Glycogen storage disease type II (GSD II - Pompe's disease) is caused by mutations that reduce or eliminate the activity of lysosomal alpha-glucosidase (GAA) (Hers 1963). The presentation of GSD II varies with the severity of the mutation: patients with little or no GAA activity are affected shortly after birth and multiple tissues - heart, liver, and skeletal muscle - are severely affected. Patients with higher levels of GAA activity present later in life, often with symptoms restricted to skeletal muscle (Leslie & Tinkle). At a cellular level, symptoms of the disease are due to accumulation of structurally normal glycogen in lysosomes. Glycogen, thought to enter lysosomes via autophagy, is fully degraded by GAA (Brown et al. 1970), but accumulates if the enzyme is absent or reduced in activity.
The two mutant alleles annotated here are associated with near-complete loss of enzyme activity and early onset of disease (Hermans et al. 1991; Zhong et al. 1991). Many other mutant alleles have been described and their residual activities correlated with disease presentation (e.g., Kroos et al. 2012).