Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-745bb68f8f-s22k5 Total loading time: 0 Render date: 2025-01-27T13:33:21.092Z Has data issue: false hasContentIssue false

Chapter 34 - Inborn Errors of Fatty Acid Oxidation

from Section IV - Metabolic Liver Disease

Published online by Cambridge University Press:  19 January 2021

By
Jerry Vockley
Edited by
Frederick J. Suchy ,
Ronald J. Sokol  and
William F. Balistreri
Edited in association with
Jorge A. Bezerra ,
Cara L. Mack  and
Benjamin L. Shneider
Frederick J. Suchy
Affiliation:
University of Colorado, Children’s Hospital Colorado, Aurora
Ronald J. Sokol
Affiliation:
University of Colorado, Children’s Hospital Colorado, Aurora
William F. Balistreri
Affiliation:
Cincinnati Children’s Hospital Medical Center, Cincinnati
Jorge A. Bezerra
Affiliation:
Cincinnati Children’s Hospital Medical Center, Cincinnati
Cara L. Mack
Affiliation:
University of Colorado, Children’s Hospital Colorado, Aurora
Benjamin L. Shneider
Affiliation:
Texas Children’s Hospital, Houston
Get access

Summary

Mitochondrial fatty acid β-oxidation (FAO) is an essential component of energy production and homeostasis in humans. During periods of limited glucose supply, FAO in the liver provides energy for hepatic function and the acetyl-CoA substrate needed for hepatocytes to synthesize and release ketone bodies into circulation. Ketone bodies provide an alternative energy substrate for peripheral tissues when glucose supply is limited. Other tissues such as skeletal and cardiac muscle rely on FAO for energy production. The oxidation of fatty acids can provide up to 80% of the energy requirements for cardiac and skeletal muscle while sparing glucose for use by the brain and CNS during moderate exercise, fasting, or illness. Disorders in the ability to use fatty acids for energy production manifest during periods of increased energy demands or reduced caloric intake.

Type
Chapter
Information
Liver Disease in Children , pp. 611 - 627
Publisher: Cambridge University Press
Print publication year: 2021

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Wanders, RJ, et al. The enzymology of mitochondrial fatty acid beta-oxidation and its application to follow-up analysis of positive neonatal screening results. J Inherit Metab Dis 2010;33(5):479–94.Google Scholar
Longo, N, Frigeni, M, Pasquali, M. Carnitine transport and fatty acid oxidation. Biochim Biophys Acta 2016;1863(10):2422–35.Google Scholar
Saudubray, JM, et al. Recognition and management of fatty acid oxidation defects: a series of 107 patients. J Inherit Metab Dis 1999;22(4):488–502.CrossRefGoogle ScholarPubMed
Rinaldo, P, Matern, D, Bennett, MJ. Fatty acid oxidation disorders. Annu Rev Physiol 2002;64:477–502.Google Scholar
Vockley, J, Whiteman, DA. Defects of mitochondrial beta-oxidation: a growing group of disorders. Neuromuscul Disord 2002;12(3):235–46.Google Scholar
Lindner, M, Hoffmann, GF, Matern, D. Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis 2010;33(5):521–6.Google Scholar
Bennett, MJ, et al. Newborn screening for metabolic disorders: how are we doing, and where are we going? Clin Chem 2012;58(2):324–31.Google Scholar
McGarry, JD, Foster, DW. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem 1980;49:395–420.CrossRefGoogle ScholarPubMed
Gulick, T, et al. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci U S A 1994;91(23):11012–16.Google Scholar
Swigonova, Z, Mohsen, AW, Vockley, J. Acyl-CoA dehydrogenases: dynamic history of protein family evolution. J Mol Evol 2009;69(2):176–93.Google Scholar
Strauss, AW, et al. Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood. Proc Natl Acad Sci U S A 1995;92(23):10496–500.Google Scholar
Eder, M, et al. Characterization of human and pig kidney long-chain-acyl-Coa dehydrogenases and their role in beta-oxidation. Eur J Biochem 1997;245(3):600–7.CrossRefGoogle ScholarPubMed
Indo, Y, et al. Immunochemical characterization of variant long-chain acyl-CoA dehydrogenase in cultured fibroblasts from nine patients with long-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 1991;30(3):211–15.CrossRefGoogle ScholarPubMed
Ikeda, Y, Dabrowski, C, Tanaka, K. Separation and properties of five distinct acyl-CoA dehydrogenases from rat liver mitochondria. Identification of a new 2-methyl branched chain acyl-CoA dehydrogenase. J Biol Chem 1983;258(2):1066–76.Google Scholar
Finocchiaro, G, Ito, M, Tanaka, K. Purification and properties of short chain acyl-CoA, medium chain acyl-CoA, and isovaleryl-CoA dehydrogenases from human liver. J Biol Chem 1987;262(17):7982–9.Google Scholar
Oey, NA, et al. Acyl-CoA dehydrogenase 9 (ACAD 9) is the long-chain acyl-CoA dehydrogenase in human embryonic and fetal brain. Biochem Biophys Res Commun 2006;346(1):33–7.CrossRefGoogle ScholarPubMed
Indo, Y, et al. Molecular cloning and nucleotide sequence of cDNAs encoding human long-chain acyl-CoA dehydrogenase and assignment of the location of its gene (ACADL) to chromosome 2. Genomics 1991;11(3):609–20.Google Scholar
Ensenauer, R, et al. Human acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial beta-oxidation of unsaturated fatty acids. J Biol Chem 2005;280(37):32309–16.Google Scholar
Repp, BM, et al. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective? Orphanet J Rare Dis;2018;13(1):120.Google Scholar
Andresen, BS, et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet 1996;5(4):461–72.Google Scholar
He, M, et al. Identification and characterization of new long chain acyl-CoA dehydrogenases. Mol Genet Metab 2011;102(4):418–29.Google Scholar
Matsubara, Y, et al. Molecular cloning of cDNAs encoding rat and human medium-chain acyl-CoA dehydrogenase and assignment of the gene to human chromosome 1. Proc Natl Acad Sci U S A 1986;83(17):6543–7.Google Scholar
Corydon, MJ, et al. Structural organization of the human short-chain acyl-CoA dehydrogenase gene. Mamm Genome 1997;8(12):922–6.Google Scholar
Uchida, Y, et al. Novel fatty acid beta-oxidation enzymes in rat liver mitochondria. II. Purification and properties of enoyl-coenzyme A (CoA) hydratase/3-hydroxyacyl-CoA dehydrogenase/3-ketothiolase trifunctional protein. J Biol Chem 1992;267:1034–41.CrossRefGoogle ScholarPubMed
Wanders, RJ, et al. Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Biochem Biophys Res Commun 1992;188(3):1139–45.Google Scholar
Ijlst, L, et al. Common missense mutation G1528 C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene. J Clin Invest 1996;98(4):1028–33.Google Scholar
Kanazawa, M, et al. Molecular cloning and sequence analysis of the cDNA for human mitochondrial short-chain enoyl-CoA hydratase. Enzyme Protein 1993;47(1):9–13.Google Scholar
He, XY, Yang, SY, Schulz, H. Assay of L-3-hydroxyacyl-coenzyme A dehydrogenase with substrates of different chain lengths. Anal Biochem 1989;180(1):105–9.Google Scholar
Yang, SY, He, XY, Schulz, H. Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase. Trends Endocrinol Metab 2005;16(4):167–75.Google Scholar
Brunengraber, H, Roe, CR. Anaplerotic molecules: current and future. J Inherit Metab Dis 2006;29(2–3):327–31.Google Scholar
Vockley, J, et al. UX007 for the treatment of long chain-fatty acid oxidation disorders: safety and efficacy in children and adults following 24 weeks of treatment. Mol Genet Metab 2017;120(4):370–7.Google Scholar
Passi, S, et al. Saturated dicarboxylic acids as products of unsaturated fatty acid oxidation. Biochim Biophys Acta 1993;1168(2):190–8.Google Scholar
Roe, DS, et al. Oxidation of unsaturated fatty acids by human fibroblasts with very-long-chain acyl-CoA dehydrogenase deficiency: aspects of substrate specificity and correlation with clinical phenotype. Clin Chim Acta 2001;312(1–2):55–67.CrossRefGoogle ScholarPubMed
Longo, N, Amat di San Filippo, C, Pasquali, M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006;142(2):77–85.CrossRefGoogle Scholar
Celestino-Soper, PB, et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A 2012;109(21):7974–81.Google Scholar
Brown, NF, et al. Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme. J Lipid Res 2001;42(7):1134–42.Google Scholar
Brivet, M, et al. Defects in activation and transport of fatty acids. J Inherit Metab Dis 1999;22(4):428–41.Google Scholar
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 2010;33(5):527–32.Google Scholar
Pena, LD, et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab 2016;118(4):272–81.CrossRefGoogle ScholarPubMed
Spiekerkoetter, U, Mayatepek, E. Update on mitochondrial fatty acid oxidation disorders. J Inherit Metab Dis 2010;33(5):467–8.Google Scholar
Spiekerkoetter, U, et al. Tandem mass spectrometry screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. J Pediatr 2010;157(4):668–73.Google Scholar
Vianey-Saban, C, et al. Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients. Clin Chim Acta 1998;269(1):43–62.CrossRefGoogle ScholarPubMed
Andresen, BS, et al. The mutational spectrum in very long-chain acyl-Coa dehydrogenase deficiency. J Inherit Metab Dis 1996;19(2):169–72.Google Scholar
Gregersen, N, Andresen, BS, Bross, P. Prevalent mutations in fatty acid oxidation disorders: diagnostic considerations. Eur J Pediatr 2000;159(Suppl 3):S213–18.Google Scholar
He, M, et al. A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency. Am J Hum Genet 2007;81(1):87–103.Google Scholar
Schiff, M, et al. Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. Hum Mol Genet 2015;24(11):3238–47.Google Scholar
Spiekerkoetter, U, et al. Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations. Hum Mutat 2003;21(6):598–607.Google Scholar
Spiekerkoetter, U, et al. General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. Pediatr Res 2004;55(2):190–6.Google Scholar
Gillingham, M, et al. Dietary management of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). A case report and survey. J Inherit Metab Dis 1999;22(2):123–31.Google Scholar
Gillingham, MB, et al. Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency. Mol Genet Metab 2005;86(1–2):124–33.Google Scholar
Xia, C, et al. Crystal structure of human mitochondrial trifunctional protein, a fatty acid beta-oxidation metabolon. Proc Natl Acad Sci U S A 2019;116(13):6069–74.Google Scholar
Tanaka, K, et al. Mutations in the medium chain acyl-CoA dehydrogenase (MCAD) gene. Hum Mutat 1992;1(4):271–9.CrossRefGoogle ScholarPubMed
Bentler, K, et al. 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: findings from the Inborn Errors of Metabolism Collaborative. Mol Genet Metab 2016;119(1–2):75–82.Google Scholar
Brackett, JC, et al. A novel mutation in medium chain acyl-CoA dehydrogenase causes sudden neonatal death. J Clin Invest 1994;94(4):1477–83.Google Scholar
Yusupov, R, et al. Sudden death in medium chain acyl-coenzyme a dehydrogenase deficiency (MCADD) despite newborn screening. Mol Genet Metab 2010;101(1):33–9.Google Scholar
Matsubara, Y, et al. Identification of a common mutation in patients with medium-chain acyl-CoA dehydrogenase deficiency. Biochem Biophys Res Commun 1990;171(1):498–505.Google Scholar
Andresen, BS, et al. Molecular diagnosis and characterization of medium-chain acyl-CoA dehydrogenase deficiency. Scand J Clin Lab Invest Suppl 1995;220:9–25.Google ScholarPubMed
Yokota, I, et al. Impaired tetramer assembly of variant medium-chain acyl-coenzyme A dehydrogenase with a glutamate or aspartate substitution for lysine 304 causing instability of the protein. J Biol Chem 1992;267(36):26004–10.Google Scholar
Waisbren, SE, et al. Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. Dev Disabil Res Rev 2013;17(3):260–8.Google Scholar
Gallant, NM, et al. Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California. Mol Genet Metab 2012;106(1):55–61.Google Scholar
Pedersen, CB, et al. The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level. Hum Genet 2008;124(1):43–56.Google Scholar
Nguyen, TV, et al. Purification and characterization of two polymorphic variants of short chain acyl-CoA dehydrogenase reveal reduction of catalytic activity and stability of the Gly185Ser enzyme. Biochemistry 2002;41(37):11126–33.Google Scholar
Molven, A, et al. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 2004;53(1):221–7.Google Scholar
Flanagan, SE, et al. Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees. J Clin Endocrinol Metab 2011;96(3):E498–502.Google Scholar
Kamijo, T, et al. Medium chain 3-ketoacyl-coenzyme A thiolase deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Pediatr Res 1997;42(5):569–76.Google Scholar
Frerman, FE, Goodman, SI. Deficiency of electron transfer flavoprotein or electron transfer flavoprotein: ubiquinoneoxidoreductase in glutaric acidemia type II fibroblasts. Proc Natl Acad Sci U S A 1985;82(13):4517–20.Google Scholar
Loehr, JP, Goodman, SI, Frerman, FE. Glutaric acidemia type II: heterogeneity of clinical and biochemical phenotypes. Pediatr Res 1990;27(3):311–15.CrossRefGoogle ScholarPubMed
Olsen, RK, et al. ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 2007;130(Pt 8):2045–54.CrossRefGoogle Scholar
Spaan, AN, et al. Identification of the human mitochondrial FAD transporter and its potential role in multiple acyl-CoA dehydrogenase deficiency. Mol Genet Metab 2005;86(4):441–7.Google Scholar
Olsen, RKJ, 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.Google Scholar
Schiff, M, et al. SLC25A32 mutations and riboflavin-responsive exercise intolerance. N Engl J Med 2016;374(8):795–7.Google Scholar
Duran, M, et al. Sudden child death and “healthy” affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency. Pediatrics 1986;78(6):1052–7.Google Scholar
Harpey, J-P, Charpentier, C, Paturneau-Jouas, M. Sudden infant death syndrome and inherited disorders of fatty acid b-oxidation. Biol Neonate 1990;58(Suppl 1):70–80.Google Scholar
Bennett, MJ, et al. Medium-chain acyl-CoA dehydrogenase deficiency: postmortem diagnosis in a case of sudden infant death and neonatal diagnosis of an affected sibling. Pediatr Pathol 1991;11(6):889–95.Google Scholar
Bennett, MJ, Powell, S. Metabolic disease and sudden, unexpected death in infancy. Hum Pathol 1994;25(8):742–6.Google Scholar
Rashed, MS, et al. Inborn errors of metabolism diagnosed in sudden death cases by acylcarnitine analysis of postmortem bile. Clin Chem 1995;41(8 Pt 1):1109–14.CrossRefGoogle ScholarPubMed
Waisbren, SE, et al. Effect of expanded newborn screening for biochemical genetic disorders on child outcomes and parental stress. JAMA 2003;290(19):2564–72.CrossRefGoogle ScholarPubMed
Rinaldo, P, Cowan, TM, Matern, D. Acylcarnitine profile analysis. Genet Med 2008;10(2):151–6.Google Scholar
Rinaldo, P, et al. Newborn screening of metabolic disorders: recent progress and future developments. Nestle Nutr Workshop Ser Pediatr Program 2008;62:81–93; discussion 93–6.CrossRefGoogle ScholarPubMed
Smith, EH, Matern, D. Acylcarnitine analysis by tandem mass spectrometry. Curr Protoc Hum Genet 2010;17(8):1781–20.Google Scholar
McHugh, D, et al. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. Genet Med 2011;13(3):230–54.Google Scholar
Vockley, J, Singh, RH, Whiteman, DA. Diagnosis and management of defects of mitochondrial beta-oxidation. Curr Opin Clin Nutr Metab Care 2002;5(6):601–9.Google Scholar
Spiekerkoetter, U, et al. Current issues regarding treatment of mitochondrial fatty acid oxidation disorders. J Inherit Metab Dis 2010;33(5):555–61.Google Scholar
Stanley, CA, et al. Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. Pediatr Res 1983;17(11):877–84.CrossRefGoogle ScholarPubMed
Derks, TG, et al. Safe and unsafe duration of fasting for children with MCAD deficiency. Eur J Pediatr 2007;166(1):5–11.Google Scholar
Longo, N, et al. Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet 2011;157(1):72–8.Google Scholar
Rinaldo, P, et al. Effect of treatment with glycine and L-carnitine in medium-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr 1993;122(4):580–4.CrossRefGoogle ScholarPubMed
Gillingham, MB, et al. Effects of higher dietary protein intake on energy balance and metabolic control in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab 2007;90(1):64–9.Google Scholar
Ruiz-Sanz, JI, et al. Polyunsaturated fatty acid deficiency during dietary treatment of very long-chain acyl-CoA dehydrogenase deficiency. Rescue with soybean oil. J Inherit Metab Dis 2001;24(4):493–503.Google Scholar
Roe, CR, et al. Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. J Clin Invest 2002;110(2):259–69.Google Scholar
Kinman, RP, et al. Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. Am J Physiol Endocrinol Metab 2006;291(4):E860–6.Google Scholar
Roe, CR, Brunengraber, H. Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: review of 15 years’ experience. Mol Genet Metab 2015;116(4):260–8.Google Scholar
Vockley, J, et al. Long-term major clinical outcomes in patients with long chain fatty acid oxidation disorders before and after transition to triheptanoin treatment–A retrospective chart review. Mol Genet Metab 2015;116(1–2):53–60.Google Scholar
Gillingham, MB, et al. Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial. J Inherit Metab Dis. 2017;40(6):831–43.Google Scholar
Vockley, J, et al. 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 2019;42(1):169–77.Google Scholar
Bonnefont, JP, et al. Bezafibrate for an inborn mitochondrial beta-oxidation defect. N Engl J Med 2009;360(8):838–40.CrossRefGoogle ScholarPubMed
Bonnefont, JP, et al. Long-term follow-up of bezafibrate treatment in patients with the myopathic form of carnitine palmitoyltransferase 2 deficiency. Clin Pharmacol Ther 2010;88(1):101–8.Google Scholar
Ibdah, JA, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med 1999;340(22):1723–31.Google Scholar
den Boer, ME, et al. Heterozygosity for the common LCHAD mutation (1528 g>C) is not a major cause of HELLP syndrome and the prevalence of the mutation in the Dutch population is low. Pediatr Res 2000;48(2):151–4.CrossRefGoogle Scholar
Nelson, J, Lewis, B, Walters, B. The HELLP syndrome associated with fetal medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 2000;23(5):518–19.CrossRefGoogle ScholarPubMed
Mutze, S, et al. Neither maternal nor fetal mutation (E474Q) in the alpha-subunit of the trifunctional protein is frequent in pregnancies complicated by HELLP syndrome. J Perinat Med 2007;35(1):76–80.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×