PGAM2 – Glycogen Storage Disease due to Phosphoglycerate Mutase Deficiency

Phosphoglycerate mutase 2 (PGAM2) deficiency is a rare metabolic myopathy that manifests primarily with exercise-induced myalgia, myoglobinuria, and muscle weakness. Multiple independent case reports and multi‐patient studies have established a strong association between PGAM2 and glycogen storage disease due to phosphoglycerate mutase deficiency (PMID:19783439, PMID:19273759). Evidence indicates that patients typically present in childhood or adulthood with episodic symptoms precipitated by strenuous activity.

Genetic investigations consistently reveal an autosomal recessive inheritance pattern. Diverse variant types including missense, nonsense, and frameshift mutations have been identified in unrelated probands. For example, the variant c.29G>A (p.Arg10Gln) exemplifies the reported genetic alterations and underscores the molecular heterogeneity of PGAM2 deficiency. Several studies report genetic findings in cohorts of 13 or more patients, with confirmatory segregation data across families (PMID:19783439).

The variant spectrum in PGAM2 encompasses both loss-of-function and hypomorphic alleles. Numerous case reports detail compound heterozygous changes, where different mutations co-occur to disrupt enzyme activity. Recurrent mutations, such as c.233G>A (p.Trp78Ter) in other reports, further reinforce the causal link. The detection of these variants across diverse ethnicities emphasizes the reproducibility of PGAM2’s contribution to the disease phenotype.

Functional evidence further solidifies the association. In vitro studies and animal models have demonstrated that mutations in PGAM2 lead to impaired glycolytic flux and altered myogenic differentiation. Specifically, experiments reveal that loss of proper PGAM2 function disturbs metabolic homeostasis in muscle cells (PMID:36589741), aligning well with the clinical phenotype observed in patients.

While some reports note atypical presentations or negative exercise testing results (PMID:30310767), the overall convergence of genetic and functional data leaves little doubt regarding the gene-disease relationship. Minor phenotypic variability does not detract from the well-established pathogenic mechanism driven by reduced phosphoglycerate mutase activity.

In conclusion, the robust genetic evidence, consistent segregation of pathogenic variants, and corroborative functional studies all support a strong gene-disease association. Key take‑home: incorporating PGAM2 sequencing into diagnostic panels is clinically valuable for early and accurate detection of glycogen storage disease due to phosphoglycerate mutase deficiency.

References

• Neuromuscular disorders : NMD • 2009 • Unusual presentation of phosphoglycerate mutase deficiency due to two different mutations in PGAM-M gene PMID:19783439
• Archives of neurology • 2009 • Muscle phosphoglycerate mutase deficiency revisited PMID:19273759
• Molecular genetics and metabolism reports • 2018 • Novel heterozygous mutations in the PGAM2 gene with negative exercise testing PMID:30310767
• Frontiers in cell and developmental biology • 2022 • Sumoylation-deficient phosphoglycerate mutase 2 impairs myogenic differentiation PMID:36589741

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