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A heterozygous missense mutation in adolescent-onset very long-chain acyl-CoA dehydrogenase deficiency with exercise-induced rhabdomyolysis.
Tohoku J Exp Med. 2015 04; 235(4):305-10.TJ

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+Show Affiliations

Department of Neurology, School of Medicine, Sapporo Medical University.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25843429

Citation

Hisahara, Shin, et al. "A Heterozygous Missense Mutation in Adolescent-onset Very Long-chain acyl-CoA Dehydrogenase Deficiency With Exercise-induced Rhabdomyolysis." The Tohoku Journal of Experimental Medicine, vol. 235, no. 4, 2015, pp. 305-10.
Hisahara S, Matsushita T, Furuyama H, et al. A heterozygous missense mutation in adolescent-onset very long-chain acyl-CoA dehydrogenase deficiency with exercise-induced rhabdomyolysis. Tohoku J Exp Med. 2015;235(4):305-10.
Hisahara, S., Matsushita, T., Furuyama, H., Tajima, G., Shigematsu, Y., Imai, T., & Shimohama, S. (2015). A heterozygous missense mutation in adolescent-onset very long-chain acyl-CoA dehydrogenase deficiency with exercise-induced rhabdomyolysis. The Tohoku Journal of Experimental Medicine, 235(4), 305-10. https://doi.org/10.1620/tjem.235.305
Hisahara S, et al. A Heterozygous Missense Mutation in Adolescent-onset Very Long-chain acyl-CoA Dehydrogenase Deficiency With Exercise-induced Rhabdomyolysis. Tohoku J Exp Med. 2015;235(4):305-10. PubMed PMID: 25843429.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A heterozygous missense mutation in adolescent-onset very long-chain acyl-CoA dehydrogenase deficiency with exercise-induced rhabdomyolysis. AU - Hisahara,Shin, AU - Matsushita,Takashi, AU - Furuyama,Hiroyasu, AU - Tajima,Go, AU - Shigematsu,Yosuke, AU - Imai,Tomihiro, AU - Shimohama,Shun, PY - 2015/4/7/entrez PY - 2015/4/7/pubmed PY - 2015/12/15/medline SP - 305 EP - 10 JF - The Tohoku journal of experimental medicine JO - Tohoku J. Exp. Med. VL - 235 IS - 4 N2 - 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. SN - 1349-3329 UR - https://www.unboundmedicine.com/medline/citation/25843429/A_heterozygous_missense_mutation_in_adolescent_onset_very_long_chain_acyl_CoA_dehydrogenase_deficiency_with_exercise_induced_rhabdomyolysis_ L2 - https://doi.org/10.1620/tjem.235.305 DB - PRIME DP - Unbound Medicine ER -