title: A heterozygous missense mutation in adolescent-onset very long-chain acyl-CoA dehydrogenase deficiency with exercise-induced rhabdomyolysis.
abstract: Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is characterized by impaired mitochondrial β-oxidation of fatty acids. The fatty acid oxidation plays a significant role in energy production especially in skeletal muscle. VLCAD is one of four acyl-CoA dehydrogenases with different-chain length specificity and catalyzes the initial step in mitochondrial β-oxidation of fatty acids. While the clinical phenotypes in neonates and infants are described as severe, adolescent-onset or adult-onset VLCAD deficiency has a more benign course with only skeletal muscle involvement. These myopathic phenotypes are characterized by episodic muscle weakness and rhabdomyolysis triggered by fasting and strenuous exercise. We report a male teenager who manifested repeated episodes of rhabdomyolysis immediately after exertional exercise. Rhabdomyolysis was diagnosed based on the marked elevation of serum creatine kinase and myoglobinuria. Acylcarnitine analysis by tandem mass spectrometry (MS/MS) revealed elevation of serum tetradecenoylcarnitine (C14:1-AC), which represents an abnormal acylcarnitine profile associated with the mitochondrial β-oxidation defect. High performance liquid chromatographic analysis showed decreased production of 2-hexadecenoyl-CoA (C16:1) from palmitoyl-CoA (C16:0), indicating the defect of VLCAD activity. Direct sequencing of the acyl-CoA dehydrogenase, very long-chain gene (ACADVL) that codes VLCAD revealed a heterozygous mutation (c.1242G>C) in exon 12 (E414D), which is a novel mutation in myopathic-type VLCAD deficiency. Because VLCAD functions as a homodimer, we assume that this heterozygous mutation may exhibit dominant-negative effect. This patient remains asymptomatic thereafter by avoiding exertional exercise. The findings of reduction of enzyme activity and clinical features associated with this novel missense mutation of VLCAD are discussed.
authors.affiliation: Department of Neurology, School of Medicine, Sapporo Medical University.
authors.forename: Shin
authors.initials: S
authors.lastname: Hisahara
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Furuyama
authors.forename: Go
authors.initials: G
authors.lastname: Tajima
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Shigematsu
authors.forename: Tomihiro
authors.initials: T
authors.lastname: Imai
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000097:blood / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D000080984:Congenital Bone Marrow Failure Syndromes; D015444:Exercise; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D028361:Mitochondrial Diseases / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012206:Rhabdomyolysis / Q000150:complications* / Q000209:etiology*; D016415:Sequence Alignment
chemical_list: C116917:acylcarnitine; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine