30 research outputs found
ANĂLISE DOS RESULTADOS DE DIAGNĂSTICO PRĂ-NATAL DE MUCOPOLISSACARIDOSES REALIZADOS PELA REDE MPS BRASIL
ANĂLISE DO FUNCIONAMENTO DO DISQUE MPS:SERVIĂO TELEFĂNICO GRATUITO DE INFORMAĂĂES SOBRE MUCOPOLISSACARIDOSES
Morquio-like dysostosis multiplex presenting with neuronopathic features is a distinct GLB1-related phenotype
Background Morquio B disease (MBD) is a distinct GLB1-related dysostosis multiplex presenting a mild phenocopy of GALNS-related Morquio A disease. Previously reported cases from European countries carry the W273L variant on at least one GLB1 allele and exhibit a pure skeletal phenotype (pure MBD). Only a minority of MBD cases have been described with additional neuronopathic findings (MBD plus). Objectives and Methods With the aim to further describe patterns of MBD-related dysostosis multiplex, we analyzed clinical, biochemical, and genetic features in 17 cases with GLB1-related dysostosis multiplex living and diagnosed in Brazil. Results About 14 of the 17 individuals had three or more skeletal findings characteristic of Morquio syndrome. Two had no additional neuronopathic features (pure MBD) and 12 exhibited additional neuronopathic features (MBD plus). Three of the 17 cases had mild dysostosis without distinct features of MBD. Seven of the 12 MBD plus patients had signs of spinal cord compression (SCC), as a result of progressive spinal vertebral dysostosis. There was an age-dependent increase in the number of skeletal findings and in the severity of growth impairment. GLB1 mutation analysis was completed in 10 of the 14 MBD patients. T500A occurred in compound heterozygosity in 8 of the 19 alleles. Conclusion Our study extends the phenotypic spectrum of GLB1-related conditions by describing a cohort of patients with MBD and GM1-gangliosidosis (MBD plus). Targeting the progressive nature of the skeletal manifestations in the development of new therapies for GLB1-related conditions is warranted
Relative frequency and estimated minimal frequency of Lysosomal Storage Diseases in Brazil: Report from a Reference Laboratory
Mucopolysaccharidosis I, II, and VI: Brief review and guidelines for treatment
Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions
Mucopolissacaridose tipo I: avaliação de um novo instrumento para classificação fenotĂpica
Introdução: A mucopolissacaridose tipo I Ă© comumente classificada em trĂȘs sĂndromes clĂnicas (Hurler, Hurler-Scheie e Scheie), de acordo com a gravidade do fenĂłtipo. Devido Ă alta heterogeneidade da doença e Ă sobreposição de sintomas em pacientes, alguns autores consideram esta forma de classificação ultrapassada e defendem que a doença apresenta um espectro fenotĂpico mais amplo. Para tanto, seria muito Ăștil o desenvolvimento de novas ferramentas que possam contribuir para uma melhor classificação dos pacientes. Objetivo: Avaliar um novo instrumento para a classificação fenotĂpica da MPS I e verificar a correlação dos resultados obtidos com o mesmo com as caracterĂsticas bioquĂmicas e moleculares dos pacientes avaliados. Materiais e MĂ©todo: Um instrumento elaborado por um grupo de especialistas foi por nĂłs adaptado para avaliar a gravidade do fenĂłtipo ao diagnĂłstico de 43 pacientes brasileiros com MPS I. Uma nota de zero a 14 foi obtida com a aplicação deste instrumento pela avaliação da presença ou ausĂȘncia dos seguintes sinais e sintomas ao diagnĂłstico: atraso no desenvolvimento neuropsicomotor e/ou declĂnio cognitivo, rigidez articular/artropatia/contraturas articulares, cifose, disostose multiplex, macrocefalia e bossa frontal. Os pacientes incluĂdos foram tambĂ©m avaliados em relação aos mesmos parĂąmetros do instrumento e quanto ao seu fenĂłtipo por trĂȘs geneticistas com reconhecida experiĂȘncia com essa doença. Dados bioquĂmicos e moleculares tambĂ©m foram utilizados para comparação com os resultados da aplicação do instrumento. Resultados: Os pontos de corte com melhor balanço de sensibilidade e especificidade encontrados a partir da aplicação do instrumento e a partir da avaliação dos geneticistas foram, respectivamente 7 e 9. Os parĂąmetros do instrumento para os quais foi observada diferença estatisticamente significativa foram atraso do desenvolvimento neuropsicomotor/declĂnio cognitivo (entre o fenĂłtipo Hurler e os fenĂłtipos Hurler-Scheie e Scheie) e disostose mĂșltipla (entre os fenĂłtipos Hurler e Scheie). NĂŁo foi observada correlação entre a nota obtida no instrumento e os valores de GAGs urinĂĄrios, nos diferentes fenĂłtipos. A maior parte dos pacientes com mutaçÔes sem sentido foi classificada como grave, tanto a partir do instrumento quanto pela avaliação dos geneticistas. ConclusĂ”es: Os pontos de corte encontrados podem ser Ășteis para a classificação dos pacientes em dois grupos distintos â grave e atenuado. O atraso no dsenvolvimento neuropsicomotor/declĂnio cognitivo e a disostose mĂșltipla sĂŁo achados importantes para predizer a gravidade da doença. MutaçÔes sem sentido parecem determinar o fenĂłtipo mais grave da sĂndrome. NĂŁo foi possĂvel distinguir os diferentes fenĂłtipos a partir dos valores de GAGs na urina. A ferramenta desenvolvida parece ser Ăștil para auxiliar na classificação da gravidade da MPS I, mas Ă© recomendĂĄvel sua aplicação em um nĂșmero maior de pacientes para melhor dimensionar sua potencial aplicação.Introduction: Mucopolysaccharidosis type I is usually classified into three clinical syndromes (Hurler, Hurler-Scheie and Scheie) according to the severity of the phenotypic expression. Some authors believe this classification is not accurate because of disease variation and overlapping findings in some patients, and suggest that its phenotypic spectrum is wider. With this view, it would be useful the development of new tools which could contribute to a better classification of patients. Objective: To evaluate a new tool the phenotypic classification of MPS I and investigate whether the results obtained are correlated with biochemical and molecular characteristics of the patients. Material and methods: A tool developed by a group of specialists was adapted by us for the evaluation of the phenotypic severity at diagnosis in 43 Brazilian patients with MPS I. A score of zero to 14 was obtained using this tool, which evaluated presence or absence of the following signs and symptoms: delay in neurological and psychomotor development and cognitive decline; joint stiffness, arthropathy and joint contractures; kyphosis; dysostosis multiplex; macrocephaly; and frontal bossing. The same patients had the same parameters evaluated by three MDs with expertise in MPS who also provided their impression about the phenotype. Biochemical and molecular findings were also compared with the results obtained in the proposed tool. Results: The cut-off points with better balance of sensitivity and specificity found with the use of the tool and according to the experts' evaluations were 7 and 9, respectively. The tool parameters with statistically significant differences were neurological and psychomotor development delay and cognitive decline (when the Hurler phenotype was compared with the Hurler-Scheie and Scheie phenotypes), and dysostosis multiplex (for the comparison between the Hurler and Scheie phenotypes). There was no correlation between the scores obtained when using the tool and the urinary GAG values across the different phenotypes. Most patients with nonsense mutations were classified as severe according to the tool scores and to the expertsâ evaluations. Conclusions: The cut-off points found in this study may be useful for the classification of patients into two distinct groups - severe and attenuated. Neurological and psychomotor developmental delay and cognitive decline, as well as dysostosis multiplex, are important findings to predict disease severity. Nonsense mutations seem to determine the most severe syndrome phenotype. The urinary GAG values do not allow differentiating the different phenotypes. The tool developed seems to be useful to help in the classification of the severity of MPS I, but it would be advisable its application in a larger number of patients to better evaluate its potential application
Rede MPS Brasil: uma iniciativa para promover o diagnĂłstico e facilitar o manejo das mucopolisacaridoses no Brasil
Rede MPS Brasil: uma iniciativa para promover o diagnĂłstico e facilitar o manejo das mucopolisacaridoses no Brasil
Mucopolissacaridoses : um estudo abrangente sobre a epidemiologia da doença no Brasil
Introdução: As mucopolissacaridoses (MPS) sĂŁo doenças raras causadas pela deficiĂȘncia de enzimas lisossĂŽmicas responsĂĄveis pela degradação dos glicosaminoglicanos. SĂŁo doenças graves, crĂŽnicas e progressivas. Embora existam diversos estudos disponĂveis na literatura mĂ©dica sobre a frequĂȘncia das MPS em diferentes paĂses, nĂŁo hĂĄ estudos publicados no Brasil. Avaliar a frequĂȘncia dos diferentes tipos de MPS nas diferentes regiĂ”es do Brasil Ă© importante para dimensionar as necessidades de atendimento destes pacientes. Objetivo: O objetivo deste estudo foi estimar a prevalĂȘncia ao nascimento das MPS no Brasil, avaliando os diferentes tipos e a distribuição dos casos pelas regiĂ”es do Brasil, alĂ©m de avaliar o perfil genĂ©tico-molecular dos pacientes. Para isso, foram revisados todos os casos registrados na Rede MPS Brasil e no Instituto Vidas Raras e a prevalĂȘncia ao nascimento foi calculada a partir do nĂșmero de nascidos vivos (NV) no paĂs. AlĂ©m disso, tambĂ©m foi pesquisada a variante mais frequente nos pacientes com MPS I (p.Trp402Ter) em indivĂduos saudĂĄveis a fim de estimar a frequĂȘncia de heterozigotos e, posteriormente, homozigotos para esta variante. Um cĂĄlculo de proporcionalidade foi realizado para estimar a frequĂȘncia da MPS I e dos demais tipos de MPS. Quanto Ă anĂĄlise do genĂłtipo dos pacientes, estes foram classificados por tipo de MPS e conforme regiĂŁo de origem no paĂs, e as variantes foram classificadas conforme o Human Gene Mutation Database (HGMD). Apenas casos-Ăndice foram considerados nesta Ășltima anĂĄlise. Resultados: Foram incluĂdos 1472 pacientes brasileiros neste estudo, tendo MPS II se revelado como a forma mais frequente. A prevalĂȘncia ao nascimento considerando o total de NV foi (por 100.000 NV): MPS em geral: 1,25; MPS I: 0,24; MPS II: 0,37; MPS III: 0,21; MPS IV: 0,14; MPS VI: 0,28; MPS VII: 0,02; A frequĂȘncia da variante encontrada em 1.000 indivĂduos saudĂĄveis foi 0,002. A partir desta frequĂȘncia, a prevalĂȘncia mĂnima da MPS I e dos outros tipos de MPS foi estimada em (por 100.000 NV): MPS em geral: 4,62; MPS I: 0,95; MPS II: 1,32; MPS III: 0,56; MPS IV: 0,57; MPS VI: 1,02; MPS VII: 0,05. Em 499 pacients foi possĂvel obter informaçÔes sobre o genĂłtipo. As variantes mais frequentes foram as substituiçÔes nas MPS tipos I, II, IIIB, IVA e VI, sendo a maior parte com troca de sentido. Diferenças regionais na proporção de variantes foram observadas na MPS IIIB, na qual as pequenas deleçÔes foram mais frequentes no Sul, e na MPS VI, na qual as variantes em sĂtio de splicing foram mais comuns em pacientes do Nordeste. Uma grande heterogeneidade alĂ©lica foi observada em todos os tipos de MPS. DiscussĂŁo: A prevalĂȘncia estimada das MPS em geral foi bastante superior Ă encontrada nos demais paĂses e muito semelhante Ă estimada em Portugal. A MPS I teve prevalĂȘncia mais elevada do que na maioria dos estudos semelhantes, principalmente quando comparada aos paĂses asiĂĄticos. A MPS II teve a prevalĂȘncia ao nascimento mais alta no Brasil, em relação aos outros tipos, e tambĂ©m esteve entre as mais altas no mundo. As MPS III e IV tiveram resultado intermediĂĄrio quando comparado aos outros paĂses. Na MPS VI a prevalĂȘncia encontrada supera os valores estimados em quase todos os demais paĂses. A MPS VII, assim como nos outros estudos, tambĂ©m teve prevalĂȘncia baixa no Brasil. Em relação ao perfil genĂ©tico de pacientes brasileiros com MPS, observou-se que Ă© semelhante ao registrado no HGMD e indica que a maioria dos pacientes tem variantes classificadas como substituiçÔes. ConclusĂŁo: Este estudo relata dados originais sobre a prevalĂȘncia ao nascimento das MPS e sobre a frequĂȘncia relativa dos tipos de MPS no Brasil, baseando-se na frequĂȘncia da variante patogĂȘnica mais comum no gene da IDUA e em registros de centros de referĂȘncia. Esta metodologia pode ser aplicada a outras doenças genĂ©ticas e pode ser Ăștil a pacientes, cuidadores, autoridades em saĂșde e pesquisadores. AlĂ©m disso, o estudo mostrou que a maioria dos pacientes (considerando a subamostra em que foi possĂvel obter dados sobre o genĂłtipo), poderia se beneficiar de terapĂȘuticas que atuam na estabilização de proteĂnas mal dobradas (chaperonas, para mutaçÔes com troca de sentido) ou na supressĂŁo de cĂłdons de parada prematura (stop cĂłdon read through).Introduction: Mucopolysaccharidoses (MPS) are rare diseases caused by the deficiency of lysosomal enzymes responsible for the degradation of glycosaminoglycans. They are serious, chronic and progressive diseases. Although there are several published studies on the frequency of MPS in different countries, there are no studies published in Brazil. Evaluating the frequency of different types of MPS in the different regions of Brazil is important to estimate the needs of these patients. Objective: The objective of this study was to estimate the birth prevalence of MPS in Brazil, evaluating the different types and distribution of cases in Brazilian regions, as well as assessing the type of variants occruring in the patients. For this, all the cases registered at the MPS Brazil Network and at Vidas Raras Institute (Instituto Vidas Raras) were reviewed and the birth prevalence was calculated from the number of live births (LBs) in the country. In addition, the most frequent IDUA variant in patients with MPS I (p.Trp402Ter) was tested in healthy volunteers in order to estimate the frequency of heterozygotes and, subsequently, homozygotes for this variant. A proportionality calculation was performed to estimate the frequency of MPS I and other MPS types. As for the genotype analysis of the patients, they were classified by MPS type and according to region of origin in the country, and the variants were classified according to the Human Gene Mutation Database classification. Only index cases were considered in this analysis. Results: A total of 1,472 Brazilian patients were included in this study, most of whom were diagnosed with MPS II. Birth prevalence considering total LBs was (per 100,000 LBs): MPS in general: 1.25; MPS I: 0.24; MPS II: 0.37; MPS III: 0.21; MPS IV: 0.14; MPS VI: 0.28; MPS VII: 0.02; The frequency of the variant found in 1,000 healthy volunteers was 0.002. From this frequency, the minimum prevalence of MPS I and other types of MPS was estimated in (per 100,000 LBs): MPS in general: 4.62; MPS I: 0.95; MPS II: 1.32; MPS III: 0.56; MPS IV: 0.57; MPS VI: 1.02; MPS VII: 0.05. In 499 patients we could review genotype results. The most frequent variants were substitutions in the MPS types I, II, IIIB, IVA and VI, being the majority of them missense variants. Regional differences in the proportion of variants were observed in MPS IIIB, in which small deletions were more frequent in the South, and in MPS VI, in which variants at the splicing site were more common in Northeastern patients. Large allelic heterogeneity was observed in all MPS types. Discussion: The estimated prevalence of MPS in general was much higher than that found in other countries and very similar to that estimated in Portugal. MPS I had a birth prevalence higher than those found in most studies, especially when compared to Asian countries. MPS II had the highest birth prevalence in Brazil in relation to other types and was also among the highest in the world. MPS III and IV had an intermediate result when compared to the other countries. In MPS VI the birth prevalence found exceeds the values estimated in almost all other countries. MPS VII, as in other studies, also had a low birth prevalence in Brazil. Regarding the genetic profile of Brazilian patients with MPS, we observed that it is similar to that registered in HGMD and it indicates that most patients have variants classified as substitutions. Conclusion: This study reports original data on the birth prevalence of MPS and the relative frequency of MPS types in Brazil, based on the frequency of the most common pathogenic variant in the IDUA gene and in records from reference centers. This methodology can be applied to other genetic diseases and can be useful to patients, caregivers, health authorities and researchers. In addition, the study showed that the majority of patients (considering the subsample from whom genotype result was available) could benefit from therapies that act to stabilize misfolded proteins (chaperones, for missense variants), or to suppress premature stop codons (stop codon read through)