Glycogen Storage Disease Type II (Pompe Disease) via the GAA Gene, Exon 18 Deletion

Glycogen Storage Disease Type II (GSDII, also known as Pompe Disease or acid maltase deficiency) is caused by defects in the lysosomal degradation of glycogen. Symptoms consist primarily of weakness in muscles, including cardiac and respiratory muscles. Pompe disease has a broad clinical spectrum with variable age of onset, severity of symptoms, and rate of disease progression. Phenotypes range from a rapidly progressive infantile form to a slowly progressive late-onset form (Leslie and Tinkle 2013; Chen et al. 2014; Adeva-Andany et al. 2016). The classic infantile form of Pompe Disease is the most severe and is usually fatal. Affected infants present with profound hypotonia, muscle weakness, hyporeflexia, enlarged tongue, and hypertrophic cardiomyopathy. Diagnosis may be based on typical EKG findings which include large QRS complexes and shortened PR intervals (Kishnani et al. 2006). In the juvenile form of the disease, affected children have hypotonia and weakness of limb girdle and truncal muscles, but there is no overt cardiac disease. Adult-onset Pompe Disease has a long latency and affected individuals may live to old age. Decreased muscle strength and weakness develop, most commonly in the third or fourth decade, but cardiac involvement, if any, is minimal (Leslie and Tinkle 2013; Chen et al. 2014; Adeva-Andany et al. 2016). It should be noted that enzyme replacement therapy (ERT) with alglucosidase alfa is a treatment option that is commercially available for all forms of Pompe Disease (van der Ploeg and Reuser 2008; Leslie and Tinkle 2013; Doerfler et al. 2016).

Glycogen Storage Disease Type II is caused by a deficiency of α-1,4-glucosidase, an enzyme required for the degradation of lysosomal glycogen (Hers 1963). The disorder is inherited in an autosomal recessive manner, and the estimated disease incidence is approximately 1 in 40,000 to 1 in 50,000. Pathogenic variants within the GAA gene encoding the acid alpha-glucosidase enzyme are the only known cause of the disease, and over 400 different GAA pathogenic variants have been reported (Erasmus MC. Pompe Center; Human Gene Mutation Database). The pathogenic variants are distributed throughout the length of the gene. Missense and nonsense pathogenic variants predominate, although splicing and regulatory pathogenic variants as well as small and gross deletions and insertions have all been reported. Some correlations have been made between specific pathogenic variants and disease severity (Hermans et al. 2004; Wan et al. 2008; Kroos et al. 2012). One common pathogenic variant in intron 1 of the GAA gene, defined as c.-32-13T>G, has been found in almost two-thirds of patients with adult onset disease (Huie et al. 1994). Pompe Disease can be found in ethnically diverse populations, including European Whites, Hispanics, and Asians. Although founder mutations are known in some genetically isolated populations, in the overall American population no pathogenic variants are predominant.

Deletion of exon 18 has been reported to be a relatively common pathogenic variant in the GAA gene, accounting for up to 13% of total pathogenic alleles by some reports (Van der Kraan et al. 1994; Oba-Shinjo et al. 2009). The borders of the deletion include a repeated DNA sequence (AGGGGCCG), thought to be important in the mutational event (Van der Kraan et al. 1994). The exon 18 deletion has been reported in multiple ethnic groups.

This deletion is reported to be one of the most common causative pathogenic variants in the GAA gene. Van den Kraan et al. (1994) found the exon 18 deletion in the compound heterozygous state in 10 out of 39 White patients with confirmed Glycogen Storage Disease (GSD) Type II, for a detection rate of ~13%. Oba-Shinjo et al. (2009) reported the exon 18 deletion in the homozygous or compound heterozygous state in 4 out of 41 patients with confirmed GSD Type II, for a detection rate of ~6%. The exon 18 deletion has also been reported in several studies with smaller numbers of patients (Huie et al. 1994; Sacconi et al. 2014).

This test involves amplification of patient DNA with several sets of specific PCR primers that flank the site of the common GAA exon 18 deletion. In a patient with the deletion, two separate primer sets amplify across the deletion resulting in 336 bp and 554 bp products. Other control primers are used to detect the normal allele. This test permits the identification of patients with normal genotypes and patients who are heterozygotes for the exon 18 deletion. We should also be able to confirm a homozygous deletion using our PCR strategy. This test is designed to detect only the common exon 18 deletion. Other deletions in the GAA gene may not be detectable via this method, but may be detectable via GAA-specific array CGH (Test #600). PreventionGenetics also offers a sequencing test for the GAA gene (Test #223).