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

Mucopolissacaridoses : um estudo abrangente sobre a epidemiologia da doença no Brasil

Introdução: As mucopolissacaridoses (MPS) são doenças raras causadas pela deficiência de enzimas lisossômicas responsáveis pela degradação dos glicosaminoglicanos. São doenças graves, crônicas e progressivas. Embora existam diversos estudos disponíveis na literatura médica sobre a frequência das MPS em diferentes países, não há estudos publicados no Brasil. Avaliar a frequência dos diferentes tipos de MPS nas diferentes regiões do Brasil é importante para dimensionar as necessidades de atendimento destes pacientes. Objetivo: O objetivo deste estudo foi estimar a prevalência ao nascimento das MPS no Brasil, avaliando os diferentes tipos e a distribuição dos casos pelas regiões do Brasil, além de avaliar o perfil genético-molecular dos pacientes. Para isso, foram revisados todos os casos registrados na Rede MPS Brasil e no Instituto Vidas Raras e a prevalência ao nascimento foi calculada a partir do número de nascidos vivos (NV) no país. Além disso, também foi pesquisada a variante mais frequente nos pacientes com MPS I (p.Trp402Ter) em indivíduos saudáveis a fim de estimar a frequência de heterozigotos e, posteriormente, homozigotos para esta variante. Um cálculo de proporcionalidade foi realizado para estimar a frequência da MPS I e dos demais tipos de MPS. Quanto à análise do genótipo dos pacientes, estes foram classificados por tipo de MPS e conforme região de origem no país, e as variantes foram classificadas conforme o Human Gene Mutation Database (HGMD). Apenas casos-índice foram considerados nesta última análise. Resultados: Foram incluídos 1472 pacientes brasileiros neste estudo, tendo MPS II se revelado como a forma mais frequente. A prevalência 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 frequência da variante encontrada em 1.000 indivíduos saudáveis foi 0,002. A partir desta frequência, a prevalência mínima 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 possível obter informações sobre o genótipo. As variantes mais frequentes foram as substituições 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 deleções foram mais frequentes no Sul, e na MPS VI, na qual as variantes em sítio de splicing foram mais comuns em pacientes do Nordeste. Uma grande heterogeneidade alélica foi observada em todos os tipos de MPS. Discussão: A prevalência estimada das MPS em geral foi bastante superior à encontrada nos demais países e muito semelhante à estimada em Portugal. A MPS I teve prevalência mais elevada do que na maioria dos estudos semelhantes, principalmente quando comparada aos países asiáticos. A MPS II teve a prevalência ao nascimento mais alta no Brasil, em relação aos outros tipos, e também esteve entre as mais altas no mundo. As MPS III e IV tiveram resultado intermediário quando comparado aos outros países. Na MPS VI a prevalência encontrada supera os valores estimados em quase todos os demais países. A MPS VII, assim como nos outros estudos, também teve prevalência baixa no Brasil. Em relação ao perfil genético de pacientes brasileiros com MPS, observou-se que é semelhante ao registrado no HGMD e indica que a maioria dos pacientes tem variantes classificadas como substituições. Conclusão: Este estudo relata dados originais sobre a prevalência ao nascimento das MPS e sobre a frequência relativa dos tipos de MPS no Brasil, baseando-se na frequência da variante patogênica mais comum no gene da IDUA e em registros de centros de referência. Esta metodologia pode ser aplicada a outras doenças genéticas e pode ser útil a pacientes, cuidadores, autoridades em saúde e pesquisadores. Além disso, o estudo mostrou que a maioria dos pacientes (considerando a subamostra em que foi possível obter dados sobre o genótipo), poderia se beneficiar de terapêuticas que atuam na estabilização de proteínas mal dobradas (chaperonas, para mutações com troca de sentido) ou na supressão de códons de parada prematura (stop códon 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)

Relative frequency and estimated minimal frequency of Lysosomal Storage Diseases in Brazil: report from a reference laboratory

Lysosomal storage diseases (LSDs) comprise a heterogeneous group of more than 50 genetic conditions of inborn errors of metabolism (IEM) caused by a defect in lysosomal function. Although there are screening tests for some of these conditions, diagnosis usually depends on specific enzyme assays, which are only available in a few laboratories around the world. A pioneer facility for the diagnosis of IEM and LSDs was established in the South of Brazil in 1982 and has served as a reference service since then. Over the past 34 years, samples from 72,797 patients were referred for investigation of IEM, and 3,211 were confirmed as having an LSD (4.41%, or 1 in 22), with 3,099 of these patients originating from Brazil. The rate of diagnosis has increased over time, in part due to the creation of diagnostic networks involving a large number of Brazilian services. These cases, referred from Brazilian regions, provide insight about the relative frequency of LSDs in the country. The large amount of data available allows for the estimation of the minimal frequency of specific LSDs in Brazil. The reported data could help to plan health care policies, as there are specific therapies available for most of the cases diagnosed

Relative frequency and estimated minimal frequency of Lysosomal Storage Diseases in Brazil: report from a reference laboratory

Lysosomal storage diseases (LSDs) comprise a heterogeneous group of more than 50 genetic conditions of inborn errors of metabolism (IEM) caused by a defect in lysosomal function. Although there are screening tests for some of these conditions, diagnosis usually depends on specific enzyme assays, which are only available in a few laboratories around the world. A pioneer facility for the diagnosis of IEM and LSDs was established in the South of Brazil in 1982 and has served as a reference service since then. Over the past 34 years, samples from 72,797 patients were referred for investigation of IEM, and 3,211 were confirmed as having an LSD (4.41%, or 1 in 22), with 3,099 of these patients originating from Brazil. The rate of diagnosis has increased over time, in part due to the creation of diagnostic networks involving a large number of Brazilian services. These cases, referred from Brazilian regions, provide insight about the relative frequency of LSDs in the country. The large amount of data available allows for the estimation of the minimal frequency of specific LSDs in Brazil. The reported data could help to plan health care policies, as there are specific therapies available for most of the cases diagnosed