Pompe disease (PD) is a recessive metabolic disorder characterized by acid α-glucosidase (GAA) deficiency, an enzyme that catalyzes the hydrolysis of α-1, 4 and α-1, 6 glucosidic bonds of glycogen. This deficiency results in lysosomal accumulation of glycogen in all tissues, especially in skeletal muscles. PD patients display a large spectrum of phenotypes with regard the age of onset, the disease progression rate and the severity of symptoms. The clinical course of the disease is mainly determinated by the nature of GAA genetic variations which lead to different degrees of enzyme deficiency. Up till now, close to 400 distinct GAA sequence variations have been described, and in some cases the genotype-phenotype correlation is not immediately evident. In this study, we described the first clinical and genetic analysis of Colombian PD patients performed in 13 affected individuals. GAA open reading frame sequencing revealed 8 distinct mutations related to PD etiology including to novel missense mutations, c. 1106T> C (p. Leu369Pro) and c. 2236T> C (p. Trp746Arg). In vitro functional studies showed that the structural changes conferred by both mutations do not inhibit the synthesis of the 110 KD GAA precursor form but affect the processing and intracellular transport of GAA. In addition, analysis of previously described variants located at this position (p. Trp746Gly, p. Trp746Cys, p. Trp746Ser, p. Trp746X) reveled new insights in the molecular basis of PD. Notably, we found that p. Trp746Cys mutation, which was previously described as polymorphism as well as a causal mutation displays a mild deleterious effect
