Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)--10-year follow-up of patients who previously participated in an MPS VI Survey Study

Abstract

Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetylgalactosamine-4-sulfatase activity. A cross-sectional Survey Study in individuals (n = 121) affected with MPS VI was conducted between 2001 and 2002 to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of disease. We conducted a Resurvey Study (ClinicalTrials.gov: NCT01387854) to obtain 10-year follow-up data, including medical histories and clinical assessments (n = 59), and survival status over 12 years (n = 117). Patients received a mean (SD) of 6.8 (2.2) years of galsulfase ERT between baseline (Survey Study) and follow-up. ERT patients increased in height by 20.4 cm in the 4-7-year-old baseline age group and by 16.8 cm in the 8-12-year-old baseline age group. ERT patients <13 years-old demonstrated improvement in forced vital capacity (FVC) by 68% and forced expiratory volume in 1 sec (FEV1) by 55%, and those ≥13 years-old increased FVC by 12.8% and maintained FEV1. Patients with >200 µg/mg baseline uGAG levels increased FVC by 48% in the <13-year-old baseline age group and by 15% in the ≥13-year-old baseline age group. ERT patients who completed the 6-min walk test demonstrated a mean (SD) increase of 65.7 (100.6) m. Cardiac outcomes did not significantly improve or worsen. Observed mortality rate among naïve patients was 50% (7/14) and 16.5% (17/103) in the ERT group (unadjusted hazard ratio, 0.24; 95% CI, 0.10-0.59). Long-term galsulfase ERT was associated with improvements in pulmonary function and endurance, stabilized cardiac function and increased survival.

Keywords: Maroteaux-Lamy syndrome; N-acetylgalactosamine-4-sulfatase; enzyme replacement therapy; exercise tolerance; follow-up studies; mucopolysaccharidosis VI; multicenter study [publication type]; respiratory function tests; survival rate.

FIGURE 1

Urinary GAG levels of patients at baseline and follow-up. Each red circle represents an individual patient at baseline and blue crosses indicate patients at resurvey. The X-axis represents the age at baseline and at resurvey.

FIGURE 2

FVC and FEV1 at baseline and follow-up. The error bars are SD. The number of patients in each group, absolute values and ranges are shown in Supplementary eTable II (in supporting information online).

FIGURE 3

Product-limit survival estimates of Resurvey Study patients. (A) Kaplan-Meier survival curves of ERT (n=103) (blue dashed line) and naïve (n=14) (red solid line) patient groups. The 95% confidence limits are indicated by blue (ERT) or red (naïve) shaded boxes. The calculated P values were: Logrank P=.0006, Wilcoxan P=.0002. (B) Kaplan-Meier survival curves of patients analyzed by baseline age and baseline uGAG levels. Survival probability curves are as follows: low baseline uGAG and <13 year-old age (blue solid line), low baseline uGAGs and ≥13 year-old (red dashed line), high baseline uGAG and <13 year-old age (green dashed line), and high baseline uGAGs and ≥13 year-old (brown dashed line). Three ERT patients with missing baseline uGAG values were excluded in this analysis. The calculated P values (Logrank P=.0906, Wilcoxan P=.0689) for the differences in survival were not statistically significant (at P=.05), as 95% CI bands were generally overlapping. These results do not indicate statistically significant differences among the four ERT subgroups.

FIGURE 3

Product-limit survival estimates of Resurvey Study patients. (A) Kaplan-Meier survival curves of ERT (n=103) (blue dashed line) and naïve (n=14) (red solid line) patient groups. The 95% confidence limits are indicated by blue (ERT) or red (naïve) shaded boxes. The calculated P values were: Logrank P=.0006, Wilcoxan P=.0002. (B) Kaplan-Meier survival curves of patients analyzed by baseline age and baseline uGAG levels. Survival probability curves are as follows: low baseline uGAG and <13 year-old age (blue solid line), low baseline uGAGs and ≥13 year-old (red dashed line), high baseline uGAG and <13 year-old age (green dashed line), and high baseline uGAGs and ≥13 year-old (brown dashed line). Three ERT patients with missing baseline uGAG values were excluded in this analysis. The calculated P values (Logrank P=.0906, Wilcoxan P=.0689) for the differences in survival were not statistically significant (at P=.05), as 95% CI bands were generally overlapping. These results do not indicate statistically significant differences among the four ERT subgroups.