Anthropometric data of 14 patients with mucopolysaccharidosis I: Retrospective analysis and efficacy of recombinant human α-l-iduronidase (laronidase)

doi:10.1016/j.ymgme.2009.08.008

Molecular Genetics and Metabolism

Volume 99, Issue 1, January 2010, Pages 10-17

https://doi.org/10.1016/j.ymgme.2009.08.008 Get rights and content

Abstract

Objectives: Our goal was to evaluate growth patterns in terms of body height, weight, head and chest circumference in patients with mucopolysaccharidosis type I (MPS I) without treatment and after enzyme replacement therapy (ERT) with α-l-iduronidase (laronidase). Patients and methods: Anthropometric features of 14 patients with MPS I were followed from birth until the introduction of ERT (group 1–1st year of life, group 2 ⩾3rd year of life), after 52–260 weeks of ERT and periodically during treatment. The data since birth until beginning of treatment was obtained by retrospective review of patients’ charts. Patients received intravenous laronidase at 100 U/kg (0.58 mg/kg) weekly for 52–260 weeks. Results: Patients from group 1 (n = 7) and group 2 (n = 7) had similar characteristics at the time of birth but showed significant difference when compared with healthy population. Growth patterns were associated significantly with the MPS I at birth. After 96–260 weeks of ERT, patients receiving laronidase (group 1) compared with group 2 did not show statistically significant improvement. Conclusions: Anthropometric features of patients with MPS I significantly differ from the healthy population. Children with MPS I grew considerably slower, and differences between healthy and affected children increased with age. In studied patients with MPS I, laronidase did not appear to alter the growth patterns.

Introduction

The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders attributable to defective catabolism of glycosaminoglycans (GAGs), leading to severe joint and bone disease [1]. As glycosaminoglycans accumulate within the lysosomes, progressive organ dysfunction and widespread tissue damage results [1]. Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of the enzyme α-l-iduronidase (IDUA; EC 3.2.1.76) [1]. MPS I has a wide spectrum of clinical severity and three different clinical phenotypes have been described, each representing different degrees of disease severity within a continuous spectrum: Hurler syndrome (severe, OMIM 607016), Hurler–Scheie syndrome (intermediate, OMIM 607015), and Scheie syndrome (attenuated, OMIM 607016) [1], [2], [3].

MPS I leads to profound disruption in the normal mechanism of growth and development. A major feature of this disorder is abnormal bone and cartilage development leading to anterior hypoplasia of lumbar vertebrae, enlarged diaphyses of long bones, underdeveloped epiphyseal centers, marked dwarfism and degenerative joint disease [1]. These abnormalities arise from a lack of skeletal remodelling, disordered endochondral and intramembranous ossification, disruption of normal elastogenesis and the infiltration by GAGs [4], [5]. It has been shown that inflammation, secondary to GAG accumulation, is a critical aspect of MPS disorder and contributes to the bone disease [6].

Currently, both hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) using laronidase (recombinant human α-l-iduronidase, Aldurazyme) are available for MPS I. ERT has been shown to be effective in ameliorating some of the clinical manifestation of MPS disease. Among positive effects are decreased hepatosplenomegaly, improved respiratory function and physical capacity [2], [7]. However, long-term effect of ERT on the natural history of growth patterns is less clear and there are no studies dealing exclusively with detailed anthropometric features after treatment with ERT. Moreover, in none of the previous studies adequate anthropometric measuring techniques were applied and performed by the same anthropology specialist.

The objective of this study was to analyze the general growth patterns (body height, weight, head and chest circumference) in 14 patients with MPS I with respect to standards from a general population and to assess differences in anthropometric features both retrospectively since birth until introduction of ERT as well as after 52–260 weeks of treatment with laronidase (Aldurazyme).

Section snippets

Study design

The study objectives were as follows:

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To evaluate growth patterns in terms of body height, weight, head and chest circumference in patients with MPS I without treatment since birth until introduction of ERT.
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To evaluate the effectiveness of laronidase (Aldurazyme, BioMarin Pharmaceutical Inc., Novato, Calif and Genzyme Corporation, Cambridge, Mass) on anthropometric features such as height, weight, head and chest circumference in patients with MPS I.

All patients were enrolled at The Children’s

Patients

Fourteen patients (patients 1–14, Table 1) were born at term and received a diagnosis of MPS I at a mean age of 2.1 years (ranging from 5 months to 7 years, median 1.25 years). They began ERT with laronidase at a mean age of 4.8 years (range from 1 to 15 years, median 4 years). Out of 14 patients, 7 were 1-year-old (group 1) and 7 were 3 years of age or older (between 3–15 years, median 7 years, group 2) at the time of introduction of ERT. All were Caucasian and the majority was male (78.6%). Nine

Discussion

There is a scarcity of literature reporting detailed anthropometric data of both untreated children with MPS I as well as children on ERT. Most studies addressing anthropometric features focused only on growth and weight rates [13], [14], [15], [16]. Kakkis et al. reported that the rate of growth in height and weight had increased by a mean of 85% and 131%, respectively, at 52 weeks in six prepubertal children [13]. In another study, Wraith et al. reported seven study patients who showed a net

Conclusion

Our data show that anthropometric features of patients with MPS I significantly differ from healthy population. Children with MPS I grew considerably slower, and differences between healthy and affected children increased with age. In the MPS I patients studied, laronidase did not appear to alter the growth patterns. No apparent difference was observed between the growth rates in treated patients and the untreated disease. New approaches for the management and treatment of MPS disorders may be

Acknowledgments

The authors acknowledge the contribution of the study patients and their families who gave their time and participated in this study. We also thank all study personnel.

References (26)

A. Hinek et al.
Impaired elastogenesis in Hurler disease. Dermatan sulfate accumulation linked to deficiency in elastin-binding protein and elastic fiber assembly
Am. J. Pathol.
(2000)
C.M. Simonaro et al.
Mechanism of glycosaminoglycan-mediated bone and joint disease: implications for the mucopolysaccharidoses and other connective tissue diseases
Am. J. Pathol.
(2008)
J.E. Wraith et al.
Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human α-l-iduronidase (laronidase)
J. Pediatr.
(2004)
G.M. Pastores et al.
The MPS I registry: design, methodology, and early findings of a global disease registry for monitoring patients with mucopolysaccharidosis type I
Mol. Genet. Metab.
(2007)
N.J. Terlato et al.
Can mucopolysaccharidosis type I disease severity be predicted based on a patient’s genotype? A comprehensive review of the literature
Genet. Med.
(2003)
M. Sifuentes et al.
A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years
Mol. Genet. Metab.
(2007)
R.W. Norrdin et al.
Characterization of osteopenia in feline mucopolysaccharidosis VI and evaluation of bone marrow transplantation therapy
Bone
(1993)
E.F. Neufeld et al.
The mucopolysaccharidoses
L.A. Clarke et al.
Long term efficacy and safety of laronidase in the treatment of mucopolysaccharidoses I
Pediatrics
(2009)
M. Roubicek et al.
The clinical spectrum of a-l-iduronidase deficiency
Am. J. Med. Genet.
(1985)

G.M. Pastores et al.

Musculoskeletal complications associated with lysosomal storage disorders: Gaucher disease and Hurler–Scheie syndrome (mucopolysaccharidosis type I)

Curr. Opin. Rheum.

(2005)

C.A. Pennock

A review and selection of simple laboratory methods used for the study of glycosaminoglycans excretion and the diagnosis of mucopolysaccharidoses

J. Chem. Pathol.

(1976)

A. Malinowski, Dziecko poznanskie. Normy i metody kontroli rozwoju fizycznego. Seria antropologia, third ed., Poznan,...

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Delayed development of ossification centers in the tibia of prenatal and early postnatal MPS VII mice
2018, Molecular Genetics and Metabolism
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Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are clinically approved therapies for MPS patients. Although a small increase in growth velocity is observed in some MPS I, II and VI patients post HSCT or as a result of ERT [9–14], the long term benefit is limited [15–22]. The majority of bones in the human skeleton are formed by the process of endochondral ossification (EO) in which a cartilage template is replaced by bone.
Short stature is a characteristic feature of most of the mucopolysaccharidoses, a group of inherited lysosomal storage disorders caused by a single enzyme deficiency. MPS patients present with progressive skeletal defects from an early age, including short stature due to impaired cartilage-to-bone conversion (endochondral ossification). The aim of this study was to determine which murine MPS model best reproduces the bone length reduction phenotype of human MPS and use this model to determine the earliest developmental stage when disrupted endochondral ossification first appears. Gus^mps/mps mice representing severe MPS VII displayed the greatest reduction in bone elongation and were chosen for histopathological analysis. Tibial development was assessed from E12.5 to 6 months of age. Chondrocytes in the region of the future primary ossification center became hypertrophic at a similar age to normal in the MPS VII mouse fetus, but a delay in bone deposition was observed with an approximate 1 day delay in the formation of the primary ossification centre. Likewise, chondrocytes in the region of the future secondary ossification center also became hypertrophic at the same age as normal in the MPS VII early postnatal mouse. Bone deposition in the secondary ossification centre was delayed by two days in the MPS VII proximal tibia (observed at postnatal day 14 (P14) compared to P12 in normal). The thickness of the tibial growth plate was larger in MPS VII mice from P9 onwards. Abnormal endochondral ossification starts in utero in MPS VII and worsens with age. It is characterized by a normal timeframe for chondrocyte hypertrophy but a delay in the subsequent deposition of bone in both the primary and secondary ossification centres, accompanied by an increase in growth plate thickness. This suggests that the signals for vascular invasion and bone deposition, some of which are derived from hypertrophic chondrocytes, are altered in MPS VII.
Outcomes of Long-Term Treatment with Laronidase in Patients with Mucopolysaccharidosis Type I
2016, Journal of Pediatrics
Citation Excerpt :
Results of this study are similar to previously reported short-term outcomes and demonstrate that laronidase reduces GAG storage4,6,8,12,15,21-26 and may stabilize or improve respiratory function,4,6,12,15,24,26 growth,6,15,21,24 mobility,4,12,15,22,24 some cardiac manifestations,6,12,15,24,25 corneal clouding,6,12 and visual acuity.6,12,14,15 This study suggests that treatment effectiveness persisted for up to 10 years; however, as shown in previous studies, treatment may not prevent deterioration in all patients.6,7,12,27 Although GAG clearance may be a biomarker of treatment response, irreversible damage secondary to GAG-induced inflammatory responses may occur.
To evaluate long-term outcomes of laronidase enzyme replacement therapy in patients with attenuated mucopolysaccharidosis type I.
Retrospective analyses of case notes, laboratory results, and data from clinical trials were used to evaluate urinary glycosaminoglycans, forced vital capacity (FVC), 6-minute walk test (6MWT), height-for-age Z score, cardiac valve function, corneal clouding, and visual acuity in 35 patients with attenuated mucopolysaccharidosis type I (Hurler-Scheie and Scheie syndromes) for up to 10 years following the initiation of laronidase therapy.
Statistically significant (P < .001) reductions in mean urinary glycosaminoglycan levels relative to baseline were observed 6 months after treatment initiation and were sustained throughout follow-up. Disease remained stable after treatment initiation with no statistically significant changes in mean FVC, 6MWT, or height-for-age Z score. At last assessments, mitral and aortic valve function remained stable in 65% (22/34) of patients; corneal clouding remained stable in 78% (18/23); visual acuity remained stable in 33% (8/24) and improved in 42% (10/24) of patients. Younger patients (<10 years at treatment initiation) maintained disease measures closer to norms for age for FVC, 6MWT, and height and showed fewer deteriorations in mitral and aortic valve disease and corneal clouding compared with patients aged ≥10 years at treatment initiation.
Laronidase treatment resulted in disease stabilization in the majority of patients with a mean follow-up of 6.1 years. Data suggest that early treatment may result in better outcomes.
Can Macrosomia or Large for Gestational Age Be Predictive of Mucopolysaccharidosis Type I, II and VI?
2016, Pediatrics and Neonatology
Citation Excerpt :
GAG storage in MPS induces a complex sequence of molecular abnormalities leading to inflammation, apoptosis (cartilage), and hyperplasia (synovial membranes), resulting in poorly organized and metabolically abnormal connective tissue matrices.7,9–11 In our previous studies, we evaluated and compared growth patterns in patients with MPS I (n = 14) and MPS II (n = 28).12–14 In this study, which deals exclusively with birth parameters, additional data as well as MPS VI patients were added to compare birth body length and weight between MPS I, II, VI, and the general population.
The objective of the study was to compare mean values for birth body length and weight between patients with mucopolysaccharidosis (MPS) and the general population.
A retrospective analysis of birth anthropometric data was performed for patients (n = 103) with MPS I, II, and VI. Two-tailed t tests were used to compare mean values for body length and weight at birth between patients with MPS and the general population.
Mean values for birth body length and weight for all studied groups were greater than in the general population. For body length the differences were statistically significant. When considered individually, 53% of patients were large for gestational age (LGA) and 30% were macrosomic. The highest percentage of LGA was observed in MPS II males and MPS VI females (55% and 56%, respectively), while the highest percentage of macrosomia was observed in MPS VI males (36%).
At the time of birth, MPS patients were larger than those in the general population. High birth weight and/or LGA can be suggestive of MPS disease and should raise suspicion aiding early disease recognition.
Osteoimmunology in mucopolysaccharidoses type I, II, VI and VII. Immunological regulation of the osteoarticular system in the course ofmetabolic inflammation
2013, Osteoarthritis and Cartilage
Citation Excerpt :
The anthropometric features of patients and the body proportions with all types of MPS are significantly different from the healthy population and differences increase with age. Growth retardation might be minor in patients with attenuated forms of the disease39–41. Similarly, in animals with MPS VI impairment in longitudinal bone growth and vertebral body growth compared to controls was observed42,43.
Mucopolysaccharidoses (MPSs) are rare genetic diseases caused by a deficient activity of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. These metabolic blocks lead to the accumulation of GAGs in various organs and tissues, resulting in a multisystemic clinical picture. The pathological GAG accumulation begins a cascade of interrelated responses: metabolic, inflammatory and immunological with systemic effects. Metabolic inflammation, secondary to GAG storage, is a significant cause of osteoarticular symptoms in MPS disorders.
The aim of this review is to present recent progress in the understanding of the role of inflammatory and immune processes in the pathophysiology of osteoarticular symptoms in MPS disorders and potential therapeutic interventions based on published reports in MPS patients and studies in animal models.
The immune and skeletal systems have a number of shared regulatory molecules and many relationships between bone disorders and aberrant immune responses in MPS can be explained by osteoimmunology. The treatment options currently available are not sufficiently effective in the prevention, inhibition and treatment of osteoarticular symptoms in MPS disease. A lot can be learnt from interactions between skeletal and immune systems in autoimmune diseases such as rheumatoid arthritis (RA) and similarities between RA and MPS point to the possibility of using the experience with RA in the treatment of MPS in the future. The use of different anti-inflammatory drugs requires further study, but it seems to be an important direction for new therapeutic options for MPS patients.
Enzyme replacement therapy in an attenuated case of mucopolysaccharidosis type i (scheie syndrome): A 6.5-year detailed follow-up
2012, Pediatric Neurology
We present the 6.5-year follow-up of a boy with Scheie syndrome whose therapy was initiated at age 2.5 years. Detailed anthropometric features, echocardiography, ophthalmologic and audiologic examinations, psychologic tests, joint range of motion, skeletal radiographs, ultrasound studies of liver and spleen volumes, urinary glycosaminoglycans, and antibodies were documented. After 6.5 years of enzyme replacement therapy, the patient experienced a decline in overall status, and the disease progressed significantly despite treatment. The patient’s height at age 9 was equal to that at age 6. The patient developed heart insufficiency and a deterioration of airway flow. The patient’s intelligence quotient remained unchanged, i.e., at the average level of 86 on the Terman-Merill Scale. Magnetic resonance imaging revealed cervical spinal canal stenosis and marked spinal cord compression with myelopathy. A worsening of carpal tunnel syndrome was also evident. Ophthalmologic evaluation revealed increased central corneal thickness and intraocular pressure. In audiologic assessment, the patient’s results were similar to those after 3 years of treatment. The only benefit involved temporarily improved passive and active shoulder flexion. Overall, the benefit of enzyme replacement therapy with laronidase on Scheie syndrome appeared minimal.
Skeletal response to lentiviral mediated gene therapy in a mouse model of MPS VII
2012, Molecular Genetics and Metabolism
Mucopolysaccharidosis VII (MPS VII) is an autosomal recessive, lysosomal storage disorder caused by β-glucuronidase (GUSB) deficiency, resulting in the accumulation of glycosaminoglycans (GAGs), in a variety of cell types. Severe, progressive skeletal pathology, termed dysostosis multiplex, is a prominent clinical feature of MPS VII. We have evaluated a gene therapy protocol for its efficacy in preventing the development and progression of bone pathology in MPS VII mice treated with a lentiviral vector at birth or at 7 weeks. Two weeks after injections, high levels of vector expression were observed in liver, spleen and bone marrow and to a lesser extent in kidney, lung and heart. Widespread clearance of GAG storage was observed in somatic tissues of both groups and some clearance of neuronal storage was observed in mice treated from birth. Micro-CT analysis demonstrated a significant decrease in vertebral and femoral bone mineral volume, trabecular number, bone surface density and cortical bone thickness in both treatment groups. Lumbar and femoral bone lengths were significantly decreased in untreated MPS VII mice, while growth plate heights were increased and these parameters did not change upon treatment. Small improvements in performance in the open field and rotarod behaviour tests were noted. Overall, systemic lentiviral-mediated gene therapy results in a measurable improvement in parameters of bone mass and architecture as well as biochemical and enzymatic correction. Conversely, growth plate chondrocytes were not responsive to treatment, as evidenced by the lack of improvement in vertebral and femoral bone length and growth plate height.

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Anthropometric data of 14 patients with mucopolysaccharidosis I: Retrospective analysis and efficacy of recombinant human α-l-iduronidase (laronidase)

Abstract

Introduction

Section snippets

Study design

Patients

Discussion

Conclusion

Acknowledgments

Am. J. Pathol.

Am. J. Pathol.

J. Pediatr.

Mol. Genet. Metab.

Genet. Med.

Mol. Genet. Metab.

Bone

The mucopolysaccharidoses

Long term efficacy and safety of laronidase in the treatment of mucopolysaccharidoses I

Pediatrics

The clinical spectrum of a-l-iduronidase deficiency

Am. J. Med. Genet.

Musculoskeletal complications associated with lysosomal storage disorders: Gaucher disease and Hurler–Scheie syndrome (mucopolysaccharidosis type I)

Curr. Opin. Rheum.

A review and selection of simple laboratory methods used for the study of glycosaminoglycans excretion and the diagnosis of mucopolysaccharidoses

J. Chem. Pathol.