strategies accounted for inter-patient differences in disease severity, natural history, and treatment responses as well as the negative burden of therapy and the importance of multidisciplinary care. The consensus therapeutic goals and proposed patient management algorithm take into account the need for early disease-specific therapy to delay or slow the progression of disease as well as non-specific adjunctive therapies that prevent or treat the effects of organ damage on quality of life and long-term prognosis. Conclusions These consensus recommendations help advance Fabry disease management by considering the balance between anticipated clinical benefits and potential therapy-related challenges in order to facilitate individualized treatment, optimize patient care and improve quality of life. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked lysosomal storage disorder caused by the accumulation of glycosphingolipids in various tissues and body fluids, leading to progressive organ damage and life-threatening complications. Phenotypic classification is based on disease progression and severity and can be used to predict outcomes. Patients with a classic Fabry phenotype have little to no residual α-Gal A activity and have widespread organ involvement, whereas patients with a later-onset phenotype have residual α-Gal A activity and disease progression can be limited to a single organ, often the heart. Diagnosis and monitoring of patients with Fabry disease should therefore be individualized, and biomarkers are available to support with this. Disease-specific biomarkers are useful in the diagnosis of Fabry disease; non-disease-specific biomarkers may be useful to assess organ damage. For most biomarkers it can be challenging to prove they translate to differences in the risk of clinical events associated with Fabry disease. Therefore, careful monitoring of treatment outcomes and collection of prospective data in patients are needed. As we deepen our understanding of Fabry disease, it is important to regularly re-evaluate and appraise published evidence relating to biomarkers. In this article, we present the results of a literature review of evidence published between February 2017 and July 2020 on the impact of disease-specific treatment on biomarkers and provide an expert consensus on clinical recommendations for the use of those biomarkers. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is a rare X-linked disorder caused by a deficiency of lysosomal α-galactosidase A (GLA) activity. Neutralizing anti-drug antibodies (ADA) against enzyme replacement therapy (ERT) are associated with disease progression in male patients. Recently we demonstrated that ADAs can be supersaturated during infusions. In the current work we hypothesized that supersaturated patients benefit from better clinical outcomes. Twenty-six male patients with FD receiving ERT (mean 98±70 months) and positive for ADAs were recruited. Free ADAs were isolated from patients' sera and the amount of ERT necessary for antibody supersaturation was determined. Clinical outcomes including measurements of eGFR and septum thickness of supersaturated patients were compared to non-supersaturated patients. ADA titers decreased in all patients (n=26) during infusion (p<0.0001) and the capacity to bind ADAs was similar for agalsidase-alfa and agalsidase-beta (r²=0.9740 p<0.0001). Patients with supersaturated ADAs (n=14) presented with a yearly loss of eGFR (-2.7±2.2 ml/min/1.73m² p=0.0015), a stable septum thickness (p=0.4628) and decreasing lyso-Gb3 levels (-13.1±16.3 ng p=0.0099) since ERT initiation. By contrast, non-supersaturated patients (n=12) suffered from a more severe yearly loss of eGFR (-5.1±5.0 ml/min/1.73m² p=0.0005), an increasing septum thickness (0.3±0.4 mm p=0.0039) and worse lyso-Gb3 reduction (p=0.2834). Dose-escalation resulted in partially elevated ADA titers, but importantly in reduced lyso-Gb3 levels in 3 patients. We conclude that measuring neutralizing ADA titers is feasible to calculate and control the required amount of enzyme to supersaturate ADAs during infusions. A non-supersaturated status is associated with a progressive loss of eGFR and ongoing cardiac hypertrophy. Dose escalation can result in supersaturation of ADAs and decreasing lyso-Gb3 levels, but may also lead to increased ADA titers. [ABSTRACT FROM AUTHOR]