Longitudinal Study of Bone Disease in Children With Mucopolysaccharidoses (MPS) I, II, and VI
Condition: Mucopolysaccharidoses
MeSH terms: Mucopolysaccharidoses
Study type: Observational

Summary: 
      Approximately 85% of individuals with Mucopolysaccharidosis (MPS) type I, II, or VI report
      weekly pain and 50-60% have significant limitations in their activities of daily living due
      to MPS related musculoskeletal disease despite treatment with enzyme replacement therapy
      (ERT). Thus there is a critical need to identify additional therapies to alleviate the burden
      of musculoskeletal disease in order to improve the health and quality of life of individuals
      with MPS. However, disease progression needs to be quantified to be able to determine
      efficacy of new therapies. This study is a multi-institutional, 5-year, longitudinal study of
      musculoskeletal disease in MPS. The objective is to quantitatively describe the progression
      of skeletal disease and identify biomarkers that either predict disease severity or could be
      used as therapeutic targets in individuals with MPS I, II, and VI. A database of standardized
      measurements of musculoskeletal disease in MPS will allow the field to efficiently move
      forward with therapeutic clinical trials in patients with MPS.
    

Detailed description: 
      Although children with MPS I, II, and VI who are treated with hematopoietic cell
      transplantation (HCT) and/or enzyme replacement therapy (ERT) are now living into adulthood
      with good cognitive development, their quality of life is significantly impacted by their
      skeletal abnormalities (i.e., kyphosis, scoliosis, genu valgum), joint contractures, pain,
      and severe short stature. Additional therapies (e.g., post-HCT supplemental ERT, anti-TNFα
      drugs, stop codon suppression drugs, gene therapy) to decrease the burden of skeletal disease
      and improve growth are needed. However, prior to these therapeutic studies, control data
      quantifying the progression of skeletal disease in individuals with MPS I, II and VI treated
      with ERT and/or HCT are needed, along with biomarkers to be used as early predictors of
      response to treatment.

      Osteoporosis has been described in animal models of MPS. It is unknown whether abnormalities
      seen in animal models of MPS can be extrapolated to osteoporosis or increased risk of
      fracture in children and adults affected with MPS. Preliminary data suggest that children and
      adolescents with MPS I, II and VI have low bone mineral density (BMD) after adjustment for
      short stature and abnormal bone geometry and that markers of bone remodeling are
      cross-sectionally associated with BMD. It is unknown whether this decreased BMD during
      childhood will result in osteoporosis and increased fracture risk in adulthood. Determining
      the risk for osteoporosis in MPS I, II and VI has become particularly important as these
      individuals are now healthier and more mobile with new and improved treatments and thus have
      a greater opportunity for fracture.

      Glycosaminoglycan (GAG) deposition has been identified in bone and cartilage in animal models
      of MPS. GAG deposition in cartilage has specifically been shown to induce inflammation (e.g.
      increased tumor necrosis-alpha [TNF- α ] levels in serum and synovial fluid), chondrocyte
      apoptosis, and hyperplasia of the synovial membranes. We have found that serum TNF-α is
      elevated in children and adolescents with MPS I, II and VI and is associated with bodily pain
      and poor physical function.

      Our long-term goal is to identify and test new therapies for musculoskeletal disease in MPS.
      The objective of this proposed longitudinal observational study is to document the
      progression of skeletal disease and identify biomarkers that either predict disease severity
      or could be used as therapeutic targets in individuals with MPS I, II, and VI. The rationale
      for this project is to obtain baseline data for future therapeutic clinical trials and to
      identify potential therapeutic targets. Our central hypothesis is that skeletal disease will
      progress over time and that biomarkers of inflammation, and bone and cartilage turnover, will
      predict the severity of skeletal disease over time. Therefore, this study has the following
      specific aims (SA):

      SA1: To characterize the progression of skeletal disease from childhood into young adulthood
      for individuals with MPS I, II and VI. Our hypothesis is that there will be a progressive
      decrease in bone health as this population matures into young adulthood due to decreasing
      mobility, chronic inflammation, and intrinsic MPS related bone disease.

      SA2: To identify prognostic biomarkers of inflammation, bone remodeling, and cartilage
      turnover that can predict the progression of skeletal disease and impaired physical function
      in MPS I, II and VI. Our hypothesis is that biomarkers of inflammation, bone remodeling, and
      cartilage turnover, will be predictive of change in physical function, BMD, range of motion,
      hip dysplasia, kyphoscoliosis, quality of life, and height over 5 years.

      At the completion of this study we expect to quantify the progression of skeletal disease in
      MPS I, II and VI treated with ERT and/or HCT to be used in future therapeutic clinical
      trials. In addition, we will obtain biomarkers of skeletal disease progression that could
      identify early treatment efficacy. Finally, we will gain further insight into the mechanism
      of persistent skeletal disease in MPS that will provide potential therapeutic targets.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        community sample
      
Biospecimen description: 
      Serum, plasma, white cells for DNA extraction, and urine will be retained.