Updated Birth Prevalence and Relative Frequency of Mucopolysaccharidoses Across Brazilian Regions

Genetics and Molecular Biology 44 1 e2020138 2021 Copyright Sociedade Brasileira de Genética DOI httpsdoiorg10159016784685GMB20200138 Research Article Human and Medical Genetics Send correspondence to Juliana Alves Josahkian Hospital Universitário de Santa Maria Departamento de Clínica Médica Av Roraima 1000 prédio 22 Camobi 97105900 Santa Maria RS Brazil Email julianajosahkiangmailcom Updated birth prevalence and relative frequency of mucopolysaccharidoses across Brazilian regions Juliana Alves Josahkian12 Franciele Barbosa Trapp345 Maira Graeff Burin345 Kristiane Michelin Tirelli345 Ana Paula Pereira Scholz de Magalhães345 Fernanda Medeiros Sebastião345 Fernanda Bender345 Jurema Fátima De Mari34 Ana Carolina BrusiusFacchin345 Sandra LeistnerSegal345 Diana Rojas Málaga6 and Roberto Giugliani2345789 1Hospital Universitário de Santa Maria Unidade de Clínica Médica Santa Maria RS Brazil 2Universidade Federal do Rio Grande do Sul Programa de PósGraduação em Genética e Biologia Molecular Porto Alegre RS Brazil 3Rede MPS Brasil Porto Alegre RS Brazil 4Hospital de Clínicas de Porto Alegre Serviço de Genética Médica Porto Alegre RS Brazil 5Hospital de Clínicas de Porto Alegre Centro de Pesquisa Experimental Grupo de Pesquisa BIODISCOVERY Porto Alegre RS Brazil 6Grupo Fleury Pesquisa e Desenvolvimento Biologia Molecular São Paulo SP Brazil 7Universidade Federal do Rio Grande do Sul Departamento de Genética Porto Alegre RS Brazil 8Instituto Nacional de Genética Médica Populacional INAGEMP Porto Alegre RS Brazil 9Hospital de Clínicas de Porto Alegre Centro de Pesquisa Clínica Grupo de Pesquisa DRBRASIL Porto Alegre RS Brazil Abstract The mucopolysaccharidoses MPS are a group of lysosomal storage disorders caused by 11 enzyme deficiencies classified into seven types Data on the birth prevalence of each MPS type are available for only a few countries and the totality of cases may be underestimated To determine the epidemiological profile of MPS in each Brazilian region we analyzed data collected between 1982 and 2019 by a national reference laboratory and identified 1652 patients Using data between 1994 and 2018 the birth prevalence by 100000 live births for MPS was 157 MPS II was the most common type of MPS in Brazil and its birth prevalence was 048 094 considering only male births Regarding the number of cases per region MPS II was the most frequent in the North and CenterWest followed by MPS VI and also in the Southeast followed by MPS I MPS I and MPS II were the most common types in the South and MPS VI was the most common in the Northeast followed by MPS II The differences observed in the relative frequencies of MPS types across Brazilian regions are likely linked to founder effect endogamy and consanguinity but other factors may be present and need further investigation Keywords Lysosomal storage diseases metabolic diseases mucopolysaccharidoses epidemiology Brazil Received April 30 2020 Accepted December 04 2020 Introduction Mucopolysaccharidoses MPS are a group of lysosomal storage disorders caused by the deficiency of enzymes involved in the catabolism of glycosaminoglycans GAGs These conditions are multisystemic progressive and have variable clinical features Neufeld and Muenzer 2014 not only among the different types but also among patients with the same type of MPS Severe cases are easier to diagnose but attenuated cases are challenging to recognize and can be confounded with more common pathologies SuarezGuerrero et al 2015 Studies of the specific enzymes involved in different steps of the GAG degradation pathway and the identification of which genes cause the disease allowed the classification of MPS in seven clinical types which correspond to 11 enzyme deficiencies currently recognized as MPS I II III A B C and D subtypes IV A and B subtypes VI VII and IX All MPS are autosomal recessive disorders except MPS II which is an Xlinked recessive condition Neufeld and Muenzer 2014 Epidemiological data about the MPS types are available for only a few countries and regions and its birth prevalence may be underestimated as a consequence of the clinical heterogeneity of this group of diseases and the difficulties for its laboratory investigation Giugliani 2012 For this reason a laboratory to provide diagnostic support for MPS was established at the Medical Genetics Service of Hospital de Clínicas de Porto Alegre MGSHCPA Brazil MGSHCPA is a wellknown reference center in the country and it has received samples from patients with suspected MPS since 1982 Giugliani et al 2017 In 2004 the demand for testing patients suspected of having MPS led to the creation of the MPS Brazil Network with a specific investigation workflow Giugliani et al 2016 In this manner this study aimed to report the Josahkian et al 2 birth prevalence and relative frequency of the different MPS types in Brazil to determine the epidemiological profile of this condition per state per region and in the country as a whole Material and Methods We analyzed the records from the MGSHCPA and the MPS Brazil Network of patients diagnosed with MPS between 1982 and 2019 MPS cases were diagnosed biochemically the investigation frequently starts with a quantitative colorimetric method with dimethylene blue and qualitative electrophoresis analysis of urinary GAGs followed by specific enzyme assays according to the first results andor by identification of pathogenic variants by molecular genetic analysis In this study we calculated the relative frequency of each MPS type in Brazil and also present data by region and state In this report we use the term birth prevalence to refer to the number of MPS cases diagnosed by the total number of live births in a specific period expressed as cases per 100000 live births as employed previously in the literature Poupetová et al 2010 Khan et al 2017 Data regarding live births from the Brazilian Health System database were available from 1994 to 2018 allowing us to calculate the birth prevalence in this period Patients with MPS who were not born during this period were not included in the analyzes The comparison between our findings and the estimations from other countries is also presented Results From 1982 to 2019 1652 Brazilian patients were diagnosed with MPS at the Medical Genetics Service of Hospital de Clínicas de Porto Alegre MPS II was the most commonly diagnosed condition 493 cases 2984 followed by MPS VI 351 cases 2125 MPS I 315 cases 1907 MPS III all subtypes 267 cases 1616 MPS IV both subtypes 205 cases 1241 and MPS VII 21 cases 127 We did not observe any patients diagnosed with MPS IX Regarding MPS III we identified the specific subtype A B C or D for 9550 of the cases In this subset the proportion of MPS IIIA was 2667 for IIIB 4549 for IIIC 2745 and there was just one case of IIID 039 The same approach was employed for MPS IV In 9609 of the cases we were able to identify each specific subtype A or B In this subset the proportion of MPS IVA was 9645 and the percentage of MPS IVB was 355 By extrapolating these data to the total number of MPS III and MPS IV cases we calculated the ratios presented in Table 1 When considering the number of cases diagnosed from each Brazilian region we found that MPS II was the most frequent in the North CenterWest and Southeast regions MPS I and MPS II were tied as the most common types in the South region and MPS VI was the most frequent in the Northeast region The number of cases diagnosed according to the Brazilian region and state of origin is shown in Table 1 and the distribution of these types of MPS in Brazil is shown in Figure 1 Based on data provided by the Information System on Live Births SINASC of the Brazilian Health System database between 1994 and 2018 a total of 74215086 live births occurred in Brazil 37977308 being male babies DATASUS 2020 We are aware of 1164 Brazilian patients diagnosed with MPS who were born in Brazil during this period Among these patients 217 were MPS I 358 were MPS II 199 were MPS III 54 IIIA 84 IIIB 50 IIIC 1 IIID and 10 were MPS III not specified 117 were MPS IV 110 MPS IVA 2 MPS IVB and five with MPS IV not specified 257 were MPS VI and 16 were MPS VII For calculation purposes the unspecified cases were distributed proportionally according to the frequency of MPS subtype Thus the numbers were adjusted to 57 for MPS IIIA 88 for MPS IIIB 53 for MPS IIIC and 115 for MPS IVA The calculated incidence for MPS in Brazil using the 1994 to 2018 data was 157100000 live births Regarding each MPS type the birth prevalence by 100000 live births was 029 for MPS I 048 for MPS II or 094 considering only male births 008 for MPS IIIA 012 for MPS IIIB 007 for MPS IIIC 0001 for MPS IIID 015 for MPS IVA 0003 for MPS IVB 035 for MPS VI 002 for MPS VII and 0 for MPS IX The birth prevalence was also calculated for each Brazilian region For the 358 patients 3076 without an informed place of birth the region from where samples were obtained was set as place of birth Our results showed that MPS II had the highest score in all Brazilian regions except in the Northeast where MPS VI presented the highest birth prevalence rate The number of cases diagnosed and the birth prevalence for MPS patients born from 1994 to 2018 in Brazil and each region of this country is detailed in Table 2 This study was approved by the Ethics Committee of Universidade Federal do Rio Grande do Sul Brazil CAAE 82189417500005347 This study was conducted in accordance with the ethical standards from the 1964 Declaration of Helsinki and its later amendments Our manuscript does not contain data from any individual person Discussion In this study we explored the epidemiological data of MPS in Brazil MPS II was the most common type of MPS in Brazil and the second most common lysosomal storage disease diagnosed in our laboratory in previously published studies conducted by our group Giugliani et al 2017 Since Brazil has continental dimensions analysis per region was critical for showing that MPS II is the most common in the North Southeast and CenterWest Indeed MPS I and MPS II were tied as the most common types in the South and MPS VI was the most frequent in the Northeast Birth prevalence rates calculated from 1994 to 2018 indicated that MPS II was the most frequent in all regions except the Northeast where MPS VI has the highest rate A founder effect that resulted in a high frequency of pH178L pathogenic variant in the ARSB gene responsible for MPS VI may explain the high number of cases in Brazils Northeast Federhen et al 2020 This region also has areas of geographical isolation endogamy and a high number of consanguineous marriages that may lead to increased rates of MPS VI patients CostaMotta et al 2014 Vairo et al 2015 In addition the birth prevalence of MPS II in the Northeast was similar to the one observed in other regions of Brazil which suggests that the higher incidence of MPS VI Mucopolysaccharidoses in Brazil 3 Table 1 MPS types diagnosed in Brazil per region and by statea from 1982 to 2019 MPS Type RegionState All I II IIIA IIIB IIIC IIID IVA IVB VI VII IX North 75 13 30 2 4 2 5 18 1 Acre 7 2 1 1 2 1 Amazonas 31 6 10 1 1 1 12 Amapá Pará 28 3 13 1 2 2 1 5 1 Rondônia 7 1 5 1 Roraima 1 1 Tocantins 1 1 CenterWest 103 20 33 6 8 3 6 24 3 Distrito Federal 49 12 9 4 4 2 4 13 1 Goiás 22 2 11 2 1 6 Mato Grosso 15 5 6 3 1 Mato Grosso do Sul 17 1 7 1 1 5 2 Southeast 679 140 207 33 56 37 69 6 124 7 Espírito Santo 22 11 1 4 2 3 1 Minas Gerais 135 33 22 7 15 5 15 36 2 São Paulo 388 86 126 21 23 24 36 6 62 4 Rio de Janeiro 134 21 48 4 14 6 18 23 Northeast 510 66 147 22 14 19 1 68 1 162 10 Alagoas 34 4 23 1 1 5 Bahia 111 15 34 6 7 1 1 9 1 31 6 Ceará 88 11 35 5 6 3 7 21 Maranhão 23 2 11 2 1 3 4 Paraíba 71 8 6 1 9 26 20 1 Pernambuco 118 15 20 2 5 17 58 1 Piauí 19 2 7 1 2 5 2 Rio Grande do Norte 31 6 4 2 4 15 Sergipe 15 3 7 2 3 South 285 76 76 8 40 12 50 23 Paraná 102 20 39 3 12 3 13 12 Rio Grande do Sul 142 42 32 3 21 6 28 10 Santa Catarina 41 14 5 2 7 3 9 1 Brazil total 1652 315 493 71 122 73 1 198 7 351 21 a For MPS IIIA IIIB IIIC and IIID and for MPS IVA and IVB the numbers represent an extrapolation is related to these factors and not to a lower absolute number of births with MPS II Similarly as in Brazil MPS II is the most common type found in Estonia Taiwan Japan South Korea China and Switzerland Krabbi et al 2012 Cho et al 2014 Chen et al 2016 Khan et al 2017 The higher birth prevalence of MPS II in East Asia was suggested to be a consequence of the pR468 pathogenic variants in the IDS gene Khan et al 2017 In South Korea IDSIDS2 recombination mutations were the most frequently Cho et al 2014 Molecular analysis of 103 unrelated SouthAmericans including 91 Brazilian individuals MPS II patients showed that small insertions deletions indels and point mutations in the IDS gene were responsible for the disease in 81 of cases Inversiondisruption or partialtotal deletions of the IDS gene were found in 19 of the patients and only eight pathogenic variants were found in more than one unrelated patient BrusiusFacchin et al 2014 We do not have information about the rate of de novo mutation in the IDS gene in Brazil but data from Latin America the literature estimate it as 10 Amartino et al 2014 A limitation of our study is that although responsible for the vast majority of MPS diagnosis in Brazil our laboratory is not the only to perform such tests and some Brazilian cases may have been not included Also milder cases that are challenging to diagnose may be overlooked Another estimate of the birth prevalence of MPS in Brazil based on the frequency of heterozygotes for the most common pathogenic variant of the IDUA gene pTrp402Ter in healthy blood donors and on the relative frequency of homozygosity for such variant in MPS I patients Federhen et al 2020 was reported as Josahkian et al 4 Figure 1 Distribution according to Brazilian region of the Brazilian MPS cases diagnosed at the Medical Genetics Service of Hospital de Clínicas de Porto Alegre from 1982 to 2019 BP Brazilian population as estimated in 2019 IBGE 2020 462100000 live births nearly three times higher than the one found in this study 157 In this manner although providing a comprehensive picture of the epidemiological profile of MPS in Brazil the absolute numbers found in this study are possibly underestimated A newborn screening NBS program would be more accurate to estimate the incidence of MPS Although MPS testing is not included in the public NBS program in Brazil pilot studies are being carried out in order to evaluate its feasibility for future incorporation Camargo Neto et al 2018 A previous estimation of the birth prevalence of MPS in Brazil was published with data from 1994 to 2015 Federhen et al 2020 We have updated the birth prevalence across Brazilian regions up to 2018 and also demonstrated the distribution of MPS across each Brazilian State We think this revision is important since the inclusion of only three years already demonstrated a change in the estimated birth prevalence of MPS by type in the South Region where MPS I was previously the most common Federhen et al 2020 Moreover the knowledge of the distribution by state which does not necessarily reflects the distribution by region can help the design of targeted public policies This report provides a comprehensive characterization of the epidemiological profile of the different MPS subtypes in Brazil and its variations across states and regions The birth prevalence of MPS is variable across countries and regions and is likely linked to founder effect endogamy and consanguinity but other factors that are still unclear may be present and may need further investigation Our findings may help the assess of health needs in distinct populations and the delivery of medical care for these rare diseases Mucopolysaccharidoses in Brazil 5 Table 2 Number of cases diagnosed and incidence by 100000 live birthsa calculated for MPS patients born from 1994 to 2018 in Brazil and by region MPS Region All I II IIIA IIIB IIIC IIID IVA IVB VI VII IX North 65 088 13 018 28 038 074b 2 003 4 005 2 003 4 005 11 015 1 001 Northeast 379 178 52 025 109 051 100b 18 008 13 006 14 007 1 0005 40 019 123 058 9 004 CenterWest 73 126 14 024 27 047 091b 2 003 8 014 1 002 2 003 17 029 2 003 Southeast 476 162 98 033 143 049 095b 27 009 41 014 27 009 43 015 2 0007 91 031 4 001 South 171 166 40 039 51 049 097b 8 008 22 021 9 009 26 025 15 015 Brazil total 1164 157 217 029 358 048 094b 57 008 88 012 53 007 1 0001 115 015 2 0003 257 035 16 002 a The incidence rate shown inside parenthesis was calculated using our data and the number of live births obtained from SINASC b Considering only male live births Acknowledgments The authors would like to thank the biologists biochemists biomedical undergraduate and graduate students who contributed to the work developed by the MPS BRASIL NETWORK We would also acknowledge the health professionals who are members of this network and provided samples from suspected MPS patients The authors acknowledge the support received from INAGEMP CNPQ 4655492014 CAPES 88887136366201700 FAPERGS 17255100005210 from FIPEHCPA projects GPPG 2003 0066 and 20170664 and from Fundação Médica do Rio Grande do Sul This work was performed in collaboration with the BIODISCOVERY Experimental Research Centre HCPA Porto Alegre Brazil and DRBRASIL Clinical Research Centre HCPA Porto Alegre Brazil research groups Conflict of Interest The authors declare that they have no conflict of interest Author Contributions JAJ and RG conceived this study JAJ performed formal analysis and wrote the manuscript RG supervised the study and fully revised the document RG FBT MGB KMT APPSM FMS FB JFDM ACBF SLS and DRM contributed to the investigation data collection and creation of MPS BRAZIL NETWORK online platform All authors read and approved the final version References Amartino H Ceci R Masllorens F Gal A Arberas C Bay L Ilari R Dipierri J Specola N Cabrera A et al 2014 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Federhen A Baldo G Riegel M Burin M LeistnerSegal S and Giugliani R 2015 Diagnostic and treatment strategies in mucopolysaccharidosis VI Appl Clin Genet 8245255 Internet Resources DATASUS Tecnologia da informação a serviço do SUS http tabnetdatasusgovbrcgideftohtmexesinasccnvnvufdef April 25 2020 IBGE Instituto Brasileiro de Geografia e Estatística Estimativas da população residente no brasil e unidades da federação com data de referência em 1º de julho de 2019 httpsftp ibgegovbrEstimativasdePopulacaoEstimativas2019 POP201920201006pdf October 18 2020 Associate Editor Angela ViannaMorgante License information This is an openaccess article distributed under the terms of the Creative Commons Attribution License type CCBY which permits unrestricted use distribution and reproduction in any medium provided the original article is properly cited