Pompe disease in infants and children

Abstract

Pompe disease, also referred to as glycogen storage disease type II and acid maltase deficiency, is a genetic muscle disorder caused by a deficiency of acid α-glucosidase (GAA, also referred to as acid maltose). 1 This enzyme defect results in lysosomal glycogen accumulation in multiple tissues and cell types, with cardiac, skeletal, and smooth muscle cells (Fig 1) the most seriously affected. Clinically, Pompe disease encompasses a range of phenotypes. Infantile-onset Pompe disease is uniformly lethal. Affected infants present in the first few months of life with hypotonia, generalized muscle weakness, and a hypertrophic cardiomyopathy, followed by death from cardiorespiratory failure or respiratory infection, usually by 1 year of age. 1,2 Juvenile and adult-onset disease (late-onset forms) is characterized by a lack of severe cardiac involvement and a less severe short-term prognosis. Symptoms may start at any age and are related to progressive dysfunction of skeletal muscles. With disease progression, patients become confined to wheelchairs and require artificial ventilation. Respiratory failure is the cause of significant morbidity and mortality in this form of the disease. The age of death varies from early childhood to late adulthood, depending on the rate of disease progression and the extent of respiratory muscle involvement. In addition to being a lysosomal storage disorder, Pompe disease is classified as a neuromuscular disease, a metabolic myopathy, and a glycogen storage disease (in fact, Pompe disease is the only glycogen storage disease that is also a lysosomal storage disorder). The infantile form is also considered a cardiac disorder because of the prominent cardiac involvement. There is currently no treatment other than supportive care for Pompe disease. Drugs such as epinephrine and glucagon, which enhance cytosolic glycogen breakdown, have no therapeutic effect. 3 Therapies that alter the synthesis of glycogen, such as high-protein diets and alanine, can have transient clinical benefits in some patients 4-7 but do not reduce the glycogen accumulation. Early attempts at enzyme replacement therapy with unphosphorylated GAA from Aspergillus niger or human placenta did not alter the clinical course of affected infants. 8-1 Bone marrow transplantation has not been successful. 12 However, recent clinical trials of enzyme replacement have been promising, 13-16 and for the first time, there is hope for patients with this often fatal disease. Other important advances include a better understanding of enzyme synthesis and trafficking, extensive mutation analysis in patients with different forms ofthe disease, generation of animal models for preclinical studies to direct therapeutic endeavors, and development of viral vectors for gene transfer. 17 With enzyme replacement therapy likely to become available in the near future and other therapies on the horizon, early disease recognition is increasingly important so that patients can receive prompt and appropriate therapy. In infants, this recognition will be critical, because the available window of treatment after diagnosis is extremely short.