Mucopolysacccharidoses: from understanding to treatment, a century of discoveries

Abstract

After the first description of a patient recognized as a MPS case was made in 1917, several similar cases were described and identified. Observations reported in the middle of the twentieth century concerning the presence of acid mucopolysaccharides (later called glycosaminoglycans, or GAGs) in tissues and especially in urine of patients were instrumental in providing an identity for these diseases, which became referred as “mucopolysaccharidoses” (MPS). In the late 1960’s it was demonstrated that MPS were caused by defects in the breakdown of GAGs, and the specific enzyme deficiencies for the 11 types and subtypes of MPS were identified thereafter. Genes involved in the MPS were subsequently identified, and a large number of disease-causing mutations were identified in each one. Although individually rare, MPS are relatively frequent as a group, with an overall incidence estimated as 1:22,000. The increased excretion of urinary GAGs observed in the vast majority of MPS patients provides a simple screening method, the diagnosis usually being confirmed by the identification of the specific enzyme deficiency. Molecular analysis also plays a role, being helpful for phenotype prediction, prenatal diagnosis and especially for the identification of carriers. As the diseases are rare and diagnosis requires sophisticated methods, the establishment of reference laboratories for MPS identification is recommended. The successful experience of the MPS Brazil Network in providing access to information and diagnosis may be considered as an option for developing countries. The development of therapeutic strategies for MPS, including bone marrow/hematopoietic stem cell transplantation (BMT/HSCT) and enzyme replacement therapy (ERT), changed the natural history of many MPS types. However, some challenges still remain, including the prevention of cognitive decline which occurs in some MPS. Newer approaches, such as intratechal ERT, substrate reduction therapy, read-through, gene therapy and encapsulated modified cells may provide a better outcome for these diseases in the near future. As early diagnosis and early treatment seems to improve treatment outcomes, and as newborn screening is now technically feasible, pilot programs (including one in progress in an area with high-incidence of MPS VI in northeastern Brazil) should provide information about its potential impact in reducing the morbidity associated with MPS diseases.

Estimated birth prevalence of mucopolysaccharidoses in Brazil

“…This abnormal accumulation interferes with cell and organ function, leading to a wide range of clinical manifestations, which include coarse facial features, joint contractures, hepatosplenomegaly, dysostosis multiplex, hearing loss, corneal clouding, heart disease, chronic obstructive pulmonary disease, sleep apnea, and, in some cases, intellectual impairment (Neufeld & Muenzer, ). These manifestations are chronic, progressive, widely variable, and differ depending on the type of MPS (Giugliani, ). The MPS are classified by the type(s) of GAG(s) excreted and the enzyme deficiency involved.…”

“…clouding, heart disease, chronic obstructive pulmonary disease, sleep apnea, and, in some cases, intellectual impairment (Neufeld & Muenzer, 2001). These manifestations are chronic, progressive, widely variable, and differ depending on the type of MPS (Giugliani, 2012).…”

Presentation and treatments for Mucopolysaccharidosis Type II (MPS II; Hunter Syndrome)

“…Urinary GAGs have been used as biomarkers for several forms of MPS and as a surrogate marker for IDS activity in a clinical trial [9, 89]. Oguma et al first developed a method to assay specific GAGs including DS, HS, and KS using liquid chromatography tandem mass spectrometry (LC/MS/MS) [90, 94].…”

Nanotechnology applied to treatment of mucopolysaccharidoses

“…GAGs that are not degraded or are only partially degraded by alternative routes accumulate in the lysosomes, resulting in generalized cell, tissue, and organ dysfunctions that appear as coarse faces, organomegaly, skeletal disorders, and cognitive impairment in some disorders [1]. Table 3 describes the enzyme, gene, and GAGs involved in each MPS.…”