Enzyme replacement therapy in severe adult-onset glycogen storage disease type II (original) (raw)
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Progress in enzyme replacement therapy in glycogen storage disease type II
Glycogen storage disease type II (GSDII) is an autosomal recessive lysosomal disorder caused by mutations in the gene encoding alpha-glucosidase (GAA). The disease can be clinically classified into three types: a severe infantile form, a juvenile and an adult-onset form. Cases with juvenile or adult onset GSDII mimic limb-girdle muscular dystrophy or polymyositis and are often characterized by respiratory involvement. GSDII patients are diagnosed by biochemical assay and by molecular characterization of the GAA gene. Ascertaining a natural history of patients with heterogeneous late-onset GSDII is useful for evaluating their progressive functional disability. A significant decline is observed over the years in skeletal and respiratory muscle function. Enzyme replacement therapy (ERT) has provided encouraging results in the infantile form. It is not yet known if ERT is effective in late-onset GSDII. We examined a series of 11 patients before and after ERT evaluating muscle strength by MRC, timed and graded functional tests, 6-minute walk test (6MWT), respiratory function by spirometric parameters and quality of life. We observed a partial improvement during a prolonged follow-up from 3 to 18 months. The use of different clinical parameters in the proposed protocol seems crucial to determine the efficacy of ERT, since not all late-onset patients respond similarly to ERT.
Journal of Inherited Metabolic Disease, 2012
We examined the efficacy of 2-year enzyme replacement therapy (ERT) using recombinant human αglucosidase (GAA; Myozyme®) in five long-term ventilatordependent adults and aged patients with advanced, late-onset glycogen storage disease type II (GSDII, also known as Pompe disease). Although all patients had advanced respiratory failure and were ventilator-dependent for more than 6 years, four showed obvious improvements in muscle strength, pulmonary function, and activities of daily living after ERT. Improvement in each parameter was more prominent in the first year than in the second year. Values in the second year were still significantly better than those at study entry and indicate stabilization in the clinical status of all patients. These results suggest that ERT continues to be effective in the second year of treatment even in patients suffering from advanced late-onset GSDII disease with severe respiratory failure.
Journal of Inherited Metabolic Disease, 2010
Objectives Type II glycogenosis (GSDII) is a lysosomal storage disorder due to acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase (rhGAA) has been demonstrated to be effective in the treatment of infantile forms of GSDII, but little information is available concerning late-onset phenotypes. Long-term follow-up studies are not available at present. The aim of this study was to evaluate the ERT long-term effects in late-onset GSDII.
Journal of Neurology, 2012
The objective of this study was to describe a large Italian cohort of patients with late-onset glycogen storage disease type 2 (GSDII) at various stages of disease progression and to evaluate the clinical effectiveness of alglucosidase alpha enzyme replacement therapy (ERT). Previous studies showed in late-onset patients ERT efficacy against placebo and variable response in uncontrolled studies. Seventy-four juvenile or adult GSDII patients were treated with ERT in a multicenter open label, non-randomized study, from 12 months up to 54 months. Recombinant human alpha glucosidase (rh-GAA) was injected by intravenous route at 20 mg/kg every second week. Patients were divided into three groups according to ERT duration: Group A received treatment for 12-23 months (n = 16), Group B for 24-35 months (n = 14), and Group C for more than C. Angelini, T. Mongini, A. Toscano: Coordinators of the Italian Group on GSDII.
Molecular Genetics and Metabolism, 2013
This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Brief Communication Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for glycogen storage disease type III
Human Mutation, 2004
Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid a-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid a-glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid a-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease.
Paediatrics and Child Health, 2011
Glycogen storage disorders are a group of inborn errors of metabolism characterized by accumulation of glycogen in various tissues. This accumulation is the histological hallmark of these disorders although the phenotype shows variable overlap. Hepatomegaly, hypoglycaemia, elevated lactate and urate with or without neutrophil dysfunction are the classical presentations for the commonest disorders namely GSD types I a, 1b and III. Elevated creatine kinase, weakness, hypertrophic cardiomyopathy with or without rhabdomyolysis represent the commonest muscle subtypes with the best known ones being GSD II, III and V. Control of glucose deficiency by added calories, tube feeding or modified cornstarch is frequently the main basis of treatment. Supportive therapies are needed to establish near normality. Potential curative therapies are enzyme replacement therapies by mode of liver transplantation, bone marrow transplantation or use of recombinant enzyme. Keywords bone marrow transplantation; cornstarch; enzyme replacement therapy; GSD or glycogen storage disease; hypertrophic cardiomyopathy; inborn error of glycogen metabolism; liver transplantation; rhabdomyolysis SYMPOSIUM: INBORN ERRORS OF METABOLISM PAEDIATRICS AND CHILD HEALTH 21:2 84
Long term longitudinal study of muscle function in patients with glycogen storage disease type IIIa
Molecular Genetics and Metabolism, 2017
Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme. Current therapy is based on dietary adaptations but new preclinical therapies are emerging. The identification of outcome measures which are sensitive to disease progression becomes critical to assess the efficacy of new treatments in upcoming clinical trials. In order to prepare future longitudinal studies or therapeutic trials with large cohorts, information about disease progression is required. In this study we present preliminary longitudinal data of Motor Function Measure (MFM), timed tests, Purdue pegboard test, and handgrip strength collected over 5 to 9 years of followup in 13 patients with GSDIII aged between 13 and 56 years old. Follow-up for nine of the 13 patients was up to 9 years. Similarly to our previous cross-sectional retrospective study, handgrip strength significantly decreased with age in patients older than 37 years. MFM scores started to decline after the age of 35. The Purdue pegboard score also significantly reduced with increasing age (from 13 years of age) but with large inter-visit variations. The time to stand up from a chair or to climb 4 stairs increased dramatically in some but not all patients older than 30 years old. In conclusion, this preliminary longitudinal study suggests that MFM and handgrip strength are the most sensitive muscle function outcome measures in GSDIII patients from the end of their third decade. Sensitive muscle outcome measures remain to be identified in younger GSDIII patients but is challenging as muscle symptoms remain discrete and often present as accumulated fatigue.