Author + information
- Received June 14, 2004
- Revision received October 18, 2004
- Accepted November 22, 2004
- Published online March 15, 2005.
- Ross T. Murphy, MD,
- Jens Mogensen, MD, PhD,
- Kate McGarry, MD,
- Ajay Bahl, MD,
- Alison Evans, PhD,
- Eyman Osman, BSc,
- Petros Syrris, PhD,
- Grainne Gorman, MRCPI,
- Michael Farrell, FRCPI,
- Janice L. Holton, PhD,
- Michael G. Hanna, MD,
- Sian Hughes, PhD,
- Perry M. Elliott, MD, FACC,
- Calum A. MacRae, MB, ChB and
- William J. McKenna, MD, FACC* ()
- ↵*Reprint requests and correspondence:
Dr. William J. McKenna, The Heart Hospital, 16-18 Westmoreland Street, London W1G 8PH, United Kingdom
Objectives The aim of this study was to investigate the clinical expression of adenosine monophosphate-activated protein kinase (AMPK) gene mutations (PRKAG2) in adenosine monophosphate (AMP) kinase disease based on 12 years follow-up of known mutation carriers and to define the prevalence of PRKAG2 mutations in hypertrophic cardiomyopathy (HCM).
Background Adenosine monophosphate-activated protein kinase gene mutations cause HCM with Wolff-Parkinson-White syndrome and conduction disease.
Methods Clinical evaluation of 44 patients with known AMP kinase disease was analyzed. Mutation analysis of PRKAG2 was performed by fluorescent single-strand confirmation polymorphism analysis and direct sequencing of abnormal conformers in 200 patients with HCM.
Results Only one additional mutation was identified. The mean age at clinical diagnosis in the 45 gene carriers was 24 years (median 20 years, range 9 to 55 years). Symptoms of palpitation, dypspnea, chest pain, or syncope were present in 31 (69%) gene carriers; 7 (15%) complained of myalgia and had clinical evidence of proximal myopathy. Skeletal muscle biopsy showed excess mitochondria and ragged red fibers with minimal glycogen accumulation. Disease penetrance defined by typical electrocardiogram abnormalities was 100% by age 18 years. Thirty-two of 41 adults (78%) had left ventricular hypertrophy (LVH) on echocardiography, and progressive LVH was documented during follow-up. Survival was 91% at a mean follow-up of 12.2 years. Progressive conduction disease required pacemaker implantation in 17 of 45 (38%) at a mean age of 38 years.
Conclusions The AMP kinase disease is uncommon in HCM and is characterized by progressive conduction disease and cardiac hypertrophy and includes extracardiac manifestations such as a skeletal myopathy, consistent with a systemic metabolic storage disease. Defects in adenosine triphosphate utilization or in specific cellular substrates, rather than mere passive deposition of amylopectin, may account for these clinical features.
Drs. Murphy, Mogensen, and McKenna were supported by the British Heart Foundation. Dr. Murphy also received a Postgraduate Traveling Fellowship from the University of Dublin, Trinity College.
- Received June 14, 2004.
- Revision received October 18, 2004.
- Accepted November 22, 2004.
- American College of Cardiology Foundation