Enzyme replacement therapy in 12 patients with MPS I–H/S with homozygous p.Leu490Pro mutation

Abstract

We describe a cohort of 14 Hurler-Scheie patients homozygous for the p.Leu490Pro missense mutation in the alpha-L-iduronidase gene. Now based in the UK, they are all of Pakistani/Kashmiri descent; 64% were female; 11/14 (79%) had a sibling or cousin with MPS I and the parents are consanguineous in all cases. The median age at diagnosis was 1.8 years (range from antenatal diagnosis to 16.5 years). Twelve were on ERT with recombinant human alpha-L-iduronidase (IDUA; Laronidase, Genzyme) for a median duration of 22.5 months (range 2-71 months) and median age at commencement of ERT was 8.6 years (range 0.4-23.1 years). There was clear improvement in the size of liver and spleen as well as reduction in urine glycosaminoglycans (GAGs). The mean (range) urine GAG levels in mg/mmol creatinine were 63.4 (28.9-105.6), 28.3 (10.9-41.4), 22.8 (12.1-43.1), 15.7 (9.2-24.8) and 16.3 (10.1-21.0) at commencement, 3 months post ERT, 6 months post ERT, 12 months post ERT and 24 months post ERT, respectively. Effects on growth were not clear as there does not seem to be an obvious trend of increase or decrease in height after commencement of ERT and this seems to be the case regardless of the age at which ERT was started.

Laronidase Replacement Therapy and Left Ventricular Function in Mucopolysaccharidosis I

“…In fact, a good correlation was observed between LV weight and urinary uronic acid concentration. These findings are similar to the previous results of our studies and others (Arora et al 2007;Harada et al 2011;Kakkis et al 2001). These findings suggest that decreased LV weight was due to GAG degradation in cardiac tissue, resembling volume reduction of the liver or spleen.…”

Different Serum Enzyme Levels Are Required to Rescue the Various Systemic Features of the Mucopolysaccharidoses

“…In addition, despite amelioration of the visceral phenotype because of the significant reduction in tissue GAG storage (Hoogerbrugge et al, 1995;Yano et al, 2009), both approaches show limited efficacy in ameliorating several MPS features, such as ocular pathology (Gullingsrud et al, 1998;Herskhovitz et al, 1999;Koseoglu et al, 2008;Pitz et al, 2009) and skeletal abnormalities (Field et al, 1994;Herskhovitz et al, 1999;Vellodi et al, 1999;Arora et al, 2007). Moreover, because lysosomal enzymes are not expected to cross the blood-brain barrier, both therapeutic approaches show limited efficacy (or no efficacy at all) concerning neurological manifestations of the disease (Hopwood et al, 1993;Shapiro et al, 1995;Vellodi et al, 1999;Desnick and Schuchman, 2002).…”

Mucopolysaccharidoses in northern Brazil: Targeted mutation screening and urinary glycosaminoglycan excretion in patients undergoing enzyme replacement therapy

“…After some months of treatment, the majority of patients undergoing ERT showed an improvement of many clinical symptoms, which was correlated with a significant reduction in urinary GAG excretion (Harmatz et al , 2005, 2008; Arora et al , 2007; Sifuentes et al , 2007; Muenzer et al , 2009). …”

“…It is based on the periodic replacement of the defective enzyme, leading to higher GAG degradation in tissues and organs, promoting a significant improvement in some clinical features. However, the influence of ERT on other pathological manifestations, like progressive skeletal disease, arthropathy, central nervous system dysfunction, cardiac involvement and visual impairment, is still not well understood (Miebach, 2005; Arora et al , 2007; El Dib and Pastores, 2007; Pitz et al , 2009). …”

“…Although some data regarding the clinical evaluations were not available, this reduction, according to the literature (Harmatz et al , 2005, 2008; Arora et al , 2007; Sifuentes et al , 2007), is strictly related to the improvement of the patients’ clinical picture.…”