BACKGROUND. Pompe disease is a lysosomal storage disorder that leads to the accumulation of glycogen and subsequently to muscle weakness, organ damage, and death. Pompe disease is detectable through newborn screening, and treatment has become available recently. OBJECTIVE. Our goal was to review systematically all available evidence regarding screening for infantile Pompe disease to help policy makers determine whether Pompe disease should be added to their state9s newborn screening battery. METHODS. We searched online databases, including Medline, clinicaltrials.gov, and the Computer Retrieval of Information on Scientific Projects database, as well as Web sites maintained by federal organizations (eg, the Food and Drug Administration) and other nonprofit or private organizations (eg, the March of Dimes and Genzyme Corp), by using the terms “glycogen storage disease type II,” “Pompe disease,” and “Pompe9s disease.” We also obtained preliminary findings from a screening program in Taiwan. Data were critically appraised and extracted by 2 investigators, one who is an expert in systematic review methods and the other who is an expert in Pompe disease. RESULTS. The prevalence of Pompe disease has been estimated to be ∼1 case per 40000. Small studies suggest that enzyme therapy is highly efficacious in infantile Pompe disease and that earlier intervention leads to improved outcomes. Screening cannot distinguish between infantile and late-onset Pompe disease. The current screening program in Taiwan has a high false-positive rate; however, the threshold was purposely set low to ensure that no case would be missed. CONCLUSIONS. Pilot studies of screening are needed to identify the most efficacious strategy for screening and determine how to manage cases of late-onset Pompe disease before screening for Pompe disease is adopted widely by newborn screening programs.

Newborn screening for Pompe disease: synthesis of the evidence and development of screening recommendations

The glycogen storage diseases (GSDs) are a group of inherited metabolic disorders that result from a defect in any one of several enzymes required for either glycogen synthesis or glycogen degradation. The GSDs can be divided into those with hepatic involvement, which present as hypoglycemia, and those which are associated with neuromuscular disease and weakness. The severity of the GSDs range from those that are fatal in infancy if untreated to mild disorders with a normal lifespan. The diagnosis, treatment, and prognosis for the common types of GSDs are reviewed.

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Glycogen storage diseases: Diagnosis, treatment and outcome

Inherited deficiency of acid α-glucosidase (acid maltase, GAA) leads to glycogen storage disease type II. Clinical manifestations and prognosis of the disease depend on the age of onset and tissue involvement. GAA deficiency is extremely heterogeneous, ranging from a rapidly progressive fatal infantile-onset form to a slowly progressive adult-onset myopathy associated with respiratory insufficiency. Biochemical and immunochemical studies of the biosynthesis of the enzyme in GAA-deficient patients established the molecular diversity of the disease. Cloning and sequencing of the cDNA and the gene provided the basis for genetic analysis of the patients with different phenotypes. In this article, we summarize the data on mutations in the GAA gene and discuss the correlation between the genotype and phenotypic expression of the disease. © 1995 John Wiley & Sons, Inc.

Genetic defects in patients with glycogenosis type II (acid maltase deficiency).

Glycogen storage diseases (GSD) are inborn errors of glycogen metabolism. Of the eight human GSD types in which the enzymatic deficiency has been identified, spontaneous animal counterparts have been reported for GSD I (glucose-6-phosphatase deficiency) in the mouse, for GSD II (acid α-glucosidase deficiency) in the dog, in cattle and in the quail, for GSD III (debrancher enzyme deficiency) in the dog and for GSD VIII (phosphorylase kinase deficiency) in the rat and the mouse. Experimentally induced GSD-like conditions have been described in the rat (Acarbose-induced GSD II-like conditions, iodoacetate-induced symptoms of myophosphorylase (GSD V) and myophosphofructokinase (GSD VII) deficiency) and the chicken (ochratoxin A-induced symptoms of cyclic AMP-dependent protein kinase deficiency). Enzymatic defects that are typical of the human GSD types have not been clearly identified in the induced animal conditions. The homology of animal and human GSD types is discussed. It is concluded that clinical, pathogenic and therapeutic studies of GSD may benefit from the use of animal models. For genetic studies of human GSD these models may prove to be of limited value, as the picture of several human GSD types is already obscured by genetic heterogeneity.

Glycogen Storage Diseases in Animals and Their Potential Value as Models of Human Disease

Background

Glycogen storage disease type II (GSDII) or Pompe disease is an inherited disease of glycogen metabolism caused by a lack of functional lysosomal acid α-glucosidase (GAA). Affected individuals store glycogen in lysosomes resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe form. Even if enzyme replacement therapy (ERT) has already proven some efficacy, its results remain heterogeneous in skeletal muscle, especially in cross reactive immunological material (CRIM)-negative patients. We investigated for the first time the use of hematopoietic stem cell (HSC) gene therapy in a murine model of GSDII.



Methods

Deficient HSC were transduced with a lentiviral vector expressing human GAA or enhanced green fluorescent protein (GFP) under the control of the retroviral MND promoter and transplanted into lethally irradiated GSDII mice. Animals were then subjected to an ERT protocol for 5 weeks and monitored for metabolic correction and GAA-induced immune reaction.



Results

GAA was expressed as a correctly processed protein, allowing a complete enzymatic correction in transduced deficient cells without toxicity. Seventeen weeks after transplantation, a partial restoration of the GAA enzymatic activity was observed in bone marrow and peripheral blood cells of GSDII mice, allowing a significant glycogen clearance in skeletal muscle. ERT induced a robust antibody response in GFP-transplanted mice, whereas no immune reaction could be detected in GAA-transplanted mice.



Conclusions

Lentiviral vector-mediated HSC gene therapy leads to a partial metabolic correction and induces a tolerance to ERT in GSDII mice. This strategy could enhance the efficacy of ERT in CRIM-negative Pompe patients. Copyright © 2009 John Wiley & Sons, Ltd.

Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of alpha-glucosidase in Pompe disease.

We have studied somatic cell hybrids between thymidine kinase (EC 2.7.1.75) deficient mouse cells and human diploid fibroblasts for the expression of human acid α-glucosidase (EC 3.2.1.20). A deficiency in this enzyme is associated with the type II glycogenosis or Pompe disease. All 30 somatic cell hybrids selected in hypoxanthine/aminopterin/thymidine medium expressed human acid α-glucosidase and galactokinase (EC 2.7.1.6) and retained human chromosome 17; counterselection of the same hybrids in medium containing 5-bromodeoxyuridine resulted in the growth of hybrids that concordantly lost the expression of human acid α-glucosidase and galactokinase as well as human chromosome 17. Hybrids between thymidine kinase-deficient mouse cells and fibroblasts from a patient with Pompe disease that contained human chromosome 17 were found not to express human acid α-glucosidase. Because we have already shown that hybrids between mouse peritoneal macrophages and GM54VA simian virus 40-transformed human cells selectively retain human chromosome 17 and lose all other human chromosomes, we tested 13 independent mouse macrophage × GM54VA hybrid clones, including two that retained human chromosome 17 and no other human chromosomes, for the expression of human acid α-glucosidase and galactokinase. All 13 hybrid clones were found to express these human enzymes. Thus, we conclude that the gene coding for human acid α-glucosidase is located on human chromosome 17.

Gian G. D'Ancona

Papers

Genetics of type II glycogenosis: Assignment of the human gene for acid α-glucosidase to chromosome 17