Glycogen Storage Disease Type II (Pompe Disease) via the GAA Gene

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 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.

Through gene sequencing, Hermans et al. (2004) were able to detect at least one likely causative variant in every one of the 29 GSDII patients in their cohort. Two likely causative variants were identified in 24 out of the 29 patients. Similarly, in a study of late-onset GSD Type II patients, Montalvo et al. (2006) detected at least one likely causative variant in all 40 patients studied, and two variants in 37 of the patients. Liu et al. (2014) studied late-onset GSD Type II patients in a Chinese population and found at least one likely causative variant in all 27 patients studied and two likely causative variants in 25 of the 27 patients. Overall, this suggests a clinical sensitivity of ~95% for this test.

While most GAA pathogenic variants will be picked up by gene sequencing, at least 8 different gross deletions have been reported (Leslie and Tinkle 2013). One relatively common pathogenic variant, seen in approximately 5% to 7% of causative alleles, involves the deletion of exon 18 (Van der Kraan et al. 1994). Please see the methods tab for limitations on CNV detection.

This test provides full coverage of all coding exons of the GAA gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

The c.-32-13T>G pathogenic variant that is sometimes found in patients with late-onset disease is covered.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).