Tissue Remodeling, Toxic Molecule Accumulation Responsible for Upper Airway Involvement in MPS, Study Finds

Active tissue remodeling and treatment-resistant accumulation of toxic molecules are contributing factors in the development of persistent upper airway disease among patients with mucopolysaccharidosis (MPS), a study shows.

The study, “Substrate accumulation and extracellular matrix remodelling promote persistent upper airway disease in mucopolysaccharidosis patients on enzyme replacement therapy,” was published in the journal PLOS ONE.

MPS comprises multiple rare genetic disorders, including Sanfilippo syndrome, that share a common feature — accumulation of partially degraded glycosaminoglycans (GAGs) in tissues and organs. This is due to impaired activity of specific enzymes involved in the metabolism of GAG molecules.

Accumulation of GAGs is toxic for cells and can lead to failure of the affected organs. So MPS can manifest with cardiorespiratory, musculoskeletal, visceral, and neurocognitive symptoms.

Airway involvement is a well-recognized manifestation of different subtypes of MPS, such as MPS I, II, IV, and VI. It remains unclear what causes airway changes in these patients, but it is thought to result from the combination of both structural and inflammatory processes.

A team led by researchers from England’s University of Manchester conducted a study to further explore the underlying mechanisms involved in upper airway impairment in patients with MPS.

The study enrolled 12 participants (ages 2–12) who were indicated for surgical treatment to resolve clinical symptoms of upper airway obstruction. Among them, two had Hurler-Scheie syndrome (MPS I), one had Sanfilippo type A (MPS III), three had Morquio syndrome type A (MPS IV), and two patients had Maroteaux-Lamy syndrome (MPS VI). Four patients without MPS were enrolled as age- and sex-matched controls.

The patients had their tonsils or adenoids surgically removed to unblock the upper airways, and the team analyzed tissue samples collected during the surgeries.

They found that MPS tissue samples had higher number of lysosomal vesicles, the cellular waste system structures in which GAGs are stored. These samples also had greater accumulated amounts of GAGs compared to controls.

These findings were also observed in tissue samples of patients who were receiving enzyme replacement therapies (ERTs), which suggests that the standard treatment was unable to completely reverse the disease-impaired metabolic mechanisms.

Further analysis also showed that MPS patients’ tissue samples had increased amounts of collagen IV and laminin alpha-5, two main components of tissue’s structural matrix. In contrast, analysis of several important pro-inflammatory signals did not show any significant differences between MPS patients and those without the disease.

Overall, these findings suggest that upper airway involvement in MPS cases is mainly promoted by GAG accumulation and tissue matrix remodeling, rather than an inflammatory process.

“Our findings lend novel insight into the [MPS-associated] cascade of events,” researchers said. “We recommend that efforts be directed toward earlier diagnosis and initiation of ERT” to prevent early and progressive substrate accumulation which once established may lead “to irreversible and persistent upper airways obstruction.”