A follow-up study of MPS I patients treated with Laronidase enzyme replacement therapy for 6 years
ABSTRACT Recombinant human alpha-L-iduronidase (Aldurazyme, laronidase) was approved as an enzyme replacement therapy for patients with the lysosomal storage disorder, mucopolysaccharidosis I (MPS I). In order to assess the long-term safety and efficacy of laronidase therapy, 5 of 10 patients in the original laronidase Phase 1/2 clinical trial were re-evaluated after 6 years of treatment. Lysosomal storage was further improved at 6 years (urinary glycosaminoglycans (GAG) excretion decreased 76%; mean liver size at 1.84% of body weight). Shoulder maximum range of motion was maintained or further increased and reached a mean 33.2 (R) and 25.0 (L) degrees gained in flexion and 34.0 (R) and 27.3 (L) degrees gained in extension. Sleep apnea was decreased in four of five patients and the airway size index improved. Cardiac disease evaluations showed no progression to heart failure or cor pulmonale but pre-existing significant valve disease did progress in some patients. Substantial growth was observed for the pre-pubertal patients, with a gain of 33 cm (27%) in height and a gain of 31 kg in weight (105%). In general, the evaluated patients reported an improved ability to perform normal activities of daily living. Overall these data represent the first evidence that laronidase can stabilize or reverse many aspects of MPS I disease during long-term therapy and that early treatment prior to the development of substantial cardiac and skeletal disease may lead to better outcomes.
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- "The MSK abnormalities observed using pGALS are similar to those cited in the literature with marked and widespread joint restriction with preferential involvement of the upper limbs, most notably the shoulders  and interphalangeal joints causing fixed flexion deformities in the fingers [5,6]. Our patient group had a large spectrum of ages and in the younger children with the attenuated subtype, predominant involvement of the upper limb was observed. "
ABSTRACT: Background Children with mucopolysaccharidoses (MPS) often have musculoskeletal (MSK) abnormalities. Paediatric Gait, Arms, Legs, and Spine (pGALS), is a simple MSK assessment validated in school-age children to detect abnormal joints. We aimed to identify MSK abnormalities in children with MPS performing pGALS. Methods Videos of children with a spectrum of MPS performing pGALS were analysed. A piloted proforma to record abnormalities for each pGALS manoeuvre observed in the videos (scored as normal/abnormal/not assessable) was used by three observers blinded to MPS subtype. Videos were scored independently and rescored for intra- and inter-observer consistency. Data were pooled and analysed. Results Eighteen videos of children [12 boys, 6 girls, median age 11 years (4–19)] with MPS (13 type I [5 Hurler, 8 attenuated type I]; 4 type II; 1 mannosidosis) were assessed. The most common abnormalities detected using pGALS were restrictions of the shoulder, elbow, wrist, jaw (>75% cases), and fingers (2/3 cases). Mean intra-observer Κ 0.74 (range 0.65–0.88) and inter-observer Κ 0.62 (range 0.51–0.77). Hip manoeuvres were not clearly demonstrated in the videos. Conclusions In this observational study, pGALS identifies MSK abnormalities in children with MPS. Restricted joint movement (especially upper limb) was a consistent finding. Future work includes pGALS assessment of the hip and testing pGALS in further children with attenuated MPS type I. The use of pGALS and awareness of patterns of joint involvement may be a useful adjunct to facilitate earlier recognition of these rare conditions and ultimately access to specialist care.Pediatric Rheumatology 08/2014; 12(1):32. DOI:10.1186/1546-0096-12-32 · 1.61 Impact Factor
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- "HSCT is typically recommended for patients under 2 years of age with normal cognition (intelligence quotient >70) because early intervention increases the likelihood of maintaining cognitive abilities. For patients with Hurler–Scheie and Scheie syndromes, enzyme replacement therapy (ERT) with laronidase (recombinant human α-l-iduronidase; Aldurazyme) is the primary treatment option.6,7,8,9,10 Laronidase is administered weekly via intravenous infusion and is a lifelong therapy. "
ABSTRACT: Purpose: In this study, we aimed to describe the natural history of mucopolysaccharidosis I. Methods: Data from 1,046 patients who enrolled in the MPS I Registry as of August 2013 were available for descriptive analysis. Only data from untreated patients and data prior to treatment for patients who received treatment were considered. Age at symptom onset, diagnosis, and treatment initiation were examined by geographic region and phenotype (from most to least severe: Hurler, Hurler–Scheie, and Scheie). For each symptom, frequency and age at onset were examined. Results: Natural history data were available for 987 patients. Most patients were from Europe (45.5%), followed by North America (34.8%), Latin America (17.3%), and Asia Pacific (2.4%). Phenotype distribution was 60.9% for Hurler, 23.0% for Hurler–Scheie, and 12.9% for Scheie (3.2% undetermined) syndromes. Median age at symptom onset for Hurler, Hurler–Scheie, and Scheie syndromes was 6 months, 1.5 years, and 5.3 years, respectively; median age at treatment initiation was 1.5 years, 8.0 years, and 16.9 years, respectively. Coarse facial features and corneal clouding were among the most common symptoms in all three phenotypes. Conclusion: A delay between symptom onset and treatment exists, especially in patients with attenuated mucopolysaccharidosis I. A better understanding of disease manifestations may help facilitate prompt diagnosis and treatment and improve patient outcomes.Genetics in medicine: official journal of the American College of Medical Genetics 03/2014; 16(10). DOI:10.1038/gim.2014.25 · 7.33 Impact Factor
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- "The prevalence of corneal opacities increased in both groups, despite ERT. There is no consensus in the literature as to the effects of ERT on this clinical manifestation (Kakkis et al., 2001; Pitz et al., 2007; Sifuentes et al., 2007; Clarke et al., 2009). The increase in the reported rate of sleep apnea and hearing loss between T1 and T2 is probably attributable to improved follow-up of patients with MPS I, particularly in the ERT group, where this rate increase was clinically significant . "
ABSTRACT: Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder caused by deficiency of alpha-L-iduronidase. Few clinical trials have assessed the effect of enzyme replacement therapy (ERT) for this condition. We conducted an exploratory, open-label, non-randomized, multicenter cohort study of patients with MPS I. Data were collected from questionnaires completed by attending physicians at the time of diagnosis (T1; n = 34) and at a median time of 2.5 years later (T2; n = 24/34). The 24 patients for whom data were available at T2 were allocated into groups: A, no ERT (9 patients; median age at T1 = 36 months; 6 with severe phenotype); B, on ERT (15 patients; median age at T1 = 33 months; 4 with severe phenotype). For all variables in which there was no between-group difference at baseline, a delta of ≥ ± 20% was considered clinically relevant. The following clinically relevant differences were identified in group B in T2: lower rates of mortality and reported hospitalization for respiratory infection; lower frequency of hepatosplenomegaly; increased reported rates of obstructive sleep apnea syndrome and hearing loss; and stabilization of gibbus deformity. These changes could be due to the effect of ERT or of other therapies which have also been found more frequently in group B. Our findings suggest MPS I patients on ERT also receive a better overall care. ERT may have a positive effect on respiratory morbidity and overall mortality in patients with MPS I. Additional studies focusing on these outcomes and on other therapies should be performed.Genetics and Molecular Biology 03/2014; 37(1):23-9. DOI:10.1590/S1415-47572014000100006 · 1.20 Impact Factor