The MPS I registry: Design, methodology, and early findings of a global disease registry for monitoring patients with Mucopolysaccharidosis Type I

doi:10.1016/j.ymgme.2007.01.011

Molecular Genetics and Metabolism

Volume 91, Issue 1, May 2007, Pages 37-47

https://doi.org/10.1016/j.ymgme.2007.01.011 Get rights and content

Abstract

A global, observational disease registry has been established to characterize the course of disease and track clinical outcomes in patients with Mucopolysaccharidosis Type I (MPS I), a rare and treatable lysosomal storage disorder. This report outlines procedures for data collection and presents the recommended minimum schedule of assessments that comprise the disease-specific clinical and laboratory parameters that are tracked in the database. Aggregate data are summarized for the first 302 patients enrolled, representing entries from 24 countries. The median current age of the patients is 9.0 years (range: 0.4–64.8). Syndrome diagnoses include 47% Hurler (severe form), 25% Hurler–Scheie (attenuated form with an intermediate phenotype), 13% Scheie (most attenuated form), and 15% unknown. Younger ages at symptom onset and disease diagnosis are associated with the severe Hurler syndrome, but there is overlap among syndromes. Diagnosis was delayed by years to decades in several patients with Hurler–Scheie and Scheie syndromes. Patients with symptom onset before age 5 are more likely to have a gibbus, cognitive impairment, and pneumonia, whereas patients with symptom onset above age 5 are more likely to have carpal tunnel syndrome, myelopathy, and glaucoma. Cardiac valve abnormalities, joint contractures, corneal clouding, and hernia are reported by over 70% of patients regardless of the age of symptom onset. Approximately 80% of the patients have received enzyme replacement therapy, hematopoietic stem cell transplantation, or both. Overall, the MPS I Registry database contains a broad sample of the global patient population, providing a potentially useful tool for expanding knowledge of MPS I and facilitating evidence-based decisions about the optimal means of monitoring and treating affected individuals.

Section snippets

Overview of the MPS I registry program

The MPS I Registry (www.MPSIregistry.com) is a voluntary program designed to collect data from routine clinical and laboratory assessments related to the onset, progression, and outcomes of MPS I disease among the global patient population for a period of at least 15 years. Only observational data are acquired; no experimental interventions are involved. All patient and physician information entered into the MPS I Registry database remains confidential in compliance with international

Patient enrollment and physician participation

The MPS I Registry program was launched in June 2003, and patient enrollment began in October 2003. Data presented in this report are derived from the first 302 patients enrolled; for all patients, the diagnosis of MPS I was confirmed by enzyme assay or mutation analysis. Table 3 lists the 24 countries of origin for the patients, with the majority residing in North American and European countries. The patients were enrolled by 84 physicians, most of whom specialize in the fields of pediatrics

Discussion

The MPS I Registry has emerged as the largest computerized database for monitoring the clinical progression of MPS I disease worldwide. As demonstrated by this overview of the first 302 patients enrolled in the Registry, the design and methodology of the program have enabled acquisition of a population sample that is diverse in its composition and representative of the heterogeneous nature of MPS I. Furthermore, the first descriptive and cross-sectional analyses of this patient sample have

Acknowledgments

The MPSI Registry is funded by the BioMarin/Genzyme LLC. The paper is dedicated to the memory of Dr. William Krivit, a pioneer in the field who made significant contributions to advancing the care of patients with MPS I.

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Cited by (156)

The importance of skeletal x-ray screening for dysostosis multiplex in the early diagnosis of mucopolysaccharidosis
2024, Clinical Imaging
Our aim is the early detection of mucopolysaccharidosis (MPS) by examining the radiographs taken for reasons other than a metabolic disease, such as infection, trauma, and short stature.
The radiographs of children who applied to outpatient and emergency clinics in our hospital between 01/01/2022 and 31/12/2022 were examined by a pediatric radiologist retrospectively without knowledge of patient information. The MPS enzyme panel and urine glycosaminoglycan analysis were performed in patients having dysostosis multiplex on radiographs. In cases with MPS detected by enzyme and urine analysis, the definitive diagnosis was confirmed by genetic analysis.
Skeletal radiographs of 15.104 cases admitted to our hospital were examined (11,270 chest x-ray, 314 lumbosacral spine x-ray, 2970 hand x-ray, 253 pelvis x-ray, 162 skull x-ray, and 135 complete skeletal surveys). In 67 children, dysostosis multiplex was observed in the skeletal X-ray. Among them, seven newly diagnosed MPS cases were detected. Three cases were diagnosed with MPS type 4A, two with MPS type 6, one with MPS type 2 and one with MPS type 3B. Age at diagnosis was 46.2 ± 30.6 months (range; 20–111 months). There was a history of consanguinity in 6 (85.7%) cases.
Radiographs can provide clues for diagnosing MPS before the clinical findings become prominent in children admitted to the hospital for other complaints. Therefore, X-ray screening can be performed on children in endemic regions of MPS to search for dysostosis multiplex.
Metabolic diseases
2023, Translational Glycobiology in Human Health and Disease
Both disorders of carbohydrate metabolism and lysosomal storage diseases affect important energetic and degradation pathways, causing various manifestations on a broad spectrum of severity. This chapter will discuss first disorders of carbohydrate metabolism, including disorders of galactose metabolism (such as classic galactosemia), disorders of fructose metabolism (e.g., hereditary fructose intolerance), glycogen storage diseases, other disorders of gluconeogenesis and glycolysis (e.g., triose phosphate isomerase deficiency), disorders of glucose transport (e.g., GLUT1 deficiency), and disorders of the pentose phosphate pathway (e.g., transaldolase deficiency). Subsequently, we discuss lysosomal storage diseases involving complex carbohydrates, mainly mucopolysaccharidoses and oligosaccharidoses. We will focus on the core elements of pathophysiology, clinical manifestations, diagnosis, and treatment for many of these conditions.
Identification of a novel fusion Iduronidase with improved activity in the cardiovascular system
2022, Molecular Genetics and Metabolism Reports
Lysosomal diseases are a group of over 70 rare genetic conditions in which a protein deficiency (most often an enzyme deficiency) leads to multi-system disease. Current therapies for lysosomal diseases are limited in their ability to treat certain tissues that are major contributors to morbidity and mortality, such as the central nervous system (CNS) and cardiac valves. For this study, the lysosomal disease mucopolysaccharidosis type I (MPS I) was selected as the disease model. In MPS I, mutations in the IDUA gene cause a deficiency of the α-L-iduronidase (IDUA) enzyme activity, leading to disease pathology in tissues throughout the body, including the CNS and cardiac valves. Current therapies have been unable to prevent neurodevelopmental deficits and cardiac valvular disease in patients with MPS I. This study aimed to evaluate the delivery of IDUA enzyme, via a novel gene therapy construct, to target tissues.
MPS I mice were hydrodynamically injected through the tail vein with plasmids containing either a codon-optimized cDNA encoding the wild-type IDUA protein or one of four modified IDUAs under the control of the liver-specific human α1-antitrypsin (hAAT) promoter. Two modified IDUAs contained a ligand for the CB1 receptor, which is a highly expressed receptor in the CNS. Iduronidase activity levels were measured in the tissues and plasma using an enzyme activity assay.
The modified IDUAs did not appear to have improved activity levels in the brain compared with the unmodified IDUA. However, one modified IDUA exhibited higher activity levels than the unmodified IDUA in the heart (p = 0.0211). This modified iduronidase (LT-IDUA) contained a sequence for a six amino acid peptide termed LT. LT-IDUA was further characterized using a noncompartmental pharmacokinetic approach that directly analyzed enzyme activity levels after gene delivery. LT-IDUA had a 2-fold higher area under the curve (AUC) than the unmodified IDUA (p = 0.0034) when AUC was estimated using enzyme activity levels in the plasma.
The addition of a six amino acid peptide improved iduronidase's activity levels in the heart and plasma. The short length of this LT peptide facilitates its use as fusion enzymes encoded as gene therapy or administered as enzyme replacement therapy. More broadly, the LT peptide may aid in developing therapies for numerous lysosomal diseases.
Quantifying medical manifestations in Hurler syndrome with the infant physical symptom score: associations with long-term physical and adaptive outcomes
2022, Molecular Genetics and Metabolism
A physical symptom score (PSS) for the mucopolysaccharidosis (MPS) disorders has been developed to quantitate the somatic burden of disease across multiple organ systems. Studies have demonstrated the sensitivity and its relationship to age, IQ and adaptive functioning of the PSS in older children. With the onset of newborn screening, there is an increased need to characterize the somatic symptoms in the earliest stages of life, especially for young children under 36 months of age. Consequently, a new scale, Infant Physical Symptom Score (IPSS), was developed to score physical symptoms in infants and toddlers.
Part I. To create a measure to quantify somatic burden in patients with MPS disorders under 36 months of age. The IPSS assess outcomes and changes in somatic disease in individuals with MPS disorders diagnosed very early in life.
Part II. To determine the relationship between IPSS and other measures to evaluate its validity and utility, a) we evaluated the relationship between the IPSS and PSS in the same patients with MPS I over time to determine if the two scales are measuring the same concepts, and b) we evaluated the association between IPSS and a functional adaptive measure over time with a focus on the age at first treatment (under 36 months) to determine if the IPSS has predictive value.
Part I. The Infant Physical Symptom Score (IPSS) for the infant population in MPS disorders was established using data from 39 patients enrolled in the Lysosomal Disease Network longitudinal MPS I study (U54NS065768). All of these patients had Hurler syndrome (MPS IH) and underwent hematopoietic stem cell transplant (HSCT) at the University of Minnesota. Items for the IPSS were selected by reviewing CRFs prepared for the MPS I longitudinal study and examining medical records of these patients prior to HSCT based on the knowledge gained from the development of the PSS.
Part II. Of those 39 patients, a subset of 19 were all seen 9 to 12 years post HSCT. Having retrospectively calculated their IPSS prior to HSCT, we categorized them by age at HSCT, and examined their most recent PSS along with Composite and Daily Living Skills scores on the Vineland Adaptive Behavior Scales – Second Edition (VABS-II).
The total score on the IPSS collected prior to transplant differed by patient's age at transplant, as expected in this progressive condition. Those transplanted at ≤12 months of age had a mean score of 7.4, which was significantly lower, suggesting less somatic disease burden, compared to those transplanted at >12 to ≤24 months (mean 11.8) and > 24 to ≤36 months (mean 13.6). Higher IPSS reflects more evidence of somatic disease burden and lower IPSS reflects less evidence of disease burden. Nine to 12 years later, the severity level as measured by the PSS was comparable to severity on the IPSS suggesting that the two scales are measuring similar concepts. Retrospectively calculated pre-transplant IPSS were negatively associated with higher VABS-II Composite scores 9–12 years later (p value-0.015) and to a lesser extent Daily Living Skills scores (p value-0.081). We conclude that the IPSS appears to be a useful approach to quantifying the somatic disease burden of MPS IH patients under 36 months of age.
Quantitative brain MRI morphology in severe and attenuated forms of mucopolysaccharidosis type I
2022, Molecular Genetics and Metabolism
Citation Excerpt :
Individuals with the same enzymatic deficiency, but the later onset of clinical symptoms, are diagnosed with Scheie (mild) and Hurler-Scheie (intermediate) syndromes. As no biochemical differences have been found and clinical manifestations in Scheie and Hurler-Scheie syndromes overlap, both are referred to collectively as MPS I attenuated (MPS IA) [5,18]. Intravenous recombinant enzyme replacement therapy (ERT) is the standard of care for patients with MPS IA, as it improves somatic aspects of the disease [19].
To assess our hypothesis that brain macrostructure is different in individuals with mucopolysaccharidosis type I (MPS I) and healthy controls (HC), we conducted a comprehensive multicenter study using a uniform quantitative magnetic resonance imaging (qMRI) protocol, with analyses that account for the effects of disease phenotype, age, and cognition.
Brain MRIs in 23 individuals with attenuated (MPS IA) and 38 with severe MPS I (MPS IH), aged 4–25 years, enrolled under the study protocol NCT01870375, were compared to 98 healthy controls.
Cortical and subcortical gray matter, white matter, corpus callosum, ventricular and choroid plexus volumes in MPS I significantly differed from HC. Thicker cortex, lower white matter and corpus callosum volumes were already present at the youngest MPS I participants aged 4–5 years. Age-related differences were observed in both MPS I groups, but most markedly in MPS IH, particularly in cortical gray matter metrics. IQ scores were inversely associated with ventricular volume in both MPS I groups and were positively associated with cortical thickness only in MPS IA.
Quantitatively-derived MRI measures distinguished MPS I participants from HC as well as severe from attenuated forms. Age-related neurodevelopmental trajectories in both MPS I forms differed from HC. The extent to which brain structure is altered by disease, potentially spared by treatment, and how it relates to neurocognitive dysfunction needs further exploration.
Mucopolysaccharidosis Type I Diagnosed by Aortic and Mitral Valve Replacement
2021, JACC: Case Reports
Citation Excerpt :
Classic MPS type I, also called Hurler syndrome, is particularly severe, often causing death in untreated patients before their teenage years (2). Scheie syndrome is a milder form of MPS type I characterized by central nervous system (CNS) sparing with primarily peripheral involvement, often leading to later diagnoses and longer life spans (2). Our patient’s genetic profile may explain his unique phenotype and longevity.

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View full text

The MPS I registry: Design, methodology, and early findings of a global disease registry for monitoring patients with Mucopolysaccharidosis Type I

Abstract

Section snippets

Overview of the MPS I registry program

Patient enrollment and physician participation

Discussion

Acknowledgments

Genet. Med.

Blood

Blood

J. Pediatr.

J. Pediatr.

Am. J. Med.

J. Pediatr.

Semin. Hematol.

Semin. Hematol.

Comparison of outcomes research with clinical trials using preexisting data

Am. J. Cardiol.

Bridging regional and global perspectives

Horm. Res.

The mucopolysaccharidoses

Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications

Hum. Mutat.

Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations

Hum. Genet.