Inborn Errors of Fatty Acid Metabolism That Affect Muscle

cocukmetabolizma-5-1-2024

Ayça Burcu KAHRAMANa , Yılmaz YILDIZb

aKonya City Hospital, Clinic of Pediatric Metabolism Diseases, Konya, Türkiye
bHacettepe University Faculty of Medicine, Department of Pediatric Metabolism Diseases Ankara, Türkiye

ABSTRACT
This review includes a summary of diagnostic methodologies and therapeutic strategies of fatty acid oxidation disorders affecting skeletal muscle. Fatty acid oxidation defects lead to a spectrum of clinical symptoms, including fatigue, myalgia, exercise intolerance, muscle weakness, and exerciseinduced rhabdomyolysis. Early diagnosis is crucial to prevent misinterpretation as benign conditions like growing pains. The pathophysiology mainly affects muscle energy metabolism, impairing either fatty acid transport to mitochondria (carnitine cycle) or beta-oxidation within the mitochondrial matrix. Each condition presents similar but unique clinical and biochemical profiles. Acylcarnitine profile is critical in biochemical diagnosis. Early diagnosis not only benefits patients but also mitigates healthcare costs by reducing unnecessary medical consultations and enabling timely interventions. Treatment approaches generally revolve around dietary modifications, trigger avoidance, and supplementation. A multidisciplinary approach is necessary for accurate diagnosis and management.
Keywords: Metabolic myopathy; lipid storage myopathy; fatty acid oxidation disorder; carnitine cycle; muscle energy metabolism; rhabdomyolysis

Referanslar

  1. Finsterer J. An update on diagnosis and therapy of metabolic myopathies. Expert Rev Neurother. 2018;18(12):933-43. [Crossref]  [PubMed]
  2. Khadilkar SV, Yadav RS, Patel BA. Neuromuscular disorders: Springer; 2018. [Crossref]
  3. van Loon LJ, Greenhaff PL, Constantin-Teodosiu D, Saris WH, Wagenmakers AJ. The effects of increasing exercise intensity on muscle fuel utilisation in humans. J Physiol. 2001;536(Pt 1):295-304. [Crossref]  [PubMed]  [PMC]
  4. Tein I. Disorders of fatty acid oxidation. Handb Clin Neurol. 2013;113:1675-88. [Crossref]  [PubMed]
  5. Liang WC, Nishino I. State of the art in muscle lipid diseases. Acta Myol. 2010;29(2):351-6.
  6. Lilleker JB, Keh YS, Roncaroli F, Sharma R, Roberts M. Metabolic myopathies: a practical approach. Pract Neurol. 2018;18(1):14-26. [Crossref]  [PubMed]
  7. Bennett MJ, Santani AB. Carnitine Palmitoyltransferase 1A Deficiency. 2005 Jul 27 [Updated 2016 Mar 17]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: [Link]
  8. Lopriore E, Gemke RJ, Verhoeven NM, Jakobs C, Wanders RJ, Roeleveld-Versteeg AB, et al. Carnitine-acylcarnitine translocase deficiency: phenotype, residual enzyme activity and outcome. Eur J Pediatr. 2001;160(2):101-4. [Crossref]  [PubMed]
  9. Wieser T. Carnitine Palmitoyltransferase II Deficiency. 2004 Aug 27 [updated 2019 Jan 3]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.
  10. Knottnerus SJG, Bleeker JC, Wüst RCI, Ferdinandusse S, IJlst L, Wijburg FA, et al. Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Rev Endocr Metab Disord. 2018;19(1):93-106. [Crossref]  [PubMed]  [PMC]
  11. den Boer ME, Dionisi-Vici C, Chakrapani A, van Thuijl AO, Wanders RJ, Wijburg FA. Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement. J Pediatr. 2003;142(6):684-9. [Crossref]  [PubMed]
  12. Boese EA, Jain N, Jia Y, Schlechter CL, Harding CO, Gao SS, et al. Characterization of Chorioretinopathy Associated with Mitochondrial Trifunctional Protein Disorders: Long-Term Follow-up of 21 Cases. Ophthalmology. 2016;123(10):2183-95. [Crossref]  [PubMed]  [PMC]
  13. Rinaldo P, O'Shea JJ, Coates PM, Hale DE, Stanley CA, Tanaka K. Medium-chain acyl-CoA dehydrogenase deficiency. Diagnosis by stable-isotope dilution measurement of urinary n-hexanoylglycine and 3-phenylpropionylglycine. N Engl J Med. 1988;319(20):1308-13. Erratum in: N Engl J Med 1989;320(18):1227. [Crossref]  [PubMed]
  14. Yıldız Y, Talim B, Haliloglu G, Topaloglu H, Akçören Z, Dursun A, et al. Determinants of Riboflavin Responsiveness in Multiple Acyl-CoA Dehydrogenase Deficiency. Pediatr Neurol. 2019;99:69-75. Erratum in: Pediatr Neurol. 2019. [Crossref]  [PubMed]
  15. Gempel K, Topaloglu H, Talim B, Schneiderat P, Schoser BG, Hans VH, et al. The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain. 2007;130(Pt 8):2037-44. [Crossref]  [PubMed]  [PMC]
  16. Prasun P. Multiple Acyl-CoA Dehydrogenase Deficiency. 2020 Jun 18. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: [Link]
  17. Yıldız Y, Olsen RKJ, Sivri HS, Akçören Z, Nygaard HH, Tokatlı A. Post-mortem detection of FLAD1 mutations in 2 Turkish siblings with hypotonia in early infancy. Neuromuscul Disord. 2018;28(9):787-90. [Crossref]  [PubMed]
  18. Olsen RKJ, Koňaříková E, Giancaspero TA, Mosegaard S, Boczonadi V, Mataković L, et al. Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency. Am J Hum Genet. 2016;98(6):1130-45. [Crossref]  [PubMed]  [PMC]
  19. Schiff M, Veauville-Merllié A, Su CH, Tzagoloff A, Rak M, Ogier de Baulny H, et al. SLC25A32 Mutations and Riboflavin-Responsive Exercise Intolerance. N Engl J Med. 2016;374(8):795-7. [Crossref]  [PubMed]  [PMC]
  20. Michot C, Hubert L, Romero NB, Gouda A, Mamoune A, Mathew S, et al. Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J Inherit Metab Dis. 2012;35(6):1119-28. [Crossref]  [PubMed]
  21. Kahraman AB, Karakaya B, Yıldız Y, Kamaci S, Kesici S, Simsek-Kiper PO, et al. Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome. Neuromuscul Disord. 2022;32(11-12):931-4. [Crossref]  [PubMed]
  22. Suzuki A, Nagasaka H, Ochi Y, Kobayashi K, Nakamura H, Nakatani D, et al. Peripheral leukocyte anomaly detected with routine automated hematology analyzer sensitive to adipose triglyceride lipase deficiency manifesting neutral lipid storage disease with myopathy/triglyceride deposit cardiomyovasculopathy. Mol Genet Metab Rep. 2014;1:249-53. [Crossref]  [PubMed]  [PMC]
  23. Missaglia S, Tasca E, Angelini C, Moro L, Tavian D. Novel missense mutations in PNPLA2 causing late onset and clinical heterogeneity of neutral lipid storage disease with myopathy in three siblings. Mol Genet Metab. 2015;115(2-3):110-7. [Crossref]  [PubMed]
  24. Veerapandiyan A, Shashi V, Jiang YH, Gallentine WB, Schoch K, Smith EC. Pseudometabolic presentation of dystrophinopathy due to a missense mutation. Muscle Nerve. 2010;42(6):975-9. [Crossref]  [PubMed]  [PMC]
  25. Tarnopolsky MA. Metabolic Myopathies. Continuum (Minneap Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1829-51. [Crossref]  [PubMed]
  26. Toscano A, Barca E, Musumeci O. Update on diagnostics of metabolic myopathies. Curr Opin Neurol. 2017;30(5):553-62. [Crossref]  [PubMed]
  27. Afifi A, Olpin S, Dalton A, Bishop N, Grabowski PS. Failure to repair the c.338C>T mutation in carnitine palmitoyl transferase 2 deficient skin fibroblasts using chimeraplasty. Mol Genet Metab. 2008;93(3):347-9. [Crossref]  [PubMed]
  28. Okun JG, Kölker S, Schulze A, Kohlmüller D, Olgemöller K, Lindner M, et al. A method for quantitative acylcarnitine profiling in human skin fibroblasts using unlabelled palmitic acid: diagnosis of fatty acid oxidation disorders and differentiation between biochemical phenotypes of MCAD deficiency. Biochim Biophys Acta. 2002;1584(2-3):91-8. [Crossref]
  29. Mozrzymas R, Konikowska K, Regulska-Ilow B. Energy exchangers with LCT as a precision method for diet control in LCHADD. Adv Clin Exp Med. 2017;26(3):515-25. [Crossref]  [PubMed]
  30. Houten SM, Violante S, Ventura FV, Wanders RJ. The Biochemistry and Physiology of Mitochondrial Fatty Acid β-Oxidation and Its Genetic Disorders. Annu Rev Physiol. 2016;78:23-44. [Crossref]  [PubMed]
  31. Liang WC, Ohkuma A, Hayashi YK, López LC, Hirano M, Nonaka I, et al. ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromuscul Disord. 2009;19(3):212-6. [Crossref]  [PubMed]  [PMC]
  32. Kahraman AB, Yildiz Y, Gokmen-Ozel H, Kadayifcilar S, Sivri S. Successful management of rhabdomyolysis with triheptanoin in a child with severe long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency. Neuromuscul Disord. 2023;33(4):315-8. [Crossref]  [PubMed]