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(Circulation. 1999;99:1337-1343.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Molecular Heterogeneity in Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency Causing Pediatric Cardiomyopathy and Sudden Death

Amit Mathur, MBBS, MD, MRCP; Harold F. Sims, BA; Deepika Gopalakrishnan, MBBS, MD; Beverly Gibson, BS; Piero Rinaldo, MD; Jerry Vockley, MD, PhD; George Hug, MD; Arnold W. Strauss, MD

From the Departments of Pediatrics (A.M., H.F.S., B.G., A.W.S.), Medicine (D.G.), and Molecular Biology and Pharmacology (A.W.S.), Washington University School of Medicine and St Louis Children's Hospital, Mo; the Departments of Laboratory (P.R.) and Medical Genetics (J.V.), Mayo Clinic, Rochester, Minn; and the Department of Pediatrics, Cincinnati Children's Hospital and Medical Center (G.H.), Cincinnati, Ohio.

Correspondence to Arnold W. Strauss, MD, St. Louis Children's Hospital, One Children's Place, St Louis, MO 63110. E-mail strauss{at}kids.wustl.edu

Background—Genetic defects are being increasingly recognized in the etiology of primary cardiomyopathy (CM). Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first step in the ß-oxidation spiral of fatty acid metabolism, the crucial pathway for cardiac energy production.

Methods and Results—We studied 37 patients with CM, nonketotic hypoglycemia and hepatic dysfunction, skeletal myopathy, or sudden death in infancy with hepatic steatosis, features suggestive of fatty acid oxidation disorders. Single-stranded conformational variance was used to screen genomic DNA. DNA sequencing and mutational analysis revealed 21 different mutations on the VLCAD gene in 18 patients. Of the mutations, 80% were associated with CM. Severe CM in infancy was recognized in most patients (67%) at presentation. Hepatic dysfunction was common (33%). RNA blot analysis and VLCAD enzyme assays showed a severe reduction in VLCAD mRNA in patients with frame-shift or splice-site mutations and absent or severe reduction in enzyme activity in all.

Conclusions—Infantile CM is the most common clinical phenotype of VLCAD deficiency. Mutations in the human VLCAD gene are heterogeneous. Although mortality at presentation is high, both the metabolic disorder and cardiomyopathy are reversible.

Key Words: cardiomyopathy • death, sudden • fatty acids • genetics • metabolism

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