The GAA gene encodes the lysosomal enzyme alpha-1,4-glucosidase, which is essential for the degradation of glycogen to glucose. Three different transcripts can be produced by this gene and proteolytic processing results in many forms of the enzyme.
The GAA gene is located on chromosome 17 and spans approximately 19 kb. The number of exons contained in the GAA gene is 20 and exon one is non-coding. The gene's promoter carries the telltale signs of housekeeping genes. Other notable features include the high GC content (80%) and the lack of TATA and CCAAT motifs.
Mutations in the GAA gene result in glycogen storage disease II (Pompe disease); which is an autosomal recessive disorder with widely varying symptoms. Over 200 mutations in the GAA gene have been uncovered in people with Pompe disease; these include missense, deletions and insertions. Loss of function mutations lead to acid alpha-glucosidase deficiency thus glycogen accumulates in lysosomes and cytoplasm. This build up in glycogen damages organs and tissues throughout the body, particularly the muscles, leading to hypertrophic cardiomyopathy, feeding abnormalities, hypotonia, weakness, respiratory insufficiency, and ultimately death.
Monies et al. (2017) detailed the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, an 8-year-old female from a consanguineous family, presented with GSD type 1, bleeding tendency and hypoglycemia. Using a multigene panel for inborn errors of metabolism, she was found to have dual molecular diagnosis: a homozygous c.247C>T (p.R83C) variant in exon 2 of the G6PC gene and a homozygous c.266G>A (p.R89H) variant in exon 2 of the GAA gene. Dual molecular diagnoses were rarely detected and occurred in only 1.5% of the cohort.
Hamdan et al. (2008) reported the case of a 35-week neonate whose older sibling died of infantile Pompe disease. The first sign of the disease was detected at 32 weeks of gestation, when fetal echocardiography showed hypertrophic cardiomyopathy. Then the diagnosis was confirmed after birth through enzyme assay. The patient was homozygous for a mutation in the 8th intron of GAA. This mutation is a splice site mutation (c.1327-2A>G) which is classified among the most deleterious sequence variations in GAA. It is worth mentioning that the patient responded very well to enzyme replacement therapy that was started at 18 hours of age. Two years later, Hamdan et al. (2010) studied the cases of three patients (2 males and 1 female) with PD in the UAE. Two of these patients had a sibling with PD. Mutational analysis revealed two types of mutations in the GAA gene; c.1327-2A>G and c.340insT. These patients were selected by screening fetuses diagnosed with hypertrophic cardiomyopathy between 2006 and 2009. Enzyme replacement therapy was applied in these cases with varying degrees of success.
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