Glycogen storage disease type II (GSDII) is an autosomal recessive disorder that is more commonly known as Pompe disease or acid maltase deficiency (AMD). This disease was originally referred to as Pompe disease since Joannes Cassianus Pompe (published in 1932) made the important observation of a massive accumulation of glycogen within the vacuoles of all tissues in a 7-month-old female who died suddenly from idiopathic hypertrophy of the heart. Through the investigations carried out by the Cori's (Gerty T. Cori and Carl F. Cori) this disease was classified as glycogen storage disease type II. GSDII is the most severe of all of the glycogen storage diseases. The excess storage of glycogen in the vacuoles is the consequence of defects in the lysosomal hydrolase, acid α-glucosidase which removes glucose residues from glycogen in the lysosomes.
The acid α-glucosidase gene (GAA: glucosidase, alpha; acid) resides on chromosome 17q25.2-q25.3 spanning 20 kb and composed of 21 exons that generate three alternatively spliced mRNAs, each of which encode the same 952 amino acid preproprotein. GSDII has been shown to be caused by missense, nonsense and splice-site mutations, partial deletions and insertions. Some mutations are specific to certain ethnic groups. There are three common allelic forms of acid α-glucosidase that segregate in the general population. These forms are designated GAA1, GAA2 and GAA4. The normal function of acid α-glucosidase is to hydrolyze both α-1,4- and α-1,6-glucosidic linkages at acid pH. The activity of the enzyme leads to the complete hydrolysis of glycogen which is its natural substrate. As would be expected from this activity, deficiency in acid α-glucosidase leads to the accumulation of structurally normal glycogen in numerous tissues, most notably in cardiac and skeletal muscle.
The clinical presentation of GSDII encompasses a wide range of phenotypes but all include various degrees of cardiomegaly. Additional clinical manifestations associated with idiopathic cardiomegaly accompanied by storage of glycogen are indicative of Pompe disease. These symptoms included hepatomegaly, marked hypotonia, muscular weakness and death before 1 year of age. The different phenotypes can be classified dependent upon age of onset, extent of organ involvement and the rate of progression to death. The infantile-onset form is the most severe and was the phenotype described by JC Pompe. The other extreme of this disorder is a slowly progressing adult onset proximal myopathic disease. The late onset disease usually presents as late as the second to sixth decade of life and usually only involves the skeletal muscles. There is also a heterogeneous group of GSDII disorders that are classified generally by onset after early infancy and called the juvenile or childhood form. In addition to classical symptoms that can lead to a diagnosis of GSDII, analysis for the level and activity of acid α-glucosidase in muscle biopsies is used for confirmation.
The infantile onset form of GSDII presents in the first few months of life. Symptoms include marked cardiomegaly, striking hypotonia (leading to the designation of "floppy baby syndrome") and rapid progressive muscle weakness. Patients will usually exhibit difficulty with feeding and have respiratory problems that are frequently complicated by pulmonary infection. The prominent cardiomegaly that can be seen on chest X-ray is normally the first indication leading to a preliminary diagnosis of GSDII. There is currently no cure for GSDII. In 2006 the US FDA approved the use of Myozyme® (alglucosidase alpha) as an enzyme replacement therapy (ERT) for treatment of infantile-onset Pompe disease. Supportive therapy with attention to treatment of respiratory function can impact the course of the disease in the late-onset form.