Renal and multisystem effectiveness of 3.9 years of migalastat in a global real-world cohort: Results from the followME Fabry Pathfinders registry.

Fabry disease is a progressive, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to GLA variants. The effects of migalastat were examined in a cohort of 125 Fabry patients with migalastat-amenable GLA variants in the followME Pathfinders registry (EUPAS20599), an ongoing, prospective, patient-focused registry evaluating outcomes for current Fabry disease treatments. We report annualised estimated glomerular filtration rate (eGFR) and Fabry-associated clinical events (FACEs) in a cohort of patients who had received ≥3 years of migalastat treatment in a real-world setting. As of August 2022, 125 patients (60% male) had a mean migalastat exposure of 3.9 years. At enrolment, median age was 58 years (males, 57; females, 60) with a mean eGFR of 83.7 mL/min/1.73 m2 (n = 122; males, 83.7; females, 83.8) and a median left ventricular mass index of 115.1 g/m2 (n = 61; males, 131.2; females, 98.0). Mean (95% confidence interval) eGFR annualised rate of change in the overall cohort (n = 116) was -0.9 (-10.8, 9.9) mL/min/1.73 m2/year with a similar rate of change observed across patients with varying levels of kidney function at enrolment. Despite population age and baseline morbidity, 80% of patients did not experience a FACE during the mean 3.9 years of migalastat exposure. The incidence of renal, cardiac, and cerebrovascular events was 2.0, 83.2, and 4.1 events per 1000 patient-years, respectively. These data support a role of migalastat in preserving renal function and multisystem effectiveness during ≥3 years of migalastat treatment in this real-world Fabry population.

Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study.

BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.

Phenotypic Expression and Outcomes in Patients with the p.Arg301Gln GLA Variant in Anderson-Fabry Disease.

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.

Systems analyses of the Fabry kidney transcriptome and its response to enzyme replacement therapy identified and cross-validated enzyme replacement therapy-resistant targets amenable to drug repurposing.

Fabry disease is a rare disorder caused by variations in the alpha-galactosidase gene. To a degree, Fabry disease is manageable via enzyme replacement therapy (ERT). By understanding the molecular basis of Fabry nephropathy (FN) and ERT's long-term impact, here we aimed to provide a framework for selection of potential disease biomarkers and drug targets. We obtained biopsies from eight control individuals and two independent FN cohorts comprising 16 individuals taken prior to and after up to ten years of ERT, and performed RNAseq analysis. Combining pathway-centered analyses with network-science allowed computation of transcriptional landscapes from four nephron compartments and their integration with existing proteome and drug-target interactome data. Comparing these transcriptional landscapes revealed high inter-cohort heterogeneity. Kidney compartment transcriptional landscapes comprehensively reflected differences in FN cohort characteristics. With exception of a few aspects, in particular arteries, early ERT in patients with classical Fabry could lastingly revert FN gene expression patterns to closely match that of control individuals. Pathways nonetheless consistently altered in both FN cohorts pre-ERT were mostly in glomeruli and arteries and related to the same biological themes. While keratinization-related processes in glomeruli were sensitive to ERT, a majority of alterations, such as transporter activity and responses to stimuli, remained dysregulated or reemerged despite ERT. Inferring an ERT-resistant genetic module of expressed genes identified 69 drugs for potential repurposing matching the proteins encoded by 12 genes. Thus, we identified and cross-validated ERT-resistant gene product modules that, when leveraged with external data, allowed estimating their suitability as biomarkers to potentially track disease course or treatment efficacy and potential targets for adjunct pharmaceutical treatment.

An expert consensus on the recommendations for the use of biomarkers in Fabry disease.

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.

Screening for health-related quality of life and its determinants in Fabry disease: A cross-sectional multicenter study.

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.

Lyso-Gb3 associates with adverse long-term outcome in patients with Fabry disease.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A gene (GLA) leading to deficiency of α-galactosidase A and ultimately in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (Lyso-Gb3). The aim of the study was to assess plasma Lyso-Gb3 levels as a possible factor associated with adverse outcomes in FD. METHODS: In a cohort of 66 patients with genetically confirmed FD (26 males and 40 females), we analysed serum Lyso-Gb3 as a factor associated with adverse clinical outcomes in a long-term study. The main outcome was a composite endpoint of incident kidney replacement therapy, atrial fibrillation, pacemaker and/or implantable cardioverter defibrillator, cerebrovascular events or death, whichever occurred first. RESULTS: During the median follow-up time of 68 (40-80) months, events occurred in 19 (29%) of the patients. In a Cox multivariate regression analysis, Lyso-Gb3 levels (HR 4.62 (1.55 to 13.81); p=0.006) and the pretreatment exposure to Lyso-Gb3 (HR 3.41 (1.11 to 10.49); p=0.03) (both per SD increase) were significantly associated with adverse outcomes. If pretreatment Lyso-Gb3 exposure was added to multivariable logistic regression models containing age, sex, phenotype and enzyme replacement therapy as other covariates with the composite outcome as dependent variable, the area under the curve for the composite outcome significantly improved from 0.72 to 0.86 (p comparison=0.04). CONCLUSION: Lyso-Gb3 is a significant risk factor associated with important clinical events. Whether treatment-related amelioration of Lyso-Gb3 levels will be associated with improved long-term outcome needs to be established in prospective intervention trials.

Circular RNA-based biomarkers in blood of patients with Fabry disease and related phenotypes.

BACKGROUND: Fabry disease is a rare X-linked lysosomal storage disease caused by mutations in the galactosidase α gene. Deficient activity of α-galactosidase A leads to glycosphingolipid accumulations in multiple organs. Circular RNAs represent strong regulators of gene expression. Their circular structure ensures high stability in blood. We hypothesised that blood-based circular RNA profiles improve phenotypic assignment and therapeutic monitoring of Fabry disease. METHODS: A genome-wide circular RNA expression analysis was performed in blood of genetically diagnosed patients with Fabry disease (n=58), age-matched and sex-matched healthy volunteers (n=14) and disease control patients with acute kidney injury (n=109). Most highly dysregulated circular RNAs were validated by quantitative real-time PCR. Circular RNA biomarker sensitivity, specificity, predictive values and area under the curve (AUC) were determined. Linear regression analyses were conducted for validated circular RNA biomarkers and clinical patient characteristics. RESULTS: A distinct circular RNA transcriptome signature identified patients with Fabry disease. Level of circular RNAs hsa_circ_0006853 (AUC=0.73), hsa_circ_0083766 (AUC=0.8) and hsa_circ_0002397 (AUC=0.8) distinguished patients with Fabry disease from both healthy controls and patients with acute kidney injury. Hsa_circ_0002397 was, furthermore, female-specifically expressed. Circular RNA level were significantly related to galactosidase α gene mutations, early symptoms, phenotypes, disease severities, specific therapies and long-term complications of Fabry disease. CONCLUSION: The discovery of circular RNA-based and Fabry disease-specific biomarkers may advance future diagnosis of Fabry disease and help to distinguish related phenotypes.

Agalsidase-ß should be proposed as first line therapy in classic male Fabry patients with undetectable α-galactosidase A activity.

BACKGROUND: 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 -ß 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. METHODS: In this prospective observational study, 14 consecutive adult Fabry patients (10 males) with a classic GLA-mutation, were switched from agalsidase-α to agalsidase-ß 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. RESULTS: 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. CONCLUSION: Agalsidase-ß 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.

Rapid, proteomic urine assay for monitoring progressive organ disease in Fabry disease.

BACKGROUND: Fabry disease is a progressive multisystemic disease, which affects the kidney and cardiovascular systems. Various treatments exist but decisions on how and when to treat are contentious. The current marker for monitoring treatment is plasma globotriaosylsphingosine (lyso-Gb3), but it is not informative about the underlying and developing disease pathology. METHODS: We have created a urine proteomic assay containing a panel of biomarkers designed to measure disease-related pathology which include the inflammatory system, lysosome, heart, kidney, endothelium and cardiovascular system. Using a targeted proteomic-based approach, a series of 40 proteins for organ systems affected in Fabry disease were multiplexed into a single 10 min multiple reaction monitoring Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) assay and using only 1 mL of urine. RESULTS: Six urinary proteins were elevated in the early-stage/asymptomatic Fabry group compared with controls including albumin, uromodulin, α1-antitrypsin, glycogen phosphorylase brain form, endothelial protein receptor C and intracellular adhesion molecule 1. Albumin demonstrated an increase in urine and could indicate presymptomatic disease. The only protein elevated in the early-stage/asymptomatic patients that continued to increase with progressive multiorgan involvement was glycogen phosphorylase brain form. Podocalyxin, fibroblast growth factor 23, cubulin and Alpha-1-Microglobulin/Bikunin Precursor (AMBP) were elevated only in disease groups involving kidney disease. Nephrin, a podocyte-specific protein, was elevated in all symptomatic groups. Prosaposin was increased in all symptomatic groups and showed greater specificity (p<0.025-0.0002) according to disease severity. CONCLUSION: This work indicates that protein biomarkers could be helpful and used in conjunction with plasma lyso-Gb3 for monitoring of therapy or disease progression in patients with Fabry disease.

Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort.

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. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this article, we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and one patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual α-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations.

Obstructive sleep apnea and quality of life in Fabry disease: a prospective parallel cohort study.

STUDY OBJECTIVES: Patients with Fabry disease (FD) report impaired quality of life and excessive daytime sleepiness. Obstructive sleep apnea (OSA) is frequently reported among patients with FD; however, its prevalence and its influence on quality of life and daytime sleepiness in this population are unclear. METHODS: Patients with FD in a cohort from the University Hospital Zurich (n = 52) were one-to-two matched to healthy adult controls (n = 104) according to age, sex, and body mass index. Participants underwent structured interviews (including Short Form-36) and level-3 respiratory polygraphy. An apnea-hypopnea index of ≥ 5/h was defined as OSA and the severity of FD was quantified with the Mainz Severity Score Index (MSSI). Conditional logistic regression was used to compare the outcomes. RESULTS: In patients with FD the mean MSSI was 13.3 ± 10.5 points and OSA prevalence was 19.2% vs. 9.0% in the matched control group (p = 0.09). The apnea-hypopnea index was significantly higher in patients with FD than in the control group (0.5/h [0.2-3.0] vs. 0.2/h [0.1-1.8], p = 0.026). OSA severity was associated with impaired quality of life in four dimensions for the whole study population. Furthermore, patients with FD did report significantly higher daytime sleepiness (Epworth Sleepiness Scale 7.6 points vs. 6.3 points; p = 0.01) than healthy controls. CONCLUSION: Patients with mild FD do not have a higher OSA prevalence than matched control subjects. Differences in OSA severity did not reach clinical significance. Further studies are warranted to determine the impact of OSA in patients with moderate-to-severe FD.

External Validation of the MEESSI Acute Heart Failure Risk Score: A Cohort Study.

Background: The MEESSI-AHF (Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF) score was developed to predict 30-day mortality in patients presenting with acute heart failure (AHF) to emergency departments (EDs) in Spain. Whether it performs well in other countries is unknown. Objective: To externally validate the MEESSI-AHF score in another country. Design: Prospective cohort study. (ClinicalTrials.gov: NCT01831115). Setting: Multicenter recruitment of dyspneic patients presenting to the ED. Participants: The external validation cohort included 1572 patients with AHF. Measurements: Calculation of the MEESSI-AHF score using an established model containing 12 independent risk factors. Results: Among 1572 patients with adjudicated AHF, 1247 had complete data that allowed calculation of the MEESSI-AHF score. Of these, 102 (8.2%) died within 30 days. The score predicted 30-day mortality with excellent discrimination (c-statistic, 0.80). Assessment of cumulative mortality showed a steep gradient in 30-day mortality over 6 predefined risk groups (0 patients in the lowest-risk group vs. 35 [28.5%] in the highest-risk group). Risk was overestimated in the high-risk groups, resulting in a Hosmer-Lemeshow P value of 0.022. However, after adjustment of the intercept, the model showed good concordance between predicted risks and observed outcomes (P = 0.23). Findings were confirmed in sensitivity analyses that used multiple imputation for missing values in the overall cohort of 1572 patients. Limitations: External validation was done using a reduced model. Findings are specific to patients with AHF who present to the ED and are clinically stable enough to provide informed consent. Performance in patients with terminal kidney failure who are receiving long-term dialysis cannot be commented on. Conclusion: External validation of the MEESSI-AHF risk score showed excellent discrimination. Recalibration may be needed when the score is introduced to new populations. Primary Funding Source: The European Union, the Swiss National Science Foundation, the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel, the University of Basel, and University Hospital Basel.

Clinical Utility of Procalcitonin in the Diagnosis of Pneumonia.

BACKGROUND: The clinical utility of procalcitonin in the diagnosis and management of pneumonia remains controversial. METHODS: We assessed the clinical utility of procalcitonin in 2 prospective studies: first, a multicenter diagnostic study in patients presenting to the emergency department with acute dyspnea to directly compare the diagnostic accuracy of procalcitonin with that of interleukin 6 and C-reactive protein (CRP) in the diagnosis of pneumonia; second, a randomized management study of procalcitonin guidance in patients with acute heart failure and suspected pneumonia. Diagnostic accuracy for pneumonia as centrally adjudicated by 2 independent experts was quantified with the area under the ROC curve (AUC). RESULTS: Among 690 patients in the diagnostic study, 178 (25.8%) had an adjudicated final diagnosis of pneumonia. Procalcitonin, interleukin 6, and CRP were significantly higher in patients with pneumonia than in those without. When compared to procalcitonin (AUC = 0.75; 95% CI, 0.71-0.78), interleukin 6 (AUC = 0.80; 95% CI, 0.77-0.83) and CRP (AUC = 0.82; 95% CI, 0.79-0.85) had significantly higher diagnostic accuracy (P = 0.010 and P < 0.001, respectively). The management study was stopped early owing to the unexpectedly low AUC of procalcitonin in the diagnostic study. Among 45 randomized patients, the number of days on antibiotic therapy and the length of hospital stay were similar (both P = 0.39) in patients randomized to the procalcitonin-guided group (n = 25) and usual-care group (n = 20). CONCLUSIONS: In patients presenting with dyspnea, diagnostic accuracy of procalcitonin for pneumonia is only moderate and lower than that of interleukin 6 and CRP. The clinical utility of procalcitonin was lower than expected. SUMMARY: Pneumonia has diverse and often unspecific symptoms. As the role of biomarkers in the diagnosis of pneumonia remains controversial, it is often difficult to distinguish pneumonia from other illnesses causing shortness of breath. The current study prospectively enrolled unselected patients presenting with acute dyspnea and directly compared the diagnostic accuracy of procalcitonin, interleukin 6, and CRP for the diagnosis of pneumonia. In this setting, diagnostic accuracy of procalcitonin for pneumonia was lower as compared to interleukin 6 and CRP. The clinical utility of procalcitonin was lower than expected. CLINICALTRIALSGOV IDENTIFIER: NCT01831115.

Dose-Dependent Effect of Enzyme Replacement Therapy on Neutralizing Antidrug Antibody Titers and Clinical Outcome in Patients with Fabry Disease.

BACKGROUND: Use of enzyme replacement therapy (ERT) to treat Fabry disease, caused by deficient lysosomal α-galactosidase A activity, can lead to formation of neutralizing antidrug antibodies (ADAs). These antibodies are associated with increased accumulation of plasma globotriaosylceramide (Gb3) and disease progression. Because agalsidase ERT can saturate ADA-binding sites during infusions (achieving agalsidase/antibody equilibrium), we investigated in this open cohort study whether saturated patients (who have excess agalsidase after infusions) experience better clinical outcomes compared with not saturated patients (who have excess ADAs after infusions). METHODS: We isolated ADAs from sera of 26 men with Fabry disease receiving ERT (for a median of 94 months) and determined the amount of agalsidase necessary for antibody saturation. Clinical and biochemical outcomes included measurements of eGFR, interventricular septum thickness, and lyso-Gb3. RESULTS: ADA titers decreased significantly in all patients during infusion. Agalsidase-α and agalsidase-ß had similar ADA-binding capacity and comparable ADA saturation frequency. Fourteen patients with saturated ADAs presented with mild (but significant) loss of eGFR, stable septum thickness, and significantly decreased lyso-Gb3 levels. The 12 not saturated patients had a more pronounced and significant loss of eGFR, increased septum thickness, and a smaller, nonsignificant reduction in lyso-Gb3, over time. In three patients, dose escalation resulted in partially elevated ADA titers, but importantly, also in reduced lyso-Gb3 levels. CONCLUSIONS: A not saturated ADA status during infusion is associated with progressive loss of eGFR and ongoing cardiac hypertrophy. Dose escalation can result in saturation of ADAs and decreasing lyso-Gb3 levels, but may lead to increased ADA titers.

Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene causing deficiency of α-galactosidase A which results in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3), in body liquids and lysosomes. In a large cohort of FD patients, we aimed to establish genotype/phenotype relations as indicated by serum LysoGb3 (deacylated Gb3). METHODS: In 69 consecutive adult FD patients (males: n=28 (41%)) with a GLA-mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and measured serum LysoGb3 levels by high-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. RESULTS: Serum levels of LysoGb3 were significantly higher in Classic compared with Later-Onset phenotype and higher in the latter compared with controls, both in males (52 [40-83] vs 9.5 [4.5-20] vs 0.47 [0.41-0.61] ng/ml, P<0.001) and in females (9.9 [7.9-14] vs 4.9 [1.6-4.9] vs 0.41 [0.33-0.48] ng/ml, P<0.001), respectively. Multivariate linear regression analysis showed that LysoGb3 levels were independently associated with, serum creatinine (ß=0.09, 95%CI 0.04-0.13, P<0.001) and the presence of cardiomyopathy (ß=25, 95%CI 9.8-41, P=0.002). LysoGb3 levels were higher in males with frame-shift and nonsense mutations than in males with missense mutations (84 [72-109] vs 41 [37-52] ng/ml, P=0.002). CONCLUSION: LysoGb3 relates to disease severity, enzyme replacement response, and to the genotype severity in males. LysoGb3 supports identifying patients at risk who require intensive monitoring and treatment. LysoGb3 appears to be one marker of metabolic phenotyping of FD.

European expert consensus statement on therapeutic goals in Fabry disease.

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.

ASSESSMENT OF DRUSEN AND OTHER RETINAL DEGENERATIVE CHANGES IN PATIENTS WITH HEREDITARY HEMOCHROMATOSIS.

PURPOSE: Iron can exert oxidative damage, and increased accumulation is believed to play a role in age-related macular degeneration. Hereditary hemochromatosis leads to an increase in total body iron. Patients with HH were assessed for drusen and other retinal changes. METHODS: Descriptive uncontrolled study of spectral-domain optical coherence tomography, short-wavelength autofluorescence, and color fundus images from patients with HH were used. Diagnosis of HH was established by measuring ferritin and transferrin saturation, and confirmed by genetic testing. Classification of the patients according to initial ferritin level was: Group A >1,032 µg/L; Group B below. RESULTS: Twenty-five percent of the invited participants were enrolled. Mean age at diagnosis was 46 ± 15 years in Group A, and 38 ± 13 years in Group B, P = 0.07, whereas mean age at imaging was 60 ± 13 years in Group A, and 48 ± 15 years in Group B (P = 0.003). The median of the initial ferritin level was 1,869 (1,262-3,256) ng/mL in Group A, and 534 (439-679) ng/mL in Group B. No subject in either group revealed multiple drusen, unambiguous changes of the retinal pigment epithelium, or increased lipofuscin in any of the images. CONCLUSION: The study results did not show an increased prevalence of drusen or other retinal degenerative changes in patients with HH. Thus, it was concluded that increased intestinal iron absorption as well as increased blood iron concentration are not risk factors for the early development of retinal degenerative changes in this study population.

Evaluation of the new restandardized Abbott Architect 25-OH Vitamin D assay in vitamin D-insufficient and vitamin D-supplemented individuals.

BACKGROUND: Recently, Abbott Diagnostics has restandardized the Architect 25(OH)D assay against the NIST SRM 2972. We have evaluated the analytical and clinical performance of the restandardized Architect 25(OH)D assay and compared its performance with a NIST-traceable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and the Roche total 25(OH)D assay in vitamin D-insufficient individuals before and after vitamin D3 supplementation. METHODS: Frozen serum samples were obtained from 88 healthy subjects with self-perceived fatigue and vitamin D-insufficiency <50 nmol L-1 who were randomized to receive a single 100 000 IU dose of vitamin D3 (n = 48) or placebo (n = 40). Total 25(OH)D concentrations were measured before and 4 weeks after supplementation by the restandardized Architect 25(OH)D assay, LC-MS/MS, and Roche assay. RESULTS: The Architect 25(OH)D assay showed an intra- and inter-assay imprecision of <5%. Comparison of the Architect assay with the LC-MS/MS method showed a good correlation in both vitamin D-insufficient and vitamin D-supplemented subjects, however, with a negative mean bias of 17.4% and 8.9%, respectively. As compared to the Roche assay, the Abbott assay underestimated 25(OH)D results in insufficient subjects (<50 nmol L-1 ) with a mean negative bias of 17.1%, this negative bias turned into a positive bias in supplemented subjects. Overall there was a moderate agreement in classification of vitamin D-insufficient and -supplemented individuals into different vitamin D states between the Architect 25(OH)D method and LC-MS/MS. CONCLUSION: The routine use of the restandardized Architect 25(OH)D results in a slight underestimation of circulating total 25(OH)D levels at lower concentrations and thus potential misclassification of vitamin D status.

[The basics of lysosomal storage diseases]. / Die Grundlagen der lysosomalen Speicherkrankheiten.

The basics of lysosomal storage diseases Abstract. Lysosomal storage diseases are comprised of a group of more than 50 genetic disorders which are characterized by a defective lysosomal function. The lysosome is the recycling plant of the cell. Most of the lysosomal storage diseases are caused by a deficient hydrolase. The disturbed metabolism leads to accumulation of complex molecules. The classic classification is by the main storage molecule: Sphingolipidoses, Mucopolysaccharidoses and Glycoproteinosis. The modern classification stretches the definition and includes every disease that has a defect in a lysosomal component, which is needed for the normal function of the lysosome. That component includes lysosomal membrane proteins, activator proteins, transport proteins or non-lysosomal proteins. Lysosomal storage disease are rare diseases with a total incidence of 16 cases in 100'000 live births. Results of screening studies are hinting an underestimation of the real incidence. The most frequent lysosomal storage diseases are Gaucher's disease and Fabry's disease, two Sphingolipidoses. The similarity respective the symptoms of lysosomal storage diseases are the systemic manifestations and common cerebral involvement. The occurrence of the symptoms in the different lysosomal storage diseases are very different. The pathophysiological processes are versatile, the simple concept of overload and consecutive destruction of the cell is overdue. Over time a number of therapeutic approaches have been introduced: the substitution of the enzyme by enzyme replacement therapy, gene therapy or hematopoietic stem cell transplantation, stabilizing of the defective enzyme by pharmacologic chaperone or the decrease of the substrate by substrate reduction therapy.