Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Mitochondrial fatty acid (FA) oxidation deficiencies represent a genetically heterogeneous group of diseases in humans caused by defects in mitochondrial FA beta-oxidation (mFAO). A general characteristic of all mFAO disorders is hypoketotic hypoglycemia resulting from the enhanced reliance on glucose oxidation and the inability to synthesize ketone bodies from FAs. Patients with a defect in the oxidation of long-chain FAs are at risk to develop cardiac and skeletal muscle abnormalities including cardiomyopathy and arrhythmias, which may progress into early death, as well as rhabdomyolysis and exercise intolerance. The diagnosis of mFAO-deficient patients has greatly been helped by revolutionary developments in the field of tandem mass spectrometry (MS) for the analysis of acylcarnitines in blood and/or urine of candidate patients. Indeed, acylcarnitines have turned out to be excellent biomarkers; not only do they provide information whether a certain patient is affected by a mFAO deficiency, but the acylcarnitine profile itself usually immediately points to which enzyme is likely deficient. Another important aspect of acylcarnitine analysis by tandem MS is that this technique allows high-throughput analysis, which explains why screening for mFAO deficiencies has now been introduced in many newborn screening programs worldwide. In this review, we will describe the current state of knowledge about mFAO deficiencies, with particular emphasis on recent developments in the area of pathophysiology and treatment.
Abstract
Mitochondrial fatty acid (FA) oxidation deficiencies represent a genetically heterogeneous group of diseases in humans caused by defects in mitochondrial FA beta-oxidation (mFAO). A general characteristic of all mFAO disorders is hypoketotic hypoglycemia resulting from the enhanced reliance on glucose oxidation and the inability to synthesize ketone bodies from FAs. Patients with a defect in the oxidation of long-chain FAs are at risk to develop cardiac and skeletal muscle abnormalities including cardiomyopathy and arrhythmias, which may progress into early death, as well as rhabdomyolysis and exercise intolerance. The diagnosis of mFAO-deficient patients has greatly been helped by revolutionary developments in the field of tandem mass spectrometry (MS) for the analysis of acylcarnitines in blood and/or urine of candidate patients. Indeed, acylcarnitines have turned out to be excellent biomarkers; not only do they provide information whether a certain patient is affected by a mFAO deficiency, but the acylcarnitine profile itself usually immediately points to which enzyme is likely deficient. Another important aspect of acylcarnitine analysis by tandem MS is that this technique allows high-throughput analysis, which explains why screening for mFAO deficiencies has now been introduced in many newborn screening programs worldwide. In this review, we will describe the current state of knowledge about mFAO deficiencies, with particular emphasis on recent developments in the area of pathophysiology and treatment.
참고문헌 (71)
- Longo N, "Carnitine transport and fatty acid oxidation", Biochim Biophys Acta Mol Cell Res, 1863, pp.2422~2435 (2016)
- Houten SM, "A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation", J Inherit Metab Dis, 33, pp.469~477 (2010)
- Wanders RJ, "Biochemistry of mammalian peroxisomes revisited", Annu Rev Biochem, 75, pp.295~332 (2006)
- Van Veldhoven PP, "Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism", J Lipid Res, 51, pp.2863~2895 (2010)
- Wanders RJ, "Metabolic interplay between peroxisomes and other subcellular organelles including mitochondria and the endoplasmic reticulum", Front Cell Dev Biol, 3, pp.83~ (2016)
- Knottnerus SJ, "Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle", Rev Endocr Metab Disord, 19, pp.93~106 (2018)
- Spiekerkoetter U, "Mitochondrial fatty acid oxidation disorders : clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening", J Inherit Metab Dis, 33, pp.527~532 (2010)
- Bonnet D, "Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children", Circulation, 100, pp.2248~2253 (1999)
- Baruteau J, "Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects : a French pediatric study from 187 patients. Complementary data", J Inherit Metab Dis, 37, pp.137~139 (2014)
- Baruteau J, "Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects : a French pediatric study of 187 patients", J Inherit Metab Dis, 36, pp.795~803 (2013)
- Kim TT, "The role of CD36 in the regulation of myocardial lipid metabolism", Biochim Biophys Acta, 1861, pp.1450~1460 (2016)
- Glatz JF, "Dynamic role of the transmembrane glycoprotein CD36(SR-B2)in cellular fatty acid uptake and utilization", J Lipid Res, 59, pp.1084~1093 (2018)
- Son NH, "Endothelial cell CD36 optimizes tissue fatty acid uptake", J Clin Invest, 128, pp.4329~4342 (2018)
- Vaz FM, "Carnitine biosynthesis in mammals", Biochem J, 361, pp.417~429 (2002)
- Longo N, "Disorders of carnitine transport and the carnitine cycle", Am J Med Genet C Semin Med Genet (2006)
- McGarry JD, "Regulation of hepatic fatty acid oxidation and ketone body production", Annu Rev Biochem, 49, pp.395~420 (1980)
- McGarry JD, "The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis", Eur J Biochem, 244, pp.1~14 (1997)
- McGarry JD, "A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis", J Clin Invest, 60, pp.265~270 (1977)
- Saudubray JM, "Recognition and management of fatty acid oxidation defects : a series of 107 patients", J Inherit Metab Dis, 22, pp.488~502 (1999)
- Boese EA, "Characterization of chorioretinopathy associated with mitochondrial trifunctional protein disorders : long-term follow-up of 21 cases", Ophthalmology, 123, pp.2183~2195 (2016)
- Przyrembel H, "Glutaric aciduria type II : report on a previously undescribed metabolic disorder", Clin Chim Acta, 66, pp.227~239 (1976)
- Horvath R, "Update on clinical aspects and treatment of selected vitamin-responsive disorders II(riboflavin and CoQ 10)", J Inherit Metab Dis, 35, pp.679~687 (2012)
- Grünert SC, "Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency", Orphanet J Rare Dis, 9, pp.117~ (2014)
- Loehr JP, "Glutaric acidemia type II : heterogeneity of clinical and biochemical phenotypes", Pediatr Res, 27, pp.311~315 (1990)
- van Rijt WJ, "Prediction of disease severity in multiple acyl-CoA dehydrogenase deficiency : a retrospective and laboratory cohort study", J Inherit Metab Dis, 42, pp.878~889 (2019)
- Sathasivam S, "Brown-Vialetto-Van Laere syndrome", Orphanet J Rare Dis, 3, pp.9~ (2008)
- Dipti S, "Brown-Vialetto-Van Laere syndrome; variability in age at onset and disease progression highlighting the phenotypic overlap with Fazio-Londe disease", Brain Dev, 27, pp.443~446 (2005)
- Green P, "Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54", Am J Hum Genet, 86, pp.485~489 (2010)
- Haack TB, "Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome", J Inherit Metab Dis, 35, pp.943~948 (2012)
- Johnson JO, "Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease", Brain, 135, pp.2875~2882 (2012)
- Jaeger B, "Clinical presentation and outcome of riboflavin transporter deficiency : mini review after five years of experience", J Inherit Metab Dis, 39, pp.559~564 (2016)
- O'Callaghan B, "An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency", J Inherit Metab Dis, 42, pp.598~607 (2019)
- Olsen RK, "Riboflavin-responsive and-non-responsive mutations in FAD synthase cause multiple acyl-CoA dehydrogenase and combined respiratory-chain deficiency", Am J Hum Genet, 98, pp.1130~1145 (2016)
- Ryder B, "A novel truncating FLAD1 variant, causing multiple acyl-CoA dehydrogenase deficiency(MADD)in an 8-year-old boy", JIMD Rep, 45, pp.37~44 (2019)
- Mosegaard S, "Riboflavin deficiency—implications for general human health and inborn errors of metabolism", Int J Mol Sci, 21, pp.3847~ (2020)
- Henriques BJ, "Emerging roles for riboflavin in functional rescue of mitochondrial β-oxidation flavoenzymes", Curr Med Chem, 17, pp.3842~3854 (2010)
- Schiff M, "SLC25A32 mutations and riboflavin-responsive exercise intolerance", N Engl J Med, 374, pp.795~797 (2016)
- Hellebrekers DM, "Novel SLC25A32 mutation in a patient with a severe neuromuscular phenotype", Eur J Hum Genet, 25, pp.886~888 (2017)
- Wanders RJ, "The enzymology of mitochondrial fatty acid beta-oxidation and its application to follow-up analysis of positive neonatal screening results", J Inherit Metab Dis, 33, pp.479~494 (2010)
- Diekman EF, "Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency", Genet Med, 17, pp.989~994 (2015)
- Bleeker JC, "Proposal for an individualized dietary strategy in patients with very long-chain acyl-CoA dehydrogenase deficiency", J Inherit Metab Dis, 42, pp.159~168 (2019)
- palmitic acid : an improved tool for the diagnosis of fatty acid oxidation defects, "Clin Chim Acta", 1999, 1~17
- Iafolla AK, "Medium-chain acyl-coenzyme A dehydrogenase deficiency : clinical course in 120 affected children", J Pediatr, 124, pp.409~415 (1994)
- Pena LD, "Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database", Mol Genet Metab, 118, pp.272~281 (2016)
- Palmieri F, "The mitochondrial transporter family SLC25 : identification, properties and physiopathology", Mol Aspects Med, 34, pp.465~484 (2013)
- Chua BH, "Reversible inhibition of adenine nucleotide translocation by long chain acyl-CoA esters in bovine heart mitochondria and inverted submitochondrial particles. Comparison with atractylate and bongkrekic acid", J Biol Chem, 252, pp.6711~6714 (1977)
- Neess D, "Long-chain acyl-CoA esters in metabolism and signaling : role of acyl-CoA binding proteins", Prog Lipid Res, 59, pp.1~25 (2015)
- Spiekerkoetter U, "Treatment recommendations in long-chain fatty acid oxidation defects : consensus from a workshop", J Inherit Metab Dis, 32, pp.498~505 (2009)
- Spiekerkoetter U, "Update on mitochondrial fatty acid oxidation disorders", J Inherit Metab Dis, 33, pp.467~468 (2010)
- Arnold GL, "A Delphi clinical practice protocol for the management of very long chain acyl-CoA dehydrogenase deficiency", Mol Genet Metab, 96, pp.85~90 (2009)
- Roe CR, "Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride", J Clin Invest, 110, pp.259~269 (2002)
- Roe CR, "Carnitine palmitoyltransferase II deficiency : successful anaplerotic diet therapy", Neurology, 71, pp.260~264 (2008)
- Roe CR, "Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin : review of 15 years experience", Mol Genet Metab, 116, pp.260~268 (2015)
- Vockley J, "Results from a 78-week, single-arm, open-label phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders(LC-FAOD)", J Inherit Metab Dis, 42, pp.169~177 (2019)
- Vockley J, "Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders", Mol Genet Metab, 119, pp.223~231 (2016)
- Gillingham MB, "Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders : a double blinded, randomized controlled trial", J Inherit Metab Dis, 40, pp.831~843 (2017)
- Vockley J, "Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: results from an open-label, long-term extension study", J Inherit Metab Dis. (2020)
- Djouadi F, "Bezafibrate increases very-long-chain acyl-CoA dehydrogenase protein and mRNA expression in deficient fibroblasts and is a potential therapy for fatty acid oxidation disorders", Hum Mol Genet, 14, pp.2695~2703 (2005)
- Gobin-Limballe S, "Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts : toward a genotype-based therapy", Am J Hum Genet, 81, pp.1133~1143 (2007)
- Djouadi F, "Mitochondrial trifunctional protein deficiency in human cultured fibroblasts : effects of bezafibrate", J Inherit Metab Dis, 39, pp.47~58 (2016)
- Bonnefont JP, "Bezafibrate for an inborn mitochondrial beta-oxidation defect", N Engl J Med, 360, pp.838~840 (2009)
- Bonnefont JP, "Long-term follow-up of bezafibrate treatment in patients with the myopathic form of carnitine palmitoyltransferase 2 deficiency", Clin Pharmacol Ther, 88, pp.101~108 (2010)
- Ørngreen MC, "Bezafibrate in skeletal muscle fatty acid oxidation disorders : a randomized clinical trial", Neurology, 82, pp.607~613 (2014)
- Van Hove JL, "D, L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency(MADD)", Lancet, 361, pp.1433~1435 (2003)
- Clarke K, "Kinetics, safety and tolerability of(R)-3-hydroxybutyl(R)-3-hydroxybutyrate in healthy adult subjects", Regul Toxicol Pharmacol, 63, pp.401~408 (2012)
- Cox PJ, "Nutritional ketosis alters fuel preference and thereby endurance performance in athletes", Cell Metab, 24, pp.256~268 (2016)
- Bleeker JC, "Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency", J Inherit Metab Dis, 43, pp.787~799 (2020)
- Knottnerus SJ, "Electrophysiological abnormalities in VLCAD deficient hiPSC-cardiomyocytes can be improved by lowering accumulation of fatty acid oxidation intermediates", Int J Mol Sci, 21, pp.2589~ (2020)
- Wu J, "Palmitoyl carnitine modifies sodium currents and induces transient inward current in ventricular myocytes", Am J Physiol, 266, pp.H1034~H1046 (1994)
- Wu J, "Influence of long-chain acylcarnitines on voltage-dependent calcium current in adult ventricular myocytes", Am J Physiol, 263, pp.H410~H417 (1992)
- Mészàros J, "Electrophysiological effects of L-palmitoylcarnitine in single ventricular myocytes", Am J Physiol, 258, pp.H931~H938 (1990)
