PYGM – Glycogen storage disease V (McArdle disease)

Glycogen storage disease V (McArdle disease) is an autosomal recessive metabolic myopathy caused by deficiency of the muscle glycogen phosphorylase encoded by the PYGM gene ([HGNC:9726]). Affected individuals present in childhood or early adulthood with exercise intolerance, muscle cramps, and recurrent myoglobinuria, often accompanied by elevated resting creatine kinase levels and a characteristic flat lactate response on forearm ischemic exercise testing ([PMID:25914343]).

Autosomal recessive inheritance is supported by numerous reports of homozygous and compound heterozygous PYGM variants in unrelated pedigrees, with clear segregation in multi‐family studies (e.g., siblings homozygous for c.2392T>C (p.Trp798Arg) and compound heterozygotes for p.Asp511fs/p.Phe710del) and absence of symptoms in heterozygous carriers ([PMID:21802952]). Pedigree analyses document at least 19 additional affected relatives with segregating variants.

To date, over 147 pathogenic PYGM mutations have been described, encompassing nonsense (e.g., c.148C>T (p.Arg50Ter)), missense (e.g., c.613G>A (p.Gly205Ser)), small insertions/deletions (e.g., c.1531del (p.Asp511fs)), and splice‐site changes ([PMID:25914343]; [PMID:21802952]). The common p.Arg50Ter allele accounts for 43–68% of mutated alleles in Caucasian cohorts, while other variants show population specificity without clear genotype–phenotype correlation.

Functional studies demonstrate that premature termination codon (PTC) mutations such as p.Arg50Ter elicit nonsense‐mediated mRNA decay, reducing PYGM transcript levels by >90% in patient muscle ([PMID:17994553]). In vitro cell models expressing PYGM cDNA show absent or unstable myophosphorylase protein for PTC and misfolded missense variants, with no detectable AMP‐independent activity and partial restoration upon aminoglycoside‐induced read‐through in engineered constructs ([PMID:22818872]).

Integration of genetic and functional data supports a Strong gene–disease association: autosomal recessive segregation in >123 unrelated patients, consistent biochemical deficiency, and replication across populations. The genetic evidence reaches ClinGen Strong (over 100 pathogenic variants in >123 probands; multi‐family segregation; AR inheritance), and functional assays provide Moderate support (demonstrated NMD and protein instability).

Key take‐home: PYGM variant analysis, combined with forearm exercise testing and muscle biopsy, enables definitive diagnosis of McArdle disease, guiding genetic counseling and targeted management.

References

• Human mutation • 2015 • McArdle Disease: Update of Reported Mutations and Polymorphisms in the PYGM Gene PMID:25914343
• Neuromuscular disorders • 2011 • Molecular and clinical study of McArdle's disease in a cohort of 123 European patients. Identification of 20 novel mutations. PMID:21802952
• Human mutation • 2008 • Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay. PMID:17994553
• Neuromuscular disorders • 2013 • Cell models for McArdle disease and aminoglycoside-induced read-through of a premature termination codon. PMID:22818872

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