Alternative titles; symbols
HGNC Approved Gene Symbol: GAA
SNOMEDCT: 274864009; ICD10CM: E74.02;
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38) : 17:80,101,581-80,119,881 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Glycogen storage disease II | 232300 | Autosomal recessive | 3 |
Alpha-1,4-glucosidase (GAA; EC 3.2.1.20) is a lysosomal enzyme involved in the degradation of glycogen within cellular vacuoles.
Martiniuk et al. (1986) isolated a cDNA with the characteristics of a cDNA for lysosomal acid alpha-glucosidase. They found that this cDNA hybridized to a 3.4-kb mRNA consistent with the size of the enzyme protein (about 105 kD).
Hoefsloot et al. (1988) derived the amino acid sequence of acid maltase from the nucleotide sequence of cloned cDNA. The cDNA consisted of 3,636 nucleotides and hybridized with a mRNA of about 3.6 kb. A remarkable homology was observed between a soluble lysosomal alpha-glucosidase and the membrane-bound intestinal brush border sucrase-isomaltase enzyme complex. The similarity led Hoefsloot et al. (1988) to propose that these enzymes derived from the same ancestral gene.
Dennis et al. (2000) reported cDNA and genomic sequence of the bovine Gaa gene, from the initiation codon to the most 3-prime polyadenylation signal. The 2,814-bp coding sequence predicts a 937-amino acid protein, which shows 83% amino acid sequence identity to the human protein.
Hoefsloot et al. (1990) demonstrated that the GAA gene spans approximately 20 kb and contains 20 exons. The first exon is noncoding. The coding sequence of the putative catalytic site domain is interrupted in the middle by an intron of 101 bp. The promoter has features characteristic of a 'housekeeping' gene. The GC content is high (80%) and distinct TATA and CCAAT motifs are lacking.
Yan et al. (2001, 2001) identified elements within a 25-bp region of intron 1 that, when bound by either HRY (139605) or YY1 (600013), silenced GAA transcription in a hepatocyte cell line. In a later study, Yan et al. (2002) found activation of GAA in human fibroblasts with HRY or YY1 binding. The authors noted that the dual function of the transcription factors is likely to contribute to subtle tissue-specific control of GAA activity.
By human-mouse somatic cell hybridization, D'Ancona et al. (1979) and Solomon et al. (1979) assigned the gene for acid alpha-1,4-glucosidase (GAA) to chromosome 17. Mouse and human enzymes were distinguished by differences in affinity to starch gel of the rare human GAA-2 phenotype. Differences in the thermostability of the mouse and human enzymes were also exploited. They concluded that GAA is probably on 17q. By dosage effect, Sandison et al. (1982) narrowed the assignment of the GAA locus to 17q22-qter. By in situ hybridization, Halley et al. (1984) mapped the GAA locus to 17q23-q25. By study of somatic cell hybrids, Martiniuk et al. (1985) refined the regional localization of GAA to 17q21.2-q23. Combined with the assignment by Halley et al. (1984), this finding gives the smallest region of overlap (SRO) to be 17q23.
By fluorescence in situ hybridization, Kuo et al. (1996) mapped both GAA and the thymidine kinase gene (188300) to 17q25.2-q25.3 and showed that GAA is distal to TK1.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Multiple mutations in the GAA gene have been shown to cause glycogen storage disease II (GSD2; 232300). Martiniuk et al. (1986) tested cell lines of 2 infantile-onset patients with alpha-glucosidase deficiency with a cDNA with characteristics of acid alpha-glucosidase. In 1 of 2 cell lines, the 3.4-kb enzyme mRNA was not detectable, whereas in an adult-onset cell line, an mRNA of reduced size and amount was found. Examination of DNA digested with restriction enzymes did not reveal any major deletions in the genomic DNA of these patients.
Hoefsloot et al. (1988) found that acid maltase mRNA was absent in fibroblasts in 2 patients with glycogenosis type II. Van der Ploeg et al. (1989) demonstrated heterogeneity of this disease at the molecular level. Two affected infants from a consanguineous Indian family living in South Africa were found to have an acid alpha-glucosidase precursor of reduced size.
Wokke et al. (1995) studied 16 patients with adult-onset acid maltase deficiency. All the patients were compound heterozygotes carrying a T-to-G transversion at position -13 of intron 1 (IVS1-13T-G; 606800.0006). Three of these patients were asymptomatic at presentation, whereas symptoms began between ages 17 and 45 in the others. Symptomatic patients presented with abnormal fatigue and/or proximal weakness in the legs. All patients deteriorated when seen at follow-up. Creatine kinase was elevated between 1.5 and 15 times the upper limit of normal, EMG showed only myopathic changes in 8 of 13 patients, and skeletal muscle biopsy specimens were histologically and histochemically normal in 3 patients. A modest decrease of alpha-glucosidase activity was demonstrated in all muscle biopsy and peripheral blood specimens. Respiratory insufficiency was never a presenting complaint, but deterioration of vital capacity was demonstrable on follow-up. Overall, the clinical course resembled that of polymyositis or limb girdle muscular dystrophy.
In the family described by Koster et al. (1978) and Loonen et al. (1981), Kroos et al. (1997) demonstrated that the grandfather was a compound heterozygote for IVS1-13T-G and deletion of a single basepair, 525T (606800.0014); the affected third-generation offspring with severe disease was homozygous for c.525delT mutation. The disease phenotypes in this family were in accordance with the genotypes since the intronic mutation reduced acid alpha-glucosidase synthetase by 60 to 80%, whereas the single-nucleotide deletion completely prohibited formation of catalytically active enzyme.
Martiniuk et al. (1990) concluded that a minimum of 6 different mutations existed among 14 GAA-deficient cell lines (606800.0001). Martiniuk et al. (1998) analyzed genomic DNA from 928 randomly selected normal individuals for 7 of the most common mutations in the GAA gene. These 7 mutations account for 29% of the chromosomes from infantile- and adult-onset patients, in their experience. Various racial groups were represented. Three individuals who were heterozygotes for 1 of these mutations were found among the 928 normal individuals.
Ko et al. (1999) studied the molecular defect of the GAA gene in 11 unrelated Taiwanese families of Chinese origin in which at least 1 member had Pompe disease. They identified 7 different mutations in 17 alleles but failed to identify the defects in the other 5 alleles.
Three mutations in the GAA gene are common in the Dutch patient population: IVS1-13T-G (606800.0006), 525delT (606800.0014), and EX18DEL (606800.0012). Sixty-three percent of Dutch GSD II patients carry 1 or 2 of these mutations, and the genotype-phenotype correlation is known (Kroos et al., 1995).
Hermans et al. (2004) investigated 29 cases of type II glycogen storage disease and identified 55 pathogenic mutations of the GAA gene. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and 2 other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice site mutation was investigated by real-time PCR analysis. These analyses supported the notion that the clinical phenotype of GSD II is largely dictated by the nature of the mutations in the GAA alleles. Of the 29 patients with widely diverse ethnicity, 18 were classified as suffering from the infantile form, 9 were classified as juvenile, and 2 were of the adult type, 1 of them having onset presumably at the age of 65 years. The cases were classified as infantile when onset was in the first half year of life with cardiomegaly and less than 1.5 years survival. The juvenile form was used as a category when onset was after the first year, but before adulthood, and survival was prolonged. Adult type GSD II was onset after 20 years of age.
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 (606800.0006), present in heterozygosity in 34 (85%) of 40 patients (allele frequency 42.3%).
Gort et al. (2007) identified 23 GAA mutations, 9 of which were novel, among 22 Spanish patients with GSD II. The 2 most common mutations were splice site mutations (606800.0006 and 606800.0018), occurring at frequencies of 25% and 14%, respectively.
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.
De Faria et al. (2021) reported an update to the 2016 Pompe disease GAA variant database, which included a literature search of relevant articles up to January 2020. The updated database contained a total of 648 disease-associated mutations in the GAA gene, 26 mutations that were identified via newborn screening but with an unknown disease association, and 237 additional mutations with an unknown disease association. Of the 648 disease-associated mutations in the GAA gene, 336 could be associated with a clinical phenotype, including 266 patients with classic infantile disease, 11 patients with classic infantile or childhood disease, 32 patients with childhood disease, 15 patients with childhood or adult disease, and 12 patients with adult disease. Missense mutations were enriched in the catalytic core of the GAA enzyme. De Faria et al. (2021) additionally tested the enzyme activity of GAA with the following mutations in COS-7 cells: C103G, G219R, R224W, L552P, and R600C. All the mutations fully abrogated enzyme activity.
Aung-Htut et al. (2020) identified biallelic mutations in the GAA gene in 3 unrelated patients (patients 1, 2, and 9) with adult-onset Pompe disease. All 3 patients had compound heterozygous mutations in the GAA gene, with 1 of the mutations in each being the common IVS1-13T-G (606800.0006). The second mutation in patient 1 was Q692X (606800.0019), the second mutation in patient 2 was Leu637_Val639del (606800.0020), and the second mutation in patient 9 was P361R (606800.0021). Full-length GAA protein content was reduced in fibroblasts from all 3 patients.
Raben et al. (1998) found that Gaa-null mice accumulated glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter. By 3.5 weeks of age, these mice had markedly reduced mobility and strength. They grew normally, however, reached adulthood, remained fertile, and, as in the human adult disease, older mice accumulated glycogen in the diaphragm. By 8 to 9 months of age, the animals developed obvious muscle wasting and a weak, waddling gait.
Dennis et al. (2000) identified mutations in the bovine Gaa gene that led to generalized glycogenosis in the Brahman and Shorthorn breeds. All 3 mutations resulted in premature termination of translation. The authors also presented evidence for a missense mutation segregating with the Brahman population, which is responsible for a 70 to 80% reduction in alpha-glucosidase activity.
Using Gaa-knockout mice and transgenes containing cDNA for the human enzyme under muscle- or liver-specific promoters controlled by tetracycline, Raben et al. (2001) demonstrated that the liver provided enzyme far more efficiently. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising less than 5% of body weight, secreted 100-fold more enzyme, all of which was in the active 110-kD precursor form. Skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early.
DeRuisseau et al. (2009) found that Gaa-null mice had increased glycogen levels in cervical spinal cord motor neurons and larger soma size of phrenic neurons. Gaa-null mice had decreased ventilation during quiet breathing and under hypercapnic challenge compared to wildtype mice, indicating respiratory insufficiency. Mice with skeletal muscle-specific Gaa (MTP) expression showed normal diaphragm force generation similar to wildtype mice, but 30% decreased ventilation during quiet breathing, similar to Gaa-null mice. The compromised ventilation observed in both mutant mouse models was associated with decreased phrenic nerve motor output. Spinal cord samples from a patient with Pompe disease showed increased neuronal glycogen. DeRuisseau et al. (2009) suggested that respiratory impairment in individuals with Pompe disease results from a combination of muscular and neural deficits.
Douillard-Guilloux et al. (2010) analyzed the effect of a complete genetic elimination of glycogen synthesis in a murine GSDII model. Gaa/Gys1 (138570) double-knockout mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in Gaa/Gys1 double-knockout mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in Gaa/Gys1 double-knockout mice, resulting in improved exercise capacity. Douillard-Guilloux et al. (2010) concluded that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in the GSDII mouse model and offers a novel perspective for the treatment of Pompe disease.
Alpha-glucosidase (GAA) exhibits a genetic polymorphism, with 3 alleles (GAA*1, GAA*2, and GAA*4) segregating in the population. GAA*2 allozyme can be identified by starch-gel electrophoresis, since the enzyme has less affinity for the starch and thus migrates more rapidly to the anode despite its basic pI. Martiniuk et al. (1990) demonstrated a 271G-A transition in the GAA gene, resulting in an asp91-to-asn (D91N) substitution, as the basis for this feature. The bp substitution abolished a TaqI site.
In a patient with infantile-onset glycogen storage disease II (GSD2; 232300), Zhong et al. (1991) identified a 953T-C transition in the GAA gene, resulting in a met318-to-thr (M318T) substitution. The mutation was not detected in 37 additional GAA-deficient chromosomes. The patient was a genetic compound with the second allele expressing almost no GAA mRNA.
In 2 children affected with Pompe disease (GSD2; 232300) from a consanguineous Indian family, Hermans et al. (1991) identified a homozygous G-to-A transition in exon 11 of the GAA gene, resulting in a glu521-to-lys (E521K) substitution, just 3 amino acids downstream from the catalytic site of the enzyme at asp518. Both parents were heterozygous for the mutant allele. Functional expression studies showed that the E521K mutation caused abnormal physical properties of the enzyme precursor in the patients and prevented formation of a catalytically active enzyme.
In a patient with an adult form of glycogen storage disease type II (GSD2; 232300), case 1 reported by Trend et al. (1985), Hermans et al. (1993) demonstrated compound heterozygosity for 2 mutations in the GAA gene: a 1927G-A transition in exon 14, resulting in a gly643-to-arg (G643R) substitution, and a 2173C-T transition in exon 15, resulting in an arg725-to-trp (R725W; 606800.0005) substitution. Functional expression studies showed that neither mutation interfered with the synthesis of mutant enzyme precursors, but both were associated with impairment of intracellular transport and maturation. As a result, there was an overall deficiency of catalytic activity. Residual enzyme activity in the patient was at the 1 to 2% level.
For discussion of the 2173C-T transition in exon 15 of the GAA gene, resulting in an arg725-to-trp (R725W) substitution, that was found in compound heterozygous state in a patient with an adult form of glycogen storage disease II (GSD2; 232300) by Hermans et al. (1993), see 606800.0004.
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.
In 3 patients (patients 1, 2, and 9) with adult-onset Pompe disease, Aung-Htut et al. (2020) identified compound heterozygosity for the IVS1-13T-G mutation and 3 different mutations in the GAA gene. Patient 1 also carried a c.2074C-T transition resulting in a gln692-to-ter (Q692X; 606800.0019) early termination. Patient 2 also carried a 9-bp deletion (c.1910_1918del) resulting in deletion of residues Leu637_Val639 (606800.0020). Patient 9 also carried a c.1082C-G transversion resulting in a pro361-to-arg (P361R; 606800.0021) mutation. The mutations, which were identified by sequencing of DNA and RNA from patient fibroblasts, were confirmed by Sanger sequencing. Full-length GAA protein content was reduced in fibroblasts from all 3 patients.
For discussion of the lys903del mutation in the GAA gene that was found in compound heterozygous state in a patient with Pompe disease (GSD2; 232300) by Boerkoel et al. (1995), see 606800.0012.
For discussion of the leu299-to-arg (L299R) mutation in the GAA gene that was found in compound heterozygous state in a patient with Pompe disease (GSD2; 232300) by Boerkoel et al. (1995), see 606800.0012.
In a Japanese patient with adult-onset glycogen storage disease II (GSD2; 232300), Tsunoda et al. (1996) identified a change of nucleotides 1585 and 1586 from TC to GT in the GAA gene. The mutation resulted in a ser529-to-val (S529V) substitution. A study of transient expression of the mutant allele indicated that the S529V substitution resulted in loss of catalytic activity of the enzyme. The patient developed skeletal muscle weakness at 28 years.
Lin and Shieh (1996) identified a 1935C-A transversion at the 5-prime end of exon 14 in the GAA gene in 4 Chinese patients with the infantile form of Pompe disease (GSD2; 232300) in Taiwan. This change resulted in an asp645-to-glu (D645E) substitution. The mutation was found in 20 of 25 additional Chinese patients with Pompe disease, but not in 40 healthy controls. Lin and Shieh (1996) concluded that the D645E substitution is the main mutation responsible for Pompe disease in Chinese infants in Taiwan.
Shieh and Lin (1998) identified the D645E mutation in 19 of 25 Chinese Pompe patients in heterozygous or homozygous state. All the mutant alleles in these patients were linked to a specific haplotype, which had a frequency of 0.95 in the 19 Chinese patients and 0.17 in 42 healthy controls.
The normal population exhibits 3 genetic biochemical polymorphic GAA allozymes, GAA*1, GAA*2, and GAA*4, with gene frequencies of 0.9, 0.03, and 0.06, respectively. The molecular basis of the GAA*2 allozyme is a 271A-G transition (606800.0001) leading to a D91N amino acid substitution as compared with the more common GAA*1 allozyme. Huie et al. (1996) demonstrated that the molecular basis of the GAA*4 allozyme is a 2065G-A transition, predicting a glu689-to-lys (E689K) substitution.
Van der Kraan et al. (1994) reported that deletion of exon 18 of the GAA gene is a frequent mutation in Pompe disease (GSD2; 232300). Huie et al. (1994) found this mutation in patients with both infantile and adult forms of this disease. Vorgerd et al. (1998) found homozygosity for the exon 18 deletion in 2 affected sibs and an unrelated patient with adult-type GSD II.
Boerkoel et al. (1995) found a deletion of exon 18 of the GAA gene in 3 unrelated compound heterozygous patients, 2 of whom were infants, and 1 an adult. The second mutation in each of these patients was different. The infants with Pompe disease were French Canadian and Dutch. The adult was a woman of German extraction who had first consulted her physician at age 39 years for progressive proximal muscle weakness and respiratory insufficiency. In retrospect, she could recall limitation in her activity as far back as early adulthood. In one of the infants, there was deletion of lys903 (606800.0007); in the other, there was a leu299-to-arg substitution (606800.0008). In the adult, the authors observed a T-to-G transversion at position -13 of intron 1 (606800.0006).
Although Kroos et al. (1995) found deletion of exon 18 in the infantile and adult forms of the disease, those homozygous for this mutation and heterozygous for this mutation in combination with deletion of 525T (606800.0014) had the infantile form of Pompe disease; however, patients with deletion of exon 18 or deletion of 525T in combination with transversion of T to G at position -13 (606800.0006) had the juvenile or the adult form, suggesting that the intronic mutation was a mild mutation.
In a woman with adult-onset glycogen storage disease II (GSD2; 232300), Hermans et al. (1994) identified a homozygous 1634C-T transition in the GAA gene, resulting in a pro545-to-leu (P545L) substitution. She was diagnosed at age 42 years and died at age 51 years. This mutation was compatible with normal synthesis, but hindered enzyme activity and resulted in 92% loss of GAA activity. Another unrelated girl with juvenile-onset GSD II was compound heterozygous for P545L and 525delT (606800.0014).
In a girl with the juvenile form of Pompe disease (GSD2; 232300), Hermans et al. (1994) identified compound heterozygosity for 2 mutations in the GAA gene: P545L (606800.0013) and a 1-bp deletion (525delT), resulting in premature termination of the protein at nucleotide positions 658 to 660.
Kroos et al. (1995) reported that although the 525delT mutation was equally frequent (0.11 to 0.16) in all clinical forms of glycogen storage disease II, all 5 patients homozygous for this mutation had the infantile form with less than 1% GAA activity.
Becker et al. (1998) found a high frequency of the arg854-to-ter (R854X) mutation of the GAA gene in compound heterozygous or homozygous state in cases of glycogen storage disease II (GSD2; 232300) in various African populations and in African American patients.
In a patient with adult-onset glycogen storage disease II (GSD2; 232300), Anneser et al. (2005) identified compound heterozygosity for 2 mutations in the GAA gene: a 719C-T transition in exon 4, resulting in an ala237-to-val (A237V) substitution, and an 877G-A transition in exon 5, resulting in a gly293-to-arg (G293R; 606800.0017) substitution. Neither mutation was identified in 40 control individuals. The patient had dilatative angiopathy of the intracerebral vessels, especially of the basilar artery, with calcifications of the carotid and medial cerebral arteries, and had experienced several stroke-like episodes.
For discussion of the 877G-A transition in exon 5 of the GAA gene, resulting in a gly293-to-arg substitution, that was found in compound heterozygous state in a patient with adult-onset glycogen storage disease II (GSD2; 232300) by Anneser et al. (2005), see 606800.0016.
Gort et al. (2007) identified a G-to-C transversion in intron 6 of the GAA gene (1076-1G-C) in 14% of mutant alleles among 22 Spanish patients with glycogen storage disease II (GSD2; 232300). One patient who was homozygous for the mutation had severe infantile onset, with cardiomyopathy, cardiomegaly, and hepatomegaly.
For a discussion of the c.2074C-T transition (c.2074C-T, NM_000152.4) in the GAA gene resulting in a gln692-to-ter (Q692X) that was identified in compound heterozygous state in patient 1 with adult-onset glycogen storage disease II (GSD2; 232300) by Aung-Htut et al. (2020), see 606800.0006.
For a discussion of the 9-bp deletion (c.1910_1918del, NM_000152.4) in the GAA gene resulting in deletion of residues Leu637_Val639 that was identified in compound heterozygous state in patient 2 with adult-onset glycogen storage disease II (GSD2; 232300) by Aung-Htut et al. (2020), see 606800.0006.
For a discussion of the c.1082C-G transversion (c.1082C-G, NM_000152.4) in the GAA gene resulting in a pro361-to-arg (P361R) that was identified in compound heterozygous state in patient 9 with adult-onset glycogen storage disease II (GSD2; 232300) by Aung-Htut et al. (2020), see 606800.0006.
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