The challenges of organizing an international course in Latin America

The Latin American School of Human and Medical Genetics (ELAG) is the main course of its kind in the genetics field in Latin America. Here we describe the main challenges regarding the organization of such event, including how we obtain funding and how we proceed with student selection. Thus, we aim to share our experience with other groups that intend to follow this format to create similar events in other areas in this region of the worl

Prevalence of thrombophilia and thrombotic events in patients with fabry disease in a Reference Center for Lysosomal Disorders in Southern Brazil

Introduction: Venous thromboembolism (VTE) is a multifactorial genetic disorder that occurs in approximately one in a thousand adults per year. Because there is no laboratory test or clinical marker useful for predicting which patients with Fabry disease may develop thrombotic events, this study aimed to determine whether there is a hereditary predisposition to hypercoagulation in these patients. Methods: The prevalence of p.R506Q mutation in the factor V gene and of c.G20210A mutation in Factor II (prothrombin) gene was evaluated in 39 patients with Fabry disease from Southern Brazil and correlated with clinical findings. The DNA analysis was performed by real-time polymerase chain reaction on genomic DNA using TaqMan probes. Results: In this group of patients, the frequency of mutation in the prothrombin gene was 1.28%, whereas no patient showed mutation in the factor V gene; additionally, there was no correlation between these mutations and the incidence of thrombotic events. Conclusion: Hereditary thrombophilia due to mutations in factor V and prothrombin genes does not seem to be related to thrombotic events in Fabry patients in our cohort, although studies in larger cohorts and the inclusion of additional factors may be required to determine if a correlation exists

Rare disease landscape in Brazil : report of a successful experience in inborn errors of metabolism

Brazil is a country of continental dimensions, with many social inequalities. The latter are reflected on its health system, which comprises a large public component called SUS, a small paid health insurance component and a third very small private component, in which patients pay personally for medical services. Seventy five percent of the population depends on SUS, which thus far does not provide adequate coverage for genetic medical procedures. In 2014, SUS introduced the “Policy for the Integral Attention to Subjects with Rare Diseases”, establishing guidelines for offering diagnosis and treatment. The policy defines the two main axes, genetic and non-genetic rare diseases. In this fashion, public genetic services in SUS will be installed and funded not by themselves, but as part of the more general policy of rare diseases. Unfortunately, up to now this policy is still depending on financial allowances to be effectively launched. In this article, our intention was to describe activities developed in the area of inborn errors of metabolism by a Brazilian reference center. In spite of the lack of support of SUS, thousands of Brazilian families affected by rare genetic metabolic disorders, and many health professionals from all regions of Brazil, already have benefited from the services, training programs and research projects provided by this comprehensive center

Precision medicine for lysosomal disorders

Precision medicine (PM) is an emerging approach for disease treatment and preventionthat accounts for the individual variability in the genes, environment, and lifestyle of each person.Lysosomal diseases (LDs) are a group of genetic metabolic disorders that include approximately70 monogenic conditions caused by a defect in lysosomal function. LDs may result from primarylysosomal enzyme deficiencies or impairments in membrane-associated proteins, lysosomal enzymeactivators, or modifiers that affect lysosomal function. LDs are heterogeneous disorders, and thephenotype of the affected individual depends on the type of substrate and where it accumulates,which may be impacted by the type of genetic change and residual enzymatic activity. LDs areindividually rare, with a combined incidence of approximately 1:4000 individuals. Specific therapiesare already available for several LDs, and many more are in development. Early identification mayenable disease course prediction and a specific intervention, which is very important for clinicaloutcome. Driven by advances in omics technology, PM aims to provide the most appropriatemanagement for each patient based on the disease susceptibility or treatment response predictionsfor specific subgroups. In this review, we focused on the emerging diagnostic technologies that mayhelp to optimize the management of each LD patient and the therapeutic options available, as well asin clinical developments that enable customized approaches to be selected for each subject, accordingto the principles of PM

Enzyme replacement therapy for Fabry disease: a systematic review and meta-analysis

The specific treatment available for Fabry disease (FD) is enzyme replacement therapy (ERT) with agalsidase alfa or beta. A systematic review and meta-analysis was conducted to assess the efficacy and safety of ERT for FD. Only double-blind, randomized clinical trials (RCTs) comparing agalsidase alfa or beta and placebo were included. ERT with either agalsidase alfa or beta was considered similar for the purposes of analysis. Ten RCTs were identified, which showed improvements in neuropathic pain, in heart abnormalities and in globotriaosylceramide (GL-3) levels. A meta-analysis showed increased odds for fever, rigors, development of IgG antibodies to agalsidase, and no significant association with development of hypertension or reduction in the QRS complex duration on electrocardiogram. The RCTs included in this comparison enrolled few patients, were highly heterogeneous, and were focused mainly on surrogate endpoints, limiting any conclusions as to the real effect of ERT for FD. The available evidence suggests that response to ERT is variable across patient subgroups and that agalsidase may slow progression of FD, with slight improvement of existing changes. Nevertheless, many uncertainties remain, and further studies are necessary

Prevalence of thrombophilia and thrombotic events in patients with fabry disease in a Reference Center for Lysosomal Disorders in Southern Brazil

Introduction: Venous thromboembolism (VTE) is a multifactorial genetic disorder that occurs in approximately one in a thousand adults per year. Because there is no laboratory test or clinical marker useful for predicting which patients with Fabry disease may develop thrombotic events, this study aimed to determine whether there is a hereditary predisposition to hypercoagulation in these patients. Methods: The prevalence of p.R506Q mutation in the factor V gene and of c.G20210A mutation in Factor II (prothrombin) gene was evaluated in 39 patients with Fabry disease fromSouthern Brazil and correlated with clinical findings. The DNA analysis was performed by real-time polymerase chain reaction on genomic DNA using TaqMan probes. Results: In this group of patients, the frequency of mutation in the prothrombin gene was 1.28%, whereas no patient showed mutation in the factor V gene; additionally, there was no correlation between these mutations and the incidence of thrombotic events. Conclusion: Hereditary thrombophilia due to mutations in factor V and prothrombin genes does not seem to be related to thrombotic events in Fabry patients in our cohort, although studies in larger cohorts and the inclusion of additional factors may be required to determine if a correlation exists.     Introdução: O tromboembolismo venoso (TEV) é uma desordem genética multifatorial que ocorre em aproximadamente um em cada mil adultos por ano. Pelo fato de não existir nenhum teste de laboratório ou marcador clínico útil para predizer quais pacientes com a doença de Fabry podem desenvolver eventos trombóticos, este estudo foi realizado com o objetivo de determinar se existe uma predisposição hereditária para hipercoagulação nesses pacientes. Métodos: A prevalência da mutação p.R506Q no gene do fator V e da mutação c.G20210A no gene do fator II (protrombina) foi avaliada em 39 pacientes com doença de Fabry do Sul do Brasil e associada com achados clínicos. A análise do DNA genômico foi realizada por reação em cadeia da polimerase (polymerase-chain reaction, PCR) em tempo real utilizando sondas TaqMan. Resultados: Neste grupo de pacientes, a frequência da mutação no gene da protrombina foi de 1,28%, enquanto que nenhum paciente apresentou a mutação no gene do fator V, não havendo correlação entre essas mutações e a incidência de eventos trombóticos. Conclusão: A trombofilia hereditária devido às mutações nos genes fator V e protrombina parece não estar relacionada a eventos trombóticos em pacientes com Fabry em nossa coorte, embora estudos em coortes maiores e a inclusão de fatores adicionais possam ser necessários para determinar se existe uma correlação

Magnetic resonance imaging findings of the posterior fossa in 47 patients with mucopolysaccharidoses : a cross-sectional analysis

Background: Mucopolysaccharidoses (MPS) is a group of hereditary multisystemic lysosomal disorders. Most neuroimaging studies in MPS have focused on the supratentorial compartment and craniocervical junction abnormalities, and data regarding posterior fossa findings are scarce in the literature. Thus, our purpose is to describe posterior fossa findings on magnetic resonance imaging (MRI) of MPS patients. Methods: We reviewed routine MRI scans of MPS patients being followed up at our institution (types I, II, III, IV, and VI), focusing on posterior fossa structures. Results: Forty-seven MPS patients were included. MRI-visible perivascular spaces were commonly found in the midbrain and adjacent to the dentate nuclei (85% and 55% of patients, respectively). White-matter lesion was not identified in most cases. Its most frequent localizations were in the pons and cerebellum (34% and 30% of patients, respectively). Enlargement of cerebrospinal fluid (CSF) spaces in the posterior fossa was present in 55% of individuals and was more frequent in neuronopathic patients (73% vs 40%; P = .02). Cerebellar volume was classified as normal, apparent macrocerebellum, atrophic, and hypoplastic in 38%, 38%, 21%, and 3% of patients, respectively. A depression of the posterior fossa floor in the midline sagittal plane was found in 22 patients (47%), which was statistical significantly associated with enlargement of CSF spaces (P = .02) and with apparent macrocerebellum (P = .03). Conclusion: The present study compiled the main posterior fossa findings in MPS patients. Classically described in the supratentorial compartment, MRI-visible perivascular spaces, white matter lesions, and enlarged perivascular spaces were also found in the posterior fossa. However, atrophy, which commonly affects cerebral hemispheres, was not the most frequent cerebellar morphology found in our study. Moreover, potential findings for future research were described