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 beta-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.
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 beta-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 acidoxidation 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 humanVLCAD gene are heterogeneous. Although mortality at presentation is high, both the metabolic disorder and cardiomyopathy are reversible.
Authors: Marcus J Miller; Lindsay C Burrage; James B Gibson; Meghan E Strenk; Edward J Lose; David P Bick; Sarah H Elsea; V Reid Sutton; Qin Sun; Brett H Graham; William J Craigen; Victor Wei Zhang; Lee-Jun C Wong Journal: Mol Genet Metab Date: 2015-09-02 Impact factor: 4.797
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Authors: S Gobin-Limballe; F Djouadi; F Aubey; S Olpin; B S Andresen; S Yamaguchi; H Mandel; T Fukao; J P N Ruiter; R J A Wanders; R McAndrew; J J Kim; J Bastin Journal: Am J Hum Genet Date: 2007-10-29 Impact factor: 11.025
Authors: Dingding Xiong; Huamei He; Jeanne James; Chonan Tokunaga; Corey Powers; Yan Huang; Hanna Osinska; Jeffrey A Towbin; Enkhsaikhan Purevjav; James A Balschi; Sabzali Javadov; Francis X McGowan; Arnold W Strauss; Zaza Khuchua Journal: Am J Physiol Heart Circ Physiol Date: 2013-11-27 Impact factor: 4.733