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Multiple acyl-COA dehydrogenase deficiency in elderly carriers

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Multiple acyl-CoA dehydrogenase deficiency, or glutaric aciduria type II, is an autosomal recessive disorder of fatty acid oxidation due to defects in electron transfer flavoprotein (ETF) encoded by ETFA and ETFB, or in electron transfer flavoprotein dehydrogenase (ETFDH) encoded by the ETFDH gene. The disease may present as a severe neonatal onset form and a mild late-onset form which is heterogeneous for the age at onset and clinical presentation. We describe two patients in their seventies, referred for a nonspecific myopathy, which resulted to manifest carriers of ETFDH gene mutation. Treatment with riboflavin and l-carnitine improved the clinical picture and the biochemical profile. This condition should be included in the differential diagnosis of myopathies even at an old age.

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  1. 1.

    Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B et al (2007) ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 130:2045–2054

  2. 2.

    Colevas AD, Edwards JL, Hruban RH, Mitchell GA, Valle D, Hutchins GM (1988) Glutaric acidemia type II. Comparison of pathologic features in two infants. Arch Pathol Lab Med 112(11):1133–1139

  3. 3.

    Grunert SC (2014) Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency. Orphanet J Rare Dis 9:117

  4. 4.

    Liang WC, Ohkuma A, Hayashi YK, López LC, Hirano M, Nonaka I et al (2009) ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromuscul Disord 19:212–216

  5. 5.

    Doimo M, Lopreiato R, Basso V, Bortolotto R, Tessa A, Santorelli FM et al (2016) Heterologous expression in yeast of human ornithine carriers ORNT1 and ORNT2 and of ORNT1 alleles implicated in HHH syndrome in humans. JIMD Rep 28:119–126

  6. 6.

    Zhang J, Frerman FE, Kim JJ (2006) Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool. Proc Natl Acad Sci USA 103:16212–16217

  7. 7.

    Sugai F, Baba K, Toyooka K, Liang WC, Nishino I, Yamadera M et al (2012) Adult-onset multiple acyl CoA dehydrogenation deficiency associated with an abnormal isoenzyme pattern of serum lactate dehydrogenase. Neuromuscul Disord 22:159–161

  8. 8.

    Wen B, Li D, Shan J, Liu S, Li W, Zhao Y et al (2013) Increased muscle coenzyme Q10 in riboflavin responsive MADD with ETFDH gene mutations due to secondary mitochondrial proliferation. Mol Genet Metab 109:154–160

  9. 9.

    Izumi R, Suzuki N, Nagata M, Hasegawa T, Abe Y, Saito Y et al (2011) A case of late onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency manifesting as recurrent rhabdomyolysis and acute renal failure. Intern Med 0:2663–2668

  10. 10.

    Peng Y, Zhu M, Zheng J, Zhu Y, Li X, Wei C et al (2015) Bent spine syndrome as an initial manifestation of late-onset multiple acyl-CoA dehydrogenase deficiency: a case report and literature review. BMC Neurol 15:114

  11. 11.

    Quang D, Chen Y, Xie X (2015) DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics 31:761–763

  12. 12.

    Manfredi G, Silvestri G, Servidei S, Ricci E, Mirabella M, Bertini E et al (1993) Manifesting heterozygotes in McArdle's disease: clinical, morphological and biochemical studies in a family. J Neurol Sci 115:91–94

  13. 13.

    Wieser T (2004) [updated 2019 Jan 3] Carnitine palmitoyltransferase II deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2019. Available from https://www.ncbi.nlm.nih.gov/books/NBK1253/PubMed (PMID: 20301431)

  14. 14.

    Liu A, Wu Q, Guo J, Ares I, Rodriguez JL, Martinez-Larranaga MR et al (2019) Statins: adverse reactions, oxidative stress and metabolic interactions. Pharmacol Ther 195:54–84

  15. 15.

    Bouitbir J, Singh F, Charles AL, Schlagowski AI, Bonifacio A, Echaniz-Laguna A et al (2016) Statins trigger mitochondrial reactive oxygen species-induced apoptosis in glycolytic skeletal muscle. Antioxid Redox Signal 24:84–98

  16. 16.

    Phillips P, Ciaraldi TP, Kim DL, Verity MA, Wolfson T, Henry RR (2009) Myotoxic reactions to lipid-lowering therapy are associated with altered oxidation of fatty acids. Endocrine 35:38–46

  17. 17.

    Clément K, Viguerie N, Diehn M, Alizadeh A, Barbe P, Thalamas C et al (2002) In vivo regulation of human skeletal muscle gene expression by thyroid hormone. Genome Res 12:281–291

  18. 18.

    Sinclair C, Gilchrist JM, Hennessey JV, Kandula M (2005) Muscle carnitine in hypo- and hyperthyroidism. Muscle Nerve 32:357–359

  19. 19.

    Larsson L, Degens H, Li M, Salviati L, Lee YI, Thompson W et al (2019) Sarcopenia: aging-related loss of muscle mass and function. Physiol Rev 99:427–511

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LS was supported by a Grant from Fondazione IRP Città della Speranza.

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Correspondence to Paola Tonin.

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The authors declare that they have no conflict of interest.

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The study was approved by the local Ethics Committee and written informed consent was obtained from the patients.

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Macchione, F., Salviati, L., Bordugo, A. et al. Multiple acyl-COA dehydrogenase deficiency in elderly carriers. J Neurol (2020). https://doi.org/10.1007/s00415-020-09729-z

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  • Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD)
  • Myopathy
  • ETFDH gene mutations
  • Fatty acid oxidation
  • Riboflavin treatment