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.

Fabry disease in W162C mutation: a case report of two patients and a review of literature.

BACKGROUND: Fabry disease is a multisystemic disorder characterized by deposition of globotriaosylceramide (Gb3) and its deacylated form in multiple organs, sometimes localized in specific systems such as the nervous or cardiovascular system. As disease-modifying therapies are now available, early diagnosis is paramount to improving life quality and clinical outcomes. Despite the widespread use of non-invasive techniques for assessing organ damage, such as cardiac magnetic resonance imaging (MRI) for patients with cardiac disease, organ biopsy remains the gold standard to assess organ involvement. CASE PRESENTATION: The cases of two patients, father and daughter with a W162C mutation, are described. The father presented with late-onset, cardiac Fabry disease, subsequently developing systolic dysfunction and heart failure. His daughter, while asymptomatic and with normal cardiac assessment (except for slightly reduced native T1 values by cardiac MRI), had already initial myocyte Gb3 deposits on the endomyocardial biopsy, allowing her to start therapy precociously and potentially modifying the course of her disease. A review of the literature concerning the W162C mutation is then provided, showing that it is usually associated to classic, multisystemic Fabry disease rather than the cardiac-restricted form as in these two cases. CONCLUSIONS: Three main points can be concluded from this report. First, the W162C mutation can present with a more variegate phenotype than that predicted on a molecular basis. Second, endomyocardial biopsy was shown in this case to precede non-invasive investigation in determining organ involvement, justifying further studies on this potentially reliable technique, Third, difficulties can arise in the management of asymptomatic female carriers.

Patient-reported experience with Fabry disease and its management in the real-world setting: results from a double-blind, cross-sectional survey of 280 respondents.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a heterogeneous clinical presentation. Patients with FD may exhibit early signs/symptoms including neuropathic pain, gastrointestinal complaints, and dermatologic manifestations. FD may ultimately progress to renal, neurologic, and cardiac dysfunction. Current treatments for FD have significantly improved the management and outcomes for patients with FD, but important clinical and convenience limitations still exist. METHODS: To illuminate the impact of FD on daily life from the patient's perspective, we asked adult patients (≥ 18 years old) with FD in the United States and Canada to complete a 33-question online survey to assess patient-reported disease severity, management, and treatment outcomes. RESULTS: A total of 280 respondents with FD completed the survey; they had a mean age of 47 years, and 68% (191/280) were women. Most were currently receiving FD treatment (84%, 234/280) with enzyme replacement therapy (ERT) (89%, 208/234) or chaperone therapy (11%, 26/234). Common symptoms included low energy/fatigue (72%, 201/280), tingling (62%, 174/280) or pain in the hands/feet (60%, 168/280), ringing in ears/hearing loss (54%, 151/280), general body pains/pain crises (51%, 143/280), and abdominal/stomach pain (50%, 140/280). More than half (51%, 144/280) of respondents reported their symptoms as bothersome (38%, 106/280) or difficult to control (14%, 38/280). Temporary symptom worsening between infusions was reported by about half of respondents: 51% (108/211) currently receiving ERT and 48% (14/29) previously receiving ERT. Only 48% (59/122) of respondents reported their symptom worsening to their physician. Of those who reported it, 41% (24/59) said that their physician prescribed medication to manage their symptoms or changed their treatment regimen. CONCLUSIONS: Our analysis highlights the gap between current standard-of-care in disease monitoring and patient perception of disease progression among patients with FD. This information may be helpful for healthcare providers and drug developers seeking to improve the care of patients with FD by addressing unmet needs of high relevance.

Inflammation and Exosomes in Fabry Disease Pathogenesis.

Fabry Disease (FD) is one of the most prevalent lysosomal storage disorders, resulting from mutations in the GLA gene located on the X chromosome. This genetic mutation triggers glo-botriaosylceramide (Gb-3) buildup within lysosomes, ultimately impairing cellular functions. Given the role of lysosomes in immune cell physiology, FD has been suggested to have a profound impact on immunological responses. During the past years, research has been focusing on this topic, and pooled evidence strengthens the hypothesis that Gb-3 accumulation potentiates the production of pro-inflammatory mediators, revealing the existence of an acute inflammatory process in FD that possibly develops to a chronic state due to stimulus persistency. In parallel, extracellular vesicles (EVs) have gained attention due to their function as intercellular communicators. Considering EVs' capacity to convey cargo from parent to distant cells, they emerge as potential inflammatory intermediaries capable of transporting cytokines and other immunomodulatory molecules. In this review, we revisit the evidence underlying the association between FD and altered immune responses and explore the potential of EVs to function as inflammatory vehicles.

Diet and Physical Activity in Fabry Disease: A Narrative Review.

Fabry disease (FD) is caused by mutations in the galactosidase alpha (GLA) gene which lead to the accumulation of globotriaosylceramide (Gb-3). Enzyme replacement therapy (ERT) and oral chaperone therapy are the current pharmacological treatments for this condition. However, in the literature, there is a growing emphasis on exploring non-pharmacological therapeutic strategies to improve the quality of life of patients with FD. In particular, the nutritional approach to FD has been marginally addressed in the scientific literature, although specific dietary interventions may be useful for the management of nephropathy and gastrointestinal complications, which are often present in patients with FD. Especially in cases of confirmed diagnosis of irritable bowel syndrome (IBS), a low-FODMAP diet can represent an effective approach to improving intestinal manifestations. Furthermore, it is known that some food components, such as polyphenols, may be able to modulate some pathogenetic mechanisms underlying the disease, such as inflammation and oxidative stress. Therefore, the use of healthy dietary patterns should be encouraged in this patient group. Sports practice can be useful for patients with multi-organ involvement, particularly in cardiovascular, renal, and neurological aspects. Therefore, the aim of this review is to summarize current knowledge on the role of nutrition and physical activity in FD patients.

Elevated interleukin-8 expression by skin fibroblasts as a potential contributor to pain in women with Fabry disease.

Fabry disease (FD) is a lysosomal storage disorder of X-linked inheritance. Mutations in the α-galactosidase A gene lead to cellular globotriaosylceramide (Gb3) depositions and triggerable acral burning pain in both sexes as an early FD symptom of unknown pathophysiology. We aimed at elucidating the link between skin cells and nociceptor sensitization contributing to FD pain in a sex-associated manner. We used cultured keratinocytes and fibroblasts of 27 adult FD patients and 20 healthy controls. Epidermal keratinocytes and dermal fibroblasts were cultured and immunoreacted to evaluate Gb3 load. Gene expression analysis of pain-related ion channels and pro-inflammatory cytokines was performed in dermal fibroblasts. We further investigated electrophysiological properties of induced pluripotent stem cell (iPSC) derived sensory-like neurons of a man with FD and a healthy man and incubated the cells with interleukin 8 (IL-8) or fibroblast supernatant as an in vitro model system. Keratinocytes displayed no intracellular, but membrane-bound Gb3 deposits. In contrast, fibroblasts showed intracellular Gb3 and revealed higher gene expression of potassium intermediate/small conductance calcium-activated potassium channel 3.1 (KCa 3.1, KCNN4) in both, men and women with FD compared to controls. Additionally, cytokine expression analysis showed increased IL-8 RNA levels only in female FD fibroblasts. Patch-clamp studies revealed reduced rheobase currents for both iPSC neuron cell lines incubated with IL-8 or fibroblast supernatant of women with FD. We conclude that Gb3 deposition in female FD patient skin fibroblasts may lead to increased KCa3.1 activity and IL-8 secretion. This may result in cutaneous nociceptor sensitization as a potential mechanism contributing to a sex-associated FD pain phenotype.

Pregnancy outcomes of Fabry disease in Austria (PROFABIA)-a retrospective cohort-study.

BACKGROUND: Pregnancy and delivery outcomes in women with Fabry disease are not well described. METHODS: Retrospective cohort-study of women with Fabry disease in Austria using a specific questionnaire and the Austrian Mother-Child Health Passport. RESULTS: Out of a total of 44 enrolled women (median age at study entry 44 years, p25: 30, p75: 51), 86.4% showed signs and symptoms of Fabry disease with an increase in pain burden during pregnancy, primarily in women with moderate pain before pregnancy. Thirty-two of 44 women with Fabry disease reported a total of 70 pregnancies (median age at first pregnancy 24 years, p25: 21, p75: 31), 61 (87.1%) of which resulted in 64 live births including 3 sets of twins, six miscarriages (8.6%) in five women, and three induced abortions (4.3%) in two women. Risk factors for poor maternal and foetal outcomes during pregnancy, overrepresented in our cohort as compared to the general population, were hypertension (n = 10, 16.4%), proteinuria (n = 17, 27.9%) and smoking (n = 24, 39.3%). Preeclampsia was reported in 7 pregnancies (11.5%). Fifty-one (79.7%) children were born at term and 13 (20.3%) were preterm (including one neonatal death), with a median gestational age of 39 weeks (p25: 38, p75: 40) and delivery by C-section in 15 pregnancies (24.6%). Thirteen (20.3%) children presented with low birth weight and 18 (28.1%) were small for their gestational age. In comparison to global and national data-sets, preeclampsia, prematurity, low birth weight, being small for their gestational age as well as inpatient stay were significantly more common in patients with Fabry disease. CONCLUSIONS: Our cohort-study in women with Fabry disease shows an increase of pain burden during pregnancies and clearly points to an increased risk for preeclampsia, prematurity, and neonates small for gestational age. With a substantial number of high-risk pregnancies, neonatal outcomes are somewhat worse in Fabry disease than in the general public. Thus, we provide valuable data enabling informed decision-making in pregnancy counselling for Fabry disease.

Long-Term Clinical-Pathologic Results of Enzyme Replacement Therapy in Prehypertrophic Fabry Disease Cardiomyopathy.

BACKGROUND: The limited ability of enzyme replacement therapy (ERT) in removing globotriaosylceramide from cardiomyocytes is recognized for advanced Fabry disease cardiomyopathy (FDCM). Prehypertrophic FDCM is believed to be cured or stabilized by ERT. However, no pathologic confirmation is available. We report here on the long-term clinical-pathologic impact of ERT on prehypertrophic FDCM. METHODS AND RESULTS: Fifteen patients with Fabry disease with left ventricular maximal wall thickness ≤10.5 mm at cardiac magnetic resonance required endomyocardial biopsy because of angina and ventricular arrhythmias. Endomyocardial biopsy showed coronary small-vessel disease in the angina cohort, and vacuoles in smooth muscle cells and cardiomyocytes ≈20% of the cell surface containing myelin bodies at electron microscopy. Patients received α-agalsidase in 8 cases, and ß-agalsidase in 7 cases. Both groups experienced symptom improvement except 1 patients treated with α-agalsidase and 1 treated with ß-agalsidase. After ERT administration ranging from 4 to 20 years, all patients had control cardiac magnetic resonance and left ventricular endomyocardial biopsy because of persistence of symptoms or patient inquiry on disease resolution. In 13 asymptomatic patients with FDCM, left ventricular maximal wall thickness and left ventricular mass, cardiomyocyte diameter, vacuole surface/cell surface ratio, and vessels remained unchanged or minimally increased (left ventricular mass increased by <2%) even after 20 years of observation, and storage material was still present at electron microscopy. In 2 symptomatic patients, FDCM progressed, with larger and more engulfed by globotriaosylceramide myocytes being associated with myocardial virus-negative lymphocytic inflammation. CONCLUSIONS: ERT stabilizes storage deposits and myocyte dimensions in 87% of patients with prehypertrophic FDCM. Globotriaosylceramide is never completely removed even after long-term treatment. Immune-mediated myocardial inflammation can overlap, limiting ERT activity.

Flow Cytometry-Based Assay to Detect Alpha Galactosidase Enzymatic Activity at the Cellular Level.

BACKGROUND: Fabry disease is a progressive, X chromosome-linked lysosomal storage disorder with multiple organ dysfunction. Due to the absence or reduced activity of alpha-galactosidase A (AGAL), glycosphingolipids, primarily globotriaosyl-ceramide (Gb3), concentrate in cells. In heterozygous women, symptomatology is heterogenous and currently routinely used fluorometry-based assays measuring mean activity mostly fail to uncover AGAL dysfunction. The aim was the development of a flow cytometry assay to measure AGAL activity in individual cells. METHODS: Conventional and multispectral imaging flow cytometry was used to detect AGAL activity. Specificity was validated using the GLA knockout (KO) Jurkat cell line and AGAL inhibitor 1-deoxygalactonojirimycin. The GLA KO cell line was generated via CRISPR-Cas9-based transfection, validated with exome sequencing, gene expression and substrate accumulation. RESULTS: Flow cytometric detection of specific AGAL activity is feasible with fluorescently labelled Gb3. In the case of Jurkat cells, a substrate concentration of 2.83 nmol/mL and 6 h of incubation are required. Quenching of the aspecific exofacial binding of Gb3 with 20% trypan blue solution is necessary for the specific detection of lysosomal substrate accumulation. CONCLUSION: A flow cytometry-based assay was developed for the quantitative detection of AGAL activity at the single-cell level, which may contribute to the diagnosis of Fabry patients.

Updated Evaluation of Agalsidase Alfa Enzyme Replacement Therapy for Patients with Fabry Disease: Insights from Real-World Data.

The clinical use of agalsidase alfa as enzyme replacement therapy (ERT) for Fabry disease (FD) has spread since 2001, and a large body of evidence of its effectiveness has been collected. This review presents the clinical and laboratory results achieved with agalsidase alfa, which has been published in the literature. Agalsidase alfa infusion slows down or stops the progression of renal damage, expressed by reduction or stabilization of the annual decline of the glomerular filtration rate; yearly decrease of glomerular filtration rate (slope) sometimes is reduced until its stabilization. ERT prevents or reduces the occurrence of hypertrophic cardiomyopathy or slows the increase over time if it is already present. Moreover, regarding neurological manifestations, ERT improves neuropathic pain and quality of life, and recent data indicated that it may also prevent the burden of cerebrovascular disease. In addition to ERT's clinical benefits, crucial topics like the most appropriate time to start therapy and the role of anti-drug antibodies (ADA) are analyzed. Treatment with agalsidase alfa in patients with FD substantially improves their outcomes and enhances their quality of life in patients with FD.

Vericiguat improves cardiac function and microcirculation of a male patient with Fabry disease: A case report.

Fabry disease (FD) is a rare X chromosome-linked disorder and can be easily misdiagnosed. Here, we report the case of a 69-year-old male patient with FD who developed heart failure and showed extremely high pulmonary artery pressure. His initial symptom was recurrent atrial fibrillation. The left and right atrial inner diameters were large, and the ventricular wall was thick. Gene analysis which showed GLA c.215T>C p.Met72Thr mutation and single photon emission computed tomography indicated the diagnosis of FD with coronary microvascular dysfunction. The patient was prescribed anti-heart failure drugs, including vericiguat. Following the treatment, his heart function and microvascular perfusion significantly improved, which might be due to the beneficial effects of vericiguat.

A systematic literature review on the health-related quality of life and economic burden of Fabry disease.

BACKGROUND: Fabry disease (FD) is a rare lysosomal storage disease associated with glycolipid accumulation that impacts multiple physiological systems. We conducted a systematic literature review (SLR) to characterize the humanistic (quality of life [QoL]) and economic burden of FD. METHODS: Searches were conducted in the Embase, MEDLINE®, and MEDLINE® In-Process databases from inception to January 19, 2022. Conference abstracts of specified congresses were manually searched. Additional searches were performed in the Cochrane and ProQuest databases for the humanistic SLR and the National Health Service Economic Evaluations Database for the economic SLR. Studies of patients with FD of any sex, race, and age, and published in the English language were included. There was no restriction on intervention or comparator. For the humanistic SLR, studies that reported utility data, database/registry-based studies, questionnaires/surveys, and cohort studies were included. For the economic SLR, studies reporting economic evaluations or assessing the cost of illness and resource use were included. RESULTS: Of the 1363 records identified in the humanistic search, 36 studies were included. The most commonly used QoL assessments were the 36-item Short-Form Health Survey (n = 16), EQ-5D questionnaire descriptive system or visual analog scale (n = 9), and the Brief Pain Inventory (n = 8). Reduced QoL was reported in patients with FD compared with healthy populations across multiple domains, including pain, physical functioning, and depressive symptoms. Multiple variables-including sex, age, disease severity, and treatment status-impacted QoL. Of the 711 records identified in the economic burden search, 18 studies were included. FD was associated with high cost and healthcare resource use. Contributors to the cost burden included enzyme replacement therapy, healthcare, and social care. In the seven studies that reported health utility values, lower utility scores were generally associated with more complications (including cardiac, renal, and cerebrovascular morbidities) and with classical disease in males. CONCLUSION: FD remains associated with a high cost and healthcare resource use burden, and reduced QoL compared with healthy populations. Integrating information from QoL and economic assessments may help to identify interventions that are likely to be of most value to patients with FD.

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.

Is just enzyme replacement therapy enough for Fabry disease treatment? Have we missed a trick? / ¿Es suficiente la terapia enzimática para tratar la enfermedad de Fabry? ¿Nos falta algún detalle?

Background and aim: In Fabry disease (FD), primary factors such as glycosphingolipid deposition that initiate kidney damage and secondary factors that advance kidney damage to fibrosis are different. Periostin is a molecule of proven importance in renal inflammation and fibrosis. It was previously shown that periostin plays an essential role in the process leading to renal fibrosis and its expression is increased in many kidney diseases. In the present study, we aimed to reveal the relationship between periostin and Fabry nephropathy. Material-method: This cross-sectional study included 18 FD patients (10 males, 8 females) with enzyme replacement therapy (ERT) indications and 22 healthy control patients of similar age and gender. At the time of diagnosis, plasma alpha-galactosidase A (α-gal-A) and globotriaosylsphingosine (lyso-Gb3), proteinuria, and kidney function tests of all FD patients before ERT were scanned from the hospital system. Periostin was studied from serum samples collected and stored before ERT. Parameters related to serum periostin levels in Fabry disease were investigated. Results: In FD patients, serum periostin was negatively correlated with age of first symptom and GFR; and positively correlated with proteinuria and lyso-Gb3. In regression analysis, we found that serum periostin was the only independent determinant of proteinuria in patients with Fabry disease. The serum periostin levels were significantly lower in patients with low proteinuria, and the serum periostin levels were correlated with proteinuria. Discussion: Periostin may be a valuable marker of Fabry nephropathy and proteinuria. Periostin seems to be one of the molecules that may have an important role in the management of the fibrotic process in Fabry nephropathy. We think that the role of periostin among these mechanisms is worth investigating... (AU)

Antecedente y objetivo: En la enfermedad de Fabry (EF), son diferentes los factores primarios tales como el depósito de glicoesfingolípidos que inicia el daño renal, y los factores secundarios que progresan de daño renal a fibrosis. Periostina es una molécula de importancia probada en la inflamación renal y la fibrosis. Se ha demostrado previamente que periostina juega un papel esencial en el proceso que causa la fibrosis renal, y que su expresión se incrementa en muchas enfermedades renales. En el presente estudio, nuestro objetivo fue revelar la relación entre la periostina y la nefropatía de Fabry. Material y método: Este estudio transversal incluyó 18 pacientes con EF (10 varones y 8 mujeres) con indicación de terapia enzimática (ERT) y 22 controles sanos con edad y sexo similares. En el momento del diagnóstico se escanearon del sistema hospitalario las pruebas de alfa-galactosidasa A (α-gal-A) plasmática y globotriaosilsfingosina (lyso-Gb3), proteinuria y función renal de todos los pacientes con EF antes de la ERT. Se analizó el nivel de periostina en las muestras séricas recogidas y almacenadas antes de realizar la ERT. Se investigaron los parámetros relacionados con los niveles séricos de periostina en la enfermedad de Fabry. Resultados: En los pacientes con EF, el nivel de periostina sérica se correlacionó negativamente con la edad del primer síntoma y la GFR, y positivamente con proteinuria y lyso-Gb3. En el análisis de regresión, encontramos que el nivel de periostina sérico fue el único determinante independiente de proteinuria en los pacientes con EF. Los niveles séricos de periostina fueron significativamente menores en los pacientes con baja proteinuria, correlacionándose los niveles séricos de periostina con proteinuria. Discusión: La periostina puede ser un marcador valioso de nefropatìa de Fabry y proteinuria.... (AU)

Anderson-Fabry disease management: role of the cardiologist.

Anderson-Fabry disease (AFD) is a lysosomal storage disorder characterized by glycolipid accumulation in cardiac cells, associated with a peculiar form of hypertrophic cardiomyopathy (HCM). Up to 1% of patients with a diagnosis of HCM indeed have AFD. With the availability of targeted therapies for sarcomeric HCM and its genocopies, a timely differential diagnosis is essential. Specifically, the therapeutic landscape for AFD is rapidly evolving and offers increasingly effective, disease-modifying treatment options. However, diagnosing AFD may be difficult, particularly in the non-classic phenotype with prominent or isolated cardiac involvement and no systemic red flags. For many AFD patients, the clinical journey from initial clinical manifestations to diagnosis and appropriate treatment remains challenging, due to late recognition or utter neglect. Consequently, late initiation of treatment results in an exacerbation of cardiac involvement, representing the main cause of morbidity and mortality, irrespective of gender. Optimal management of AFD patients requires a dedicated multidisciplinary team, in which the cardiologist plays a decisive role, ranging from the differential diagnosis to the prevention of complications and the evaluation of timing for disease-specific therapies. The present review aims to redefine the role of cardiologists across the main decision nodes in contemporary AFD clinical care and drug discovery.

Lessons learned from the Canadian Fabry Disease Initiative for future risk-sharing and managed access agreements for pharmaceutical and advanced therapies in Canada.

Risk sharing agreements (RSAs) and managed access agreements have emerged as tools to overcome evidentiary uncertainty and contain costs of pharmaceuticals; however, Canada has relatively little experience with these health policy instruments. This article describes one of the few examples of national RSAs. Enzyme replacement therapies (ERT) were introduced in Canada to treat Fabry disease in the early 2000s through an RSA. Based on qualitative interviews with key participating actors, this article explains how this RSA ensured continuity of treatment for patients already on ERT, and collected robust real-world evidence to secure treatment for future Fabry patients. We show the importance of partnerships, collaborations, and active patient communities in establishing RSAs, as well as the critical role of robust registries for the collection, storage, and use of that real-world data. In doing so, this paper points to reasons that explain the relative dearth of RSAs in Canada, which can be resource (both human and finance) intensive and are difficult to broker in a federalist health system. Through these findings, policy lessons are developed concerning the need for technological and governance platforms on how RSA in Canada can be more effectively supported going forward in a broader move towards "social pharmaceutical innovation".

What should rheumatologists know about Gaucher disease and Fabry disease? Connecting the dots for an overview.

Gaucher and Fabry diseases are lysosomal storage disorders in which deficient enzyme activity leads to pathological accumulation of sphingolipids. These diseases have a broad phenotypic presentation. Musculoskeletal symptoms and pain complaints are frequently reported by patients. Thus, rheumatologists can be contacted by these patients, contributing to the correct diagnosis, earlier indication of appropriate treatment and improvement of their prognosis. This review describes important concepts about Gaucher and Fabry diseases that rheumatologists should understand to improve patients' quality of life and change the natural history of these diseases.

Assessing brain involvement in Fabry disease with deep learning and the brain-age paradigm.

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.

[Genotype-phenotype analysis of Fabry disease caused by GLA gene variation in a pedigree].

Objective: To investigate the clinical phenotype and genetic characteristics of patients with Fabry disease caused by a GLA variant, IVS4+919G>A. Methods: It was a prospective study. Fabry disease screening was conducted among high-risk population in Ninghai from October 2021 to August 2023. Those children with decreased α-galactosidase enzyme activity<2.40 µmol/(L·h) or elavated Lyso-GL-3 level>1.10 µg/L in dried blood spot (DBS) method underwent GLA genetic testing for diagnosis confirmation. Meanwhile, family screening was carried out. A proband and his family members diagnosed with Fabry disease were research subjects. The clinical and genetic characteristics of patients with Fabry disease caused by the GLA variant (IVS4+919G>A) were analyzed. Results: The female proband aged 9.8 years with pain in both lower limbs as the initial symptom was found to have a heterozygous GLA variant IVS4+919G>A among 102 patients. In family screening, there were 4 family members (proband's father, elder sister, elder male cousin and elder female cousin) with Fabry disease and a family member (proband's fifth aunt) with a GLA variant. Among these 4 diagnosed family members, the elder male cousin of the proband, a boy aged 13.2 years had a heterozygous GLA variant, IVS4+919G>A with intermittent pain in both lower limbs as the initial symptom. The proband's father had knee joint pain. The proband's elder sister had decreased vision and his elder female cousin had no obvious symptoms. The proband's fifth aunt with a GLA variant had decreased vision. Conclusions: High-risk screening in children and family screening are helpful for early diagnosis and treatment of Fabry disease. Neuropathic pain may be a early symptom in children with Fabry disease caused by the GLA variant, IVS4+919G>A.