Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the gamma2-subunit of AMP-activated protein kinase.
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 gamma2 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.
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA, and Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
Hasan O
HO
Akman
James N
JN
Sampayo
Fiona A
FA
Ross
John W
JW
Scott
Gregory
G
Wilson
Lee
L
Benson
Claudio
C
Bruno
Sara
S
Shanske
D Grahame
DG
Hardie
Salvatore
S
Dimauro
D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004452:Echocardiography; D004562:Electrocardiography; D017809:Fatal Outcome; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006008:Glycogen Storage Disease / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007231:Infant, Newborn; D009097:Multienzyme Complexes / Q000235:genetics*; D009154:Mutation; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010764:Phosphorylase Kinase / Q000172:deficiency* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D009097:Multienzyme Complexes; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D006003:Glycogen; D010764:Phosphorylase Kinase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases