Mucopolysaccharidosis (MPS) is a rare genetic disease involving active storage of glycosaminoglycans (GAGs). Accumulation of GAGs in the connective tissues of airways leads to progressive pulmonary dysfunction. Studies conducted in Taiwan revealed mainly restrictive pulmonary dysfunction, whereas the same studies in Egypt and California revealed obstructive pulmonary dysfunction. The contradictory results and lack of studies of respiratory system in patients with MPS in Asian populations are an indication to study pulmonary impairment in patients with MPS in Kazakhstan. The prospective study of respiratory system in patients with MPS was conducted in the Scientific Centre of Paediatrics and Paediatric Surgery. Patients with MPS (n = 11) were examined for respiratory function. Different types of pulmonary dysfunction were present in MPS patients, they were mainly of a restrictive pathology. One patient with MPS II had obstructive dysfunction. Enzyme replacement therapy was provided for an average duration of four years, leading to improvements in respiratory function in two patients with total normalization in one. All observed patients had respiratory dysfunction, mainly of the restrictive type. Pulmonary impairment in patients with MPS is the main reason for death. Thus, it is necessary to follow up with pulmonary function assessments in children with MPS.

Idursulfase and idursulfase beta currently used for enzyme replacement therapy of mucopolysaccharidosis type II (MPS II) do not cross the blood-brain barrier (BBB), which significantly limits the treatment of neurocognitive impairment in patients. Verenafusp alfa (Clotilia®, GENERIUM JSC) contains a recombinant modified iduronate-2-sulfatase enzyme covalently linked to the Fab fragment of a monoclonal antibody against the human insulin receptor, which crosses the BBB. Objective: The aim of this multicenter, open-label, multicohort phase II–III study was to evaluate the safety, pharmacokinetics, pharmacodynamics (PD), efficacy, and optimal dose selection of verenafusp alfa in different age groups of patients. Materials and methods: The interim analysis included data from 18 patients under 18 years of age in 6 age cohorts. Cohort enrollment was performed sequentially with decreasing patient age, first for the 2 mg/kg dose (Group 1) in cohorts 2, 3, 5, and then for the 3 mg/kg dose (Group 2) in cohorts 4, 6, 7. The study included 52 weekly infusions of verenafusp alfa. The PD criterion was the level of glycosaminoglycans (GAGs) in urine, blood, and cerebrospinal fluid (CSF). Efficacy parameters included assessment of somatic manifestations and neurocognitive functions; safety parameters included assessment of adverse events (AEs) and the dynamics of anti-drug antibody (ADA) formation. Results: The increase in verenafusp alfa concentration in CSF was more pronounced in Group 2 (3 mg/kg) – 252.5 [221.4; 351.54] pg/mL, as well as in the group of children under 6 years of age – 302.02 [244.72; 388.83] pg/mL. The decrease in heparan sulfate (HS) levels in CSF at week 52 was more pronounced in Group 2 (3 mg/kg) – 49% (p=0.084), and also in the group of patients under 6 years of age – 53% (p=0.027). Urinary and blood GAG levels remained stable, taking into account prior idursulfase therapy in 94% of patients. An 18% increase in the 6-minute walk test distance was observed in the overall group of patients under 18 years of age (p=0.020), accompanied by a statistically significant increase in range of motion in the shoulder, knee, and left hip joints. Liver and spleen volumes remained stable. Stabilization and/or improvement of neurocognitive function parameters were observed in patients with MPS II. The AEs observed in 50% of patients were non-serious, classified as infusion reactions of mild or moderate severity, with a predictable and manageable spectrum and frequency. ADA formation against the drug was observed in 40% of patients. Conclusion: Weekly intravenous administration of verenafusp alfa for one year achieved control of urinary GAG levels, stabilization and/or improvement of neurocognitive functions, and reduction of somatic manifestations of MPS II in previously treated patients with idursulfase drugs aged 2 to 16 years. After one year of therapy, an increase in verenafusp alfa concentration and a decrease in HS levels in CSF were observed, confirming its ability to cross the BBB and prevent neurodegenerative changes in the CNS.

Objectives: Mucopolysaccharidosis type VI is rare lysosomal storage disorder due to arylsulfatase B enzyme deficiency, leading to progressive multisystem disease and complex airway. Acute respiratory infections can precipitate airway embarrassment. A structured treatment guideline is currently lacking. We present 7 years old MPS VI male with respiratory distress highlighting the challenges in management. Methods: Case review focusing on clinical presentation, imaging findings, multidisciplinary deci-sion making during acute deterioration. Results: A child diagnosed with MPS VI at age of 3.5 years old, due to low arylsulfatase B enzyme activity and homozygous for c.275C>A p.(Thr92Lys) variant in ARSB gene. At 7 years, he presented with dyspnoea, increased respiratory effort with bilateral crepitations, noisy breathing. Initial man-agement included facemask oxygen, nebulised adrenaline, corticosteroids, bronchodi-lators. Computer tomography scan of the neck, chest showed complex upper airway, multiple tracheal narrowing, tortuosity, extra loop of truncus brachiocephalicus from arch of aorta. Potential interventions carried substantial risks due to abnormal airway and multisystem disease. Following extensive multidisciplinary discussion after careful consideration of the significant risks associated with invasive airway interventions, a shared decision was reached with the family to adopt a comfort focused palliative care approach. Despite the best supportive care, the child unfortunately passed away after 3 months. The family were involved in every decision process, were fully supported. Conclusion: MPS VI is associated with complex airways, multisystem disease. Multi-disciplinary decision making with family is critical to safe and appropriate care. The rarity of the disease, lack of guidelines, complex airways, multiple comorbidities make management challenging.

Background and Clinical Significance: Mucopolysaccharidosis type VI is a rare lysosomal storage disorder due to arylsulfatase B enzyme deficiency, leading to progressive multisystem disease and complex airway. Acute respiratory infections can precipitate airway embarrassment. A structured treatment guideline is currently lacking. We present a 7-year-old MPS VI male with respiratory distress, highlighting the challenges in management. Case Presentation: Case review focusing on clinical presentation, imaging findings, and multidisciplinary decision-making during acute deterioration. A child diagnosed with MPS VI at the age of 3.5 years old, due to low arylsulfatase B enzyme activity and homozygous for c.275C>A p.(Thr92Lys) variant in the ARSB gene. At 7 years of age, he showed the signs of dyspnoea, increased respiratory effort with bilateral crepitations, and noisy breathing. Initial management included facemask oxygen, nebulised adrenaline, corticosteroids, and bronchodilators. Computer tomography scan of the neck and chest showed a complex upper airway, multiple tracheal narrowing, tortuosity, and an extra loop of truncus brachiocephalicus from the arch of the aorta. Potential interventions carried substantial risks due to abnormal airway and multisystem disease. Following extensive multidisciplinary discussion after careful consideration of the significant risks associated with invasive airway interventions, a shared decision was reached with the family to adopt a comfort-focused palliative care approach. Despite the best supportive care, the child unfortunately passed away after 3 months. The family was involved in every decision process and was fully supported. Conclusions: MPS VI is associated with complex airways and multisystem disease. Multidisciplinary decision-making with family is critical to safe and appropriate care. The rarity of the disease, lack of guidelines, complex airways, and multiple comorbidities make management challenging.