Submission Details

The PYGM gene, gene encodes the muscle isoform of the enzyme glycogen phosphorylase involved in glycogenolysis, which catalyses the breakdown of glycogen into glucose-1-phosphate, to be utilized within the muscle cell (PMID:17915571). Decreased or completely absent activity of muscle glycogen phosphorylase has been observed with mutations in the PYGM gene and result in McArdle disease or Glycogen Storage Disease Type V (GSD-V; MIM # 232600). (PMID:12031624,18667317). Clinical features of GSD- V include exercise intolerance with fatigue, cramps, myalgia, ‘second-wind’ phenomenon (characterized by the ability to resume exercise with less difficulty, following a short period of rest at the first appearance of fatigue), moderate to high levels of serum creatine kinase (CK) at rest, and episodic myoglobinuria (PMID:18667317, 34373715). GSD -V is inherited in an autosomal recessive inheritance pattern and seen to exhibit genetic heterogeneity. The mode of inheritance of McArdle disease is autosomal-recessive. Summary of case- based evidence: The first variants in the PYGM gene were identified in 1993 with few such as, nonsense mutation in the first exon (R50X) which is the most frequent mutation in Caucasians (PMID:8316268, 11809171). Thirteen unique variants, including missense, splice site, deletions, frameshift mutations and insertion, have been documented in individuals, both families and unrelated individuals across 13 publications (PMIDs:18667317, 34373715, 11809171, 25873271, 12031624, 35022222, 15262743, 37701325, 25240406, 37760875, 31747538, 32075227) are included in this curation. Summary of Experimental evidence: Studies on knock-in (p.R50X/p.R50X) mouse disease model analysed for maximal endurance exercise capacity and the molecular consequences of an absence of enzyme, showed that the levels of this enzyme were also significantly lower in homozygous and heterozygous mutant mice compared to wild type in three types of muscles (slow-twitch: soleus, intermediate twitch: gastrocnemius and fast twitch: Extensor digitorum longus muscles). Similar results were found for PYGM transcript levels for both the genotype and muscle effect (PMID: 25873271). Further, study on gene knockdown resulted in a reduced enzyme levels in zebrafish morphants, with features such as altered muscle structural changes and accumulation of glycogen granules in the subsarcolemmal region mimicking the symptoms of GSD-V in humans (PMID: 31747538). Further, human iPSC-based skeletal muscle model derived from a McArdle patient and a healthy control were both successfully differentiated into skeletal muscle cells. The created McArdle skeletal muscle model showed the absence of enzyme and the generated patient iPSC-based skeletal muscle model mimicked the main biochemical aspects of McArdle disease (PMID:37760875). A study on enzyme expression in white blood cells (WBCs), it was found that T lymphocytes expressed the enzyme in healthy donors, but expression was significantly lower in McArdle patients (p<0.001). PYGM mRNA levels were also lower in white blood cells from McArdle patients (PMID:25240406). The activity of enzyme in muscle homogenate of McArdle patients was extremely reduced. Also, histochemical staining of enzyme in tested biopsies showed no or minimal enzyme activity in comparison to healthy controls along with marked sub-sarcolemmal glycogen deposition in Periodic acid-Schiff (PAS) staining (PMID:32075227). Finally, a study on effects of fatiguing activity on glycogen and glycogen phosphorylase associated with sarcoplasmic reticulum demonstrated that glycogen and glycogen phosphorylase enzyme associated with skeletal muscle sarcoplasmic reticulum are reduced after fatiguing activity. (PMID:1156145). In summary, PYGM is definitively associated with autosomal recessive Glycogen Storage Disease type V and the same has been demonstrated in both the cases diagnosed and experimental studies. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date [February 28, 2025] (SOP Version 10).