Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the γ2-subunit of AMP-activated protein kinase

Hasan O. Akman, James N. Sampayo, Fiona A. Ross, John W. Scott, Gregory Wilson, Lee Benson, Claudio Bruno, Sara Shanske, D. Grahame Hardie, Salvatore DiMauro

Research output: Contribution to journalArticlepeer-review

Abstract

A 10-wk-old infant girl with severe hypertrophy of the septal and atrial walls by cardiac ultrasound, developed progressive ventricular wall thickening and died of aspiration pneumonia at 5 mo of age. Postmortem examination revealed ventricular hypertrophy and massive atrial wall thickening due to glycogen accumulation. A skeletal muscle biopsy showed increased free glycogen and decreased activity of phosphorylase b kinase (PHK). The report of a pathogenic mutation (R531Q) in the gene (PRKAG2) encoding the γ2 subunit of AMP-activated protein kinase (AMPK) in three infants with congenital hypertrophic cardiomyopathy, glycogen storage, and "pseudo PHK deficiency" prompted us to screen this gene in our patient. We found a novel (R384T) heterozygous mutation in PRKAG2, affecting an arginine residue in the N-terminal AMP-binding domain. Like R531Q, this mutation reduces the binding of AMP and ATP to the isolated nucleotide-binding domains, and prevents activation of the heterotrimer by metabolic stress in intact cells. The mutation was not found in DNA from the patient's father, the only available parent, and is likely to have arisen de novo. Our studies confirm that mutations in PRKAG2 can cause fatal infantile cardiomyopathy, often associated with apparent PHK deficiency.

Original languageEnglish
Pages (from-to)499-504
Number of pages6
JournalPediatric Research
Volume62
Issue number4
DOIs
Publication statusPublished - Oct 2007

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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