GSD, type II, is an autosomal recessive disorder caused by mutations in the acid alpha-glucosidase gene (17q25.3) that result in the deficiency or dysfunction of the lysosomal hydrolase acid alpha-glucosidase (GAA). This enzymatic defect results in lysosomal glycogen accumulation in multiple tissues, with cardiac and skeletal muscle tissues most severely affected.
Classification
Classic infantile onset: May be apparent in utero but more often presents in the 1st month of life with hypotonia, motor delay/muscle weakness, cardiomegaly and hypertrophic cardiomyopathy, feeding difficulties, failure to thrive, respiratory distress, and hearing loss.
Nonclassic infantile onset: Usually presents within the 1st year of life with motor delays and/or slowly progressive muscle weakness.
Late onset (i.e., childhood, juvenile, and adult onset) is characterized by proximal muscle weakness and respiratory insufficiency without cardiac involvement; these patients may have residual GAA activity <40% of normal when measured in skin fibroblasts.
Relevant Tests and Diagnostic Value
Chemical tests
Serum CK: Elevated as high as 2,000 IU/L (normal: 60–305 IU/L) in classic infantile onset and in the childhood and juvenile variants but may be normal in adult-onset disease. However, because serum CK concentration is elevated in many other conditions, this test is nonspecific.
Urinary oligosaccharides: Elevation of a certain urinary glucose tetrasaccharide is highly sensitive in Pompe disease but is also seen in other glycogen storage diseases. In addition, it may be normal in late-onset disease.
Biochemical testing
Acid α-GAA enzyme activity in cultured skin fibroblasts, whole blood, or dried bloodspot (confirmation by a second method is preferred). Activity <1% of normal controls (complete deficiency) is associated with classic infantile-onset Pompe disease. Activity 2–40% of normal controls (partial deficiency) is associated with the nonclassic infantile-onset and the late-onset forms.
Muscle biopsy
: Glycogen storage may be observed in the lysosomes of muscle cells as vacuoles of varying severity that stain positively with periodic acid–Schiff. However, 20–30% of individuals with late-onset type II GSD with documented partial enzyme deficiency may not show these muscle-specific changes.
Molecular testing
:
GAA
is the only gene known to be associated with GSD II.
Targeted mutation analysis: Depending on ethnicity and phenotype, an individual could be tested first for one of the three common mutations—Asp645Glu, Arg854X, and IVS1—13T>G—before proceeding to full-sequence analysis.
Gene sequence analysis: In 83–93% of individuals with confirmed reduced or absent GAA enzyme activity, two mutations can be detected by sequencing genomic DNA.
Deletion/duplication analysis: Deletion of exon 18 was seen in approximately 5–7% of alleles; single-exon deletions as well as multiexonic deletions have been seen rarely.
