G6PC – Glycogen Storage Disease I

Glycogen storage disease type Ia (GSDIa) is an autosomal recessive metabolic disorder caused by deficiency of glucose-6-phosphatase, leading to severe fasting hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and hepatomegaly. Pathogenic variants in the G6PC gene underlie GSDIa (Glycogen storage disease I). Early detection of G6PC mutations is critical to avoid invasive liver biopsy and to guide dietary and molecular therapies.

1. Clinical Validity

Extensive genetic studies demonstrate a definitive association between G6PC and GSDIa. Over 40 probands were analyzed in a cohort study ([PMID:10612834]), 48 unrelated patients in France ([PMID:11058903]), and 130 Chinese patients in a genotype–phenotype correlation ([PMID:12373566]), all showing autosomal recessive segregation and concordant enzyme deficiency. Molecular analyses in >200 patients across >100 families and decades of functional concordance support a Definitive ClinGen classification.

2. Genetic Evidence

Inheritance in GSDIa is Autosomal recessive. Segregation analyses confirm bi-allelic G6PC variants in multiple families. Case series have identified >80 unique variants including missense, nonsense, frameshift, and splice site changes. Notable missense and founder variants include c.727G>T (p.Leu216=) prevalent in East Asian cohorts and c.248G>A (p.Arg83His) in Ashkenazi Jewish patients. A representative variant is c.14T>G (p.Met5Arg), observed in a composite heterozygote presenting with acute gout and hepatomegaly ([PMID:12713862]).

3. Functional Evidence

Enzymatic assays of G6Pase mutants (p.Trp77Arg, p.Ala124Thr, p.Gln347Ter, p.Asp38Val) expressed in COS-7 cells demonstrate complete loss of activity ([PMID:10738525]). Mouse G6pc−/− models recapitulate hypoglycemia and hepatosteatosis, and treatments such as fenofibrate reduce hepatic glycogen and lipid accumulation ([PMID:31816064]). Splice-switching oligonucleotide DS-4108b corrects aberrant splicing of the c.648G>T allele, restores hepatic G6Pase activity, and prevents hypoglycemia and liver pathology in knock-in mice ([PMID:37788110]).

4. Conflicting Evidence

No studies have refuted the G6PC–GSDIa link. Variability in age at diagnosis and phenotypic severity is attributed to metabolic control, modifier genes, and environmental factors rather than alternative disease mechanisms.

5. Integration & Conclusion

The combination of consistent autosomal recessive inheritance, segregation in diverse populations, a broad spectrum of loss-of-function variants, and robust functional assays establishes Definitive clinical validity for G6PC in GSDIa. Genetic testing of G6PC enables precise diagnosis, informs family planning, and guides emerging molecular therapies, including gene editing and oligonucleotide splicing correction.

Key Take-home: Bi-allelic G6PC variants cause GSDIa via haploinsufficiency; early molecular diagnosis and targeted functional therapies can prevent life-threatening complications.

References

• Diagnostic molecular pathology • 1998 • Heteroduplex analysis: a useful screening method for glycogen storage disease type Ia. [PMID:9785010]
• Human mutation • 1999 • Identification of three novel mutations (Q54P, W70X and T108I) in the glucose-6-phosphatase gene of patients with glycogen storage disease type Ia. [PMID:10447271]
• Annals of human genetics • 1999 • Enzymatic characterization of four new mutations in the glucose-6 phosphatase (G6PC) gene which cause glycogen storage disease type 1a. [PMID:10738525]
• Human mutation • 2000 • Molecular genetic analysis of 40 patients with glycogen storage disease type Ia: 100% mutation detection rate and 5 novel mutations. [PMID:10612834]
• Human molecular genetics • 2020 • Fenofibrate rapidly decreases hepatic lipid and glycogen storage in neonatal mice with glycogen storage disease type Ia. [PMID:31816064]
• The Journal of clinical investigation • 2023 • A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T. [PMID:37788110]

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