Elsevier

The Lancet

Volume 372, Issue 9646, 11–17 October 2008, Pages 1342-1353
The Lancet

Series
Pompe's disease

https://doi.org/10.1016/S0140-6736(08)61555-XGet rights and content

Summary

Pompe's disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait characterised by acid α-glucosidase deficiency leading to lysosomal glycogen storage. Pompe's disease is also regarded as a muscular disorder, but the generalised storage of glycogen causes more than mobility and respiratory problems. The clinical spectrum is continuous and broad. First symptoms can present in infants, children, and adults. Cardiac hypertrophy is a key feature of classic infantile Pompe's disease. For a long time, there was no means to stop disease progression, but the approval of enzyme replacement therapy has substantially changed the prospects for patients. With this new development, the disease is now among the small but increasing number of lysosomal storage disorders, for which treatment has become a reality. This review is meant to raise general awareness, to present and discuss the latest insights in disease pathophysiology, and to draw attention to new developments about diagnosis and care. We also discuss the developments that led to the approval of enzyme replacement therapy with recombinant human α-glucosidase from Chinese hamster ovary cells (alglucosidase alfa) by the US Food and Drug Administration and European Medicines Agency in 2006, and review clinical practice.

Introduction

Pompe's disease (Online Mendelian Inheritance in Man [OMIM] number 232300) is an inherited metabolic myopathy. It is a generalised glycogenosis characterised by lysosomal glycogen storage caused by deficiency of the lysosomal enzyme acid α-glucosidase. Pompe's disease has an estimated frequency of one in 40 000 in African-American, one in 50 000 in Chinese, one in 40 000 in Dutch, and one in 146 000 in Australian populations.1, 2, 3, 4, 5, 6

Synonyms for the disease are glycogen-storage disease type II and acid-maltase deficiency. This disease has been untreatable, but approval in 2006 of enzyme replacement therapy with recombinant human acid α-glucosidase has shown the potential to substantially alter its prognosis. This review addresses the latest insights into Pompe's disease, with a focus on diagnostic and therapeutic challenges.

Section snippets

Clinical features

Pompe's disease presents as a spectrum of features in which symptoms can manifest at any age (figure 1).7 At the severe end of the spectrum is a subgroup of patients with a clearly defined course. This classic infantile form was first described by Pompe in 1932 and usually presents in patients within the first months of life. The median age of onset ranges from 1·6 to 2·0 months.8, 9, 10 Presenting symptoms are feeding difficulties, failure to thrive, respiratory infections, hypotonia, and very

Enzymatic and molecular diagnosis

All patients have a deficiency of the lysosomal enzyme acid α-glucosidase, and can be diagnosed on the basis of this feature.34 However, the sensitivity and specificity of the enzymatic procedure depends on the choice of tissue specimen, type of substrate, and assay conditions. Of the various tissue specimens that are used for diagnosis, cultured skin fibroblasts have by far the highest acid α-glucosidase activity and do not contain neutral α-glucosidase activities that interfere with the assay

GAA genotype and clinical course

Pompe's disease is inherited in an autosomal recessive manner. No cases of affected carriers have been documented. Thus, both GAA alleles need to harbour a pathogenic mutation before the phenotype develops. Many of the reported mutations were characterised. We usually know precisely how they affect the splicing process, the GAA-mRNA stability, or the biosynthesis of acid α-glucosidase (including the various post-translational modification steps, the intracellular transport, and finally the

Pathophysiology

Accumulation of lysosomal glycogen starts when the acid α-glucosidase activity decreases below critical.2 This threshold amount seems to vary depending on the organ. In knockout mouse models of Pompe's disease with complete enzyme deficiency, storage was seen in almost every tissue and cell type—ie, liver, heart, and skeletal muscle, smooth-muscle cells of the gastrointestinal tract, bladder, blood-vessel walls, kidney, spleen, endothelial cells, and Schwann cells and in the perineurium of

Enzyme replacement therapy

In the 1960s, Pompe's disease was the first lysosomal storage disorder for which attempts at enzyme replacement therapy were undertaken in individual patients with enzyme preparations from Aspergillus niger and human placenta. However, these attempts were without clinical benefit. With experience, we clearly know that inappropriate enzyme source and insufficient dosing were the causes of failure.92, 93 An important step forward was the knowledge that cell-surface receptors helped with uptake of

Conclusion

Several important lessons have been learned from the studies in mice and man, which showed that the acid α-glucosidase activity in blood needs to surpass a specific threshold to elicit a therapeutic response in skeletal muscles. Studies of mice and quail showed that this threshold was achieved at a dose of about 20 mg/kg.101, 103, 104, 105, 109, 110, 126 Further, studies showed that young mice with mild pathological changes in the tissue responded better to therapy than old mice with advanced

Search strategy and selection criteria

We searched Pubmed for articles with the terms “Pompe disease”, “acid alpha-glucosidase deficiency”, “acid maltase deficiency”, “glycogenosis type II”, and “enzyme (replacement) therapy”. We mainly selected publications in English from the past 7 years, but did not exclude commonly referenced and highly regarded older publications. For treatment, we focused on enzyme therapy. Articles on gene therapy were excluded, because they were beyond the scope of this review. For detailed

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