Among the 76 individuals with MPS from Ceará, MPS II (also known as Hunter syndrome, the X-linked type) was the most frequent type. Consequently, the number of male subjects in our sample universe was twice that of females. Some studies have pointed out MPS II as the more prevalent type in Brazil as a whole, which accounts for almost 30% of all MPS cases in the country (Celik et al., 2021; Josahkian et al., 2021). Hunter syndrome is reported to have a relatively high incidence in some countries (especially in Asia, where most MPS patients present type II), but in Europe its incidence was lower than that of MPS I and MPS III (Celik et al., 2021; Zhou et al., 2020).
Nine different pathogenic variants were found in 17 analyzed individuals with MPS II. Missense variants were the most common variant (8/17; 47%), in accordance with the literature (Josahkian et al., 2021). The most common pathogenic variants among them were p.Lys440Thrfs*15 in IDS (3/17; 18%) and the common IDS/IDSP1 inversion (3/17; 18%). This is the first report of the variant p.Lys440Thrfs*15, which was detected in three individuals from the same family. It is a 19 bp deletion in exon 9 of IDS, with a pathogenic effect predicted in silico by Mutation Taster (Schwarz et al., 2014) and SIFT Indel (Hu & Ng, 2013) (data not shown).
Age at first symptoms, at diagnosis, and at death varied widely between different types of MPS. According to our results, patients with MPS I had first symptoms and were diagnosed earlier. On the other hand, they also had the highest lethality and died younger. An immediate explanation for this finding is that most of these patients had the severe form of MPS I (also known as Hurler syndrome), characterized by multiorgan dysfunction leading to considerable morbidity and early mortality (Beck et al., 2014; D’Aco et al., 2012).
Another factor to be considered is the low percentage of individuals born in the capital. Geographical distance to a reference center in medical genetics and/or to multi professional health services (which are typically offered in Fortaleza, the main city of Ceará state) is one of the main factors for loss of follow-up in patients with MPS I and other types, which can contribute to a worsening in the clinical picture of patients (Personal communication, data not shown). Patients with MPS I from Ceará were diagnosed later (on average, at 2.2 years of age) than those registered in an international observational database, the MPS I Registry (overall, at 1.3 years) (D’Aco et al., 2012).
The high percentage of parental consanguinity among families with MPS VI and MPS IV-A is another result that deserves attention. In fact, many studies have investigated an important endogamic component in the population of Ceará (Araujo et al., 2016; Freire-Maia, 1957, 1990; Menezes, 1970). A high prevalence of rare genetic diseases in some geographical clusters, including type I Gaucher disease (OMIM: 231000) in the Northwest of the state (Chaves et al., 2015) and pycnodysostosis (OMIM: 265800) in the North, near the coast, both autosomal recessive and associated with high parental consanguinity in the communities studied.
Although estimates point to MPS II as the most common type in Brazil, MPS VI (also known as Maroteaux-Lamy syndrome) has been reported as the most prevalent in the Northeast region alone (Josahkian et al. 2021). Generally, MPS VI case series with molecular investigation point to a great genetic heterogeneity associated with the disease (Petry et al., 2005). Nevertheless, our results point to a spatial concentration of MPS VI cases in the Eastern region of the Ceará state who carried the same rare likely pathogenic variant (ARSB, c.1143-8T > G; ClinVar Allele ID: 15927) and who shared surnames, which indicates a possible common ancestral history.
This intronic variant was firstly described by Petry et al. (2005) in two Brazilian patients (one compound heterozygous, and the other homozygous) (Petry et al., 2005). Its deleterious effects have been discussed elsewhere, and it appears to influence mRNA stability by the nonsense-mediated mRNA decay (Garrido et al., 2007, 2008; Karageorgos et al., 2007). Other studies have reported the presence of the ARSB’s c.1143-8T > G allele only in individuals from Brazil, Argentina, Spain, and Portugal (Franco et al., 2016; Garcia et al., 2010; Garrido et al., 2007, 2008; Horovitz et al., 2015; Karageorgos et al., 2007; Leal et al., 2014; Petry et al., 2005; Tomanin et al., 2018).
Previously, a geographical cluster of MPS VI in the Brazilian Northeast was already reported by Costa-Motta et al. (2011), who described 13 cases of the disease in a small town in the countryside of the Bahia state (another state in the Northeast region), where the incidence of MPS VI was estimated at 1:5,000 live births (Costa-Motta et al., 2011). All cases carried the same pathogenic variant (p.H178L, in exon 10 of ARSB) and presented the same haplotypic distribution of 10 intragenic SNPs, which together with the historical and pedigree analysis strongly suggested a founder effect underlying the high frequency of the disease (Costa-Motta et al., 2011, 2014; R. Giugliani et al., 2019). This variant was not found in our sample.
MPS VI cases from Ceará were born in municipalities sharing historical, geographical, and cultural aspects. Generally, the communities that would give rise to these municipalities emerged between the 17th and 19th centuries after the extermination of the native population by settlers, who were composed mainly of people from Pernambuco and Bahia at the behest of the Portuguese Crown seeking territorial expansion for cattle breeding, with extermination of the native population (Catunda, 1955; IBGE, 2022; Magalhães, 1970; Menezes, 1970; Pontes et al., 2012). By the way, the path between Icó and Russas (crossing Jaguaretama and Quixeré, all municipalities identified in the Ceará cluster of MPS VI) corresponds to one of the main migration paths from Pernambuco to Ceará, which were later widely used for commercial purposes (Pontes et al., 2012).
The climate in these places is typically semi-arid, affected by long and extreme periods of drought, which contributed to historical migratory waves of individuals seeking better living conditions (T. T. Cardoso, 2007; Menezes, 1970). Population expansion with an agricultural and commercial-based economy resulted in the formation of relatively small municipalities with hierarchical societies, commonly endogamic, many of which maintained geopolitical and economic ties (Catunda, 1955; Freire-Maia, 1957; IBGE, 2022; Menezes, 1970; Pontes et al., 2012).
The likely pathogenic variant detected in the MPS VI cluster in Ceará may have arisen in a founding population, probably in the Iberian Peninsula (considering the cases of MPS VI reported in Portugal and Spain mentioned above), with its consequent arrival in the Americas (especially, Brazil and Argentina) from the 16th century. Through internal migratory processes to colonial Brazil, ARSB, c.1143-8T > G allele may have spread to Ceará territory and increased in frequency in small, semi-isolated, and endogamic communities. Future studies will be necessary to test the hypothesis of an Iberian ancestry origin of the pathogenic variant.
Regardless of ancestral origin, a geographic cluster of a recessive autosomal disease implies the existence of a number of heterozygous individuals who could benefit from adequate genetic counseling. In these populations with historical social and health vulnerabilities, a complex disease such as MPS VI may represent an important public health issue considering other affected individuals (or carriers), their families, and communities (Castilla & Schuler-Faccini, 2014; Costa-Motta et al., 2014; R. Giugliani et al., 2019; Passos-Bueno et al., 2014). In these places, it is sometimes necessary a certain degree of reorganization of health services to guarantee full and equitable access to health, given that they are rare diseases concentrated in small municipalities with notable economic limitations and with a small number of professionals with expertise in genetic diseases (Bonilla et al., 2021; Horovitz et al., 2015).
The delay in diagnosis of MPS VI can be worse in cases without a family history and in some regions where medical genetics services are scarce. Early diagnosis and appropriate care and treatment, such as enzyme replacement therapy (ERT), are critical for better disease-related outcomes and for improving patients' quality of life and prevention of irreversible damage. Early recognition of MPS remains an unmet challenge since the clinical phenotype looks normal at birth (Celik et al., 2021; Franco et al., 2016; Horovitz et al., 2015). In Ceará, identification of the MPS VI cluster leaded to the decentralization of the therapeutic process, especially with regard to ERT infusions, allowing access to therapy at home, in inland municipalities.
In Brazil, a nonprofit organization founded in 2004 has deeply changed the diagnostic landscape of MPS. Known as “MPS Brazil Network” the organization has provided necessary laboratory tests and supported clinical and laboratory development of the participating centers across the country (Kubaski et al., 2019). Through the performance of biochemical and molecular tests in a reference center, the initiative has expanded access to diagnostic tests to most parts of the huge Brazilian territory and can be a template to expand the diagnosis of other rare diseases in Brazil and in other countries with similar territorial and sociodemographic aspects.
A limitation of our study is that it might have not included all MPS cases in Ceará, especially those undiagnosed. In addition, we should point out that the MPS Brazil Network, although responsible for the vast majority of MPS diagnoses in Brazil, is not the only one to perform such tests (Josahkian et al. 2021). However, we have included cases from institutions that are references for the care of people with rare genetic diseases in Ceará state.
In general, we believe that this work reinforces the importance of studying genetic diseases in a broader perspective, taking into account factors such as the geographical space where cases are inserted and social and health determinants. The results presented here provide a comprehensive picture of MPS in an important state of the Brazilian Northeast, a region that concentrates many risk factors for rare genetic diseases, such as endogamy, inbreeding, and reproductive isolation (Cardoso-dos-Santos et al., 2020; Freire-Maia, 1957). In Brazil, it was recently approved a federal bill (PL 5043/20) in which lysosomal diseases were included in the list of conditions that should be part of the public newborn screening program, which covers all babies born in Brazil (Montenegro et al., 2022). The results presented here should help the design of targeted public policies and initiatives of health promotion to relevant patients and their communities.