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Progress and problems when considering gene therapy for GSD-II.

Glycogen storage disease type II (GSD-II), also known as Pompe disease, or acid maltase deficiency (AMD), is an autosomal recessive genetic disorder that encompasses a range of clinical phenotypes, but myopathy is common to all. This “variable expressivity” manifests primarily as variances in age of onset of disease symptoms, as well which organs are pathologically involved. The most severe form of GSD-II is the infantile-onset form, and was originally described by Dr. Pompe. These severely affected infants may appear normal at birth, but soon develop generalized muscle weakness and cardiac myopathy manifesting initially as a hypertrophic cardiomyopathy. Shortly thereafter death resulting from cardiorespiratory failure typically occurs before the age of 2 years. The juvenile (onset as early as at age 1 year) or adult onset (onset between the second or later decades) forms of GSD-II present as slowly progressive limb muscle myopathies, and lack the cardiac involvement noted in the infantile patients. The clinical picture of these later onset forms of GSD-II are dominated by a slowly progressive respiratory muscle and proximal limb muscle weakness, with truncal involvement and greater involvement of the lower, rather than the upper limbs. Although these forms of GSD-II are not lethal in the neonatal period, juvenile and adult GSD-II patients suffer from significant morbidity and mortality, the latter primarily due to the complications of respiratory insufficiency. 
 
GSD-II is caused by the inheritance of mutant alleles that either result in the complete lack of expression of acid alpha-glucosidase (GAA) protein; this is the protein which breaks down intra-lysosomal glycogen. In general, the severity of the clinical phenotypes can be correlated with the residual GAA enzyme activity levels measured in a respective patient’s tissues. For example, infantile GSD-II patients typically have less than 1% of normal GAA activity levels in their muscles, while juvenile or adult onset forms of GSD-II may have 2-40% of normal GAA tissue activity levels. Infantile patients may have nonsense mutations that prevent any GAA protein from being expressed, or missense mutations that allow for production of an enzymatically “dead” GAA protein. Juvenile or adult onset GSD-II patients, have less severe mutations (missense or splice-site mutations) that cause expression of a less than nominal GAA protein, or decreased levels of a normal GAA protein. These facts alone demonstrate that very low levels of GAA activity allow for preservation of normal cardiac function in juvenile and adult GSD-II patients. However, in juvenile and adult onset patients, GAA activity levels generally cannot be positively correlated with rate of progression and/or disease severity of respiratory or limb muscle involvement, suggesting that other genes and/or environmental factors likely significantly impact on disease severity in juvenile or adult onset GSD-II patients. The true incidence of GSD-II (in all its presenting forms) is not accurately documented, but estimates are in the range of 1 in 40,000 to 1 in 100,000 live births. Due to the relatively rare occurrence of a GSD-II diagnosis, GSD-II has been designated an orphan disease.