PRKAG2 – Lethal Congenital Glycogen Storage Disease of Heart

Fatal congenital nonlysosomal cardiac glycogenosis presents with fetal symptomatic onset, massive myocardial glycogen accumulation, and rapid progression to death. Diagnosis was confirmed in three unrelated infants harboring a recurrent heterozygous c.1592G>A (p.Arg531Gln) variant in PRKAG2, encoding the γ2 regulatory subunit of AMP-activated protein kinase (PMID:15877279). Functional assays of the recombinant R531Q mutant demonstrated a >100-fold reduction in AMP and ATP binding affinities accompanied by enhanced basal kinase activity and increased α-subunit phosphorylation, consistent with a dominant gain-of-function mechanism. Although no mutations were found in genes encoding phosphorylase kinase or glycogen phosphorylase, not all affected infants carried the PRKAG2 variant, indicating genetic heterogeneity in lethal congenital cardiac glycogenosis.

Key take-home: The PRKAG2 c.1592G>A (p.Arg531Gln) variant causes an autosomal dominant, neonatal-onset fatal cardiac glycogen storage disease and should be included in genetic testing panels for congenital cardiomyopathies.

References

• American journal of human genetics • 2005 • Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. PMID:15877279

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