In 2 patients with the adult-onset form of glycogen storage disease II (GSD2; 232300), Huie et al. (1994) identified a T-to-G transversion at position -13 of the acceptor site of intron 1 of the GAA gene, resulting in alternatively spliced transcripts with deletion of the first coding exon, exon 2. Boerkoel et al. (1995) reported an adult woman heterozygous for this mutation with a low level of active enzyme (12% of normal) that was generated from the leakage of normally spliced mRNA and sustained the patient to adult life. The patient was a genetic compound for deletion of exon 18 of the GAA gene (606800.0012).
Kroos et al. (1995) identified the IVS1 splice site mutation in 38 of 50 heterozygous persons with the adult form of GSD II and in 4 of 13 heterozygous patients with the juvenile form, but did not find the mutation in patients with the infantile form. Patients with deletion of exon 18 or deletion of 525T (606800.0014) in combination with the IVS1-13T-G transversion had the juvenile or the adult form, suggesting that the intronic mutation was a mild mutation.
Among 40 Italian patients with late-onset GSD II, Montalvo et al. (2006) identified 26 different mutations, including 12 novel mutations, in the GAA gene. The most common mutation was IVS1-13T-G, present in heterozygosity in 34 (85%) of 40 patients (allele frequency 42.3%).
Kroos et al. (2007) reported 98 Caucasian GSD II patients who were compound heterozygous for the -13T-G transversion and a second fully deleterious mutation in the GAA gene. None had the infantile form of the disease, but age at onset ranged from less than 1 to 52 years. Alpha-glucosidase activity ranged from about 3 to 20% of normal, and clinical features varied far more than anticipated, although the disease course in general was slowly progressive. Twelve different -13T-G haplotypes were identified.
Gort et al. (2007) identified the -13T-G mutation in 25% of mutant alleles from 22 Spanish patients with GSD II. All had the same haplotype, indicating a founder effect.
In a cohort of 84 patients with Pompe disease who carried the common IVS1-13T-G mutation, Herbert et al. (2019) identified 4 patients who were compound heterozygous for a different second GAA mutation and had onset of clinical symptoms before age 2 years (range, 10 days to 20 months). Herbert et al. (2019) concluded that despite the prior impression that this common mutation leads to milder, adult-onset disease, it can lead to early-onset symptoms.
