Clinically Meaningful Outcomes after 1 Year of Treatment with Setmelanotide in an Adult Patient with a Variant in SH2B1.

Introduction: Monogenic obesity is caused by a unique genetic dysfunction, often appears in childhood, and can be accompanied by neuroendocrine, skeletal, developmental, and behavioral disorders, among other manifestations. Some variants in the SH2B1 gene have been suggested as strong candidates for the development of autosomal dominant obesity.

Case Presentation: We describe here the clinical response after 1 year of setmelanotide treatment in a 22-year-old patient with an SH2B1 variant.

Baseline Characteristics of Fabry Disease "Amenable" Migalastat Patients in Argentinian Cohort.

Fabry disease (FD) is a multisystem lysosomal storage disorder induced by genetic variants in the alpha-galactosidase A (GalA) gene. Some FD patients have GLA variants with a reduction in overall GalA enzymatic activity due to mutated proteins with reduced stability, caused by protein misfolding and premature degradation, but the GalA catalytic activity remains conserved ("amenable" genetic variants). To correct this misfolding and to prevent premature degradation, migalastat, a small iminosugar molecule was developed.

Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study.

Objective: Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition of the oral chaperone therapy migalastat to the available treatment options for Fabry disease is not yet universally reflected in all treatment guidelines. These consensus recommendations are intended to provide guidance for the treatment and monitoring of patients with Fabry disease receiving migalastat.

Global reach of over 20 years of experience in the patient-centered Fabry Registry: Advancement of Fabry disease expertise and dissemination of real-world evidence to the Fabry community.

Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20 years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD.

Understanding and modifying Fabry disease: Rationale and design of a pivotal Phase 3 study and results from a patient-reported outcome validation study.

The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral substrate reduction therapy for the treatment of FD. By reducing the net globotriaosylceramide (Gb3) load in tissues, lucerastat has disease-modifying potential to improve symptoms and delay disease progression.

Fabry Disease Patient-Reported Outcome (FD-PRO) demonstrates robust measurement properties for assessing symptom severity in Fabry disease.

Background: Fabry disease (FD) is a rare, genetic disease, that if untreated, progresses to irreversible and life-threatening renal, cardiac, and cerebrovascular events. FD symptoms impact daily functioning and quality of life, but no disease-specific measure of these symptoms has been psychometrically tested.

Methods: The Fabry Disease Patient-Reported Outcome (FD-PRO) consists of 19 items that measure neuropathic symptoms (pain, tingling, numbness and burning in upper/lower extremities), headache, abdominal pain, heat intolerance, swelling, tinnitus, fatigue, hearing/vision impairment, hypohidrosis (diminished sweating) and difficulty engaging in regular physical activities in the past 24 h.

The benefits and challenges of family genetic testing in rare genetic diseases-lessons from Fabry disease.

Background: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease-specific therapies when available. Fabry disease, an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end-stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non-specificity of early symptoms.

Enzyme replacement therapy interruption in mucopolysaccharidosis type IVA patients and its impact in different clinical outcomes.

Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal recessive lysosomal storage disorder caused by mutations in the gene, which leads to deficient activity of N-acetylglucosamine-6-sulfate sulfatase. MPS IVA patients usually present skeletal dysplasia, coarse features, short stature, airway obstruction, cervical spinal cord compression, dental abnormalities, and cardiac valvular alterations. Enzyme replacement therapy (ERT) with elosulfase alfa is the only disease-specific treatment available for MPS IVA patients and has been shown to improve important clinical and biochemical parameters; however, little is known about the effects of ERT interruption on these patients.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

Background: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD.

Fabry disease and COVID-19: international expert recommendations for management based on real-world experience.

The rapid spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has raised questions about Fabry disease (FD) as an independent risk factor for severe COVID-19 symptoms. Available real-world data on 22 patients from an international group of healthcare providers reveals that most patients with FD experience mild-to-moderate COVID-19 symptoms with an additional complication of Fabry pain crises and transient worsening of kidney function in some cases; however, two patients over the age of 55 years with renal or cardiac disease experienced critical COVID-19 complications. These outcomes support the theory that pre-existent tissue injury and inflammation may predispose patients with more advanced FD to a more severe course of COVID-19, while less advanced FD patients do not appear to be more susceptible than the general population.

Improvement of gastrointestinal symptoms in a significant proportion of male patients with classic Fabry disease treated with agalsidase beta: A Fabry Registry analysis stratified by phenotype.

Background: Fabry disease is an inherited disorder of glycolipid metabolism with progressive involvement of multiple organs, including the gastrointestinal tract, in classically affected male patients. Clinical presentations in males with later-onset Fabry phenotypes are more heterogeneous and largely dependent on the level of residual α-galactosidase A activity.

Methods: We assessed agalsidase beta treatment outcomes of gastrointestinal symptoms in adult males with classic or later-onset Fabry disease.

Incidental finding of cornea verticillata or lamellar inclusions in kidney biopsy: measurement of lyso-Gb3 in plasma defines between Fabry disease and drug-induced phospholipidosis.

Introduction: Therapy with cationic amphiphilic drugs (Amiodarone or hydroxychloroquine) may result in biochemically and ultrastructurally similar lipid inclusions in many cells also affected by Fabry disease (FD). In addition, it often results in similar clinical manifestations such as cornea verticillata. This may lead to a FD misdiagnosis, especially when a complete medical history is not available to the ophthalmologist confronted with cornea verticillata or to the pathologist examining a kidney biopsy.

Fabry disease during the COVID-19 pandemic. Why and how treatment should be continued.

Fabry disease is an X-linked disease due to a deficiency of the lysosomal enzyme alpha-galactosidase A. Clinical symptoms in classically affected males include acroparesthesia, anhydrosis and angiokeratoma, which may present during childhood followed by cardiac, cerebral and renal complications. Even though pulmonary involvement is not widely appreciated by clinicians, an obstructive lung disease is another recognized component of Fabry disease.

Use of a rare disease registry for establishing phenotypic classification of previously unassigned variants: a consensus classification system by a multispecialty Fabry disease genotype-phenotype workgroup.

Background: Fabry disease (α-galactosidase deficiency) is an X-linked genetic disease caused by a variety of pathogenic variants. The phenotypic heterogeneity is considerable, with two major forms, classic and later-onset disease, but adjudication of clinical phenotype is currently lacking for many variants. We aimed to determine consensus phenotypic classification for previously unclassified variants from the -specific fabry-database.

Enzyme replacement therapy interruption in patients with Mucopolysaccharidoses: Recommendations for distinct scenarios in Latin America.

Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, leading to the progressive accumulation of glycosaminoglycans (GAGs) and the subsequent compromising of tissues and organ malfunction. Although incurable, most types of MPS can be treated with enzyme replacement therapy (ERT), an approach that has had positive effects on the natural clinical evolution and which impact has been extensively investigated. Unfortunately, to date, there is relatively little data regarding the effects of ERT interruption, especially in Latin America, where such interruption may be frequent due to a variety of issues (for instance, difficulties involving logistics, reimbursement and/or payment withdrawal).

The clinical profiles of female patients with Fabry disease in Latin America: A Fabry Registry analysis of natural history data from 169 patients based on enzyme replacement therapy status.

Background: Fabry disease is an X-linked lysosomal storage disorder with heterogeneous clinical expression in female patients ranging from asymptomatic to severe clinical presentations as in classic males. We assessed clinical profiles and compared natural history data of female patients eventually initiated on enzyme replacement therapy ("ERT-recipients") with those remaining untreated ("ERT-naïve").

Methods: We analyzed Fabry Registry data from 93 ERT-recipients, collected prior to ERT initiation, and 76 ERT-naïve females with classic or unclassified phenotypes from four Latin American countries and evaluated Fabry symptoms, interventricular septum thickness, left ventricular posterior wall thickness, estimated glomerular filtration rate, and severe clinical events.

Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative.

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies.

Prevalence of Fabry disease in male dialysis patients: Argentinean screening study.

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme Alpha-Galactosidase A (α-Gal-A) deficiency, due mutations in GLA gene. Progressive glycolipid accumulation leads to damage in kidney and other organs. The aim of this study was to estimate the prevalence of Fabry disease in Argentinean male patients undergoing dialysis.

Early decrease in the podocalyxin to synaptopodin ratio in urinary Fabry podocytes.

Background: In Fabry nephropathy, podocyturia is an early event that may lead to glomerulosclerosis and chronic kidney disease. The glycocalyx is a potential podocyte damaged compartment in glomerulopathies. We investigated glycocalyx podocalyxin in urinary detached podocytes compared with cytoplasmic synaptopodin.

Altered globotriaosylceramide accumulation and mucosal neuronal fiber density in the colon of the Fabry disease mouse model.

Background: Fabry disease (FD) is a hereditary X-linked metabolic storage disorder characterized by deficient or absent lysosomal α-galactosidase A (α-Gal A) activity. This deficiency causes progressive accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), in nearly all organ systems. Gastrointestinal (GI) symptoms can be very debilitating and are among the most frequent and earliest of the disease.

[Argentine consensus on late-onset Pompe's disease].

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013.