Enzyme replacement therapy improves joint motion and outcome of the 12‐min walk test in a mucopolysaccharidosis type VI patient previously treated with bone marrow transplantation

Abstract

Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome, OMIM #253200) is a rare disorder involving multiple organs and manifested particularly by severe skeletal abnormalities. Bone marrow transplantation (BMT) improves cardiopulmonary function and facial features, but has limited success in ameliorating skeletal abnormalities and short stature. Here, we report the outcome of enzyme replacement therapy (ERT) with recombinant human arylsulfatase-B (ASB, Naglazyme, BioMarin, Novato, CA) in an MPS VI patient who received BMT 10 years prior to ERT induction. Administration of weekly Naglazyme for 18 months was effective in improving range of motion in several joints [shoulders (improvement of flexion (Right/Left): 40°/55°; improvement of extension 30°/40°; improvement of abduction 10°/10°), elbows (improvement of flexion 25°/25°; improvement of extension 10°/15°), hips (improvement of flexion 25°/10°), and knees (improvement of flexion 45°/40°; improvement of extension 50°/60°)]. Improvement in the outcome of the 12-min walk test (70% increase) and 3-min stair-climbing test (29% increase) was also noted after ERT. Because ERT improved clinical features in an MPS VI patient who had undergone prior BMT, the role of ERT post successful BMT in MPS VI needs further investigation.

Sensory-motor behavioral characterization of an animal model of Maroteaux-Lamy syndrome (or Mucopolysaccharidosis VI)

“…They presented reduced maximal speed, increased motionless time, and reduced distance traveled, but none of these effects were statistically significant. This suggests that the affected rats' walking ability, unlike that of human patients893839 was relatively preserved at this age. However, affected animals were extremely impaired in vertical activity, especially when forced to stand on their hindlimbs without any forelimb support (rearing), and it has been shown to be one of the most affected behavioral parameters in animal models of osteoarthritis3435.…”

“…The effects of ERT in MPS VI patients are generally evaluated only on the 6–12 min walking test or climb test, and it is generally reported to improve these behavioral functions as well as urinary GAG levels793849. Nevertheless, when more detailed behavioral analysis is performed, using for instance joint motility scores, some of the therapeutic limits of ERT are generally unrevealed638.…”

“…Although, bone marrow transplantation and enzyme replacement therapy (ERT) clearly ameliorate the clinical phenotype of MPS VI patients456789, there is no cure for MPS VI or any other MPS. Preclinical basic research on spontaneous animal models of MPS VI in cats, dogs, and rats, as well as a knockout model in mice created with gene targeting, is being undertaken with the expectation that it will provide an effective novel and resolute therapy for this disorder101112131415.…”

Isokinetic muscle strength differences in patients with mucopolysaccharidosis I, II, and VI

“…Studies that have evaluated the impact of the disease on skeletal muscle have used functional tests such as the 6- or 12-minute walk test, 3-min stair-climb, and/or goniometric tests for joint mobility evaluation [2,6,7,13]. Cardoso-Santos and colleagues measured hand grip strength in MPS VI patients and reported that 23 out of the 26 patients tested could not generate enough pressure to activate the dynamometer resulting in a reading of zero pounds [13].…”

“…Despite the currently available therapies of hematopoietic cell transplantation (HCT) and/or enzyme replacement therapy (ERT), we hypothesized that all MPS subgroups studied would have decreased strength compared to the control group due to the involvement of the musculoskeletal system in MPS disease progression. Based on the severity of the MPS IH phenotype, it was suspected that MPS IH would have the greatest difference in skeletal muscle strength [1,11,16], while MPS VI and MPS IA groups would have significantly less strength than controls but more strength than the MPS IH group as a result of less neurologic involvement [1,2,13]. Finally, as would be expected based on the mode of inheritance [1], all of our MPS II subjects are male.…”