title: Adenosine monophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: natural history.
abstract: OBJECTIVE
  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.
authors.affiliation: The Heart Hospital, University College London, London, United Kingdom.
authors.forename: Ross T
authors.initials: RT
authors.lastname: Murphy
authors.forename: Jens
authors.initials: J
authors.lastname: Mogensen
authors.forename: Kate
authors.initials: K
authors.lastname: McGarry
authors.forename: Ajay
authors.initials: A
authors.lastname: Bahl
authors.forename: Alison
authors.initials: A
authors.lastname: Evans
authors.forename: Eyman
authors.initials: E
authors.lastname: Osman
authors.forename: Petros
authors.initials: P
authors.lastname: Syrris
authors.forename: Grainne
authors.initials: G
authors.lastname: Gorman
authors.forename: Michael
authors.initials: M
authors.lastname: Farrell
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.forename: Sian
authors.initials: S
authors.lastname: Hughes
authors.forename: Perry M
authors.initials: PM
authors.lastname: Elliott
authors.forename: Calum A
authors.initials: CA
authors.lastname: Macrae
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
mesh_terms: D055372:AMP-Activated Protein Kinases; D000293:Adolescent; D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis* / Q000201:enzymology* / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D017147:Defibrillators, Implantable; D003937:Diagnosis, Differential; D004452:Echocardiography; D015716:Electrocardiography, Ambulatory; D022062:Electrophysiologic Techniques, Cardiac; D017079:Exercise Tolerance / Q000502:physiology; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006329:Heart Conduction System / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014927:Wolff-Parkinson-White Syndrome / Q000175:diagnosis* / Q000201:enzymology* / Q000628:therapy
chemical_list: D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases