title: Primary carnitine deficiency and sudden death: in vivo evidence of myocardial lipid peroxidation and sulfonylation of sarcoendoplasmic reticulum calcium ATPase 2.
abstract: OBJECTIVE
  Primary carnitine deficiency is an autosomal recessive disorder caused by mutations in the SLC22A5 gene which results in impaired carnitine transport, cytosolic fatty acid accumulation and impaired beta oxidation. The disease is associated with cardiomyopathy and arrhythmias, but the mechanism is unknown. We hypothesized that carnitine deficiency results in increased myocardial oxidative stress.
  
  
  METHODS
  We evaluated a 22-year-old woman with primary carnitine deficiency and ventricular fibrillation, as well as her first-degree relatives.
  
  
  RESULTS
  Sequencing of SLC22A5 identified two deleterious mutations (A142S and R488H) and a novel mutation predicted to be a splice variant. Histology demonstrated increased myocardial lipid deposition and swollen mitochondria. Immunohistochemistry demonstrated accumulation of the reactive aldehyde 4-hydroxy-2-nonenal, indicative of increased lipid peroxidation, and sulfonylation of sarcoendoplasmic reticulum calcium ATPase 2 at cysteine 674.
  
  
  CONCLUSIONS
  These findings suggest that increased oxidant stress may contribute to myocardial dysfunction and arrhythmogenesis in this disorder.
authors: Cardiac Electrophysiology Section and Cardiovascular Medicine Section, Boston University Medical Center, Boston, MA 02118, USA. michael.mazzini@bmc.org
authors: M
authors: M
authors: Mazzini
authors: T
authors: T
authors: Tadros
authors: D
authors: D
authors: Siwik
authors: L
authors: L
authors: Joseph
authors: M
authors: M
authors: Bristow
authors: F
authors: F
authors: Qin
authors: R
authors: R
authors: Cohen
authors: K
authors: K
authors: Monahan
authors: M
authors: M
authors: Klein
authors: W
authors: W
authors: Colucci
mesh_terms: D009202:Cardiomyopathies / Q000235:genetics*; D002331:Carnitine / Q000172:deficiency / Q000235:genetics; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D017147:Defibrillators, Implantable; D004562:Electrocardiography; D005260:Female; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics*; D015227:Lipid Peroxidation / Q000235:genetics; D009135:Muscular Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D010375:Pedigree; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D000074058:Solute Carrier Family 22 Member 5; D014693:Ventricular Fibrillation / Q000235:genetics / Q000628:therapy; D055815:Young Adult
chemical_list: D027701:Organic Cation Transport Proteins; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002331:Carnitine