Submission Details

PYGL, glycogen storage disease VI (MONDO:0009294), autosomal recessive

PYGL was first described as a glycogen storage disorder (GSD)-causing gene in 1986 (Newgard et al. 1986, PMID: 2877458). The specific disease entity, glycogen storage disorder VI (also referred to as Hers disease) (MONDO:0009294, OMIM:613741), is one of at least 15 different glycogen storage disorders which affect the body and its ability to correctly use or store glycogen. Some of the most common patient phenotypes are: Hepatomegaly, hypoglycemia, growth retardation, weight retardation, elevated hepatic transaminase levels, accumulation of glycogen in the liver cells/hepatocytes and response to the use of cornstarch supplements to prevent hypoglycemia.

Twenty-six variants: (Canonical Splice Site (8 variants), Missense (10 variants), Nonsense (6 variants), Multi-Exon Deletion (1 variant), Frameshift (1 variant)) that have been reported in 25 probands and 1 family in 11 publications (PMIDs: 9529348, 9536091, 32268899, 33879691, 32961316, 28984260, 32892177, 34026552, 36105079, 32374048, 37264426) are included in this curation.

Many of the probands were diagnosed during childhood after experiencing symptoms including hepatomegaly, hypoglycemia, growth retardation, weight retardation or elevated transaminase and aminotransferase levels. However, their symptoms were largely able to be controlled through dietary changes or ingesting dosages of cornstarch. Siblings of the probands were also found to be affected to varying degrees of severity.

Overall, the mechanism of pathogenicity appears to be loss of function as shown in the probands.

This gene-disease relationship is also supported by multiple forms of experimental evidence such as Expression A (Quantity: 1), Biochemical Function B (Quantity: 1), Biochemical Function A (Quantity: 1) and Non-Human Model: Mouse (Quantity: 1) (PMIDs: 25613900, 34939084, 30659246 and 31701076). First, ProteinAtlas data showed high levels of expression of PYGL in the liver, which is consistent with the liver-related features of GSD0 (PMID:25613900). Next, Chen et al. 2022 (34939084) documented that the addition of wild-type PYGL to HEK293T cells caused a dramatic increase in glycogen phosphorylase activity (Figure 6B). Kishnani et al 2019 (PMID: 30659246) describes how both PYGL and PHKG2 are involved with glycogen breakdown in the liver. Additionally, PHKG2 probands have very similar phenotypes to PYGL including hepatomegaly, growth retardation, elevated serum transaminases, increased liver glycogen and liver fibrosis. PHKG2 was classified as having a "definitive" relationship with glycogen storage disease IXc by the General Inborn Errors of Metabolism GCEP. Lastly, Wilson et al 2019 describes a mouse model. This mouse model recapitulates many of the phenotypes seen in the human probands. The mouse model had hepatomegaly which recapitulates the same phenotype that is seen in the human proband. Both the mouse model and the human patients displayed abnormal hepatic glycogen storage. Additionally, the model also displayed hypoglycemia, just like the human probands (PMID: 31701076).

In conclusion, PYGL is definitively associated with glycogen storage disorder VI (also referred to as Hers disease). This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time.

This classification was approved by the General IEM GCEP on September 27th, 2024 (SOP Version 10).