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. After 3 months of treatment, our patient lost 5.4% of body weight. This period was followed by a 3-month period of noncompliance, in which the patient gained 4% body weight. After reinstating daily drug administration, the patient showed a 19.5% reduction in body weight and a clear improvement in all hunger scales after 1 year of treatment. CONCLUSION: These results indicate that the changes seen are drug dependent and provide positive evidence for the administration of setmelanotide in adult patients with heterozygous variants in the SH2B1 gene.

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 (αGalA) gene. Some FD patients have GLA variants with a reduction in overall αGalA enzymatic activity due to mutated proteins with reduced stability, caused by protein misfolding and premature degradation, but the αGalA catalytic activity remains conserved ("amenable" genetic variants). To correct this misfolding and to prevent premature degradation, migalastat, a small iminosugar molecule was developed. We report the clinical characteristics of FD "amenable" cohort patients from Argentina, prior to starting treatment with migalastat. Seventeen Fabry adult patients were recruited from 13 Argentinian Centers; 8 males (47.1%) and 9 females (52.9%) were included. All genotypes included were missense-type "amenables" mutations. Some classic FD typical early manifestations were more frequent in patients with "classic" versus "late-onset" FD phenotype (pain, p=0.002; cornea verticillata, p=0.019). There was a statistically significant difference in estimated glomerular filtration rate in the "classic" versus "late-onset" phenotype (p=0.026) but no difference between genders (p=0.695). Left ventricular mass was similar between genders (p=0.145) and phenotypes (p=0.303). Cardiovascular risk factors were present among "late-onset" females (obesity 50% and smoke 25%). In patients who started "de novo" migalastat, the main indications were (i) heart disease, (ii) kidney damage, and (iii) pain, while in "switched from prior enzyme replacement therapy" patients, the most frequent indication was "patient decision;" this coincides with publications by other authors.

Consenso de expertos sobre recomendaciones basadas en evidencia para el diagnóstico, tratamiento y seguimiento de enfermedad de Fabry en pediatría / Expert Consensus on Evidence-Based Recommendations for the Diagnosis, Treatment, and Follow-Up of Fabry Disease in Pediatric Patients / Consenso de especialistas colombianos sobre recomendações baseadas em evidências para o diagnóstico, tratamento e acompanhamento da doença de Fabry em pediatria

Antecedentes: la enfermedad de Fabry (Ef) es una enfermedad rara ligada a X secundaria al depósito lisosomal de glicoesfingolípidos, debido a la deficiencia de la enzima alfa galactosidasa A (α-Gal A). A pesar de su baja frecuencia, es una condición que afecta la calidad de vida de los pacientes y disminuye su esperanza de vida. Objetivo: generar recomendaciones informadas para el diagnóstico y tratamiento de pacientes pediátricos (menores de 18 años) con Ef. Material y Métodos: revisión de literatura en bases de datos y literatura gris a partir de 2010, incluyendo guías de práctica clínica, revisiones sistemáticas y estudios primarios. La calidad de evidencia se evaluó de acuerdo con el tipo. Las recomendaciones se sometieron a consenso de expertos a través de metodología Delphi modificada. El acuerdo se definió a partir del 80 %. Resultados: A partir del análisis de la evidencia recolectada se formularon un total de 45 recomendaciones para tamización, diagnóstico y tratamiento de paciente pediátrico con Ef. El panel revisor estuvo conformado por once expertos en el tema. Las recomendaciones fueron aprobadas con puntuaciones entre 82.3 % y 100 %. Conclusiones: las recomendaciones resultantes del consenso de expertos permitirán la toma de decisiones clínicas y estandarización de la práctica en la atención de pacientes pediátricos con Ef en el país y la región. El diagnóstico temprano y oportuno garantiza una disminución del impacto en la calidad de vida de los pacientes y sus familiares

Background: Fabry disease (fD) is a rare X-linked disease characterized by the accumulation of glyco- sphingolipids in lysosomes due to the deficiency in the production of alpha-galactosidase A (α-Gal A) enzyme. Despite its low frequency, this disease has a serious impact on the life expectancy and quality. Objective: To make evidence-based recommendations for the diagnosis and treatment of fD in pediatric patients (<18 years of age). Materials and Methods: A study of databases and gray literature was conducted in 2010, including clinical practice guidelines, systematic reviews, and primary research. The type of evidence was used to determine the quality of evidence. The recommendations were submitted to an expert consensus using the modified Delphi process. The agreement was set at 80%. Conclusions: The recommendations emerging from this expert consensus will enable the standardization of care provision for pediatric patients with fD in Colombia and Latin America and clinical decision-making for disease management. Notably, making an early diagnosis ensures a reduction in the impact of this disease on the quality of life of patients and their families

Fundamento: a doença de Fabry (Df) é uma rara doença ligada ao cromossomo X secundária à deposi- ção lisossômica de glicoesfingolipídeos devido à deficiência da enzima alfa galactosidase A (α-Gal A). Apesar de sua baixa frequência, é uma condição que afeta a qualidade de vida dos pacientes e diminui sua expectativa de vida. Objetivo: gerar recomendações baseadas em evidências para o diagnóstico e tratamento de pacientes pediátricos (com menos de 8 anos de idade) com Df. Materais e Métodos: foi realizada uma revisão da literatura em bases de dados e literatura cinza a partir de 2010, incluindo diretrizes de prática clínica, revisões sistemáticas e estudos primários. A qualidade da evidência foi avaliada de acordo com o tipo de evidência. As recomendações foram submetidas ao consenso de especialistas usando a metodologia Delphi modificada. A concordância foi definida a partir de 80%. Resultados: com base na análise das evidências coletadas, foram formuladas um total de 45 recomendações para triagem, diagnóstico e tratamento de pacientes pediátricos com doença de Fabry. O painel de revisão foi composto por onze especialistas no assunto. As recomendações foram aprovadas com pontuações entre 82,3% e 100%. Conclusões: as recomendações resultantes do consenso de especialistas permitirão a tomada de decisão clínica e a padronização da prática no cuidado de pacientes pediátricos com Df em nível nacional e regional; o diagnóstico precoce e oportuno garante a redução do impacto na qualidade de vida dos pacientes e seus familiares.

Consenso colombiano de expertos sobre recomendaciones basadas en evidencias para el diagnóstico, el tratamiento y el seguimiento de la enfermedad de Fabry con compromiso renal

Contexto: la enfermedad de Fabry se comporta como una enfermedad crónica con compromiso multisistémico y alto costo en salud. Objetivo: generar recomendaciones basadas en la evidencia para el diagnóstico, el tratamiento y el seguimiento de la enfermedad de Fabry con compromiso renal mediante un consenso de expertos. Metodología: a partir de la búsqueda de evidencia en Pubmed, Embase y Google Scholar entre 2010 y agosto 2020, se formulan recomendaciones sobre la definición, el diagnóstico y el tratamiento de la enfermedad de Fabry en población adulta, las cuales se consultan a un panel de expertos a través de la metodología de consenso Delphi modificado. La calidad de los documentos se evaluó por equipo metodológico aplicando herramientas en función del tipo de documento incluido. Resultados: se formularon 53 recomendaciones sobre la definición, el diagnóstico y el tratamiento. Un panel de cinco expertos clínicos nacionales e internacionales externos al grupo desarrollador participaron en la consulta preconsenso y 50 recomendaciones fueron acordadas para su inclusión, para tres de ellas se requirió una sesión formal de consenso que se dio en una ronda, incorporando tres nuevas recomendaciones. Conclusiones: las recomendaciones basadas en evidencia y experticia clínica permitirán orientar de manera estandarizada a nivel nacional y regional, el diagnóstico y el tratamiento de pacientes con sospecha o enfermedad de Fabry con compromiso renal.

Background: Fabry disease behaves like a chronic condition, with multisystem involvement and high health care costs. Objective: To generate evidence-based recommendations for the diagnosis, treatment and follow-up of the Anderson-Fabry disease with renal commitment, through an expert consensus. Methodology: Based on the search of evidence in PubMed, Embase and Google Scholar between 2010 and August, 2020, recommendations on the definition, diagnosis and treatment of Fabry Disease in adult population were formulated after consulting with an expert panel through the modified Delphi consensus methodology. The quality of the documents was assessed by methodological team applying tools according to the type of document included. Results: 53 recommendations for the definition, diagnosis and treatment were formulated. A panel of five national and international clinical experts external to the developer group participated in the pre-consensus consultation and 50 recommendations were agreed upon for their inclusion. For 3 recommendations, a formal consensus session which took place in one round was required, and 3 new recommendations were incorporated. Conclusions: The recommendations based on evidence and clinical expertise will allow us to guide the diagnosis and treatment of patients with Fabry disease with renal involvement or suspicion thereof in a standardized manner at national and regional levels.

Trasplante renal en la enfermedad de Fabry: una historia de idas y vueltas / Kidney transplant in Fabry disease: a round-trip story

La enfermedad de Fabry es una patología por depósito lisosomal causada por mutaciones en el gen GLA que resulta en la deficiencia de alfa galactosidasa A. Dentro de las complicaciones tardías más comunes se encuentra la insuficiencia renal terminal. Por medio de una revisión bibliográfica en la base PUBMed se busca evidenciar si el trasplante renal representa una opción terapéutica indiscutible para el tratamiento de la nefropatía de Fabry. Hallazgos demuestran la posibilidad de la terapia de reemplazo enzimático que permite proteger al sistema cardiovascular y nervioso del daño progresivo por acumulo lisosomal.

Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene that results in alpha galactosidase A deficiency. One of the most common late complications is end stage renal disease. Through a bibliographic review in the PUBMed database, we seek to demonstrate whether kidney transplantation represents an indisputable therapeutic option for the treatment of Fabry nephropathy. Findings demonstratethepossibility of enzymereplacementtherapythatprotects the cardiovascular and nervoussystemfromprogressivedamagebylysosomalaccumulation.

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). METHOD: A group of medical professionals from Latin America with experience in Genetics, Pediatrics and Neurology held an Advisory Board Meeting in the city of São Paulo, in October 2018, to discuss the issue of ERT interruptions in the region and recommendations health care professionals on how to deal with these interruptions and better assess the therapeutic effects of ERT. CONCLUSION: Recommendations provided by the experts may support physicians in dealing with the most common reasons for ERT interruptions in Latin America. Most importantly, recommendations for data collection at specific timepoints (at baseline, throughout the treatment and during the interruption period of ERT and after its resumption) can significantly improve the collection of real world evidence on the effects of ERT and its interruptions, supporting health care professionals and policy makers in the decision making regarding the provision of these therapies for MPS patients.

Perthes-Like Disease Masquerading Non-Classical MPS

Abstract Mucopolysaccharidoses (MPS) are inborn errors of metabolism caused by deficient lysosomal enzymes, leading to organomegaly, hip osteonecrosis, coarse facial features, bone deformities, joint stiffness, cardiac and pulmonary symptoms (MPS VI) or hypermobility (MPS IVA). Some patients may present with non-classical forms of the disease in which osteoarticular abnormalities are the initial symptoms of non-classical forms. As orthopedists and surgeons are the specialists most frequently consulted before the diagnosis, it is critical that MPS may be considered as a differential diagnosis for patients with bone dysplasia. Experts in Latin America reviewed medical records focusing on disease onset, first symptoms and the follow-up clinical and surgical outcomes of non-classical MPS VI and IVA patients. All patients displayed orthopedic issues, which worsened over time, followed by cardiac and ophthalmological abnormalities. Our findings enlighten the necessity of including non-classical MPS as possible diagnosis for patients who report osteoarticular abnormalities in absence of inflammation.

Genotype-Phenotype Variations of Renal Complications in Fabry Disease Q279X Mutation

Abstract In more than 800 GLA gene mutations causing Fabry Disease (FD), renal involvement vary according to the α-GAL A mutation. The aim is to describe the genotype/phenotype variations of renal complications in two siblings with confirmed FD with the mutation p.Q279X in exon 6. We present a retrospective study of two venezuelan male siblings, ages 34 (patient 1) and 33 (patient 2), evaluated by general lab tests, renal ultrasound, renal scintigram , and renal biopsy. Fabry disease diagnose was made by α-galactosidase A activity determined in dried blood spot. Genomic DNA was sequenced by Sanger method. Patient 1 developed CKD grade 5 and high blood pressure, treated by hemodialysis during 8 years. Patient 2 showed GFR >60 ml/min, and proteinuria less than 600 mg/24H. Renal biopsy showed segmental sclerotic lesions and hypertrophic podocytes with vacuolated cytoplasm. Both patients received ERT every two weeks since 2003. Patient 1 died because dialysis complications (hyperparathyroidism, cardiomyopathy). The genotype/phenotype variation of the c.835C>T mutation (p.Gln279Ter. Q279X) in exon 6 of the GLA gene can express an important renal variation with a wide range of clinical manifestations that cannot be predicted, therefore, an early nephrological evaluation and periodic follow-up of these patients are necessary.

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. METHODS: A prospective screening study was carried out measuring the α-Gal-A activity in dried blood spot (DBS) samples of male patients undergoing dialysis from Argentina. Those patients in which DBS α-Gal-A level was low (<4.0 µmol/hr/L), underwent GLA genetic testing for diagnosis confirmation. RESULTS: Nine thousand six hundred and four dialysis male patients from 264 centers distributed over 20 of the 23 provinces of Argentina were investigated. Twenty-four patients showed a decreased or absent α-Gal-A activity in DBS and although genetic analysis found a variant in the GLA gene in every one of these patients, we could confirm FD diagnosis in 22 cases. CONCLUSION: The prevalence rate of FD found in Argentinean male dialysis patients was 0.23%. Classic phenotype was observed in 73% of patients, whereas the remaining 27% presented as late-onset variant. This was the largest study carried out in dialysis patients from a same country at a worldwide level and the first study performed in Argentina.

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. METHODS: This was a cross-sectional study including 68 individuals: Controls (n = 20) and Fabry patients (n = 48), 15 untreated and 33 treated. Variables included age, gender, urinary protein/creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), lyso-triasocylsphingosine (lyso-Gb3) levels and enzyme replacement therapy (ERT). Podocyturia was assessed by immunofluorescence and podocyte subpopulations were analyzed. RESULTS: Fabry patients displayed higher podocyturia than controls. Fabry treated subjects (n = 33) presented significantly higher UPCR compared with untreated ones (n = 15); podocyturia, eGFR and lyso-Gb3 levels were not different. All control podocytes colocalized synaptopodin and podocalyxin; 13 Fabry patients (27%) colocalized these proteins, while 35 (73%) were only synaptopodin positive. No podocalyxin-positive/synaptopodin-negative cells were encountered. In Fabry patients, podocyturia was significantly higher and proteinuria lower in those that colocalized. CONCLUSION: Fabry patients present higher podocyturia and a presumably more damaged glycocalyx assessed by podocalyxin. Treated patients had significant higher proteinuria suggesting ERT is initiated late, at advanced stages. The degree of podocalyxin-negative podocytes was similar in both groups, but colocalization was associated with lower proteinuria. Podocyturia assessed by podocalyxin alone may be underestimated. The implications of podocyte glycocalyx damage deserve further investigations.

[Argentine consensus on late-onset Pompe's disease]. / Consenso argentino sobre enfermedad de Pompe de inicio tardío.

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. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

Consenso argentino sobre enfermedad de Pompe de inicio tardío / Argentine consensus on late-onset Pompe's disease

La enfermedad de Pompe (EP) es un desorden metabólico autosómico recesivo infrecuente, producido por la ausencia o deficiencia de la enzima lisosomal alfa-glucosidasa ácida en los tejidos de los individuos afectados. Se considera enfermedad de Pompe de inicio tardío (EPIT) en aquellos individuos de más de un año de edad al comienzo de los síntomas. El objetivo del presente consenso es el de actualizar las pautas y recomendaciones para un correcto tratamiento de los pacientes con EPIT, tomando como referencia los lineamientos del Consenso Argentino para el diagnóstico, seguimiento y tratamiento de la enfermedad de Pompe publicado en el año 2013. Se organizó un consenso que reunió profesionales con experiencia en la EP en las áreas de clínica médica, diagnóstico de laboratorio, neuropatología, neumonología, nutrición, neurología, enfermedades metabólicas, enfermedades neuromusculares y rehabilitación. Se realizó una actualización de la bibliografía sobre EPIT, con especial atención en las publicaciones relevantes de los últimos cuatro años. Los términos finales del documento fueron consensuados por todo el grupo de trabajo. Cada participante proporcionó su declaración de conflicto de intereses. El resultado es una actualización del último Consenso Argentino para la EP, con particular enfoque en su forma de comienzo tardío. Tratándose de una afección infrecuente, en la que los datos disponibles son limitados, las presentes recomendaciones deben ser consideradas como opinión de expertos.

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. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

Clinical parameters, LysoGb3, podocyturia, and kidney biopsy in children with Fabry disease: is a correlation possible?

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase enzyme deficiency. We present clinical, biochemical, and histologic findings in children with classical phenotypic presentation of Fabry disease. METHODS: A retrospective analysis was performed using charts from 14 children with confirmed diagnosis. Clinical parameters were evaluated. Globotriaosylsphingosine -lysoGb3- detection in plasma, podocyturia, and kidney biopsy were carried out in all cases. RESULTS: All patients except one demonstrated at least one symptom of Fabry disease. LysoGb3 levels were above the normal range in all patients. Podocyturia was documented in all patients. Kidney biopsy revealed glomerular, interstitial, vascular, and tubular changes on light microscopy in nearly all patients. Electron microscopy showed podocyte inclusions in all patients. CONCLUSIONS: No difference in symptomatology was discernible between boys and girls. Podocyturia was detectable in children serving as a possible early marker of kidney injury. LysoGb3 was elevated in all cases, emphasizing the importance for diagnosis especially in female patients with normal αGal A activity. A possible association between lysoGb3 and symptom severity and histological involvement in kidney biopsy should be assessed in prospective studies with enough statistical power to determine if lysoGb3 can be used to predict nephropathy in children with Fabry disease.

Expression of uPAR in Urinary Podocytes of Patients with Fabry Disease.

Background. Despite enzyme replacement therapy, Fabry nephropathy still progresses. Podocyturia is an irreversible event that antedates proteinuria and leads to chronic renal failure. We evaluated a potential mechanism of podocyte detachment via the expression of the urokinase-type Plasminogen Activator Receptor (uPAR) in urinary podocytes of Fabry patients. Methods. This is a cross-sectional study that included controls (n = 20) and Fabry patients (n = 44) either untreated (n = 23) or treated with agalsidase-ß (n = 21). Variables. Variables are estimated glomerular filtration rate (eGFR), urinary protein : creatinine ratio, and urinary uPAR+ podocyte : creatinine ratio. uPAR mRNA expression in response to lyso-Gb3, a bioactive glycolipid accumulated in Fabry disease, was studied in cultured human podocytes. Results. Controls and Fabry patients had similar age, gender, and renal function. Urinary uPAR+ podocytes were higher in patients than in controls. Untreated patients were significantly younger; had more females, and presented lower urinary protein : creatinine ratios and significantly higher urinary uPAR+ podocytes than treated subjects. In treated patients, urinary uPAR+ podocytes correlated with urinary protein : creatinine ratio (ρ = 0.5; p = 0.02). Lyso-Gb3 at concentrations found in the circulation of Fabry patients increased uPAR expression in cultured podocytes. Conclusions. Urinary podocytes expressing uPAR are increased in Fabry patients, especially in untreated patients. The potential contribution of uPAR expression to podocyte detachment merits further studies.

Effectiveness of enzyme replacement therapy in Fabry disease: Long term experience in Argentina.

Evidence regarding long term effectiveness of enzyme replacement therapy (ERT) in Fabry disease (FD) is needed. The aim of this study was to analyze in a cohort of FD patients in Argentina, the long term effectiveness of ERT on renal, cardiac and cerebrovascular parameters. METHODS: Patients with genetically proven FD were included from GADYTEF (Argentinean group for the treatment of FD) between 2001 and 2014. Renal, cardiac, and cerebral outcomes were prospectively studied in patients treated with ERT. Additionally, the occurrence of major cardiac complications, stroke, end-stage renal disease and death was analyzed during follow up. RESULTS: During the follow-up 8 major complications occurred in 5 patients (n = 2 deaths, n = 4 cases of end stage renal disease and n = 1 atrial fibrillation), 4 of them males and only 1 female who suffered an atrial fibrillation. Sudden death or stroke did not occur. Four (40%) of 10 males with baseline left ventricular hypertrophy (LVH) reduced left ventricular mass index (LVMI) from 163.1 ± 64.7 to 123.4 ± 49.8 g/m2, 2 stabilized LVMI and 4 increased LVMI from157.9 ± 32.3 to 261.6 ± 48.6 g/m2. Estimated glomerular filtration was stable in 30 patients (17 males and 13 females). CONCLUSIONS: We observed a few major complications during the follow up. Future studies are necessary to show the effectiveness of ERT in affected patients.

Enzyme replacement therapy for Anderson-Fabry disease: A complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies.

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked recessive inborn error of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Renal failure, heart and cerebrovascular involvement reduce survival. A Cochrane review provided little evidence on the use of enzyme replacement therapy (ERT). We now complement this review through a linear regression and a pooled analysis of proportions from cohort studies. OBJECTIVES: To evaluate the efficacy and safety of ERT for AFD. MATERIALS AND METHODS: For the systematic review, a literature search was performed, from inception to March 2016, using Medline, EMBASE and LILACS. Inclusion criteria were cohort studies, patients with AFD on ERT or natural history, and at least one patient-important outcome (all-cause mortality, renal, cardiovascular or cerebrovascular events, and adverse events) reported. The pooled proportion and the confidence interval (CI) are shown for each outcome. Simple linear regressions for composite endpoints were performed. RESULTS: 77 cohort studies involving 15,305 participants proved eligible. The pooled proportions were as follows: a) for renal complications, agalsidase alfa 15.3% [95% CI 0.048, 0.303; I2 = 77.2%, p = 0.0005]; agalsidase beta 6% [95% CI 0.04, 0.07; I2 = not applicable]; and untreated patients 21.4% [95% CI 0.1522, 0.2835; I2 = 89.6%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; b) for cardiovascular complications, agalsidase alfa 28% [95% CI 0.07, 0.55; I2 = 96.7%, p<0.0001]; agalsidase beta 7% [95% CI 0.05, 0.08; I2 = not applicable]; and untreated patients 26.2% [95% CI 0.149, 0.394; I2 = 98.8%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; and c) for cerebrovascular complications, agalsidase alfa 11.1% [95% CI 0.058, 0.179; I2 = 70.5%, p = 0.0024]; agalsidase beta 3.5% [95% CI 0.024, 0.046; I2 = 0%, p = 0.4209]; and untreated patients 18.3% [95% CI 0.129, 0.245; I2 = 95% p < 0.0001]. Effect differences favored agalsidase beta over agalsidase alfa or untreated patients. A linear regression showed that Fabry patients receiving agalsidase alfa are more likely to have higher rates of composite endpoints compared to those receiving agalsidase beta. CONCLUSIONS: Agalsidase beta is associated to a significantly lower incidence of renal, cardiovascular and cerebrovascular events than no ERT, and to a significantly lower incidence of cerebrovascular events than agalsidase alfa. In view of these results, the use of agalsidase beta for preventing major organ complications related to AFD can be recommended.

Recomendaciones para el inicio de la terapia de reemplazo enzimático en pacientes con Enfermedad de Fabry clásica en Latinoamérica / Guidelines to start enzyme replacement therapy in classic Fabry Disease patients in Latin America

INTRODUCCIÓN: La Enfermedad de Fabry es una entidad rara hereditaria ligada al cromosoma X, debida a la deficiencia o ausencia de la enzima α-galactosidasa A. OBJETIVO: Presentar la primera recomendación para el inicio oportuno de la terapia de reemplazo enzimático en la variante clásica de la enfermedad, en base al conocimiento y experiencia en el manejo de estos pacientes por un grupo de profesionales expertos en el tema pertenecientes a diez países de Latinoamérica: Argentina, Brasil, Colombia, Costa Rica, Chile, Ecuador, México, Perú, Uruguay y Venezuela. MATERIAL Y MÉTODOS: El coordinador del proyecto diseñó un documento fuente, basado en los criterios de inicio del tratamiento establecidos en las distintas guías internacionales publicadas a la fecha. Posteriormente, se distribuyó la encuesta a todos los participantes para su evaluación. RESULTADOS: Cincuenta expertos respondieron la encuesta online, siendo los criterios divididos en 5 secciones por especialidad, logrando un consenso entre todos ellos. Discusión: Debido a la creciente evidencia sobre la mejor respuesta y pronóstico asociada a un inicio de tratamiento precoz, se definieron los criterios que pueden llevar a una temprana indicación del tratamiento. CONCLUSIÓN: Entendemos que uno de los méritos de esta recomendación fue la inclusión de expertos pertenecientes a 10 países latinoamericanos. Sin embargo, como toda recomendación en una enfermedad multisistémica en plena descripción de nuevos mecanismos fisiopatológicos y complicaciones asociadas quedan manifestaciones no incluidas dentro de los criterios, lo que obliga a la constante necesidad de revisar estas recomendaciones, para poder incluir los cambios a medida que vayan ocurriendo en próximos reportes

INTRODUCTION: Fabry disease is a rare inherited X-linked disorder resulting from the absence or deficient activity of the α-galactosidase A enzyme. OBJECTIVE: To provide the first guideline on the best time to start enzyme replacement therapy to treat classic Fabry disease, based on the knowledge and experience of experts from ten Latin American countries: Argentina, Brazil, Colombia, Costa Rica, Chile, Ecuador, Mexico, Peru, Uruguay and Venezuela. METHODS: The project coordinator designed a survey based on the criteria for starting the treatment which are established in different international guidelines published to date. This document was later sent to all the participants for its evaluation. RESULTS: Fifty experts responded to the survey, whose criteria was divided into 5 sections according to specialty, and they arrived at a consensus. Discussion: The criteria for an early treatment were defined given the growing evidence of a better response and prognosis associated with it. CONCLUSION: We believe that the importance of this guideline relies on the participation of experts from ten Latin American countries. However, as it deals with a systemic disease whose physiopathological mechanisms and complications are still being described, some manifestations have not been included in the criteria, making it necessary to revise this guideline in order to report any changes that may arise in the future

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.

Podocyturia is significantly elevated in untreated vs treated Fabry adult patients.

BACKGROUND: Proteinuria suggests kidney involvement in Fabry disease. We assessed podocyturia, an early biomarker, in controls and patients with and without enzyme therapy, correlating podocyturia with proteinuria and renal function. METHODS: Cross-sectional study (n = 67): controls (Group 1, n = 30) vs. Fabry disease (Group 2, n = 37) subdivided into untreated (2A, n = 19) and treated (2B, n = 18). Variables evaluated: age, gender, creatinine, CKD-EPI, proteinuria, podocyte count/10 20× microscopy power fields, podocytes/100 ml urine, podocytes/g creatininuria (results expressed as median and range). RESULTS: Group 1 vs. 2 did not differ concerning age, gender and CKD-EPI, but differed regarding proteinuria and podocyturia. Group 2A vs. 2B: age: 29 (18-74) vs. 43 (18-65) years (p = ns); gender: males n = 3 (16 %) vs. n = 9 (50 %). Proteinuria was significantly higher in Fabry treated patients, while CKD-EPI and podocyturia were significantly elevated in untreated individuals. Significant correlations: group 2A: age-proteinuria, ρ = 0.62 (p = 0.0044); age-CKD-EPI, ρ = -0.84 (p < 0.0001); podocyturia-podocytes/100 ml urine, ρ = 0.99 (p = 0.0001); podocyturia-podocytes/g creatininuria ρ = 0.86 (p = 0.0003), podocytes/100 ml urine-podocytes/g urinary creatinine, ρ = 0.84 (p = 0.0004); proteinuria-CKD-EPI, ρ = -0.68 (p = 0.0013). Group 2B: podocyturia-podocytes/100 ml urine, ρ = 0.88 (p < 0.0001); podocyturia-podocytes/g creatininuria, ρ = 0.84 (p < 0.0001); podocytes/100 ml urine-podocytes/g creatininuria, ρ = 0.94 (p < 0.0001); CKD-EPI-proteinuria, ρ = -0.66 (p = 0.0028). CONCLUSIONS: Patients with Fabry disease display heavy podocyturia; those untreated present significantly higher podocyturia, lower proteinuria and better renal function than those who are treated, suggesting that therapy may be started at advanced stages. Podocyturia may antedate proteinuria, and enzyme therapy may protect against podocyte loss.