PYGL – Glycogen Storage Disease Type VI

Glycogen storage disease type VI (GSD VI; Hers disease) is an autosomal recessive disorder characterized by hepatic glycogen phosphorylase deficiency due to biallelic variants in PYGL. Patients typically present in infancy or early childhood with hepatomegaly, fasting hypoglycemia, elevated transaminases, growth retardation and hypertriglyceridemia (HP:0002240, HP:0003162, HP:0001508, HP:0004322, HP:0002155) and may develop hepatic fibrosis or cirrhosis over time (HP:0001395).

The initial identification of PYGL as the GSD VI gene was reported in three unrelated patients harboring two splice-site mutations (c.1768+1G>A, c.529-1G>C) and two conserved missense changes, including c.1016A>G (p.Asn339Ser) (PMID:9529348). Linkage in a Mennonite kindred (multipoint LOD 4.7) and subsequent confirmation of a splice-donor abnormality established autosomal recessive inheritance and provided early segregation evidence (PMID:9536091).

Multiple case series and cohort studies have expanded the variant spectrum to over 54 unique PYGL alleles. A homozygous splice variant c.345G>A (p.Gln115=) was shown by transcriptome analysis to cause exon 2 skipping in two Turkish families, correlating with recurrent hypoglycemia, hepatomegaly and short stature (PMID:33809020).

A systematic literature review identified 63 genetically confirmed GSD VI patients (median age 1.8 years at presentation) with diverse genotypes and phenotypes, underscoring clinical heterogeneity and broadening the natural history of disease (PMID:34440378). Liver biopsies in 37 patients revealed glycogen accumulation in 89%, fibrosis in 32%, and early cirrhosis in 11% of cases.

Recurrent or founder variants include a 3.6-kb deletion spanning exons 14–17 (allele frequency 0.016% in a Chinese cohort) and p.Arg172Ter, both contributing to a higher population-specific diagnostic yield (PMID:32961316).

Functional studies demonstrate that splice-site variants lead to aberrant mRNA and protein truncation, while missense changes (e.g., p.Arg399Ter, p.Asp634His) disrupt substrate or cofactor binding, supporting a loss-of-function mechanism consistent with enzymatic deficiency in patient liver tissue (PMID:17705025).

In summary, robust genetic and experimental evidence definitively link PYGL deficiency to GSD VI. Early molecular diagnosis enables dietary management with frequent feeds or uncooked cornstarch to prevent hypoglycemia and improve growth. ### Key Take-home: Genetic confirmation of PYGL variants informs treatment and prognosis in GSD VI.

References

• American journal of human genetics • 1998 • Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI PMID:9529348
• Human molecular genetics • 1998 • Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI PMID:9536091
• Diagnostics (Basel, Switzerland) • 2021 • Identification and Characterization of a Novel Splice Site Mutation Associated with Glycogen Storage Disease Type VI in Two Unrelated Turkish Families PMID:33809020
• Genes • 2021 • The Phenotypic and Genetic Spectrum of Glycogen Storage Disease Type VI PMID:34440378
• The Journal of molecular diagnostics : JMD • 2020 • A Novel, Recurrent, 3.6-kb Deletion in the PYGL Gene Contributes to Glycogen Storage Disease Type VI PMID:32961316
• Journal of inherited metabolic disease • 2007 • High frequency of missense mutations in glycogen storage disease type VI PMID:17705025

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