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. Leveraging the accumulating evidence base, multidisciplinary collaborations have resulted in the creation of 32 peer-reviewed scientific publications, which have contributed to the greatly expanded knowledge on the onset and progression of FD, its clinical management, the role of sex and genetics, the outcomes of enzyme replacement therapy with agalsidase beta, and prognostic factors. We review how the Fabry Registry has evolved from its inception to become the largest global source of real-world FD patient data, and how the generated scientific evidence has helped to better inform the medical community, individuals living with FD, patient organizations, and other stakeholders. The patient-centered Fabry Registry fosters collaborative research partnerships with the overarching goal of optimizing the clinical management of patients with FD and is well positioned to add to its past achievements.

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. RESULTS: For 169 patients with available data, median age of first Fabry symptom manifestation was 12.7 years with peripheral pain as predominant first symptom, and diagnostic delay of 10.3 years from the first reported symptom. Female patients had high symptomatic burden during natural history follow-up, with 83% reporting peripheral pain, 69%-79% cold/heat intolerance or abnormal sweating, and 32% gastrointestinal symptoms. ERT-recipients reported similar age at first symptom as ERT-naïve patients but they were older at diagnosis (median 39.2 vs 24.4 years, P < .01) and last follow-up (median 43.4 vs 28.2 years, P < .01). Reported Fabry symptom frequencies and abnormal echocardiography findings were higher in ERT-recipients. Functional renal assessments were normal and similar. CONCLUSIONS: Female patients from Latin America have notable diagnostic delays and high symptomatic burden. ERT was prescribed late in females with advanced age at diagnosis and advanced disease. There remained many female patients who had been diagnosed at younger age, had substantial Fabry manifestations, but did not receive disease-specific treatment.

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. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.

Recommendations for Evaluation and Management of Pain in Patients With Mucopolysaccharidosis in Latin America.

The mucopolysaccharidosis (MPS) constitutes a heterogeneous group of rare genetic disorders caused by enzymatic deficiencies that lead to the accumulation of glycosaminoglycans. Several types of MPS are described, historically numbered from I to IX. Clinical observations strongly suggest the presence of chronic pain in patients with all types of MPS. There are few data in the literature on the evaluation and management of pain in these patients, a fact that can compromise the quality of life even more. Professionals with extensive experience in the care for patients with MPS held a meeting in April 2017 to discuss and propose recommendations for the evaluation and management of pain in patients with MPS in Latin America. This article summarizes the content of the discussions and presents the recommendations produced at the meeting. Patients with MPS present joint, bone, and muscle pain, as well as entrapment syndromes (spinal, optic nerve, carpal tunnel). The panel suggests the use of the following instruments for pain assessment: Face, Legs, Activity, Cry and Consolability Scale for children of up to four years of age and patients unable to communicate their pain; Child Health Assessment Questionnaire Scale; Facial Pain Scale and Numerical Pain Scale for patients of five to <18 years of age; Brief Pain Inventory and Short Form Health Survey 36 scales for patients aged 18 years or older. Based on the scores verified in these scales, the panel proposes pharmacological interventions for pain relief in this population of patients.

Fabry disease: Four case reports of meningioma and a review of the literature on other malignancies.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by loss of function mutations in the GLA gene at Xq22 with subsequent functional deficiency of alpha-galactosidase A, resulting in the accumulation of globotriaosylceramide (GL-3 or Gb3) in multiple cells types throughout the body. As with other rare metabolic disorders, little is known about the incidence of malignancies in these populations and the relationship to the underlying disease, if any. We report the occurrence of meningioma in four female patients with Fabry disease. Two of the cases are from the same family and shared the same GLA mutation. All four patients underwent surgical excision of their tumor. High resolution light microscopy and electron microscopy examination of one case revealed extensive involvement of tumor cells and associated blood vessels by GL-3 accumulation. Because of the small number of Fabry-associated cancer cases reported in the literature, questions about a possible link between lysosomal storage disorders and the development of malignancy remain open.

Familial gain-of-function Nav1.9 mutation in a painful channelopathy.

OBJECTIVE: Gain-of-function mutations in Nav1.9 have been identified in three families with rare heritable pain disorders, and in patients with painful small-fibre neuropathy. Identification and functional assessment of new Nav1.9 mutations will help to elucidate the phenotypic spectrum of Nav1.9 channelopathies. METHODS: Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations in SCN9A and SCN11A. Electrophysiological recordings and multistate modelling analysis were implemented for functional analyses. RESULTS: A novel Nav1.9 mutation, p.Arg222His, was identified in patients with early-onset pain in distal extremities including joints and gastrointestinal disturbances, but was absent from an asymptomatic blood relative. This mutation alters channel structure by substituting the highly conserved first arginine residue in transmembrane segment 4 (domain 1), the voltage sensor, with histidine. Voltage-clamp recordings demonstrate a hyperpolarising shift and acceleration of activation of the p.Arg222His mutant channel, which make it easier to open the channel. When expressed in dorsal root ganglion neurons, mutant p.Arg222His channels increase excitability via a depolarisation of resting potential and increased evoked firing. CONCLUSIONS: This study expands the spectrum of heritable pain disorders linked to gain-of-function mutations in Nav1.9, strengthening human validation of this channel as a potential therapeutic target for pain.

Pain in Fabry Disease: Practical Recommendations for Diagnosis and Treatment.

AIMS: Patients with Fabry disease (FD) characteristically develop peripheral neuropathy at an early age, with pain being a crucial symptom of underlying pathology. However, the diagnosis of pain is challenging due to the heterogeneous and nonspecific symptoms. Practical guidance on the diagnosis and management of pain in FD is needed. METHODS: In 2014, experts met to discuss recent advances on this topic and update clinical guidance. RESULTS: Emerging disease-specific tools, including FabryScan, Fabry-specific Pediatric Health and Pain Questionnaire, and Würzburg Fabry Pain Questionnaire, and more general tools like the Total Symptom Score can aid diagnosis, characterization, and monitoring of pain in patients with FD. These tools can be complemented by more objective and quantifiable sensory testing. In male and female patients of any age, pain related to FD can be an early indication to start disease-specific enzyme replacement therapy before potentially irreversible organ damage to the kidneys, heart, or brain occurs. CONCLUSION: To improve treatment outcomes, pain should be diagnosed early in unrecognized or newly identified FD patients. Treatment should include: (a) enzyme replacement therapy controlling the progression of underlying pathology; (b) adjunctive, symptomatic pain management with analgesics for chronic neuropathic and acute nociceptive, and inflammatory or mixed pain; and (c) lifestyle modifications.

Determinants of white matter hyperintensity burden in patients with Fabry disease.

OBJECTIVE: Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD). METHODS: Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p < 0.05 for all analyses. RESULTS: Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 ± 14.9 (range 9.6-72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2.7 cm(3) (interquartile range 1.8-4.0). Age (ß 0.02, p = 0.008) and history of stroke (ß 1.13, p = 0.02) were independently associated with lnWMHV. However, WMH burden-as well as WMHV predictors-varied by decade of life in this cohort of patients with FD (p < 0.0001). CONCLUSIONS: In this largest-to-date cohort of patients with FD who had volumetric analysis of MRI, age and prior stroke independently predicted the burden of WMH. The 4th decade of life appears to be critical in progression of WMH burden, as novel predictors of WMHV emerged in patients aged 31-40 years. Future studies to elucidate the biology of WMH in FD and its role as potential MRI marker of disease progression are needed.

Small Fiber Neuropathy in Fabry Disease: a Review of Pathophysiology and Treatment

Abstract Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of glycolipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at a young age. Neuropathic pain and pain attacks are often the presenting symptoms of the disease and start at an average age of 9 years in male patients and 16 years in female patients, but currently a systematic literature review in early childhood showed the presence of these symptoms before the age of 5 years. Clinical studies have shown that enzyme replacement therapy may improve the overall pain scores and pain intensity in patients; improvements in pain outcomes have been sustained during the long-term follow-up, allowing many patients to reduce their use of pain medication. Some indirect evidence from dose-switching studies suggests that enzyme replacement therapy dose may be of relevance to pain outcomes. Considering that damage to small nerve fibers occurs early, prompt treatment is important in order to limit damage to the peripheral nervous system. In this article a comprehensive overview of the existing literature on small nerve fiber pathophysiology and the relationship with neuropathic pain and treatment response in children and adults with Fabry disease is presented.

Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature.

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of α-galactosidase A, resulting in the accumulation of globotriaosylceramide. Many women experience symptoms, but the understanding of placental and fetal aspects of the disease is limited. We report the pregnancy outcome in and placental pathology of a 37-year-old woman with Fabry disease. She became pregnant 2 years after starting enzyme replacement therapy and continued therapy throughout her pregnancy. At 38 weeks' gestation, she gave birth to a healthy boy with the same maternal Fabry mutation. The present case describes more extensive placental involvement by Fabry disease than has been previously reported. Globotriaosylceramide deposits were found within multiple cell types of the placenta, cord, and membranes. Because of the small numbers of cases described in the literature for comparison, it remains unclear if placental tissues are also targeted by enzyme replacement therapy.

Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel.

BACKGROUND: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. METHODS: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. RESULTS: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. CONCLUSIONS: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.

Treatment with agalsidase beta during pregnancy in Fabry disease.

Fabry disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase A, which leads to excessive accumulation of glycosphingolipids in most tissues in the body, with life-threatening clinical consequences in the kidney, heart, and cerebrovascular system. Enzyme replacement therapy using exogenously produced alpha-galactosidase has been available for treatment of this multisystem progressive disease since 2001. Two different preparations of enzyme replacement therapy for Fabry disease are available outside of the USA: agalsidase alfa and agalsidase beta. Despite being X-linked, Fabry disease affects many female patients, and this report presents a successful pregnancy of a female patient receiving agalsidase beta.

Ecografía renal en 25 pacientes con enfermedad de Fabry: incidencia de patología quística renal / Renal echography in 25 Fabry disease patients: cystic renal pathology incidence

La enfermedad de Fabry (EF) es una enfermedad por depósito lisosomal, con herencia ligada al X, causada por ladeficiencia de la enzima α-galactosidasa A, lo que lleva al acúmulo de glicoesfingolípidos en diferentes célulasdel organismo. La muerte de estos pacientes se da en el contexto de insuficiencia renal, cardiaca y cerebrovascular. Otros reportes demuestran que los pacientes con EFtienen una incidencia mayor de quistes renales que la población normal.Objetivo: evaluar en un grupo de 25 pacientes con EF los hallazgos ecográficos renales. Materiales y métodos: se evaluaron 25 pacientes (16 hemicigotas), 16-50 años, con diagnóstico confirmado por test bioquímicos y genéticos, sin insuficiencia renal. Resultados: los diámetros renales fueron normales, el24% del total de los evaluados presentaron quistes renales, con un total del grupo de los hemicigotas del 24% ydel total de las heterocigotas el 22,2% afectados. Conclusión: si bien el grupo de pacientes evaluados fue pequeño, hemos encontrado una incidencia mayor a la población normal, pero menor a los valores reportados por otros autores. (AU)

glycosphingolipid catabolism caused by the deficient activity of α-galactosidase A, that results in the progressiveaccumulation of globotriaosylceramide in different cells of organism. Patiens frequently die for renal or cardiacinsufficiency. Aim: to assess 25 patients (16 hemicygotes) with confirmdiagnosis of Fabry disease without renal insufficiency. Results: renal diameter were normal, 24% ot total patientsshowed cystic abnormalities.Conclusion: although our group was small, but we found a high incidence of cystic abnormalities compared withnormal population and smaller than other reports. (AU)

Ecografía renal en 25 pacientes con enfermedad de Fabry: incidencia de patología quística renal / Renal echography in 25 Fabry disease patients: cystic renal pathology incidence

La enfermedad de Fabry (EF) es una enfermedad por depósito lisosomal, con herencia ligada al X, causada por ladeficiencia de la enzima α-galactosidasa A, lo que lleva al acúmulo de glicoesfingolípidos en diferentes célulasdel organismo. La muerte de estos pacientes se da en el contexto de insuficiencia renal, cardiaca y cerebrovascular. Otros reportes demuestran que los pacientes con EFtienen una incidencia mayor de quistes renales que la población normal.Objetivo: evaluar en un grupo de 25 pacientes con EF los hallazgos ecográficos renales. Materiales y métodos: se evaluaron 25 pacientes (16 hemicigotas), 16-50 años, con diagnóstico confirmado por test bioquímicos y genéticos, sin insuficiencia renal. Resultados: los diámetros renales fueron normales, el24% del total de los evaluados presentaron quistes renales, con un total del grupo de los hemicigotas del 24% ydel total de las heterocigotas el 22,2% afectados. Conclusión: si bien el grupo de pacientes evaluados fue pequeño, hemos encontrado una incidencia mayor a la población normal, pero menor a los valores reportados por otros autores.

glycosphingolipid catabolism caused by the deficient activity of α-galactosidase A, that results in the progressiveaccumulation of globotriaosylceramide in different cells of organism. Patiens frequently die for renal or cardiacinsufficiency. Aim: to assess 25 patients (16 hemicygotes) with confirmdiagnosis of Fabry disease without renal insufficiency. Results: renal diameter were normal, 24% ot total patientsshowed cystic abnormalities.Conclusion: although our group was small, but we found a high incidence of cystic abnormalities compared withnormal population and smaller than other reports.

Magnetic resonance image findings in 5 young patients with Fabry disease.

INTRODUCTION: Fabry disease is an X-linked recessive lysosomal storage disease; it is due to alpha-galactosidase A deficiency, and its clinical course shows repeated small artery strokes. METHODS: Five patients diagnosed with Fabry disease (mean age +/- SD = 28.2 +/- 11.1 years) and 5 age-matched controls were evaluated with the following magnetic resonance image (MRI) sequences: T1, T2, FLAIR, diffusion, and single voxel spectroscopy at the parietal lobe. RESULTS: Conventional images did not reveal alterations. Mean apparent diffusion coefficient (ADC) +/- SD in the corona radiata of patients was 7.8 +/- 0.2 x 10 mm/s, which was significantly higher than for controls: 6.93 +/- 0.49 x 10 mm/s (P < 0.05). At the lenticular nucleus there were no differences in ADC values between patients (7.32 +/- 0.2 x 10 mm/s) and controls (7.2 +/- 0.2 x 10 mm/s). The mean ratio NAA/Cr +/- SD at the parietal lobes was 1.94 +/- 0.2 for patients and 2.1 +/- 0.13 for controls (P = n.s.). DISCUSSION: : In a group of young Fabry disease patients with normal MRIs, a significant increment of over 12% in ADC values in the corona radiata was found compared with age-matched controls. The change could reflect increased interstitial water content after the Starling equilibrium under raised cerebral blood flow, which is a known feature of Fabry disease. CONCLUSION: Raised ADC values could predate conventional MRI changes in Fabry disease and therefore be a more sensitive marker of disease progression and response to enzymatic replacement therapy.