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Pompe disease: Design, methodology, and early findings from the Pompe Registry

Department of Pediatrics, University of Florida, College of Medicine, PO Box 100296, Gainesville, FL 32610, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.83). 03/2011; 103(1):1-11. DOI: 10.1016/j.ymgme.2011.02.004
Source: PubMed

ABSTRACT Pompe disease is an autosomal recessive, progressive, debilitating, and often fatal neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA). It is characterized by the accumulation of glycogen in muscle tissue that leads to progressive muscle weakness and loss of function. It presents as a broad spectrum of clinical phenotypes, with varying rates of progression, symptom onset, degree of organ involvement, and severity. The Pompe Registry represents worldwide data collection on this rare and clinically heterogeneous disease. This report describes the design, methodology, and early findings from the Registry and presents an overview of the Registry population over a five-year period from its inception in September 2004 through September 2009. Among the 742 patients from 28 countries in the Registry, 70% (517/742) reported symptom onset >12 months of age and 23% (170/742) reported symptom onset ≤12 months of age. Seventy-eight percent (582/742) of registry patients have received enzyme replacement therapy. Overall, Registry data appear to be consistent with smaller natural history studies in terms of symptoms and disease course in classical infantile Pompe disease (≤12 months of age with cardiomyopathy) and late-onset Pompe disease (>12 months of age). In addition, a subset of patients with symptom onset ≤12 months of age do not have cardiomyopathy (14.7%); these patients appear to have a later age at first symptoms and diagnosis than their peers with cardiomyopathy. As the largest dataset on Pompe disease to date, the Pompe Registry will serve to improve recognition of the disease, enhance understanding of the variable disease course, and offer insights into treated and untreated disease course.

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Available from: Suyash Prasad, Jul 08, 2015
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    • "Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is currently the only commercially available ameliorative therapy, however it is complicated by immune responses in severe early onset patients. Severely affected Pompe patients manifest symptoms as early as 1 month after birth with severe cardiomegaly, trouble feeding, poor muscle tone and respiratory distress [1], [2]. Without enzyme replacement, these patients do not survive beyond 2 years of age [3]. "
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    ABSTRACT: Enzyme replacement therapy (ERT) with recombinant human acid-α-glucosidase (rhGAA) is the only FDA approved therapy for Pompe disease. Without ERT, severely affected individuals (early onset) succumb to the disease within 2 years of life. A spectrum of disease severity and progression exists depending upon the type of mutation in the GAA gene (GAA), which in turn determines the amount of defective protein produced and its enzymatic activity. A large percent of the early onset patients are also cross reactive immunological material negative (CRIM-) and develop high titer immune responses to ERT with rhGAA. New insights from our studies in pre-clinical murine models reveal that the type of Gaa mutation has a profound effect on the immune responses mounted against ERT and the associated toxicities, including activation of clotting factors and disseminated intravascular coagulation (DIC). Additionally, the mouse strain affects outcomes, suggesting the influence of additional genetic components or modifiers. High doses of rhGAA (20 mg/kg) are currently required to achieve therapeutic benefit. Our studies indicate that lower enzyme doses reduce the antibody responses to rhGAA, reduce the incidence of immune toxicity and avoid ERT-associated anaphylaxis. Therefore, development of rhGAA with increased efficacy is warranted to limit immunotoxicities.
    PLoS ONE 06/2014; 9(6):e98336. DOI:10.1371/journal.pone.0098336 · 3.23 Impact Factor
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    • "Individuals carrying this allele can have a very low alpha-glucosidase activity, as low as fifty percent and can be difficult to distinguish from individuals with Pompe disease in newborn screening programs, but they do not manifest a Pompe disease phenotype (16, 19, 22, 23). Few other pathogenic sequence variations occur in certain populations with higher frequency than expected, but the large majority of mutations in the GAA gene are either unique or very rare (7). "
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    ABSTRACT: Glycogen-storage disease type II, also named Pompe disease, is caused by the deficiency of the enzyme acid alpha-glucosidase, which originates lysosomal glycogen accumulation leading to progressive neuromuscular damage. Early-onset Pompe disease shows a debilitating and frequently fulminating course. To date, more than 300 mutations have been described; the majority of them are unique to each affected individual. Most early-onset phenotypes are associated with frameshift mutations leading to a truncated alpha-glucosidase protein with loss of function. Founder effects are responsible from many cases from few highprevalence world regions. Herein we described two apparently unrelated cases affected with classical early-onset Pompe disease, both pertaining to a small region from Central Mexico (the State of San Luis Potosí), the same novel homozygous frameshift mutation at gene GAA (c.1987delC) was demonstrated in both cases. This GAA gene deletion implies a change of glutamine to serine at codon 663, and a new reading frame that ends after 33 base pairs, which leads to the translation of a truncated protein. This report contributes to widen the knowledge on the effect of pathogenic mutations in Pompe disease. Here we postulate the existence of a founder effect.
    Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases 10/2013; 32(2):95-99.
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    • "Thus, research relying on participant selection from single or small groups of clinics can be problematic. Based on the successful experiences of groups focusing on rare conditions such as cystic fibrosis (Morgan et al., 1999), Pompe disease (Byrne et al., 2011), and growth hormone deficiency (Pugeat, 2004), the CDC in collaboration with the SBA has designed a registry to collect prospective and longitudinal information on patients from multiple SB clinics across the United States. In the first years of the registry, a process was developed to collect valid data, and, as of 2011, 10 clinics have submitted data on more than 2000 patients. "
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    ABSTRACT: BACKGROUND: The purpose of this study was to describe the development and early implementation of a national spina bifida (SB) patient registry, the goal of which is to monitor the health status, clinical care, and outcomes of people with SB by collecting and analyzing patient data from comprehensive SB clinics. METHODS: Using a web-based, SB-specific electronic medical record, 10 SB clinics collected health-related information for patients diagnosed with myelomeningocele, lipomyelomeningocele, fatty filum, or meningocele. This information was compiled and de-identified for transmission to the Centers for Disease Control and Prevention (CDC) for quality control and analysis. RESULTS: A total of 2070 patients were enrolled from 2009 through 2011: 84.9% were younger than 18 years of age; 1095 were women; 64.2% were non-Hispanic white; 6.5% were non-Hispanic black or African American; and 24.2% were Hispanic or Latino. Myelomeningocele was the most common diagnosis (81.5%). CONCLUSIONS: The creation of a National Spina Bifida Patient Registry partnership between the CDC and SB clinics has been feasible. Through planned longitudinal data collection and the inclusion of additional clinics, the data generated by the registry will become more robust and representative of the population of patients attending SB clinics in the United States and will allow for the investigation of patient outcomes. Birth Defects Research (Part A), 2012. © 2012 Wiley Periodicals, Inc.
    Birth Defects Research Part A Clinical and Molecular Teratology 01/2013; 97(1). DOI:10.1002/bdra.23094 · 2.21 Impact Factor
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